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P-1
NDA 21-600NDA 21-600
Marqibo
(Vincristine Sulfate Liposomes Injection)
Treatment of patients with aggressive non-Hodgkin’s lymphoma previously treated with at least two combination
chemotherapy regimens
P-2
External ConsultantsExternal Consultants
Fernando Cabanillas, MD Clinician andClinical Professor of Medicine PresenterMD Anderson Cancer Center
Medical DirectorAuxilio Mutuo Cancer Center
Jane Winter, MD ClinicianProfessor of Medicine 2nd largest site Department of Hematology/OncologyNorthwestern University
P-3
External ConsultantsExternal Consultants(Continued)(Continued)
Randy Gascoyne, MD Lymphoma Pathologist and Clinical Professor PathologistBritish Columbia Cancer Agency
Scott Gazelle, MD, MPH, Ph.D Radiologist, Associate Professor Independent ReviewMassachusetts General Hospital Panel
Sandra Chica, MD RadiologistMedical Director - RadiologistPerceptive Informatics, Inc. (Parexel)
P-4
External ConsultantsExternal Consultants(Continued)(Continued)
Shayne Gad, Ph.D, DABT, AST ToxicologistGad Consulting Services
Jean-Marie Houle, Ph.D Pharmacokineticist Houlemiron BC Enterprises Inc.
Louis Gura, MS StatisticianThree Flags Consulting
P-5
Unmet Medical Need in Aggressive NHLUnmet Medical Need in Aggressive NHL
Fernando Cabanillas, MD
Clinical Professor of Medicine MD Anderson Cancer Center
Medical Director Auxilio Mutuo Cancer Center
P-6
Overview of NHLOverview of NHL
NHLs broadly classified as aggressive vs. indolent
Aggressive NHL– 35-40% of NHL– Diffuse large B-cell lymphoma, peripheral T-cell lymphoma
DLBCL frequently presents with divergent histologies– Treatment is driven by the most aggressive histology– Response is measured the same way
– At relapse, life expectancy measured in months
Indolent NHL– At relapse, life expectancy measured in years
No new agents approved for aggressive NHL in last 17 years
P-7
Overview of Aggressive NHLOverview of Aggressive NHL
First-line therapy– R-CHOP therapy cures 50% of aggressive B-cell NHL
Second-line therapy– If <65 years, 20% cured with high dose chemo and
ASCT (only if response to salvage therapy)– If 65 years or if ASCT not feasible, 10% curable
Median survival 6 months
Response rates and duration drop with each relapse
P-8
Overview of Aggressive NHLOverview of Aggressive NHL(Continued)(Continued)
Third-line or later therapy (indicated population)– 10,000 – 15,000 patient prevalence in 2001– No standard therapy– Bone marrow frequently compromised, thus fewer
options– Reduction in tumor burden associated with symptom
improvement– Results are dismal, complete responses are rarely
achieved and survival is short
P-9
Survival After MIME as 3rd Line Survival After MIME as 3rd Line or Later Therapy for Aggressive NHLor Later Therapy for Aggressive NHL
Survival Time (mos.)
0 5 10 15 20 25 30 35 400.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cu
mu
lati
ve P
rop
ort
ion
Su
rviv
ing
By 12 months, 75% are dead
By 2 years, 96% are dead
n =72
Median = 6 months
P-10
FDA Single Agent Papers FDA Single Agent Papers Not Adequate for Comparison to VSLINot Adequate for Comparison to VSLI
Regimen/Authors ORR Histologically
Relevant n
10 Pts
No ORR for Aggressive
NHLa
# Prior
Therapies Not Comparable
b
II-2 (Lauria, n=2) 50% 2 X X
Gemcitabine (Bernell, n=3) 66% 3 X
Oxaliplatin (Germann, n=22) 40% 3 X
Oral Etoposide (Shaklai, n=20) 69% 6 X
Bortezomib (Goy, n=45) 20% 9 X X
Oxaliplatin (Younes, n=25) 24% 13 X
Cytarabinec
(Peters, n=59) 64% 22 X
Methotrexate (Canellos, n=25) 52% 25 X
Idarubicin (Case, n=31) 43% 31 X
a ORR includes ineligible histologies, e.g., indolent and mantle cell. b Median number of priors <2 or ORR not analyzed for patients with 2 regimens. c All patients treated with combination therapy.
