Clinical Protocol No. (Version 1.0 Dated 15 Feb 19) PHASE I/II S USTAINED-RELEASE T OPOTECAN E PISCLERAL P LAQUE (CHEMOPLAQUE) for R ETINO B LASTOMA STEP-RB The Retinoblastoma Program Departments of Ophthalmology and Vision Science & Pediatric Oncology The Hospital for Sick Children (SickKids) Toronto, Ontario, CANADA The Hospital for Sick Children sponsors this clinical trial. IND number assigned: 112785 ClinicalTrials.gov Identifier: THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS A RESEARCH PLAN DEVELOPED BY TARGETED THERAPY TECHNOLOGIES, LLC (DBA: 3T OPHTHALMICS) AND COLLABORATING INVESTIGATORS TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION.
Transcript
Clinical Protocol No. (Version 1.0 Dated 15 Feb 19)
PHASE I/II SUSTAINED-RELEASE TOPOTECAN EPISCLERAL PLAQUE (CHEMOPLAQUE) for RETINOBLASTOMA
STEP-RB
The Retinoblastoma Program
Departments of Ophthalmology and Vision Science & Pediatric Oncology
The Hospital for Sick Children (SickKids)
Toronto, Ontario, CANADA
The Hospital for Sick Children sponsors this clinical trial.
IND number assigned: 112785
ClinicalTrials.gov Identifier:
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS A RESEARCH PLAN DEVELOPED BY TARGETED THERAPY TECHNOLOGIES, LLC (DBA: 3T OPHTHALMICS) AND COLLABORATING INVESTIGATORS TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION.
TERMINOLOGY AND NAMING OF DRUG PRODUCTThe drug product—Episcleral Topotecan—consists of a sustained-release formulation of topotecan hydrochloride—drug substance—contained within an episcleral implant at various ascending doses. The Episcleral Implant in various publications and in this protocol is referred variously as Chemoplaque, Episcleral Device, Episcleral Topotecan, Episcleral Sustained Release Topotecan, Episcleral Reservoir, Episcleral Exoplant, Episcleral Implant, and Targeted Transscleral Delivery System (TTDS).
In the current protocol we use the term Chemoplaque. All these terms refer to the same drug product and are interchangeable. Episcleral Topotecan clinical supplies will be shipped from the manufacturer (Targeted Therapy Technologies, LLC/DBA 3T Ophthalmics) ready for use and require no further manipulation before ocular placement.
A full brochure with the drug product details provided by the manufacturer is Appendix I.
This synopsis is provided as an overview only and does not replace the more detailed protocol which follows.
Protocol Title Sustained release topotecan periocular chemotherapy via episcleral implant (Chemoplaque) for retinoblastoma
Sponsor The Hospital for Sick Children
Study Leadership Principal Investigator: Dr. Brenda Gallie
Co-Investigator: Dr. Furqan Sheikh
Phase of Development
Phase I-II trial
Study Centers The Hospital for Sick Children, Toronto, Canada
Indication Part 1. Phase I “rolling 6” Maximum Tolerated Dose (MTD) study
Any eyes with retinoblastoma refractory to conventional therapies, some vision potential and no clinical features suggestive of high risk of extraocular extension.
The episcleral implants will be provided with 0.6 mg, or 0.9 mg of topotecan HCl formulations.
A minimum of 2 evaluable patients will be required for this study (two patients each at 0.6 mg dose if both experience Dose Limiting Toxicity (DLT) and a max of 18 evaluable patients if one DLT occurs with each dose cohort. It is estimated the trial will take one to two years to complete.
Part 2. Phase II (Ammendment after MTD or Recommended Phase 2 Dose (RP2D) established in Part 1.)
Cohort TWO: Secondary Therapy, cT2 eyes with retinoblastoma refractory to conventional therapies, some vision potential and no clinical features suggestive of high risk of extraocular extension.
To describe the safety and tolerability of the Chemoplaque in patients with retinoblastoma. Secondary Objectives:
To describe the anti-tumour efficacy of the chemoplaque used as primary therapy in eye(s) with newly diagnosed cT1b and cT2 low-volume retinoblastoma (Cohort ONE).
To describe the anti-tumour efficacy of the chemoplaque as secondary therapy in eye(s) with previously treated retinoblastoma (Cohort TWO).
To determine if there is sufficient evidence of efficacy and safety to undertake further investigation of the chemoplaque in a phase III trial.
Safety Objectives: (Part 1)
Evaluate the safety of the Chemoplaque D efine and describe toxicities of sustained Topotecan to the eye
via Chemoplaque Define and describe extraocular toxicities of sustained Topotecan
to the eye via Chemoplaque
Primary Efficacy Objectives: (Part 2)
To determine effectiveness of sustained release Topotecan delivered by Chemoplaque to achieve CR of retinoblastoma.
Secondary Efficacy Objectives:
Quantify total treatment burden of non-study invasive therapies Time from Chemoplaque insertion to complete remission (CR) Eye salvage rate Overall survival (OS) at the end of study Eye survival (ES) without use of external beam radiation
at the end of study Progression free survival (PFS) Visual acuity
Sample Size Part 1: minimum 2, maximum 18 patients, depending on DLT experienced.
Part 2: Patients enrolled in Part 1 at the Phase 2 Recommended Dose will be added for this cohort efficacy assessment.
Cohort One: Annual expected new diagnoses of retinoblastoma 22; 50% low volume tumor; eligible 11/year.
Cohort Two: Annual expected new diagnoses of retinoblastoma 22: 50% high volume tumor, of which 50% fail with conventional treatment; “refractory” patients eligible 5 to 6/year.
Topotecan Route: Continuous exposure via diffusion from the Chemoplaque
Regimen: 0.6–0.9–1.2–1.5 mg in one or two Chemoplaque(s) glued to sclera under conjunctiva
Study Design Part 1. Phase 1 study for cT2 eyes with retinoblastoma refractory to conventional therapies, some vision potential and no clinical features suggestive of high risk of extraocular extension.
Inter-Patient Escalation in the rolling six phase 1 trial design will enroll two to six patients at the entry dose (0.6 mg/Chemoplaque) dependent upon:
o (1) number of patients enrolled at the current dose level,
o (2) the number of patients who have experienced DLT at the current dose level, and
o (3) the number of patients entered but with tolerability data pending at the current dose level.
Accrual is suspended when a cohort of six has enrolled or Maximum Tolerated Dose (MTD), Highest Tested Dose (HTD) or Recommended Phase 2 Dose (RP2D) have been determined.
Part 2. Phase II study:Cohort One: Any eye with retinoblastoma refractory to conventional therapy, with visible optic disc, vision potential and no clinical indication of risk of extraocular tumor spread, in a child not receiving systemic chemotherapy for the other eye, with fully visible optic nerve, bilateral or unilateral.
Cohort TWO: Primary intraocular retinoblastoma cT1b, cT2 small volume disease, bilateral or unilateral. Summary of On-Treatment Evaluations (Consort Diagram):
Physical/Eye exam: baseline, 4, 7, 10 CBC: baseline, 4, 7, 10 weeks. Examination Under Anaesthetic (EUA) with eye imaging and
scoring DEPICT HEALTH Retinoblastoma Activity Index (RAI): baseline; 4, 7, 10 weeks.
Toxicity
Any Grade 4/5 ocular or systemic toxicity: (remove Chemoplaque).
Complete Response (CR):
Chemoplaque removed week 10. Resume EUAs as standard of care with evaluations (RAI,
imaging, etc.
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define what is standard of care vs research as this will help you for you budget
For Patients with CR who do NOT progress during the treatment period: Standard of Care with EUA every 3 to 12 weeks for 6 months after completion of the therapy, then every 3 to 6 months for 4 years.
For Patients with Progressive Disease (PD):
Continue conventional management of retinoblastoma. E UAs every 6 months for 5 years after completion of
retinoblastoma therapy.
Study Inclusion Criteria
Part 1: cT2 eyes with retinoblastoma refractory to conventional therapies, some vision potential and no clinical features suggestive of high risk of extraocular extension.
Part 2:
Cohort ONE: Small volume active tumors (< 6 mm in any dimension/tumor) in eyes with cT2 (IIRC group C/D) or cT1b (IIRC group B) (location threatens fovea) in a child not receiving systemic chemotherapy for the other eye, with fully visible optic nerve; bilateral or unilateral.
Cohort TWO: Any eye with refractory retinoblastoma with visible optic disc, vision potential, minimal retinal detachment and seeding, and no clinical indication of risk of extraocular tumor spread.
Study Exclusion Criteria
1. Reported allergy to topotecan, camptothecin or derivatives thereof.2. Any eye with tumor touching the optic nerve rim. 3. Any eye features suggesting extraocular extension or high-risk
histopathology4. Neuroimaging (MRI) showing suspicion of, or definitive optic nerve
invasion5. Neuroimaging (MRI) showing suspicion of, or definitive Trilateral
Retinoblastoma 6. Eye with diffuse retinoblastoma 7. Extra-ocular extension into orbit or brain8. Metastatic retinoblastoma with or without CNS involvement
Study Outcome Measures
(Efficacy Evaluation)
Primary efficacy outcome measures:
Tumour evaluation scored with DEPICT HEALTH RAI, which incorporates circle of care Retinoblastoma Team judgement of objective tumor size and anatomic extent (ultrasound, Ultrasound Biomicroscopy
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minimal detachment and seeding.
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Work out standard of care separtely from the Research additional details; set up in xls to draft.
Complete Response (CR): Decrease in RAI by 100% from baseline.
Very good partial response (VGPR): Decrease in RAI greater than or equal to 90% and less than 100% from baseline.
Partial response (PR): Decrease in RAI greater than or equal to 20% and less than 90% from baseline.
Progressive disease (PD): Increase in RAI greater than or equal to 30% from baseline or development of new tumors requiring more than minimal focal therapy.
Secondary efficacy outcome measures:
1. Overall survival (OS), defined as the time from the date of initial Chemoplaque insertion to the date of death regardless of the cause of death. Patients who were alive at the time of the analysis will be censored at the date of the last follow up assessment. Patients without follow up assessment and patients with no post baseline information will be censored at the time of study treatment initiation.
2. Overall eye salvage (ES), defined as as the time from the date of initial Chemoplaque insertion to the date of eye removal (enucleation) regardless of the reason for enucleation.
3. Progression-free survival (PFS), defined as the time from initial Chemoplaque insertion to the occurrence of DP or death from any cause. PFS will be assessed at 6 months, 12 months, 2 years and 5 years.
4. Post-intervention treatments for study eye (recorded in DEPICT HEALTH at each clinical encounter with retinal vector-coordinated drawings, representative images):
a. Number and Type: Chemotherapy (systemic and/or intra-areterial); focal laser, cryotherapy; brachytherapy; intra-vitreal chemotherapy; external beam radiotherapy; other;
b. Number of EUAs: total, and for eye evaluation, MRI, other procedures.
