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A Phase I Study of MK-2206, an Oral Potent Allosteric Akt Inhibitor in Patients with Advanced Solid Tumors Anthony W. Tolcher, 1 Timothy A. Yap, 2 Ivy.

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Presentation on theme: "A Phase I Study of MK-2206, an Oral Potent Allosteric Akt Inhibitor in Patients with Advanced Solid Tumors Anthony W. Tolcher, 1 Timothy A. Yap, 2 Ivy."— Presentation transcript:

1 A Phase I Study of MK-2206, an Oral Potent Allosteric Akt Inhibitor in Patients with Advanced Solid Tumors Anthony W. Tolcher, 1 Timothy A. Yap, 2 Ivy Fearen, 3 Adekemi Taylor, 3 Chris Carpenter, 3 Andre T. Brunetto, 2 Muralidham Beeram, 1 Kyriakos Papdopoulos, 1 Li Yan, 3 Johann S. de Bono 2 Abstract # START (South Texas Accelerated Research Therapeutics), San Antonio, TX 2 Royal Marsden Hospital and The Institute of Cancer Research, Sutton, Surrey, UK, 3 Merck & Co., Inc., North Wales, PA

2 2 MK-2206, a novel oral, potent, allosteric inhibitor of AKT Active AKT Inhibited AKT (Incapable of membrane localization) N Kinase PH ATP PDK 1 PDK 2 P P S473 N Kinase PH T308 C MK-2206 Novel MOA  Compound binds at an allosteric, PH domain dependent site  Akt PH domains not highly conserved  Highly selective for Akt with little off-target kinase activities  IC 50 for AKT1 = 5 nM; AKT2 = 12 nM; AKT3 = 65 nM  May be less vulnerable to feedback activation on Akt compared to ATP-competitive inhibitors

3 MK-2206 Inhibits pAKT & Downstream Signaling Pathways in Human Tumor Cells MK-2206 (nM) pAkt(S473) pAkt(T308) Akt pTSC(T1462) pPRAS40(T246) pS6 (S235,236) A2780 (Ovarian) LNCaP (prostate) GaoZhen Hang & Wei Lu, Merck & Co., Inc.

4 MK-2206 Compound Profile – Preclinical Potent anti-proliferative activity against multiple tumor cell lines (breast, ovarian, prostate, lung & gastric) –IC 50 is dependent on PI3K pathway activation events (PIK3CA mutation/amplification, PTEN loss) and wild type Ras/Raf in some cases Single agent anti-tumor activity in xenograft models Synergistic or additive with chemotherapeutic and targeted agents in vitro and in vivo 4

5 5 Phase I Study Objectives Primary –Determine the safety and pharmacokinetics (PK) of oral MK-2206 administered every other day (QOD) –Define the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of oral MK-2206 administered QOD Secondary –Assess target engagement in whole blood and tumor –Describe any preliminary anti-tumor activity

6 6 Major Eligibility Criteria Advanced or metastatic solid tumors Age  18 years, ECOG PS  1 At least 4 weeks since prior chemotherapy, irradiation, or biologic therapy No primary CNS tumor, QTc prolongation, bradycardia (<50 bpm), hepatitis No history of diabetes TestLevel Hgb  9 g/dL ANC  1500/µL Platelets  100,000/µL AST and ALT  2.5 x ULN † or  5 x ULN Fasting serum glucose  110% of ULN HgbA1c  8% Potassium and Magnesium Within normal range † Upper limits of normal

7 7 Treatment Schema Cycle 1 7-Day Drug HolidayCycles † ScheduleDays Days Days MK-2206 QOD Dose QOD beginning Day 1 Off Drug Dose QOD beginning Day 36 Oral MK-2206 administered in 28-day treatment cycles † Patients permitted to continue beyond 6 cycles

8 8 Study Design Dose escalation in cohorts of 3 to 6 patients –Planned doses: 30, 60, 90, 200, and 300 mg –Intermediate dose levels incorporated after DLT DLT observation period in first 28 days Dose confirmation in a total of 18 patients –MTD determined using a dose-response curve for the percentage of patients experiencing a DLT † Target toxicity rate of ~17% † Ji et al. Clin Trials 2007; 4:235-44