P-11
FDA Papers for Comparison to VSLIFDA Papers for Comparison to VSLI
Histologically
Eligible Patients 10
No ORR for
Aggressive NHLa
Prior Therapies
Not Comparableb
Total
Comparable Papers
Single agent papers (11)
5 1 5 2
Combination therapy papers (35)
2 9 27 5
a ORR includes ineligible histologies, e.g., indolent and mantle cell. b Median number of priors <2 or ORR not analyzed for patients with 2 regimens.
P-12
Single Agent Rituximab in Aggressive NHLSingle Agent Rituximab in Aggressive NHL
Parameter Rothe (n=21)
Tobinai Histologic Subgroup
(n=50)
Coiffier Histologic Subgroup
(n=30)
Median prior regimens
2
(38% 1st relapse)
2a
(32% 1st relapse)
2a
(17% untreated, 31% 1st relapse)
CR+PR (%) 38 34 37
CR (%) 5 — —
TTP (mos) 3.8 2.0a >3.5a
a Median for entire study, not for subgroup.
P-13
Combination Regimens as 3Combination Regimens as 3rdrd Line Line or Later Therapyor Later Therapy
Publication Median # of Priors
ORR CR
IIVP-16 (Engert, n=38) 2 47 21
FLUDAP (Child, n=33) 2 39 15
CEPP(B) (Chao, n=20) 2 45 15
DHAP (Press, n=26) 3 65 —
Ifosfamide, hydroxyurea and etoposide (Gasser, n=19)
3 53 5
P-14
Unmet Clinical NeedsUnmet Clinical Needs
Patients who don’t qualify for aggressive combination regimens or who have relapsed after ASCT– Poor marrow function– Age >65– Poor performance status– No response to pre-transplant salvage therapy– Co-morbidities
Patients with compromised marrow function– Rituximab no longer a viable alternative
No compelling literature evidence for “available therapy” after 2nd relapse
Need an agent that can provide clinically meaningful benefit without excessive toxicity
P-15
Pharmacology PresentationPharmacology Presentation
Tom Madden, Ph.D
Senior Director, Technology Development and Licensing
Inex Pharmaceuticals Corporation
P-16
Vincristine Sulfate Liposomes InjectionVincristine Sulfate Liposomes Injection(VSLI)(VSLI)
Active agent: vincristine sulfate
Liposome composition: sphingomyelin/cholesterol
Liposome size: 115 nm, contains approximately 10,000 drug molecules/vesicle
Aqueous corewith vincristine
Liposomal bilayer
P-17
VSLI: Product RationaleVSLI: Product Rationale
VSLI Increases Tumor Exposure to Vincristine
• Higher vincristine tumor levels due to preferential delivery
• Longer duration of exposure due to slow vincristine release
P-18
VSLI Accumulates in Tumor Tissue by VSLI Accumulates in Tumor Tissue by Extravasation Across Tumor VasculatureExtravasation Across Tumor Vasculature
Tumor tissue demonstrating accumulation of VSLI in
interstitial space
Normal tissue showing VSLI in blood vessels with no evidence
of extravasation
P-19
Vincristine Activity is Dependent on Vincristine Activity is Dependent on Duration of ExposureDuration of Exposure
Duration of Exposure (hr)
Via
ble
Cel
ls
Reproduced from Jackson and Bender, Cancer Res. 39: 4346-9, 1979.
P-20
Vincristine is Slowly Released from VSLI Vincristine is Slowly Released from VSLI in Vivo (Rat Plasma)in Vivo (Rat Plasma)
0
20
40
60
80
100
0 20 40 60 80Time (h)
Re
lea
sed
Vin
cris
tin
e (%
)VSLI provides prolonged exposure to vincristine
P-21
Antitumor Activity of VSLI Is Significantly Antitumor Activity of VSLI Is Significantly Greater Than VCR in the Namalwa Lymphoma Greater Than VCR in the Namalwa Lymphoma
Xenograft ModelXenograft Model
Day Post-Implantation
0 10 20 30 40 50
Mea
n T
um
or
Vo
lum
e (m
m3 )
0
500
1000
1500
VSLI (4.5 mg/m2)
VCR (4.5 mg/m2)PBS Control
P-22
Plasma Vincristine Concentration-time Plasma Vincristine Concentration-time Profiles for VSLI and VCR in PatientsProfiles for VSLI and VCR in Patients
0.1
1
10
100
1000
10000
0 10 20 30 40 50
Time (h)
To
tal V
incr
isti
ne
Co
nce
ntr
atio
n (
ng
/mL
) VSLI (2.0 mg/m2, n=26)
VCR (1.2 mg/m2, n=4, Nelson 1982)
P-23
VSLI Nonclinical SummaryVSLI Nonclinical Summary
Compared to conventional vincristine– VSLI provides increased tumor exposure – VSLI provides increased antitumor activity in
nonclinical studies– VSLI elicits the same toxicities
P-24
Clinical Efficacy and SafetyClinical Efficacy and Safety
Alexandra Mancini, MSc.