Vision Outcome Measures
Primary outcome measures:
1. Digital Visual Acuity: calculated by DEPICT HEALTH algorithms from age-appropriate vision assessment tools.
2. Functional vision.
Secondary outcome measures:
1. OCT detection of fovea and retinal detachment
Quality of Life Outcome Measures
Parent-proxy measures only will be obtained for children aged 1-7
Parent-proxy and self-report will be obtained from children aged 8+.
Safety Outcome Measures
Monitoring and recording of the incidence, nature, and severity of adverse events according to National Cancer Institute Common
To describe the safety and tolerability of the Chemoplaque in patients with retinoblastoma.
To estimate the maximum tolerated dose (MTD) and Recommended Phase II Dose (RP2D).
To define and describe the toxicities of Chemoplaque.
Secondary Aims (Part 2, PhaseII)
To describe the anti-tumour efficacy of the chemoplaque used as primary therapy in eye(s) with newly diagnosed cT1b and cT2 retinoblastoma and low-volume disease (Cohort ONE).
To describe the anti-tumour efficacy of the chemoplaque used as salvage therapy in eye(s) with previously treated retinoblastoma (Cohort TWO).
To determine if there is sufficient evidence of efficacy and safety to undertake further investigation of the chemoplaque in a phase III trial.
Primary HypothesisSustained release topotecan delivered by Chemoplaque will achieve complete remission (CR) of small volume of retinoblastoma and facilitate appropriate focal therapy for residual/recurrent disease.
Secondary HypothesisSustained release topotecan delivered by Chemoplaque will reduce the burden of systemic treatment, anaesthetics, number of focal treatments, and time from diagnosis to CR for retinoblastoma.
Primary Objectives (Part 1)To describe the safety and tolerability of the chemoplaque in patients with retinoblastoma.
Secondary Objectives (Part 2)To describe the anti-tumour efficacy of the chemoplaque used as primary therapy in eye(s) with newly diagnosed cT1b and cT2 retinoblastoma and low-volume disease (Cohort ONE).
To describe the anti-tumour efficacy of the Chemoplaque used as salvage therapy in eye(s) with previously treated retinoblastoma (Cohort TWO).
To determine if there is sufficient evidence of efficacy and safety to undertake further investigation of the chemoplaque in a phase III trial.
Retinoblastoma is the most common pediatric malignant intraocular tumor that originates from the retina (the innermost layer of the ocular wall). Retinoblastoma arises when both copies the retinoblastoma tumor supressor gene, RB1, are pathogenic (non-functional) in a developing retinal cell. It affects one or both eyes, depending on the developmental timing of the first RB1 pathogenic variant: if RB1 is damaged in all cells of the person usually both eyes are independently affected by retinoblastoma when the second RB1 gene is damaged in a specific susceptible developing retinal cell. If both RB1 genes are damaged only in the developing retinal cell that becomes a tumor, only one tumor is formed, affecting one eye.
The primary goal of therapy is prevention of tumor spread outside the eye to save the child’s life. If the tumor is advanced (with a potential to spread outside the eye), removal of the eye (enucleation) is the safest option. However, if the tumor is less advanced and the optic nerve is visible, vision and eye salvage become the priorities.
In unilateral children with poor visual potential, treatment burden is weighed against potential outcome in informed discussion with the parents. For advanced, high risk disease, enucleation is a good choice that avoids invasive proceedures that might not control disease, but consume a large part of the child’s early experience. However, since bilateral disease threatens both eyes and blindness, efforts to save the worst eye may be more extensive, still recognizing that life is most important.
Cancer Staging
Staging at initial diagnosis determines treatment and prognosis. Two staging schemes to predict eye salvage have caused significant confusion in the literature, preventing proper comparison between studies.1 The International Intraocular Retinoblastoma Classification (IIRC) staged eyes as Group A (very low risk) through E (very high risk).2 A subsequent modification of this classification3 resulted in severely advanced eyes being classified with less-affected eyes, so that “Group E” did not equate to risk of extraocular disease.4-6
The 2017 American Joint Committee on Cancer (AJCC) 8th edition TNMH (tumor, node, metastasis, heritable trait) (Table 1) clinical and pathological staging system is the first evidence-based system to predict prognosis of both eye(s) and patients.1 It is informed by an international survey of 1728 eyes with retinoblastoma comparing all the previous classifications and best separates features of eye disease predictive of the likelihood to save the eye without use of external beam irradiation.
Current Retinoblastoma Treatment Removal of the eye
Primary eye removal (enucleation) remains the definitive treatment for advanced unilateral retinoblastoma (TNMH1 cT3 and IIRC2 Group E eyes), allowing the child to return to normal life and enabling histopathological determination of risk of extraocular tumor.7 For unilateral retinoblastoma, enucleation is the definitive treatment when the optic nerve is not visible and in the presence of retinal detachment (TNMH1 cT2a and IIRC2 Group D eyes) or extensive vitreous seeds (TNMH1 cT2b and IIRC2 Group D eyes) that otherwise require invasive treatments over several years that are costly to the child and family, to save an eye with poor vision. Enucleation is strongly recommended when orbital or optic nerve involvement is suspected, there is anterior segment invasion, neovascular glaucoma, intraocular hemorrhage, orbital cellulitis, and little potential for useful vision.8
Systemic chemotherapy
Systemic chemotherapy is effective to reduce size of intraocular retinoblastoma tumors. Systemic chemotherapy alone is insufficient to control tumor and focal therapy (laser, cryotherapy) consolidation
therapy are added subsequently to control tumor.9 Handheld OCT is excellent to accurately assess tumor activity related to focal therapy scars.10
The most common protocol world-wide includes Vincristine, Etoposide and Carboplatin (VEC) on a 3-weekly schedule for 4 to 6 cycles. The main indication for systemic chemotherapy is bilateral and trilateral retinoblastoma. Second line regimens for refractory retinoblastoma have been used. The St. Jude group combined Topotecan with Carboplatin and Vincristine followed by focal consolidation.10
Intra-arterial chemotherapy (IAC)
Direct delivery of one or multiple chemotheraoeutic agents (Melphalan, Toptecan) into the ophthalmic artery is currently used to treat eyes with retinoblastoma.6 First described by the Japanese and revisited by the Memorial Sloan-Kettering Cancer Center group,11-13 ocular salvage is reported to be high as both primary and salvage therapy.11,14-26 The reported data of efficacy and ocular and periocular complications is still missing important details regarding metastasis, second cancers, visual outcome and choroidal health.27 IAC is an expensive modality that is not available in many centers even in developed countries. Published evidence on efficacy or safety of IAC compared to other treatment modalities is limited, and its relative benefits and harms are not known. The published non-comparative data is voluminous, but difficult to critically assess.
Radiotherapy
The prevalence of second malignancies in H1 patients retinoblastoma patients treated for remains higher than for any other pediatric malignancy, especially following external beam radiation therapy.28,29 Therefore radiotherapy is now only used if all other eye salvage options have failed for the last eye of a bilateral retinoblastoma patient. At the cost of doubling the second câncer risk, the eye can be saved with useful vision.
Consolidation with focal laser photocoagulation or cryotherapy
Consolidation with local laser photocoagulation or cryotherapy following chemotherapy (systemic or IAC) is highly effective for cT1 (Groups A and B) eyes with intraretinal disease.30,31 However, in cT2b (Groups C-D) eyes (tumor invasion out of the retina into vitreous and/or subretinal space) focal consolidation contributes to salvage of eyes.32,33
Periocular Chemotherapy
Chemotherapy has been delivered locally to the eye. Direct injection of carboplatin into the subconjunctival or subtenon space was associated with complications including optic atrophy with profound vision loss,34 ocular motility problems,35 and periorbital cellulitis. COG ARET0321 (single arm trial of systemic and subtenon chemotherapy for Groups C and D retinoblastoma) had slower enrollment than expected which necessitated early closure of the study, in part, because of acute inflammatory response and complications of rectus muscle fibrosis causing restrictive strabismus.
Subtenon injections of Topotecan in fibrin sealant reduced small volume intraocular retinoblastoma when combined with focal therapy.36 Doses ranged from 2.01–4.62mg/m2 . Ocular toxicity was minimal and no motility restriction was observed. Systemic effects included CTCAE grade 1-4 hematologic toxicity that improved after one week and did not require intervention.
Small molecules delivered by periocular injection are rapidly cleared into systemic circulation through exposure of the agent to the conjunctival and surrounding orbital tissues in a pre-clinical model.37
Intra-vitreal Injection of chemotherapy
Vitreous seeds are generally resistant to systemic and intra-arterial chemotherapy. Intravitreal chemotherapy (IVitC) (melphalan and/or topotecan) now has good impact on the most difficult form of intraocular retinoblastoma to cure.38 IVitC is commonly repeated monthly depending on clinical response. The main complications include vitreous hemorrhage, retinal tears/detachment, damage to
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Meadows AT, Chintagumpala M, Dunkel IJ, et al. Children’s Oncology Group Trials for Retinoblastoma. In: Clinical Opthalmic Oncology. 1 ed. Philadelphia: Saunders Elsevier; 2007:491–495.
Gallie Brenda, 03/05/19,
Meadows AT, Chintagumpala M, Dunkel IJ, et al. Children’s Oncology Group Trials for Retinoblastoma. In: Clinical Opthalmic Oncology. 1 ed. Philadelphia: Saunders Elsevier; 2007:491–495.
Gallie Brenda, 03/05/19,
10. Brennan RC, Qaddoumi I, Mao S, Wu J, Billups CA, Stewart C. Ocular salvage and vision preservation using a topotecan-based regimen for advanced intraocular retinoblastoma. Journal of Clinical Oncology 2017;35: 72-77.
the lens leading to cataract, endophthalmitis and direct retinal toxicity when the drug is not well dispersed through the vitreous.39,40 A recent retrospective study of intravitreal chemotherapy injections in 10 retinoblastoma treatment centers worldwide found no extraocular extension of tumor when used with the described precautions, including selection of eyes where the source of seeds is controlled, preinjection lowering of intraocular pressure, and postinjection cryotherapy to the needle and needle track.38,41
Oncolytic vírus therapy
One recent publication42 describes the basic science of engineering an oncolytic vírus that targets cancer cells that have lost RB1, demonstrated to target RB1-deficient cells. Two patients were treated with intravitreal injections: boths eye showed very significant inflammation; one eye was enucleated with remaining active tumor on pathology.
CHALLENGES IN MEASURING RESPONSE IN RETINOBLASTOMAThere are several challenges to objectively measuring tumor response in retinoblastoma, and no previous retinoblastoma trial has described tumor responses quantitatively or as waterfall plots.
