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TREATMENT and RESULTS INTRODUCTION 1. Biesecker LG, et al. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet. 1999;84:389–95. 2. Biesecker LG. The challenges of Proteus syndrome: diagnosis and management. Eur J Hum Genet. 2006;14:1151–7. 3. Yu Y, et al. Targeting AKT1-E17K and the PI3K/AKT pathway with an allosteric AKT inhibitor, ARQ 092. PLoS ONE. 2015 10: e0140479. 4. Lindhurst MJ, et al. Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome. Sci Rep. 2015;5:17162. The authors would like to express their deepest gratitude to the patient, her family and their colleagues who participated in this study. Poster creation and design by Laurie LaRusso of Chestnut Medical Communications paid for by ArQule Inc. Personalized treatment with the AKT inhibitor miransertib in a patient with PS and a relapsed AKT1 (E17K) mutant LGSOC led to a clinically significant and sustained anti-tumor response and improvement of PS-associated symptoms. Proteus Syndrome 1,2 Proteus syndrome (PS) is an ultra-rare disease characterized by progressive, disproportionate, segmental overgrowth that can affect any organ or tissue in the body. It occurs sporadically in a mosaic form. The diagnosis is based on strict clinical criteria first defined in 1999 and confirmed by the presence of a somatic gain of function mutation c.49G>A, p.Glu17Lys in the oncogene AKT1, encoding the AKT1 kinase. Patients with PS develop numerous severe medical complications, including vascular anomalies (capillary, venous and lymphatic), deep venous thrombosis, pulmonary cystic malformation, severe scoliosis with megaspondily, epilepsy, cardiac abnormalities, renal and spleen overgrowth. AKT is a critical component in the PI3K/AKT/mTOR pathway and somatic mutations in the AKT1 gene can also act as oncogenic drivers. Patients with PS have also a higher risk of both benign and malignant tumors, and monomorphic adenomas of the parotid glands and ovarian cystoadenomas (both arising before the second decade) are useful in establishing the diagnosis. Miransertib 3,4 Miransertib (ARQ 092) is an investigational orally available potent and selective allosteric pan-AKT inhibitor that inhibits both the active and inactive forms of AKT, AKT1, AKT2, and AKT3. Lindhurst et al. demonstrated that miransertib reduced phosphorylation of AKT and downstream targets of AKT in a concentration- dependent manner in cells and tissues from patients with PS. Preclinical in vivo studies also show that miransertib exhibits strong anti-tumor activity on tumor models harboring mutant AKT1-E17K or with an activated AKT pathway. We report the efficacy of this AKT1 inhibitor treatment in a patient with PS and an AKT1 (c.49G>A; p.Glu17Lys) relapsed serous ovarian cancer. Improvements in Mobility and Bone Overgrowth ■ From approximately the 12 th week of treatment, the patient noticed progressive improvement in joint mobility (hands, spine and knees) that continued throughout miransertib therapy. ■ The patient reported significant improvement in the range of articular motion, to the point that she was able to transfer independently from the wheelchair to the bed and to lay down in a fully supine position. ■ Progressive reduction in bone overgrowth, especially in the hands, was evident on physical examination. PRETREATMENT EVALUATIONS ■ We report the first case in the medical literature of relapsed AKT1(E17K) mutant LGSOC in a patient with PS harboring the same mutation, with clinically significant and sustained tumor response associated with improvement in PS symptoms during the first 19 months of treatment with an AKT inhibitor. ■ The clinical and molecular data not only confirm the occurrence of gynecological malignancies during the second decade in PS patients, but also provide unique insight into the pathogenesis of these neoplasms. ■ The observed response to miransertib provides evidence that targeting AKT in this context can lead to improvement of the overgrowths associated with PS and to a clinically significant and durable response of the associated AKT1 (E17K) mutant ovarian cancer. Partial Response and CA-125 Normalization C. Leoni, 1 G. Gullo, 2 N. Resta, 3 A. Fagotti, 4 R. Onesimo, 1 B. Schwartz, 5 J. Kazakin, 5 C. Ranieri, 3 G. Scambia, 4 G. Zampino 1 1 Center for Rare Diseases, Fondazione Policlinico Gemelli, IRCCS, Rome, Italy; 2 Medical Oncology Department, St Vincent’s University Hospital, Dublin, Republic of Ireland; 3 Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO) University of Bari “Aldo Moro”, Bari, Italy; 4 Division of Gynecologic Oncology, Fondazione Policlinico Gemelli, IRCCS Rome, Italy; 5 ArQule, Inc., Burlington, MA, USA #1251 2018 ASHG Annual Meeting 16-20 October 2018, San Diego, CA Personalized Medicine in Rare Diseases and Cancer: A Case Report of a Lasting Response in a Young Teenage Patient with Proteus Syndrome