Senior Vice President, Clinical and Regulatory Affairs
Inex Pharmaceuticals Corporation
P-25
Efficacy Trials in Relapsed Efficacy Trials in Relapsed Aggressive NHLAggressive NHL
Supportive Phase IIa Study (DM97-162)– NHL or ALL– Investigator-sponsored at MD Anderson Cancer Center– 92 patients with relapsed aggressive NHL
Primary Phase IIb Study (CA99002)– International multicenter: 42 sites enrolled– 119 patients enrolled
Two largest trials in multiply relapsed aggressive NHL
Similar study designs and response criteria
Consistent results in 211 patients
P-26
Randomized Controlled TrialRandomized Controlled Trial
Post-approval commitment to confirm clinical benefit – 3 meetings and SPA comments from FDA– Revised protocol to be resubmitted shortly– Study to start in first half 2005
P-27
Study Conduct Issues Raised by FDA
P-28
Study Conduct Issues Raised by FDAStudy Conduct Issues Raised by FDA
Low Number of Eligible Patients
Numerous protocol amendments and exemptions
Low histologic eligibility rate
Incomplete staging in 19% of patients
Conduct of Independent Review Panel (IRP)
Wording of response criteria
Operations of core imaging lab
Amendments to IRP Charter
P-29
Protocol AmendmentsProtocol Amendments
Protocol Version Number of Patients
Enrolled
5.0 7 6.0 8 7.0 9 8.0 54 9.0 41
P-30
Protocol Version 5.0Protocol Version 5.0
Key Inclusion Criteria
Patients with a CR or CRu to 1st line chemotherapy
Patients with at least a PR to most recent therapy
A poorer prognosis population
7.07.0
at least a minor response
deleted
P-31
Other AmendmentsOther Amendments
Version 7.0 8.0
Peripheral T-cell lymphoma (1 pt)
Anaplastic large null-/T-cell lymphoma (2 pts)
Transformed NHL (11 pts)
No further changes in eligibility criteria
With each amendment FDA agreed that trial population suitable for accelerated approval
A poorer prognosis population
P-32
Protocol AmendmentsProtocol Amendments
Version 8.0 to 9.0
Additional CT scans scheduled 4 weeks after first response instead of the original 8 weeks
A clarification changed wording that these confirmatory CT scans “should” instead of “must” be obtained
P-33
Enrollment ExemptionsEnrollment Exemptions
Careful to not allow exemptions that would have enhanced apparent VSLI response rate
A poorer prognosis population
P-34
Histologic EligibilityHistologic Eligibility
19% ineligible by retrospective Central Review – Mostly indolent lymphomas
FDA excluded additional 7 patients described as ‘probably eligible’ by Central Review
Not protocol violations or due to amendments– Site pathology defined them as eligible for enrollment
P-35
Histologic Eligibility by Central Histologic Eligibility by Central Pathology Review (ITT)Pathology Review (ITT)
Histologic Eligibility
SWOG 8516 (n=1128)a 79%
SWOG 9240 (n=112)a 81%
Coiffier (2002) (n=399)a 86%
SWOG 9125 (n=100)a 90% VSLI Phase IIb (n=119) 81%
a Newly diagnosed patients
P-36
Other FDA Eligibility ExclusionsOther FDA Eligibility Exclusions
Number of Patients
CTs incomplete at study entry 3
Bone marrow biopsies >8 weeks before study or not done
9
Missing LDH at study entry 1
Missing neuro exams at study entry
13
Stage of disease was not an eligibility criterion
0
0
0
1
P-37
Response Criteria WordingResponse Criteria Wording
In some situations the criteria are ambiguous or silent
These clarifications were undertaken to uphold the rigor of the criteria
To ensure consistent interpretation in this multicenter study
P-38
Response Criteria WordingResponse Criteria Wording
April 3, 2000 Meeting with FDA
Protocol Version 5.0 with clarified response criteria wording
FDA agreed with the protocol wording
No changes to response criteria since that meeting
P-39
Operations of Core Imaging LabOperations of Core Imaging Lab