There are several reasons for this limitation. First, there is no single objective method to measure tumor dimensions due to the complexity of multiple tumors in both eyes and largely subjective “expert” interpretation of “active” vs “quiescent” vs scar remnant. Second, retinoblastoma target lesions can include the primary tumor(s) and vitreous/ subretinal seeds. There are no established criteria for retinoblastoma that describe the response of the entire eye inclusive of all target lesions and seeds. Third, there is a difference between viable disease and visible disease, and even eyes in complete remission may have large non-viable residual tumors. Unlike most other solid tumors that can only be visualized by radiologic imaging with no estimate of “viable” disease, the viable vs non-viable areas of retinoblastoma tumors can be directly visualized by the treating ophthalmologist during EUAs and captured in photographic and optical coherence tomograph (OCT) and best summarized in the retinal drawing. Since the innovation of the indirect ophthalmoscope, [C. Schepens, 1945] with a relatively large field of vision, the standardized retinal drawing with an internationally endorse color code (for example, active retinoblastoma is drawn in yellow) has been a key part of management of retinoblastoma. To overcome these limitations, we will utilize a novel measure of retinoblastoma active tumor per eye representing the “Sum of all areas of viable tumor” that will take advantage of the DEPICT HEALTH retinal e-drawing.
DEPICT HEALTH full view for life for retinoblastoma patientsDEPICT HEALTH (depictrb.technainstitute.com/username:demo-user/password:Demo1234) is a retinoblastoma-specific communication service that collects life-long retinoblastoma point-of-care data, details accessed through the timeline. Deep details are accessible in real-time by clicking on the symbol of the encounter when the date shows in the timeline. The full circle of care includes patients, families and clinicians who enter/view data depending on authorizations, in order to understand clinical features and treatments.43-45 DEPICT HEALTH has supported retinoblastoma care in SickKids since 2003, and in 2019 will be piloted to SickKids and Alberta patients to using Cloud computing.
The eligibilty criteria for the present clinical trial of the Chemoplaque will be accessed from DEPICT HEALTH within the inclusive data of each encounter and treatments, entered as is the standard care of children with retinoblastoma. Outcome data will be also collected through DEPICT HEALTH as a subset of data entered by the circle of care in routine quality care, irrespective of the Chemoplaque Trial.
The retinal drawings in DEPICT HEALTH are vector co-ordinated diagrams based on the standard for retinal drawings and color codes, with yellow representing “active” retinoblastoma. The total active tumor per eye will be quantitated by total pixel count for yellow in the drawing (Retinoblastoma Activity
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There are several challenges to objectively measuring tumor response in retinoblastoma, and no previous retinoblastoma trial has described tumor responses quantitatively or as waterfall plots. There are several reasons for this limitation. First, there is no single objective method to measure tumor dimensions (Brenda to add details as to why). Second, retinoblastoma target lesions can include the primary tumor or the vitreous seeds or both. There are no established criteria for RB that describe the response of the entire eye inclusive of all target retinal lesions and vitreous seeds. Third, there is a difference between viable disease and visible disease, and even eyes in complete remission may have large non-viable residual tumors. Unlike most other solid tumors that can only be visualized by radiologic imaging and provide no estimate of viable disease, the viable vs non-viable areas of retinoblastoma tumors can be directly visualized by the treating ophthalmologist during EUAs and captured in the Depict eye diagram. To overcome these limitations, we will utilize a novel measure of retinoblastoma response called the “Sum of all areas of viable target lesions” that will take advantage of the electronic Depict eye diagram. [Brenda to add details from here…]
Index, RAI). This novel measurement encompasses the sum of expertise of the multidisciplinary care Team. Drawing details are refined by consensus of the care Team, taking into consideration all available measures and features. Individual subjectivity to determine active tumor will become more objective by collective assessment by the Team of the various images and measures (ultasound, OCT, UBM, wide-field retinal images, MRI, etc).
IMPORTANCE OF THIS TRIALFor retinoblastoma patients, this innovative approach to deliver chemotherapy locally to the eye over a prolonged time, with minimal systemic exposure, is important to achieve salvage of more eyes. This trial acknowledges that mulitple treatments are necessary to salvage eyes. The Chemoplaque has potential to control intraocular retinoblastoma with low toxicity, and reducing the number of highly invasive therapies with serious side effects needed, thus reducing treatment burden and cost.
This trial is novel in its use of DEPICT HEALTH for retinoblastoma to access point-of-care deep retinoblastoma-specific data for eligibility and outcomes, pulled from the record of standard of care. This concept has particular relevance to rare diseases. DEPICT HEALTH is anticipated to broaden the geographic distribution of the care team, without compromizing the quality of care, since all in the circle of care, including the family and local physicians invited by the family, see all the data in real time. The clinical circle of care enters the data at the time of each encounter in routine retinoblastoma care, so there is no need to pull trial data from the health record. Trial specific data will be extracted from DEPICT HEALTH and stored in RedCap C.
PRECLINICAL STUDIES
Animal studiesPurpose: To determine the safety, tolerability, and the pharmacokinetics (ocular and plasma) of various dosages of topotecan hydrochloride (TPT) formulated in the Targeted Transscleral Delivery Systems (TTDS) designed as Episcleral Chemoplaques(Episcleral Topotecan) and implanted onto the sclera of New Zealand White rabbits.
Methods: Female rabbits (n=87) assigned to toxicity (n=5 per dose group) or pharmacokinetics (n=3 per time point) groups, were implanted in the right eye with the test article TTDS Episcleral Implant containing doses ranging from 0.3 mg to 0.9 mg topotecan HCl. For the pharmacokinetic arm of the study, rabbits were euthanized after 24 hours, 48 hours, and 7, 14, 21, 28, 42, and 56 days (n=3 per time point). Plasma, ocular tissues (that were divided into distal and proximal sections relative to the implant site), and the test articles were collected from each animal during necropsy.
Ocular tolerability and toxicity were assessed by ocular examination (slit lamp biomicroscopy and indirect ophthalmoscopy), applanation tonometry (pneumatonometer), and electroretinography (ERG). Retinal findings were documented by fundus photography. Systemic tolerability was assessed by weight progression and observations for signs of toxicity.
Topotecan was assayed in the plasma and ocular tissue samples using a validated high-pressure liquid chromatography (HPLC) method for the detection and quantification of total topotecan and its lactone isoform (LLOQ = 1 ng/ml or ng/gram). Drug distribution is reported as Cmax (maximum concentration), Tmax (time when it reached maximum concentration), TLC90 (time above topotecan LC90 in retinoblastoma cell lines, 5 ng/ml or gram) and AUC (area under the time concentration curve).
Results: All studied doses of Episcleral Topotecan were well tolerated systemically. No measurable concentrations of topotecan—either total topotecan or its lactone isoform—were found in the plasma after implantation of any dose of Episcleral Topotecan. All rabbits gained weight during the study period of 84 days. There was no evidence of a systemic response to topotecan treatment in the body weight data or daily health observations.
Tissue distribution of topotecan is shown in Table 1. After implantation with Episcleral Topotecan 0.3 mg (containing 0.3 mg topotecan HCl), the proximal ocular tissues with therapeutically relevant exposure to topotecan’s active (lactone) isoform (Cmax, Tmax, TLC90) were: Choroid (2.7 ug/g, day 2, 14 days), sclera (1.3 ug/g, day 2, 21 days), retina (0.86 ug/g, day 2, 14 days). Topotecan (lactone isoform) also reached therapeutic concentrations in the distal sclera on days 2 and 14. (
After implantation with Episcleral Topotecan 0.6 mg (containing 0.6 mg topotecan HCl), the proximal ocular tissues with therapeutically relevant exposure to topotecan’s active (lactone) isoform (Cmax, Tmax, TLC90) were: Choroid (10.6 ug/g, day 2, 21 days), retina (1.1 ug/g, day 1, 21 days), sclera (1 ug/g, day 21), and vitreous humor (8.2 ng/ml, day 21). In addition, topotecan lactone isoform was also detected at relevant concentrations in the distal tissues—sclera (126.3 ng/g on day 21), retina (50 ng/g on day 2), and vitreous (30 ng/ml on day 2).
After implantation with Episcleral Topotecan 0.9 mg (containing 0.9 mg topotecan HCl), the proximal ocular tissues with therapeutically relevant exposure to topotecan’s active (lactone) isoform (Cmax, Tmax, TLC90) were: Choroid (21.6 ug/g, day 2, 21 days), retina (2 ug/g, day 1, 28 days), sclera (6.9 ug/g, day 2, 21 days), and vitreous humor (10.21 ng/ml, day 21). In the distal tissues relevant distribution of topotecan lactone was found in the sclera (36.71 ng/g, day 14, 21 days), choroid (166.23 ng/g, day 7, 21 days), retina (87.32 ng/g, day 7, 21 days) and vitreous (5.72 ng/ml on day 21).
Ocular Toxicity
Between days 1 and 7 after the implantation of any dose of Episcleral Topotecan (0.3, 0.6 and 0.9 mg of Topotecan HCl) a mild discharge, congestion and swelling of the conjunctiva, predominantly near the implantation site, was observed.
Between days 1 and 14, peaking on day 7, some degree of hyperemia of the choroid was noticed in all the eyes exposed to Episcleral Topotecan. It was predominantly mild (decrease of the white reflex between the mid-to-large choroidal vessels), but appeared to increase in extension and slightly in intensity from mild to moderate (blurred delineation of the mid-to-large choroidal vasculature) as a function of the dose.
Serous exudative retinal detachment was observed in eyes exposed to any dose of Episcleral Topotecan starting on day 7 and subsiding before day 21—mostly between days 7 and 14. Spontaneous and complete resolution occurred before day 28 in all cases. It was mostly located in the quadrant directly exposed to the test article, superior-temporal, but it was also sporadically found in the adjacent inferior quadrant (inferior-temporal) in the 0.6-mg and 0.9-mg dose groups.
Table 1. Pharmacokinetics of topotecan (total and lactone) after implantation of Episcleral Topotecan containing 0.3, 0.6 or 0.9 mg of topotecan HCl: Area under the time-curve (AUC), maximum concentration (Cmax) and time to maximum concentration (Tmax) (*ng/g).
Atrophy of the choroid was observed as mild starting at day 21 and it evolved up to day 42 to moderate (grade II) in dose groups 0.3-mg and 0.6-mg, or to severe (grade III) in dose group 0.9-mg.
It invariably stabilized between days 56 and 83. The presence of atrophy in the adjacent inferior-temporal quadrant, was more frequent in eyes exposed to higher doses.
In animals implanted with Episcleral Topotecan 0.3 mg, there was no substantial difference in the intraocular pressure between the right eye (implanted) and the left eyes (controls) during the follow-up period (Figure 1). After Episcleral Topotecan 0.6 mg implantation, implanted eyes demonstrated a significant decrease in the intraocular pressure on days 7 (9 mmHg, CI 95% 2.4-15.6) and 14 (7.6 mmHg, CI 95% 2.2-13) compared to the control eyes. In the Episcleral Topotecan 0.9 mg group the average decrease in the IOP in tested vs. control eyes was also significant on day 7 (10.6 mmHg, CI 95% 2.17 to 19.03).
Figure 1. Intraocular pressure (IOP) progression
before and after implantation of Episcleral Topotecan containing 0.3, 0.6, or 0.9 mg of topotecan HCl. Tested eye: OD. Control eye: OS.