and Secondary Ovarian Cancer DISCUSSION CONCLUSIONS REFERENCES & ACKNOWLEDGEMENTS March 2017 baseline evaluation: - Full-body CT scan: target lesion maximum diameter 6.29 cm; CA-125: 95kU/L - Full body CT scan and CA 125 measurements were performed every 8 weeks for first 24 weeks and every 12 weeks thereafter ↓ May 2017 Resolution of ascites; CA-125 decreased to 38 kU/L; stable measurable disease on CT ↓ July 2017 CA-125 normalized (at 16 weeks of treatment) ↓ September 2017 CT showed partial response (PR) according to RECIST 1.1 criteria; residual pelvic mass 4.39 cm (-30% from baseline) ↓ June 2018 15-month CT scan confirmed ongoing PR; residual pelvic mass 3.23 cm (-50% from baseline); CA-125 still within normal limits ↓ October 2018 19-month CT scan confirmed ongoing PR; residual pelvic mass 2.32 cm (-63% from baseline) CT Images of the Target Lesion (Longest Diameter) Pelvic Relapse of Low Grade Serous Ovarian Carcinoma at Baseline, 6 Months, 15 Months, and 19 Months Read alignment views with Alamut software of the patient’s derived ovarian cancer cells. Alamut displays varying level of data detail depending on the zoom level. The position of the mutated base with respect to the reference is delimited with blue bars, in the grey box frequency data and reads number are shown (A). Sanger sequencing validation of the c.49G>A [p.E17K] mutation in the AKT1 gene detected by targeted deep sequencing (B). Photos of the Patient’s Hands at Baseline and after 19 Months of Treatment PS Progression Complicated by Development of Ovarian Cancer A 16-year-old female was diagnosed with PS at the age of 3 years old in Rome, Italy. During the first 6 years of life, the patient underwent several surgical procedures for PS, including amputations of fingers on both hands. Later she developed a progressive severe rotoscoliosis and hyperostotic fusion of all cervical vertebrae causing her to need a wheelchair at the age of 10. At the age of 12, she underwent bilateral salpingo-oophorectomy, hysterectomy and peritoneal staging for a low grade serous ovarian carcinoma arising from a borderline ovarian serous tumor, with non- invasive omental implants. Two years after surgical treatment, she developed a pelvic recurrence associated with pelvic ascites. She also developed a partial thrombosis of the extrahepatic segment of the portal vein. Major surgery was deemed not feasible due to her multiple significant comorbidities, including vertebral synostosis in the cervical spine, making invasive ventilation extremely difficult. Due to portal vein thrombosis, treatment with chemotherapy or hormonal therapy with an aromatase inhibitor was not recommended. We submitted an application to the Institutional EC to treat this patient with miransertib made available by ArQule for single patient use. Upon approval on March 21 st 2017, she underwent staging and started treatment. Targeted deep sequencing assay of PI3K/AKT pathway genes was performed on her derived tumor cells and ovarian cancer. A targeted deep sequencing assay with the Ion AmpliseqTM Comprehensive Cancer Panel (TFS) to target all coding exons of 409 cancer-related genes in her derived tumor cells and blood sample was also performed. CASE HISTORY The presence of the AKT1 mutation E17K in the ovarian cancer with mutant allele frequency of 15% was detected. No mutations in patient’s blood sample were present. Any mutations on genomic DNA obtained from paired tissues, cancer and blood sample in ovarian cancer-related genes included in the commercial panel and in BRCA1 and BRCA2 genes have been detected. On 21 st March 2017 the patient underwent a baseline evaluation with full-body CT scan, which confirmed the presence of a secondary neoplastic mass in the pelvis (maximum diameter 6.3 cm) and multiple peritoneal implants with moderate-volume ascites. CA-125 was elevated (95kU/L). Baseline pre-treatment assessment also included a trans-thoracic echocardiogram and 12-lead ECG, both normal. 21 st March 2017 Starting dose: oral miransertib 50 mg/daily 5 days on, 8 days off, every 2 weeks ↓ No side effects observed during first 4 weeks of treatment. To achieve higher drug exposure, dose was increased in accordance with dosing schedules in prospective clinical trials ↓ From Week 5 onward, miransertib 100 mg/daily 7 days on, 7 days off, every 14 days ↓ Patient developed transient Grade 1* skin rash on the trunk, Grade 1-2* elevation of glycaemia and Grade 1-2* transaminases AST/GPT and ALT/GOT considered related to miransertib. ↓ Hyperglycemia and transaminases elevation resolved spontaneously but required occasional delay of subsequent treatment cycles by up to 1 week. No Grade 3 or 4 adverse events observed so far. Current dose of miransertib: 100 mg 7 day on, 7 days off. Miransertib Treatment Course A B Baseline (6.29 cm) 6 Months (4.39 cm) 15 Months (3.23 cm) 19 Months (2.32 cm) Baseline 19 Months