FDA review noted that procedures manual was dated 1 year after review of images began
Earlier version in place before reviews began
No changes to core lab procedures for entire IRP process
P-40
Amendments to IRP CharterAmendments to IRP Charter
No changes to conduct of IRP radiology and oncology reviews
Amendments in place before reviews began
A few clarifications for situations not previously anticipated requested by Dr. Scott Gazelle– Amendments documented what was done
All images read in chronologic sequence and locked
P-41
Conclusions Regarding Conclusions Regarding Study Conduct IssuesStudy Conduct Issues
Protocol amendments and exemptions defined a population with a poorer prognosis
Histologic eligibility comparable to literature rates
Only 9 patients (8%) ineligible for efficacy evaluation due to protocol violations
IRP process was well conducted
Well defined and reliable assessment of objective response in the indicated population
Adequate and well-controlled trial
P-42
Pivotal Study Presentation
P-43
Key Eligibility CriteriaKey Eligibility Criteria
Aggressive de novo or transformed NHL
At least 2 prior combination regimens including an anthracycline
At least a minor response to 1st line therapy
P-44
Key Eligibility CriteriaKey Eligibility Criteria(Continued)(Continued)
No maximum number of prior regimens
No requirement of response to prior salvage therapies
No upper limit on age
ECOG PS 0-3 accepted
Grade 1-2 neuropathy permitted
Granulocytes0.5 x 109/L
Platelets 50 x 109/L
P-45
2 mg/m2 without dose capping, 1hr IV infusion
Repeat every 2 weeks
12 cycles maximum, 2 cycles after CR
VSLI Monotherapy RegimenVSLI Monotherapy Regimen
2 mg/m2 without dose capping, 1hr IV infusion
Repeat every 2 weeks
12 cycles maximum, 2 cycles after CR
At least 2x dose intensity of vincristine
P-46
Efficacy Endpoints and PopulationsEfficacy Endpoints and Populations
Efficacy Endpoints
Primary– Objective response rate (CR + CRu + PR)
Secondary– Duration of response– Time to progression – Overall survival
Efficacy Populations
Intent-to-Treat Population (ITT) (n=119)
Per-Protocol Population (PP) (n=77)
P-47
Efficacy EvaluationsEfficacy Evaluations
International Workshop Criteria (Cheson et al 1999)– CTs of chest, abdomen, pelvis– 6 indicator lesions– Response does not require confirmation
Independent Review Panel (IRP)– Primary efficacy assessment– Blinded to site opinion of response – Independent selection of indicator lesions
P-48
Patient Population
P-49
Extent of Prior Therapy (ITT)Extent of Prior Therapy (ITT)
25%23%
33%
19%
1%0
5
10
15
20
25
30
35
1 2 3 4 5-10
# of Regimens
% o
f P
atie
nts
(n
=11
9)
• Mean: 3.8; Median: 3 • 33% had prior ASCT
• Predominantly at 4th-5th line
P-50
Response to Prior TherapyResponse to Prior Therapy
CR+PR
(%)
CR (%)
Response Duration
(mos)
First line 92 50 8
Second line 41 20 5
Last line 35 13 5
75% received a combination regimen as last therapy
P-51
Sensitivity to Last Qualifying Therapy (ITT)Sensitivity to Last Qualifying Therapy (ITT)
% of Patients
(n=119)
Resistant 67 Refractory (no response) 50 Early relapse (response duration <3
months) 17
Sensitive (response duration 3 months) 33
P-52
Efficacy Data (ITT)
P-53
Objective Response Rate (ITT) Objective Response Rate (ITT) by IRPby IRP
Best Tumor Response Number (%) of
Patients (n=119)
Responders (ORR) 30 (25) CR, CRu 8 (7) PR 22 (18)
Nonresponders SD 31 (26) PD 32 (27) UE 26 (22)
P-54
Objective Response Rate ComparisonsObjective Response Rate Comparisons
% of Patients
Best Response
ITT
(n=119)
Per Protocol (n=77)
FDA
Eligible (n=65)
ORR 25 27 22
[95% CI] [18, 34] [18, 39] [12, 34]
CR 3 1 2
CRu 3 4 2
PR 18 22 18
SD 26 29 —
P-55
Is Objective Response Likely to Predict Clinical Benefit?