After implantation of 0.3-mg, 0.6-mg or 0.9-mg Episcleral Topotecan, due to the large variability inherent to the measured ERG responses in normal and control eyes, mostly non-significant changes were detected in either the amplitude or the implicit time of the studied parameters under the different stimuli conditions (Figure 2). On day 84, although mostly within the 95% confidence intervals of the control eye ERG readouts, a trend in the implanted eyes was observed towards a decrease of approximately 20 to 40% in the amplitude of a and b waves in scotopic and photopic conditions.
Non-significant decrease (within 95% confidence intervals of the ERG responses between tested and
control eyes) were seen in both directions and mostly within the 95% confidence intervals. Significant but sporadic findings included changes after exposure to doses of topotecan at 0.3 mg in b-wave amplitude (scotopic 10 on day 84), and at 0.6 mg in the b-wave implicit time (photopic 3000 on day 14). Significant and consistent differences across different stimuli parameters were seen after 0.9 mg of topotecan on day 84, in the a-wave amplitude (scotopic 10000) and the b wave amplitude (scotopic 10 and 10000, and photopic 3000).
Explanted episcleral Chemoplaqueswere completely depleted of topotecan at day 28 in all dose groups. Assay of the implant content of the 0.3 and 0.9 mg doses collected at necropsy on Day 21 showed that the content of the implant had decreased by 100%. The 0.6 mg dose decreased by 97% on day 21 and 100% by Day 28.
Histology. In general the Chemoplaques were well tolerated. Both globes, the implant site, bulbar conjunctiva, both eyelids and the lacrimal glands were examined histopathologically. There was a small amount of chronic inflammation and mineralization in the wall of the implant pocket in some animals in all groups. Similarly, there was mild subacute inflammation in the bulbar conjunctiva in the right eye of some animals in all groups, probably nonspecific and secondary to the surgical and handling procedures. There was no meaningful difference between the three treatment groups. The left eye was normal in all animals.
Figure 2. Electroretinography implicit time and amplitude 84 days after implantation of episcleral topotecan containing 0.3, 0.6 or 0. 9 mg topotecan HCl (TPT). Tested eye: OD, Control eye: OS.
distribution of topotecan lactone after implantation of Episcleral Topotecan containing 0.3, 0.6, or 0.9 mg of topotecan HCl. Plasma concentrations < LLOQ. LLOQ for plasma and ocular tissues: 1 ng/ml or 1 ng/gram.
PILOT COMPASSIONATE USE Two patients have been treated with the Chemoplaque under the jurisdiction of Health Canada’s Special Access Program. Both patients were close to losing their last eye to retinoblastoma and the remaining treatment options were judged to be dangerous to vision or to have serious lifelong implications of increasing second cancer risk to close to 50%. These inevitable risks were greater than the theortectical risks of the “Never before in Human” Chemoplaque. Each patient experienced no eye or systemic toxicity. Both eyes had a rapid regression of small volume disease. One patient had further treatments for recurrence of disease at Day 135; the second patient had further therapy at Day 110 to repair ocular complications from treatments preceding the Chemoplaque. At Days 250 (8 months) and 132 (4 months) the eyes show no active retinoblastoma and have vision better than 20/100.
These children fit Cohort ONE, secondary therapy for eyes with retinoblastoma refractory to conventional therapies, some vision potential and no clinical features suggestive of high risk of extraocular extension.
Patient ONEA child with a constitutional RB1 gene pathogenic variant was diagnosed with both eyes stage1 cT2b (Group D murphree classification2 ) retinoblastoma. After 4 months treatment (Figure 4a) with systemic chemotherapy his left eye was removed because extensive refractory retinoblastoma threatened the optic nerve and choroidal invasion.
His right eye received systemic chemotherapy (2 different regimens, 8 total cycles, partial response, then recurrence) and intra-arterial chemotherapy (2 cycles, no response). After 8 months, there was still refractory multiply-recurrent extensive disease (Figure 4a). The large nasal tumor (paritally calcified, 6.5 mm elevation adjacent but not contiguous to the optic disc) showed growth of the main tumor in every direction with adjacent “greasy” vitreous seeds. Throughout the retina were 23–30 laser- and chemo-resistant tumors. The foveal pit was intact (excellent visual potential) but detached by new serous retinal detachment related to the active large nasal tumor. The only remaining conventional treatments were plaque radiotherapy, iexternal beam irradiation and removal of his only eye.
Figure 4a. DEPICT HEALTH graphic display of treatments since diagnosis of retinoblastoma in Patient One.
Health Canada authorized the first human application compassionate use of the Chemoplaque. The Target tumors were (i) the 30+ small volume tumors for 360o near the ora serrata, (ii) the partially calcified tumor nasal to the optic nerve.
On Day 0 the Chemoplaque was glued to sclera under conjunctiva. Blood tests and pain scores were normal (no pain). No ocular or systemic toxicities were observed.
Response:(i) Small volume tumors
Day 12: Partial response (PR) (A decrease in tumour parameter greater than or equal to 20% and less than 90% from baseline.) Day 28: Complete response (CR) (decrease in tumour parameter by 100% from baseline, or no viable residual disease by imaging including OCT, ultrasound and ultrasound biomicroscopy.) duration ?
(ii) Partially calcified nasal tumorDay 28: Partial response (PR) (A decrease in tumour parameter greater than or equal to 20% and less than 90% from baseline.)Day 156: Progressive disease (PD) (Increase in tumor parameter by greater than or equal to 30% from baseline or development of new tumors requiring more than minimal focal therapy.
A Chemoplaque (0.6mg Topotecan) was inserted in the inferonasal quadrant and glued to sclera on day 0. Blood tests and pain scores were normal (no pain). No local or systemic toxicities were observed. Vision improved by Day 12 (fóvea center of vision reattached). At examinations under anesthesia (EUAs) at days 12, 28, 42, 70 no ocular toxicity was detected. Vitreous seeds and all but one of the small retinal recurrent tumors disappeared by day 12; all disappeared by day 28 (Figure 4b). The nasal calcified tumor showed shrinkage and on day 70 laser therapy to consolidate and flatten the surrounding tumor was started. Minimal superficial vitreous hemorrhage was seen over of the central mass shrinking-edge, that disappeared at day 70 and is more likely due to tumor necrosis than Chemoplaque toxicity.
The Chemoplaque was removed on Day 70, with no evidence of local toxicity. Ultrasound biomicroscopy showed normal scleral thickness where the chemoplaque had been placed. At day 98, there were no tumor recurrences and 20/80 vision (Figure 4b).
On Day 135, the nasal calcified tumor showed tumor regrowth while the peripheral tumors remained scarred. At Day 156, the nasal calcified tumor continued growing and a ruthenium plaque was placed Day 175. The small tumors all remain scarred. At removal of the ruthenium plaque, vitreous seeds were noted and vitreous hemorrhage was evident partially obscuring fundus view, and vision decreased. On Day 185 intravitreal chemotherapy was given.
On Day 197 pars plana vitrectomy46 with melphalan in the irrigation fluid removed vitreous blood and seeds, in order to facilitate observation and focal treatment and control of vitreous seeds. Cytopathologic evaluation of the vitreous washout identified no tumor cells. Eight months after insertion of the Chemoplaque there has been no Chemoplaque-related toxicity. The small-volume multiply resistant tumors have not recurred. Vision is 20/100.
Figure 4b: Retinoblastoma in right eye from Day 0 (Chemoplaque insertion), Day 98, and follow-up treatments (ruthenium plaque, vitrectomy, I12 plaque) for the Day 156 recurrence in calcified nasal tumor. No recurrence in the 30 distributed small volume tumors at day 250 (8 months); 20/80 vision.
Patient TwoThis child had bilateral retinoblastoma, both eyes treated with systemic chemotherapy (2 different regimens, 10 total cycles, partial responses), IAC (2 cycles, non-responsive) and external beam irradiation therapy over one year (Figure 5a). Four months later there was massive recurrence in both eyes. The right eye was removed.
The left eye had dispersed tumor recurrences with vitreous seeding and vitreoretinal fibrous proliferation. The fovea was detached with a serous retinal detachment. The tractional retinal detachment was covered with highly active retinoblastoma (Figure 5a). There were no more conventional options for this last eye except removal of the child’s last eye. Health Canada authorized compassionate use of the Chemoplaque (0.6mg Topotecan).
Figure 5a: DEPICT HEALTH graphic display of treatments since diagnosis Patient Two.
Health Canada authorized the second human compassionate use of the Chemoplaque. The Target tumors were the small volume primary original tumor and the dispersed active tumor attached to vitreous traction lines and floating vitreous seed.
On Day 0 the Chemoplaque was glued to sclera under conjunctiva. Blood tests and pain scores were normal (no pain). No ocular or systemic toxicities were observed.
Day 28 Partial response (PR) (A decrease in tumour parameter greater than or equal to 20% and less than 90% from baseline.)
Day 48 Very good partial response (VGPR) (A decrease in tumour parameter greater than or equal to 90% and less than 100% from baseline.)
Day 110 Very good partial response (VGPR) (decrease in tumour parameter greater than or equal to 90% and less than 100% from baseline); the residual tumor was only detected by vitrectomy to release the retinal traction.
Day 132 Complete response (CR) (decrease in tumour parameter by 100% from baseline, or no viable residual disease by imaging including OCT, ultrasound and ultrasound biomicroscopy.)
Dispersed small tumors showed 50% reduction and marked reduction of vitreous seeds Day 28 (Figure 5b). No active-appearing tumors or seeds were visible by Day 48 and the fovea had re-attached. No signs of local or systemic toxicity were observed. Minimal superficial vitreous hemorrhage was seen over of the shrinking masses of tumor that disappeared by Day 48, perhaps related to tumor necrosis rather than chemoplaque toxicity. The Chemoplaque was removed at Day 77. At1,there were nvision 260. Day 110 pawith melphalan irrigation wrelease t Although no active tumor was visible, the cytology from the vitrectomy fluid showed active retinoblastoma tumor clumps. At Day 132 there was no active tumor deteted by visual examination and OCT which showed only scarring in the vitreous traction, and confirmed that the shifting yellow exudate under the retina was indeed dead tumor cells.
Figure 5b: Retinoblastoma in right eye from Day 0 (Chemoplaque insertion), Day 98, and follow-up treatments (ruthenium plaque, vitrectomy, I12 plaque) for the Day 156 recurrence in calcified nasal tumor. No recurrence in the 30 distributed small volume tumors at day 250 (8 months); 20/80 vision.
TREATMENT PROGRAMPart 1. Dose Escalation Schema
Inter-Patient EscalationThe rolling six phase 1 trial design will be used for the conduct of this study.{Skolnik, 2008 #21991} Two to six patients can be concurrently enrolled onto a dose level, dependent upon (1) the number of patients enrolled at the current dose level, (2) the number of patients who have experienced DLT at the current dose level, and (3) the number of patients entered but with tolerability data pending at the
current dose level. Accrual is suspended when a cohort of six has enrolled or when the study endpoints have been met.
Dose level assignment is based on the number of participants currently enrolled in the cohort, the number of DLTs observed, and the number of participants at risk for developing a DLT (i.e., participants enrolled but who are not yet assessable for toxicity). For example, when three participants are enrolled onto a dose cohort, if toxicity data is available for all three when the fourth participant entered and there are no DLTs, the dose is escalated and the fourth participant is enrolled to the subsequent dose level. If data is not yet available for one or more of the first three participants and no DLT has been observed, or if one DLT has been observed, the new participant is entered at the same dose level. Lastly, if two or more DLTs have been observed, the dose level is de-escalated. This process is repeated for participants five and six. In place of suspending accrual after every three participants, accrual is only suspended when a cohort of six is filled. When participants are inevaluable for toxicity, they are replaced with the next available participant if escalation or de-escalation rules have not been fulfilled at the time the next available participant is enrolled onto the study.
The following table provides the decision rules for enrolling a patient at (i) the current dose level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether the study is suspended to accrual:
# Pts Enrolled
# Pts with DLT
# Pts without DLT
# Pts Data Pending
Decision next subject
Dose (mg)
next patient
2 0 or 1 0, 1 or 2 0, 1 or 2 Same dose 0.6 #32 2 0 0 De-escalate* Suspend?
3 0 0, 1 or 2 1, 2 or 3 Same dose 0.6 #43 1 0, 1 or 2 0, 1 or 2 Same dose 0.63 0 3 0 Escalate** 0.93 ≥ 2 0 or 1 0 or 1 De-escalate* 0.6 MTD
4 0 0, 1, 2 or 3 1, 2, 3 or 4 Same dose 0.94 1 0, 1, 2 or 3 0, 1, 2 or 3 Same dose 0.94 0 4 0 Escalate** 0.6 x 2 #54 ≥ 2 0, 1 or 2 0, 1 or 2 De-escalate* 0.9 MTD/RP2D
5 0 0, 1, 2, 3 or 4 1, 2, 3, 4 or 5 Same dose 0.6 x 2
5 1 0, 1, 2, 3 or 4 0, 1, 2, 3 or 4 Same dose 0.6 x 2
If two or more of a cohort of up to six patients experience DLT at a given dose level, then the MTD has been exceeded and dose escalation will be stopped (see Section 11.2.2 for exception to rule).
In addition to determination of the MTD, a descriptive summary of all toxicities will be reported.
Analyses of Tumour Response: Change in Sum of Tumour Area:
The sum of areas of all active target lesions (yellow pixels, see section **page) will be measured at the pre-treatment EUA and all subsequent on-study EUAs from the DEPICT HEALTH retinal drawing, quantitating the sum of active tumor in the study eye, representing the collective estimate by designated Team experts of area with active tumor, as described in section __.
The change in the sum of area of active tumor in the study eye will be shown as spaghetti plots, which convey longitudinal changes in active disease across time for all study eyes (patients) in a single diagram.
The percentage change in sum of all areas from the initial EUA to the point of maximal response will be described numerically for each eye and shown as a waterfall plot. The time to maximal response, and the overall duration of response, will be tabulated for each patient.
Quantitation of Target Tumor:
In addition to total tumor area per eye, Target tumor(s) (the tumor(s) for which the chemoplaque is intended) will be determined when eligibility is considered and then documented at the first study EUA when the Chemoplaque is inserted. The Target lesion(s) can include the primary tumor, selected vitreous or subretinal seeds, or both.
The maximal height of the Target tumor in the quadrant where the initial Chemoplaque is placed will be measured at the first study EUA and at subsequent on-study EUAs using ultrasound and/or OCT. Sub-retinal, intraretinal and vitreous seeds will be counted and scored for features. Percentage change in relevant quantitative measures (maximal tumor height, number of seeds) on study will be measured for each patient and shown as a waterfall plot.
Degree of Response
Based on the above quantitative tumour response parameters, at each EUA each eye/patient will be classified as follows:
Progressive disease (PD): Increase in tumor parameter by greater than or equal to 30% from baseline or development of new tumors requiring more than minimal focal therapy (laser or cryotherapy).
Stable disease (SD): A change in tumor parameter between 30% increase and 20% decrease from baseline.
Partial response (PR): A decrease in tumour parameter greater than or equal to 20% and less than 90% from baseline.
Very good partial response (VGPR): A decrease in tumour parameter greater than or equal to 90% and less than 100% from baseline.
Complete response (CR): a decrease in tumour parameter by 100% from baseline, or no viable residual disease by wide field imaging to ora serrata, OCT, ultrasound and ultrasound biomicroscopy.
The number and proportion of patients experiencing each type of response will be summed to calculate the following rates:
Disease response rate: Proportion of patients who experienced a PR, VGPR, or CR.
Disease control rate: Proportion of patients who experienced SD, PR, VGPR, or CR.
Duration of response: Time from documentation of disease response to objective progression.
Analyses of Clinical Benefits:In addition to the measures of tumor response describe above, we will describe each of the following statistics as an estimate of clinical benefits or utilities derived by patients.
Eye Salvage Rate: Number and proportion of eyes that avoid enucleation.
Enucleation-free survival: A Kaplan-Meier time-to-event analysis where an event is defined as enucleation or death, and patients are censored at time of last follow-up.
Treatment success rate: Number and proportion of eye(s) that avoided enucleation, external beam radiation, systemic metastases, or death. This statistic conveys the proportion of patients who avoided the most clinically significant endpoints of retinoblastoma after all clinical management, of which the Chemoplaque was one component.
Failure-free survival: A Kaplan-Meier time-to-failure analysis where a failure is defined as enucleation, external beam radiation, systemic metastases, or death, and patients are censored at date of last follow-up.
Rate of avoidance of further therapy: Number and proportion of eye(s) that avoided any further need for retinoblastoma-directed therapy after the Chemoplaque(s), not counting minimally invasive focal treatments such as laser or cryotherapy. Retinoblastoma-directed therapy can include enucleation, external beam radiation, plaque radiation, or systemic, intravitreal, or intra-arterial chemotherapy. This statistic conveys the proportion of patients for whom the chemoplaque was continuously effective as sole last therapy.
Further-treatment free survival: A Kaplan-Meier time-to-event analysis where an event is defined as the need for further therapy as defined above, or death, and patients are censored at time of last follow-up.
Vision assessment: Vision will be measured for each eye using age-apropriate vision tests, and reported in Decimal in DEPICT HEALTH clinic encounters.
Vision (Decimal) over the entire tr course for each eye, both before and after the Chemoplaque, will be extracted from DEPICT HEALTH vision assessment for each patient (see Appendix _BG), and summarized graphically as swimmer plots.
Analyses of Toxicities: As part of good patient care, unscheduled visits and procedures are allowed in this protocol. Any unscheduled visits must be documented in DEPICT HEALTH, on the site source document and the CRF.
Grading of Adverse Events
Any suspected or confirmed dose-limiting toxicity (DLT) should be reported within 24 hours to the Study Principal Investigator.
DLTs will be local (ocular) or systemic and sufficiently severe that they require cessation of treatment and removal of the episcleral device. DLT are defined to occur with the first 29 days (four weeks) of Chemoplaque insertion and are possibly, probably, or definitely attributable to the Chemoplaque.
Systemic DLT: Grade 3 or higher non-ocular toxicities that are possibly, probably or definitely attributable to episcleral delivery of topotecan. Non-ocular toxicity will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (http://ctep.cancer.gov).
Ocular DLT: Toxicities defined in the table below that are possibly, probably or definitely attributable to the episcleral delivery of topotecan and which satisfy either of the following criteria:
• Grade 2 or higher eye pain as defined by CTCAE version 4.03,
• Grade 3 ocular toxicities are not present at baseline,
[EXCEPT Grade 3 conjunctival response in the quadrant containing the Chemoplaque is expected and not considered an ocular DLT.]
Independent Review CommitteeLocal IRC/REB approval of the study must be obtained by a site/institution prior to enrolling and treating patients.
Data Monitoring CommitteeA Data Safety Monitoring Board (DSMB) will be created following the study approval to evaluate the study for safety reasons. The DSMB will review study data on a bi-annual basis.
A regular and careful review of treatment and patient safety will be undertaken by the DSMB and will include the frequent monitoring of eye and systemic serious adverse events and adverse events of special interest. The DSMB may recommend that the study stop earlier on the basis of safety concerns. Please see section x for more details.
END OF STUDYThe end of the study is defined as the date when the last patient, last study visit occurs. The last patient is expected to be enrolled approximately 36 months after the first patient enrolled. Patients will be followed for 5 years post treatment.
Objective response rate (partial, very good partial or complete response) occurring within 3 months of insertion of Chemoplaque(s) #1
Response rate is composed of the combination of minor response (MR), partial response (PR) and complete response (CR). The response to be measured at EUA by........
Secondary Efficacy Outcome Measures
Overall survival (OS), defined as the time from the date of Chemoplaque insertion to the date of death regardless of the cause of death. Patients who were alive at the time of the analysis will be censored at the date of the last follow up assessment.
Progression-free survival (PFS), defined as the time from the date of Chemoplaque(s) #1 insertion to the date of disease progression, as determined by change in RAI.
The difference between the OS and PFS will be assessed using a Kaplan-Meier Estimator and the log-rank test.
Safety Outcome Measures
1. Monitoring and recording of the incidence, nature, and severity of adverse events including adverse events of special interest according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03).
2. Safety analysis will include all patients who received at least one simultaneous Chemoplaque(s), with patients grouped according to the treatment(s) actually received.
SUBJECT SELECTIONThis trial will be conducted in compliance with the protocol, GCP, Health Canada, Food & Drug Administration and the European Medicines Agency Regulations. The following criteria must be met at the time of enrollment. All eligibility questions should be addressed prior to the time of enrollment. Waivers will not be granted for this study.
Inclusion Criteria1. Children from birth to 18 years (See Appendix I). 2. All patients on study must have measurable active intraocular retinoblastoma.3. Patient is able to start treatment within 14 working days. 4. Parents/guardians must provide written informed consent and to agree that they (and the
patient) will comply with the study protocol.5. Written assent by patient according to institutional guidelines.
Exclusion CriteriaPatients who meet any of the following criteria will be excluded from study entry:
1. Children over 18 years of age.2. Use of any investigational agent, systemic, targeted or immunotherapy prior to the first study
treatment.
PATIENT ENROLLMENT All patients will be screened by one of the principal investigators or sub-investigators prior to entry into this study. An explanation of the study and discussion of the expected side effects and full disclosure of the “informed consent” document will take place. Assent will be obtained as per local institutional guidelines. Parents/Legal Guardians will be required to sign the Consent Form. Eligible patients will be enrolled on the study.
Procedures conducted as part of the subject’s routine clinical management (e.g., participation in DEPICT HEALTH, imaging studies, etc) prior to signing of informed consent will be utilized for baseline assessment provided the procedure meets the protocol-defined criteria and has been performed in the timeframe of the study.