P-56
8 patients with CR or CRu– 3 patients asymptomatic– Remaining 5 patients either had resolution of
symptoms or improved ECOG PS
22 patients with PR– 15 had improvements in symptoms or ECOG PS
Symptom Improvement in RespondersSymptom Improvement in Responders
P-57
Time-to-Event Endpoints
P-58
Duration of Response Duration of Response
Kaplan-Meier Analysis
IRP Review
(n=30)
FDA Analysis (n=30)
Median duration of response (days)
>85a
72
95% CI [72, —]b [37, —]b
a Probability of ongoing response 52% at last event of PD. b Upper limit cannot be calculated.
P-59
Time to Progression (ITT)Time to Progression (ITT)by IRPby IRP
Kaplan-Meier Analysis ITT
(n=119) Responders
(n=30)
Median TTP (days) 89 >127a
95% CI [64, 217] [113, —]b
a Progression-free probability 45% at last event of PD. b Upper limit cannot be calculated.
P-60
Survival (ITT)Survival (ITT)
119 68 47 41 35 26 15 5 0
Patients at Risk
Censored Observations
Median 6.7 months
25% alive at 2 years
P-61
Subgroup Analyses
P-62
ORR by Number of Prior Regimens and ORR by Number of Prior Regimens and Sensitivity to Last Qualifying RegimenSensitivity to Last Qualifying Regimen
ORR (% of Patients)
2 Regimensa(n=24) 46
Sensitivea(n=11) 64
Resistant (n=13) 31
>2 Regimens (n=95) 20
Sensitive (n=28) 32
Resistant (n=67) 15
a Includes one patient (sensitive) who had
only one prior regimen and responded to VSLI.
P-63
Consistent Results in Both Studies (n=211)Consistent Results in Both Studies (n=211)
ORR (% of Patients)
Combined Studies Phase
IIb
Phase IIa
Combined
2 Regimens (n=49) 46 52 49
Sensitive (n=28) 64 65 64
Resistant (n=21) 31 25 29
>2 Regimens (n=161) 20 24 22
Sensitive (n=43) 32 47 37
Resistant (n=118) 15 18 16
P-64
Univariate AnalysesUnivariate AnalysesObjective Response RateObjective Response Rate
Subgroup ORR
(% of Patients) 95% CI
Prior ASCT
Yes (n=39) 26 [13, 42]
No (n=80) 25 [16, 36]
Age
60 years (n=60) 25 [15, 38]
>60 years (n=59) 25 [15, 38]
>70 years (n=28) 36 [19, 56]
P-65
VSLI Efficacy Compared to VSLI Efficacy Compared to Single-Agent RituximabSingle-Agent Rituximab
Parameter Rothe (n=21)
Tobinai
Subgroup (n=50)
Coiffier
Subgroup (n=30)
Phase IIb Subgroup
(n=24)
Phase IIb (n=119)
Median prior regimens
2
(38% 1st relapse)
2a (32% 1st relapse)
2a (17% untreated, 31% 1st relapse)
2b 3
CR+PR (%) 38 34 37 46 25
CR (%) 5 — — 0 7
Duration of response (mos)
— — — 2.0 3.0
TTP (mos) 3.8 2.0a >3.5a 3.0 3.0
a Median for entire study, not for subgroup.
b 1 patient had only 1 prior regimen.