Enrollment will be completed through .......
No patient can receive protocol treatment until eligibility has been confirmed by the treating investigator. All eligibility criteria must be met at the time of enrollment. As part of confirming eligibility ....
ENROLLMENT This section is completed by the site at the time of enrollment.
Protocol treatment should begin within 14 working days. All eligible patients enrolled into the study will be entered into a patient enrollment log.
Note: It is the responsibility of the investigator in charge to satisfy him or herself that the patient is indeed eligible before enrollment and randomization.
Drug SubstanceTopotecan HCl is the drug substance contained in Episcleral Topotecan Drug Product.
Topotecan HCl Drug Substance Nomenclature and Pharmacological Class:
The full chemical name of the drug substance—topotecan hydrochloride—is: (S)-10-[(dimethylamino)methyl]-4- ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7] indolizino-[1,2-b]quinoline-3,14-(4H,12H)-dione 1.25 hydrochloride.
The Chemical Abstract Service (CAS) registry number: 1228035-86-6.
Dg Topoisomerase I inhibitor.
Dr: Antineoplastic agent.
Drug Substance Molecular Formula, Weight, and Structure:
Topotecan hydrochloride (HCl) molecular formula is C23H23N3O5·1.25 HCl; molecular weight is 467.02. Molecular structure is provided in Figure x.
NN
O
O
OOH
OH
N
H Cl
Figure x. Molecular structure of topotecan hydrochloride
Source and Pharmacology
Topotecan hydrochloride is a semi-synthetic derivative of camptothecin (an alkaloid derived from the camptothecin tree which grows widely throughout Asia) and is an anti-tumor drug with topoisomerase I-inhibitory activity. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents re-ligation of these single strand breaks. The cytotoxicity of topotecan is thought to be due to double strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double strand breaks. Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. At pH ≤ 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. In vitro studies in human liver microsomes indicate that metabolism of topotecan to an N-demethylated metabolite represents a minor metabolic pathway. Systemically-administered topotecan exhibits multi-exponential pharmacokinetics with a terminal half-life of 2 to 3 hours. Total exposure (AUC) is approximately dose-proportional. Binding of topotecan to plasma proteins is about 35%.
Formulation and Stability of the Episcleral Topotecan Chemoplaque Product
Sustained release topotecan is delivered from an episcleral implant (Chemoplaque). T uTopotecan (drug product) consists of topotecan hydrochloride (drug substance), formulated in poly(D,L-lactide-co-glycolide) [PLGA] excipient at 50:50 monomer ratio that is a cGMP-grade FDA-approved polymer excipient that provides sustained release capability, and a medical-grade silicone episcleral implant (also referred to as an episcleral reservoir) that encases the formulation consisting of the drug substance-excipient matrix.
The Chemoplaque is prepared by formulating the drug substance, topotecan HCl, and PLGA, in a suitable solvent following precision dispensing into the episcleral silicone reservoirs, after which the whole system is lyophilized, thereby removing the process solvents (Table x). Episcleral reservoirs containing the formulation matrix are then packaged in primary and secondary packaging systems.
The formulated topotecan is stable when exposed to temperature and pH conditions similar to those expected in the treated conditions and topotecan is released over time from the matrix-drug formulation in both lactone and carboxylate forms. The pH media where the drug is released ultimately determines which form is prevalent. Both forms of topotecan—lactone and carboxylate—are adequately present throughout the release period indicating that the matrix preserves the “yet-to-be released” topotecan while in the reservoir. Topotecan undergoes a pH-dependent reversible hydrolysis from the lactone form to the biologically inactive carboxylate form. The lactone form is predominant at lower pH (i.e. < 4) while the carboxylate form is mostly favored at higher pH (i.e. > 9). At physiological pH, both forms are present.
Prior to use Chemoplaque should be stored at 2-8º C (36-46ºF).
The episcleral implant is intended for periocular use by placement under the conjunctiva in contact with the episclera—the outer side of the sclera. The episcleral implant does not penetrate the sclera or the eye.
The chief benefit of the episcleral implant is to allow doses of the drug substance to be delivered to the eye in a controlled manner while preventing unnecessary systemic absorption and providing therapeutic concentrations in the eye tissues.
The episcleral implant was designed to be attached to the episclera and sequester the topotecan HCl from unnecessary systemic absorption by the lymphatic/vasculature of the conjunctiva and Tenon/periocular tissues thereby preventing the topotecan HCl from bypassing the eye. By blocking this route of egress, the episcleral implant enables unidirectional (one-way) drug delivery to the interior of the eye thereby enabling sustained-release ocular drug delivery otherwise unfeasible, and simultaneously greatly reducing (essentially eliminating) systemic exposure.
An additional critical feature of Episcleral Topotecan is that the Chemoplaque can be removed along with all its contents, therefore ceasing further drug release from the implant to the eye—a feature that could be particularly useful should toxicity occur.
The dose of Episcleral Topotecan in each Chemoplaque to be used in this study is 0.6 mg of topotecan HCl in an E1-050 silicone implant. Each dosage unit is composed by weight of one part topotecan HCl—drug substance—and nine parts of PLGA—biodegradable polymer excipient, formulated in a medical-grade silicone episcleral implant that is placed under the conjunctiva, glued to the sclera.
Table x: Chemoplaque components for 0.6 mg dosage.
Component Amount per unit Function Quality Standard
Topotecan HCl 0.6 mg/unit Drug substance cGMP
PLGA 5.4 mg/unit Biodegradable excipient cGMP, for human use
Component Amount per unit Function Quality Standard
E1-050 1 Inert episcleral implant cGMP
Primary Packaging System
Figure x. Primary packaging of Episcleral Topotecan, consisting of P-01 container and P-02 lid.
Figure x. Episcleral Topotecan inside P-01 container with its corresponding P-02 lid: Episcleral Topotecan 0.6 mg using E1-050 inert silicone implant.
Secondary packaging chevron foil pouch with product unit with primary packaging inside is provided in Figure x. The secondary packaging chevron pouch includes label and sterilization detector that changes from light yellow/orange to dark red following terminal sterilization. The chevron foil pouch limits exposure to humidity, light, particulate matter, and maintains sterility.
IND number assigned: 112785. See package insert for further information.
Chemoplaque OrderingTo be determined.
Accountability and Destruction of ChemoplaqueThe principal Investigator (or an authorized designee) must maintain a careful record of the inventory of Topotecan Chemoplaques using the Drug Accountability Form.
CONCOMITANT MEDICATIONS
Permitted Concomitant Medications The following medications are permitted during the study:
Non-anti-cancer medications, ie common treatments for other documented illnesses Supportive care as per individual institutional guidelines
Prohibited Concomitant Medications The following medications are prohibited during the study:????
Ie? No concomitant chemotherapy/focal therapy etc
TUMOUR AND RESPONSE EVALUATIONS
Best Response Two objective status determinations of CR before progression are required for best response of CR. Two determinations of PR or better before progression, but not qualifying for a CR, are required for a best response of PR. Two determinations of minor response or better before progression, but not qualifying for a CR, are required for a best response of Minor Response. Two determinations of stable/no response or better before progression, but not qualifying as CR or PR are required for a best response of stable/no response; if the first objective status is unknown, only one such determination is required. Patients with an objective status of progression on or before the second evaluations (the first evaluation is the first radiographic evaluation after chemotherapy has been administered) will have a best response of PD. Best response is unknown if the patient does not qualify for a best response of PD and if all objective statuses after the first determination and before progression are unknown.
Complete, partial, minor responses and stable disease will be considered positive responses in this protocol.
SAFETY AND REPORTING PROCEDURES
ADVERSE EVENT
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product during the course of a study and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational product, whether or not considered related to the medicinal product.
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to the use of the product are not considered AEs after administration of the study product unless they reoccur after the subject has recovered from the pre-existing condition or they represent an exacerbation in intensity or frequency.
Only laboratory test abnormalities that are considered clinically relevant (e.g. causing the subject to withdraw from the study, requiring treatment or causing apparent clinical manifestations) or judged relevant by the Investigator should be reported as an adverse event.
ADVERSE EVENT DOCUMENTATION Adverse events will be captured from Cycle 1 Day 1 until the date of the Safety Visit or 28 days after discontinuation of study treatment. Adverse events will use the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE). This study will utilize the CTCAE Version 4.03 for adverse event reporting.
All AEs must be documented in the subject’s file. Each event should be described in detail along with start and stop dates, severity, relationship to investigational product as judged by the Investigator, action taken and outcome. The following will be recorded in the electronic case report forms (eCRFs, in SickKids RedCap database):
Adverse Events (regardless of causality) ≥ Grades 3 Adverse Events of Special Interest (regardless of causality) All SAEs All clinically significant abnormal laboratory results
Note: Grade 1 and 2 adverse events are not required to be entered into the CRF but must be documented in patient source and attribution assessed by the investigator.
Unscheduled Assessments
* If multiple assessments are completed on the same day, please enter only one assessment which corresponds to the highest grade of AE that day. For example, if an unscheduled visit is done and an AE is observed, all the assessments completed during that unscheduled visit must be recorded.
Serious Adverse Event A Serious Adverse Event (SAE) or Reaction is any AE occurring at any dose that:
Results in death; Is life-threatening; Requires inpatient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability/incapacity; Is an important medical event that may not be immediately life threatening or result in death or
hospitalization, but may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above (example: intensive treatment in an emergency room or at home for bronchospasm, convulsions that do not result in hospitalization). Medical and scientific judgment should be exercised in deciding whether some events should be considered as serious because their quick reporting to the sponsor may be of interest for the overall conduct of the study;
Suspected transmission of an infectious agent by the Chemoplaque.
Life-threatening: The term “life-threatening” in the definition of “serious” refers to an AE in which the subject was at risk of death at the time of the event. It does not refer to an AE that hypothetically might have caused death if it were more severe.
Hospitalization: Any AE leading to hospitalization or prolongation of hospitalization will be considered as Serious, UNLESS at least one of the following exceptions are met:
The admission is pre-planned (i.e., elective or scheduled surgery arranged prior to the start of the study).
OR
The admission is not associated with an adverse event.
OR
The admission results in a hospital stay of less than 12 hours
However, it should be noted that invasive treatment during any hospitalization may fulfill the criteria of ‘medically important’ and as such may be reportable as a SAE dependent on clinical judgment.
Disability means a substantial disruption of a person’s ability to conduct normal life’s functions.
Important medical event: Any AE may be considered serious because it may jeopardize the subject and may require intervention to prevent another serious condition.
Any death (regardless of cause) that occurs from the time of insertion of the Chemoplaque until 28 days after removal of the Chemoplaque, and any death occurring after this time that is judged at least possibly related to prior treatment with the Chemoplaque, will be promptly reported.
The SAE reporting period begins at insertion of the Chemoplaque. For the SAEs that have been deemed by the investigator as unrelated to protocol treatment, the SAE reporting period ends on the date of Safety Visit or 28 days after removal of the Chemoplaque, whichever is later. For the SAEs that have been deemed by the investigator as at least possibly related to protocol treatment, the SAE must be reported even if this occurs after the date of scheduled Safety Visit or past 28 days after removal of the Chemoplaque.
All SAEs must be recorded on eCRFs. In addition, all serious adverse events are subject to reporting using the SAE form and must be submitted within 24 hours of becoming aware of the event as specified in Section 10.5.
Reporting Serious Adverse Events
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse events must be recorded on electronic case report forms (eCRFs). In addition, all SAEs must be reported by using the SAE form to the DSMB.
Follow Up of Adverse and Serious Adverse Events
The investigator shall provide follow-up information as and when available in a new follow-up SAE form. All SAEs must be followed until resolved, become chronic, or stable unless the subject is lost to follow up. Resolution status of such an event should be documented on the eCRF.
The eCRF should capture all AEs occurring from insertion of the Chemoplaque till the date of Safety Visit or 28 days after removal of the Chemoplaque, whichever is later.
In addition, any known untoward event of any severity that occurs subsequent to the AE reporting period that the Investigator assesses as at least possibly related to the study therapy (i.e., the relationship cannot be ruled out) should also be reported as an AE.
RelationshipFor all AEs, relationship to study drug will be reported on the appropriate AE eCRF page. The Investigator must judge whether the Chemoplaque caused or contributed to the AE in which case it is considered to be an Adverse Drug Reaction, and report it as either:
Related (definitely, probably or possibly):
There is a reasonable possibility that the Chemoplaque caused or contributed to the AE; this conclusion may be supported by the following observations, though these are not required for the determination of relatedness:
There is a plausible time sequence between onset of the AE and study drug administration; There is a plausible biological mechanism through which study drug may have caused or
contributed to the AE;
Not related (unlikely, unrelated):
It is highly unlikely or impossible that the study drug caused or contributed to the AE; this conclusion may be supported by the following observations, though these are not required for a determination of not related:
another cause of the AE is evident and most plausible; the temporal sequence is inconsistent between the onset of the AE and study drug
administration; a causal relationship is considered biologically implausible.
STATISTICAL CONSIDERATIONS AND ANALYSIS OF PLAN
Sample Size and Study DurationPart 1.
1.1 Definitions
1.1.1 Evaluable For Adverse Effects Any patient who experiences DLT at any time during protocol therapy is considered evaluable for Adverse Effects. Patients without DLT who receive at least 85% of the prescribed dose per protocol guidelines and had the appropriate toxicity monitoring studies performed are also considered evaluable for Adverse Effects. Patients who are not evaluable for Adverse Effects at a given dose level will be replaced.
1.1.2 Maximum Tolerated Dose
The MTD will be the maximum dose at which fewer than one-third of patients experience DLT (See Section 5.5) during Cycle 1 of therapy. In the event that two DLTs observed out of 6 evaluable patients are different classes of Adverse Effects (e.g. hepatotoxicity and myelosuppression), expansion of the cohort to 12 patients will be considered if all of the following conditions are met:
• One of the DLTs does not appear to be dose-related
• The Adverse Effects are readily reversible
• The study chair, DVL statistician, DVL committee chair or vice chair, and IND sponsor all agree that expansion of the cohort is acceptable
If fewer than 1/3 of patients in the expanded cohort experience dose-limiting toxicities, the dose escalation can proceed.
Determination of Sample Size
EFFICACY ANALYSESPrimary Efficacy Endpoint
CR
Duration CR
Target tumor:
Small volume, large volume, calcified partial, vitreous seeds, subretinal seeds scored separately.
Total active tumor per eye will be pseudoquantified by yellow pixel count in DEPICT HEALTH retinal drawing.
Two children with advanced muliply refractory retinoblastoma have been treated with the Chemoplaque. In both, the target small volume refractory disease achieved stable CR at one month, maintained at 9 months and 5 months respectively. In one child the non-target partially calcified tumor showed PR at one month and Progressive Disease (PD) at 4.4 months. In both children target vitreous seeds showed CR at one month but recurred at 7.3 and (subclinical) 3.6 months respectively.
All reasonable attempts will be made to minimize the amount of missing data, although it is recognized that some missing data is inevitable. Whenever possible, the reason for missing data will be captured and reported, however, no interpolation of missing data will be performed for any outcome.
12.0 FOLLOW UPDuration of Follow-Up
Patients will be followed for up to 5 years post treatment or progression. The frequency of the visits and the assessments completed during the follow-up period is dependent on whether the patient progressed. Please refer to the study calendar for details.
Patients who progress during the treatment period or follow-up period will have less frequent visits during the follow-up and these visits can be completed by telephone or in conjunction with their standard of care visits. They will be followed for overall survival, further progression and information on further lines of treatment (if any). Patients who choose to withdraw from treatment (but not from the study) will be required to complete the Safety Visit and will be followed-up for related adverse events as applicable.
Withdrawal From Study
Patients and/or their legal guardians are at any time free to withdraw from study (study medication and assessments), without prejudice to further treatment (withdrawal of consent). Such patients and/or their legal guardians will always be asked about the reason(s) and the presence of any adverse events. If possible, they will be seen and assessed by an investigator. Adverse events will be followed up as per section 10.7.
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separate standard of care from research data and timing.
If a patient does not return for a scheduled visit, every effort should be made to contact the patient and/or their legal guardians. In any circumstance, every effort should be made to document patient outcome and reason for withdrawal, if possible. The investigator should request the patient return for a final visit, if applicable, and follow-up with the subject regarding any unresolved adverse events.
If the patient and/or their legal guardians withdraws from the trial and also withdraws consent for disclosure of future information, no further evaluations should be performed and no additional data should be collected. The sponsor may retain and continue to use any data collected before such withdrawal of consent.
Patients will be withdrawn from treatment in case of:
Disease progression Unacceptable toxicity Patient lost to follow-up Patient and/or legal guardians choice to withdraw from treatment (follow-up permitted by
patient and/or legal guardians) Patient and/or legal guardians choice to withdraw consent to study (cessation of follow-up)
The reason for study removal and the date the patient was removed must be documented in the eCRF.
13.0 ETHICSInformed Consent
Subject / Legally acceptable representative (LAR) (as applicable) consent/assent must be obtained according to local Institutional and/or University Human Experimentation Committee requirements prior to any study-specific baseline procedures.
Ethics Board Approval
Health Canada REB Attestation Form must be completed and signed by the REB representative. Alternatively, an attestation may be included in the signed local ethics approval document.
Initial approval: Full board local ethics approval of the protocol and consent form by the appropriate REB/IRB/IEC/HREC/RGO is required prior to commencement of the clinical trial.
Continuing approval: Annual (or as required by the REB/IRB/IEC/HREC/RGO) re-approval may be required for as long as subjects are being followed on protocol. It will be investigator’s responsibility to apply for and obtain the re-approval.
Amendment: All protocol amendments will be confirmed in writing and submitted, as appropriate, for review by the REB/IRB/IEC/HREC/RGO and health authorities. Amendments will be reviewed and approved by applicable regulatory authorities prior to central implementation of the amendment, and by REB/IRB/IEC/HREC/RGOs prior to local implementation, EXCEPT when the amendment eliminates an immediate hazard to clinical trial subjects or when the change(s) involves only logistical or administrative aspects of the trial.
14.0 DOCUMENTATION, RECORD ACCESS AND MAINTENANCE OF STUDY RECORDS
14.1 DOCUMENTATION OF SUBJECT’S PARTICIPATIONA statement acknowledging the participation of a subject in this clinical trial must be documented in the subject’s medical records along with the signed ICF.
14.2 REGULATORY REQUIREMENTSThe following documents are required:
All Investigators must complete and sign the Health Canada Qualified Investigator Undertaking form. The completed forms must be returned to 3T Ophthalmics prior to any drug shipment.
All applicable regulatory documents as listed in the Protocol Activation Checklist provided 3T Ophthalmics.
3T Ophthalmics will submit via fax to Health Canada a completed Health Canada Clinical Trial Site Information Form after local activation of the Canadian centre.
14.3 SUBJECT CONFIDENTIALITY AND ACCESS TO SOURCE DATA/DOCUMENTSAny research information obtained about the subject in this study will be kept confidential. A subject will not be identified by name, only by their patient number and his/her initials. The subject’s name or any identifying information will not appear in any reports published as a result of this study.
However, information obtained from individual subject’s participation in the study may be disclosed with his/her consent to the health care providers for the purpose of obtaining appropriate medical care. The subject’s medical records/charts, tests will be made available to 3T Ophthalmics , the Hospital for Sick Children its potential eventual partners, the Canadian HPFB/TPD, the REB/IRB and any other regulatory authorities. This is for the purpose of verifying information obtained for this study. Confidentiality will be maintained throughout the study within the limits of the law.
A subject’s name will not be given to anyone except the researchers conducting the study, who have pledged an oath of confidentiality. All identifying information will be kept behind locked doors, under the supervision of the study Principal Investigator and will not be transferred outside of the hospital.
A subject may take away his/her permission to collect, use and share information about him/her at any time. If this situation occurs, the subject will not be able to remain in the study. No new information that identifies the subject will be gathered after that date. However, the information about the subject that has already been gathered and transferred may still be used and given to others as described above in order to preserve the scientific integrity and quality of the study.
14.4 CONFIDENTIALITY OF THE STUDY Data generated as a result of this study are to be available for inspection on request by local health authority auditors, the Sponsor’s Study Monitors and other personnel (as appropriate) and by the IRB/EC. The Investigator shall permit sponsor, authorized agents of the sponsor, CRO and regulatory agency employees to enter and inspect any site where the drug or records pertaining to the drug are held, and to inspect all source documents. The protocol and other study documents contain confidential information and should not be shared or distributed without the prior written permission of sponsor.
14.5 REGISTRATION OF CLINICAL TRIALPrior to the first subject being enrolled into this study, the Sponsor will be responsible for ensuring that the clinical trial is registered appropriately to remain eligible for publication in any major peer-reviewed journal, adhering to the guidelines put forth by the International Committee of Medical Journal Editors (ICMJE).
14.6 DATA REPORTINGThe data will be collected using DEPICT HEALTH and electronic CRFs.
14.7 CASE REPORT FORMSThe CRFs for the study will be electronic and will be provided by 3T Ophthalmics.
Please see the study specific eCRF completion guidelines for timelines and details for submission of CRFs.
14.8 MAINTENANCE OF STUDY RECORDSTo enable evaluations and/or audits from Regulatory Authorities, 3T Ophthalmics or the Sponsor, the Investigator agrees to keep records, including the identity of all participating subjects (sufficient information to link records, CRFs and hospital records), all original signed informed consent forms, source documents, and detailed records of treatment disposition.
The Research Site will retain these records for 25 years after study close-out as required by Canadian regulations or as specified in the Clinical Trial Agreement, whichever is longer.