P-66
Objective Tumor Response by IRP Objective Tumor Response by IRP Single-Agent Rituximab as Last TherapySingle-Agent Rituximab as Last Therapy
Number (%) of Patients
(n=20)
Best Tumor Response
Rituximab VSLI
ORR 5 (25) 8 (40)
CR 0 (0) 2 (10)
CRu 0 (0) 1 (5)
PR 5 (25) 5 (25)
MR+SD 4 (20) 4 (20)
PD+UE 11 (55) 8 (40)
P-67
Safety Data
P-68
Extent of Treatment with VSLI (ITT)Extent of Treatment with VSLI (ITT)
(n=119)
Number of Cycles Received Mean 4.6 Median (range) 4.0 (1-20)
Dose Intensity (mg/m2/wk) Median 0.98
P-69
Safety – Major EndpointsSafety – Major Endpoints
14% of patients withdrawn due to associated AEs, mostly neuropathy
No treatment-associated deaths
P-70
Neuropathy
P-71
Prior Neurotoxic Therapies (ITT)Prior Neurotoxic Therapies (ITT)
% of Patients (n=119)
Number of Prior Regimens Containing Neurotoxic Agents
1 14 2 56 3-5 30
Neurologic Abnormality at Baseline 85
P-72
Worst Neuropathy on Study by Grade at Study EntryWorst Neuropathy on Study by Grade at Study Entry(Pain, Paresthesia, Numbness, (Pain, Paresthesia, Numbness,
Weakness, Constipation)Weakness, Constipation)
% of Patients
Worst Grade on Study Study Entry Grade Grade 0 Grade 1 Grade 2 Grade 3 Grade 4
Grade 0 (n=39) 8 26 33 26 0
Grade 1 (n=46) 0 24 41 26 4
Grade 2 (n=21) 0 5 38 52 5
P-73
Mean Change from Baseline for Cycles 1 to 6 Mean Change from Baseline for Cycles 1 to 6 for Hand Numbnessfor Hand Numbness
Hand Numbness
n=94 n=81 n=70 n=50 n=33 n=23
0.0
1.0
2.0
C1 C2 C3 C4 C5 C6Cycle
Ch
ang
e fr
om
Bas
elin
e (+
/-
SE
M)
*Significant change from baseline
*
*
*
*
*
*
P-74
Dose to Grade 3 or 4 NeuropathyDose to Grade 3 or 4 Neuropathy(Pain, Paresthesia, Numbness, (Pain, Paresthesia, Numbness,
Weakness, Constipation)Weakness, Constipation)
Kaplan-Meier Analysis (n=115)
Number (%) of patients with Grade 3 or 4 neuropathy
37 (32)
Grade 3 neuropathy 34 (30) Grade 4 neuropathy 3 (3)
Estimated median cumulative dose
21.2 mg/m2
(~11 doses)
• Equivalent to 15 doses of conventional vincristine
P-75
Comparison of Neuropathy in Responders Comparison of Neuropathy in Responders vs. Nonresponders (Numbness)vs. Nonresponders (Numbness)
% of Patients
Grade Changes From Baseline to Worst Value
Parameter No Change
1
Grade
2 Grades
3
Grades
4 Grades
Responders, CR+CRu+PR (n=29)
14 41 24 21 0
Nonresponders, SD+PD+UE (n=74)
55 24 16 4 0
PD or UE only (n=48) 69 19 10 1 0
P-76
Timing of Antitumor EffectTiming of Antitumor Effect vs. Neuropathy vs. Neuropathy
Antitumor activity evident early in patients who responded, usually within 2 weeks (1st dose)– Symptomatic improvements– Reduced palpable adenopathy– Decreased LDH
Development of neuropathy is gradual and predictable
Informed treatment decisions can be made before significant neuropathy develops
P-77
Hematologic Abnormalities
P-78
Hematologic Abnormalities at Study EntryHematologic Abnormalities at Study Entry
% of Patients (n=119)
Hematologic Abnormality At Study Entry
Anemia 78 Neutropenia 15 Thrombocytopenia 40
ANC <1.5 or Platelets <100K 33
P-79
Hematology CTC Grade Changes from Hematology CTC Grade Changes from Baseline to Worst GradeBaseline to Worst Grade
% of Patients
Grade Change
Parameter No Change
1
Grade
2 Grades
3
Grades
4 Grades
Hemoglobin (n=118) 47 40 9 1 0
Neutrophils (n=117) 52 15 11 15 5
Platelet count (n=118) 56 32 6 1 0
P-80
Hematologic ToxicityHematologic Toxicity
Neutropenia
• 8% Grade 4 neutropenia (<0.5 ANC)
• 3% febrile neutropenia
• 2% prophylactic filgrastim usage
Thrombocytopenia
• 1% Grade 4 thrombocytopenia (<10x109/L)
• 6% platelet transfusions
P-81
Patients with Net Clinical BenefitPatients with Net Clinical Benefit
Fernando Cabanillas, MD
Clinical Professor of Medicine MD Anderson Cancer Center
Medical Director Auxilio Mutuo Cancer Center
P-82
Patient Benefit SummariesPatient Benefit Summaries
FDA requested patient benefit summaries to facilitate review for clinical benefit
38 patients considered to be responders by either IRP or Investigator
5 patients with SD (minor response) had evidence of clinical benefit
Total of 43 individual patient benefit-risk assessments
P-83
41 Patients Had Evidence of 41 Patients Had Evidence of Net Clinical BenefitNet Clinical Benefit
Improvement in symptoms or ECOG PS
Tumor response to VSLI that permitted stem cell transplant
Durable complete response
Durable PR or prolonged SD
Better response than with prior regimen
Improvement in laboratory parameters
In case studies
P-84
Clinical Benefit: Symptomatic and Clinical Benefit: Symptomatic and ECOG PS ImprovementsECOG PS Improvements
Category of Improvement Number (%) of
Patients (n=43)
Symptomatic improvement (B symptoms or other symptoms)
20 (47)
ECOG PS improved 13 (30)
Symptomatic or ECOG PS improvement
26 (60)
P-85
Clinical Benefit: Stem Cell TransplantClinical Benefit: Stem Cell Transplant
6 patients were able to receive transplants after VSLI study, 5 allogeneic, 1 autologous
Responsiveness to VSLI therapy and maintenance of good performance status enabled consideration for transplant
5 patients alive (1 died at 29 months)– 1 with disease (survival of 28+ months)– 4 with no evidence of disease (27+, 29+, 31+,
39+ months)
P-86
Case Studies ofSelected Patients with Clinical Benefit
P-87
Patient 35-01Patient 35-01
56 y/o F, Stage IV-B, IPI=1
Primary mediastinal DLCL, weight loss, fever, night sweats, anemia
Prior Rx: 1) CHOPPR for 3 months; 2) ESHAPPD; 3) RICEPD
20 cycles VSLI/38 weeks CRu of ~1 yr
Transient Grade 4 neutropenia at Cycle 5
Attained CRu after being refractory to all prior Rx; resolution of B symptoms and anemia
P-88
Patient 40-01Patient 40-01
76 y/o F, DLCL-B, IPI=3
Multiple pulmonary metastases
Low platelets (72k)
Prior Rx: 1) CHOPCR; 2) CTX-VP16-DTIC-Rituxan-PredCR
8 cycles VSLI/14 weeks PR 8+ mos, platelets normalized
No Grade 3-4 toxicities
Residual pulmonary nodules not changed @ 2.5 years (fibrotic tissue?)
Chemo-free interval of 27+ mos, a longer remission than with any prior therapies
P-89
Patient 33-06Patient 33-06
47 y/o M, Stage IV-B, DLCL-B, IPI=1
Mediastinal mass and marrow involvement
Prior Rx: 1) CHOPMR; 2) RICEPD
8 cycles VSLI/14 weeks PR 9+ mos (IRP); CR 14+
mos (INV)
No Grade 3-4 toxicities
Alive with no evidence of disease at 30+ mos, with no subsequent therapies
Attained CR after being refractory to all prior Rx; resolution of B symptoms and anemia
P-90
Benefit-Risk Conclusions
P-91
Summary of Patient PopulationSummary of Patient Population
Median 3 prior regimens 4th-5th line therapy
33% had prior ASCT
33% with low blood counts
50% refractory to last therapy
24% >70 years
66% with elevated LDH
P-92
Summary of VSLI BenefitsSummary of VSLI Benefits
25% ORR in heavily pretreated patients with highly resistant disease and compromised marrow– 46% ORR in those treated on 2nd relapse
Clinically important ORR for this population
22% of patients with symptomatic or ECOG PS improvement
Median duration of response of 3 months, 4 months for time to progression for a population with a median survival of 7 months
P-93
Summary of RisksSummary of Risks
Neuropathy is dose-limiting toxicity– Gradual cumulative development– Only 13% withdrew for neuropathy
Well tolerated compared to other agents– Low incidence of severe myelotoxicity and
hospitalizations– Low incidence of severe nausea and vomiting or
alopecia
P-94
Favorable Benefit-Risk ProfileFavorable Benefit-Risk Profile
Symptomatic improvement and antitumor activity evident early, allowing informed treatment decisions before significant neuropathy develops
Favorable benefit-risk profile for this population with no standard treatment options
P-95
Why Do We Need VSLI?Why Do We Need VSLI?
Effective and well-tolerated agent for– Patients at 3rd line or later– Patients who don’t qualify for aggressive combination
regimens or who have relapsed after ASCT– Patients with compromised marrow function
Benefits 1 in 4 patients with minimal toxicity