US sites must retain protocols, amendments, IRB approvals, signed and dated consent forms, medical records, case report forms, drug accountability records, all correspondence, and any other documents pertaining to the conduct of the study. According to 21CFR312.62(c), the Investigator shall retain records required to be maintained under this part until two years after the investigation is discontinued and the FDA is notified.
If the investigator relocates, retires, or for any reason withdraws from the study, then the Sponsor should be prospectively notified. The study records must be transferred to an acceptable designee, such as another investigator, another institution, or to the Sponsor. The investigator must obtain the Sponsor’s written permission before disposing of any records.
15.0 QUALITY ASSURANCE AND QUALITY CONTROL As per the Guidelines of Good Clinical Practice (CPMP/ICH/135/95), the sponsor will be responsible for implementing and maintaining quality assurance and quality control systems.
15.1 ON SITE MONITORING/AUDITING 3T Ophthalmics will organize on-site monitoring of this study to be conducted at each site depending on accrual and as per the monitoring plan.
As this trial is conducted under a CTA with Health Canada, your site may be subject to an inspection by the Health Products and Food Branch Inspectorate. Other audits may be conducted by the study sponsor, 3T Ophthalmics , the company supplying the drug for the study and regulatory authorities from participating countries such as; the FDA, or the European Union.
ADMINISTRATIVE PROCEDURES
Amendements to the ProtocolModifications of the signed protocol are only possible by approved protocol amendments or protocol clarification memos authorized by the Sponsor. All protocol amendments will be approved by the REB or IRB/EC prior to implementation. The Investigator must not implement any deviation from, or change to the protocol, except where it is necessary to eliminate an immediate hazard to trial subject or when the change(s) involves only logistical or administrative aspects of the trial.
Protocol Deviations and ViolationsAll violations or deviations are to be reported to the site’s REB (as per REB guidelines and local regulations). All REB correspondence is to be forwarded to Ozmosis Research. The site must notify Ozmosis Research and/or sponsor immediately of any protocol violations.
Premature Discontinuation of the Study The Sponsor reserves the right to discontinue the trial for any reason but intends only to exercise this right for valid scientific or administrative reasons. After such a decision, the Investigators must contact all participating patients immediately after notification. Standard therapy and follow-up for subjects will be assured and, where required by the applicable regulatory requirement(s), the relevant regulatory authority(ies) will be informed.
The REB or IRB/EC will be informed promptly and provided with a detailed written explanation for the termination or suspension.
As directed by the Sponsor, all study materials must be collected and all eCRFs completed to the greatest extent possible.
LEGAL ASPECTS
Publication Policies and Disclosure of DataFor publications, the first author will be the Principal Investigator of the study. Additional authors will be those who have made the most significant contribution to the overall success of the study. This contribution will be assessed, in part but not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the Principal Investigator.
SCREENING AND STUDY ENROLLMENT PROCEDURES1.1 Inclusion Criteria
1.1.1 Primary therapy: Small volume active tumors (< 6mm in any dimension/tumor)An eye with
retinoblastoma classified as cT1b (IIRC group B) (location threatens fovea) in a child not receiving systemic chemotherapy for the other eye (bilateral or unilateral).
A unilateral cT2 (IIRC group C ) (visible optic nerve)Salvage therapy:Any eye with refractory retinoblastoma that shows a visible optic disc, vision potential and no imminent risk for tumor spread.
1.1.2 Palliative therapy: for vision with incurable systemic retinoblastoma metastases
Exclusion CriteriaAny eye with tumor touching the optic nerve rim. Any suggestion of high-risk histopathology
1.1.3 Reported allergy to topotecan, camptothecin or derivatives thereof.Eyes with spreading tumors:
1.1.4 Extra-ocular extension into orbit or brain, or1.1.5 Metastatic retinoblastoma with or without CNS involvement, or1.1.6 Neuroimaging (MRI) showing suspicion of, or true optic nerve invasion.
Informed ConsentThe trial objectives, procedures and treatments (potential risks and complications, and alternative therapies) will be meticulously explained to the patient’s parents or guardian and a signed informed consent will be obtained according to institutional guidelines. A dated road map follow up schedule specific for the child will be presented to the parents and signed prior to enrollment. Upon signing necessary consent forms, a specific study screening number will be assigned to each patient.1.2 Screening ProceduresDocumentation of the informed consent for screening will be maintained in the patient’s research chart. Studies or procedures that were performed for clinical indications (not
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Do we have certain tests in mind? Any blood tests or any imaging. I don’t think of any one as a prerequisite
Sameh Soliman, 03/05/19,
In my opinion minimal detachment and seeding.
Sameh Soliman, 03/05/19,
The Inclusion of the trial4.1.1 Age: Patients must be < 15 years of age and at least 3 months of age at the time the consent is signed by the parent(s) or guardian.4.1.2 Diagnosis: Recurrent Intraocular retinoblastoma that has failed in investigator’s opinion all standard available therapy including carboplatin, vincristine, etoposide (CEV), intra-arterial melphalan, and intravitreal melphalan.4.1.3 Must have demonstrated focal recurrent disease that has either failed current standard therapy or in the Investigator’s opinion and experience such standard therapy will be ineffective. 4.1.4 Demonstration of Light Perception in the tumor-bearing eye either with pupil response testing or demonstration of avoidance behavior to light presentation in the affected eye4.1.5 Performance Level: Lansky 50. 4.1.7 Organ Function Requirements:Organ function criteria:a.Adequate Bone Marrow Function Defined as: oPeripheral absolute neutrophil count (ANC) 1000/mm3oPlatelet count 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)oHemoglobin 8.0 g/dL at baseline (may receive RBC transfusions)b.Adequate Renal Function Defined as: •Creatinine clearance or radioisotope GFR 70ml/min/1.73 m2 or•A serum creatinine based on age/gender as follows:AgeMaximum SerumCreatinine (mg/dL)MaleFemale1 month to < 6 months0.40.46 months to < 1 year0.50.51 to < 2 years0.60.62 to < 6 years0.80.86 to < 7 years11The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.c.Adequate Liver Function Defined as: •Bilirubin (sum of conjugated + unconjugated) 1.5 x upper limit of normal (ULN) for age •SGPT (ALT) 110 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L. •Serum albumin 2 g/dL.
exclusively to determine eligibility) may be used for baseline values even if the studies were done before informed consent was obtained. All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated. Before the patient can be enrolled, the responsible institutional investigator must sign and date the completed eligibility checklist.
STUDY ENROLLMENTPatients are cleared to be enrolled in the study once all eligibility requirements for the study have been met. The date protocol therapy is projected to start must be no later than fourteen (14) calendar days after the date the subject is cleared to be enrolled. Once enrolled, a patient-specific enrollment number will be assigned to each patient.
Treatment
Day 0: Surgical chemoplaque insertion: After performing a routine examination under anesthesia with emphasis on the intraocular pressure, Retcam imaging and any relevant imaging procedures (optical coherence tomography, ultrasound biomicroscopy or B-scan ultrasonography), the Chemoplaque will be inserted.
Under aseptic technique, an inferior 90° conjunctival periotomy will be performed. Depending on the chosen location for the Chemoplaque, inferior and medial / lateral recti will be identified and held by 4/0 silk threads for globe manipulation. The quadrant will be exposed and bare scleral clean of an hemorrhage will be prepared for the bed on the Chemoplaque.
The Chemoplaque will be held with the T-groove facing up and one drop of surgical glue will be applied to the groove only. The chemoplaque will be applied directly on the sclera in the exposed quadrant by placing the side opposite the glue on the dry sclera and gently lowering the Chemoplaque until the glue in the groove contacts the sclera. The Chemoplaque will be held in position on the sclera for 3 minutes without movement to ensure that it is being properly glued to the sclera. The conjunctiva is closed using 7/0 Vicryl sutures. A transparent eye shield will be applied for immediate postop protection in the recovery room.
Postoperative antibiotic/steroid eye drops will be prescribed for 2 weeks. No hospitalization is required and the child will be sent home. A pain chart will be provided to the parents to be filled.
Day 1 and 8:
Examine the child in the clinic to assess eye opening, lid swelling and vision if applicable.
Day 8, 21 and 35:
Examine in the oncology clinic for blood tests.
Day 15, 29, 50, 71:
EUA to assess tumor response and potential intraocular toxicity.
Days 50 or 71:
Plaque removal: After performing a routine examination under anesthesia with emphasis on the intraocular pressure, Retcam imaging and any relevant imaging procedures (optical coherence tomography, ultrasound biomicroscopy or B-scan ultrasonography), the Chemoplaque will be removed.
Under aseptic technique, an inferior conjunctival periotomy will be performed. The quadrant where the Chemoplaque was inserted will be exposed and the anterior edge of the plaque will be identified and gently lifted off the globe. The conjunctiva is closed using 7/0 Vicryl sutures. Postoperative
antibiotic/steroid eye drops will be prescribed for 2 weeks. No hospitalization is required and the child will be sent home.
The chemoplaque removal will be removed earlier in the following situations:
Toxicity defined as grade 3 systemic or local. Tumor progression endangering tumor spread.
Post plaque follow upFollowing completion of protocol therapy, vital status and disease status will be followed based on routine clinical visits for a minimum of one year. At each follow up period, status of patients will be categorized:
Patient alive, no active disease Patient alive, active disease requires further interventions Patient died, related to the disease Patient died, not related to the disease
Outcome measures:
Tumor control Salvage rates
Data management:
Sample size Study coding Data storage Data analysis Statistics
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Edge, & F. L. Greene) Ch. 68, 819-831 (Springer, 2017).
2 Murphree, A. L. Intraocular retinoblastoma: the case for a new group classification. Ophthalmology clinics of North America 18, 41-53 (2005).
3 Shields, C. L. et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113, 2276-2280, doi:10.1016/j.ophtha.2006.06.018 (2006).
4 Novetsky, D. E., Abramson, D. H., Kim, J. W. & Dunkel, I. J. Published international classification of retinoblastoma (ICRB) definitions contain inconsistencies--an analysis of impact. Ophthalmic Genet 30, 40-44, doi:908192764 [pii]
10.1080/13816810802452168 (2009).
5 Mallipatna, A., Dimaras, H., Héon, E. & Gallie, B. Published International Classification of Retinoblastoma (Icrb) Definitions Contain Inconsistencies: An Analysis of Impact. Evidence-Based Ophthalmology 10, 183-185, doi:10.1097/IEB.0b013e3181b93c45 (2009).
6 Dimaras, H. et al. Retinoblastoma. Nat Rev Dis Primers 1, 15021, doi:10.1038/nrdp.2015.21 (2015).
7 Mallipatna, A. C., Sutherland, J. E., Gallie, B. L., Chan, H. & Heon, E. Management and outcome of unilateral retinoblastoma. J AAPOS 13, 546-550, doi:S1091-8531(09)00308-5 [pii]
8 Kletke, S., Zhao, X. F., Hazrati, L.-N., Gallie, B. L. & Soliman, S. E. Clinical predictors of low histopathologic risk features in unilateral cT2b (Group D) retinoblastoma. (Submitted, 2019).
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