9 9 Definition of DLT  Grade 4 hematologic toxicity Grade 3 neutropenia with fever and/or infection  Grade 3 non-hematologic toxicity, including –  Grade 3 signs and symptoms of glucose intolerance –Fasting glucose >250 mg/dL or 13.9 mmol/L –Non-fasting glucose >500 mg/dL or 27.8 mmol/L Diagnosis of lactoacidosis or ketoacidosis QTc interval increase >60 ms, and/or >500 ms Clinically significant bradycardia

10 10 PK/Pharmacodynamic (PD) Sampling Serial PK/PD sampling between Days 1 and 35 –Plasma for PK –Peripheral whole blood for PD P-AKT activity (MESO-scale assay method) Tumor biopsy performed: baseline, Cycle 1 D 15 Circulating nucleic acids for PIK3CA mutation Results pending –Plucked hair for pAkt inhibition performed at baseline and Cycle 1 Days 7 and 15, Cycle 2 Day 1 –Circulating tumor cells and circulating endothelial cells performed at baseline and Day 1 of each cycle

11 11 Patient Demographics Characteristics: Number of patients 34 Age, median (range) 56 (25 to 84) Male, n (%) 19 (56) ECOG PS, n (%) (35) 22 (65) Prior chemotherapy regimens, n (%) 1 2  3 2 (6) 3 (9) 29 (85) Diagnosis: Tumor Type Number of Patients Breast Melanoma Neuroendocrine Prostate Ovarian Colorectal Parotid Other: lung, pancreatic, GIST, Kaposi’s sarcoma, renal cell, DSRCT, pheochromocytoma, synovial cell sarcoma, squamous cell carcinoma transitional of urothelium 10

12 12 Dose Escalation Phase Dose (mg) No. of Patients No. of Cycles No. of DLTs Enrolled Dose Reduced 30 QOD 60 QOD 90 QOD 75 QOD 3 6 (12+)

13 13 Hematologic Toxicity: Dose Escalation and Expansion Phase Adverse Experience 30 mg QOD (n=3) 60 mg QOD (n=18) 75 mg QOD (n=3) 90 mg QOD (n=7) Anemia Grade 2 1 Leukopenia Grade 12 ANC Grade 11 Thrombocytopenia Grade 11

14 14 Non-Hematologic Toxicity: Dose Escalation and Expansion Phase Adverse Experience 30 mg QOD (n=3) 60 mg QOD (n=18) 75 mg QOD (n=3) 90 mg QOD (n=7) Skin rash Grade 1 Grade 2 Grade 3 Grade Mucosal inflammation Grade 1 Grade 2 Grade

15 15 Skin Rash

16 16 Non-Hematologic Toxicity: Dose Escalation and Expansion Phase Adverse Experience 30 mg QOD (n=3) 60 mg QOD (n=18) 75 mg QOD (n=3) 90 mg QOD (n=7) Hyperglycemia Grade 1 Grade 2 Grade Pruritus Grade 1 Grade Diarrhea Grade 1 Grade

17 17 Non-Hematologic Toxicity: Dose Escalation and Expansion Phase Adverse Experience 30 mg QOD (n=3) 60 mg QOD (n=18) 75 mg QOD (n=7) 90 mg QOD (n=3) Vomiting Grade 1 Grade Nausea Grade 1 Grade Fatigue Grade 1 Grade

18 Preliminary PK Summary of MK-2206

19 19 Preliminary PD Summary of MK mg QOD – Tumor pAkt unit (normalized to total protein) ~ 90% tumor pAkt inhibition in 5 out of 7 patients Pt 1 * C1D15 pAKT value was below LLOD Pt 1 – Kaposi sarcoma Pt 2 – DSRCT sarcoma Pt 3 – Pheochromocytoma Pt 4 – Breast Pt 5 – Breast Pt 6 – Melanoma Pt 7 – Breast Cycle 1 Baseline Cycle 1 D Patient Cycle 1 ScreeningCycle 1 D15 *

20 Circulating Nucleic Acid PIK3CA Mutations TumorGeneExonCommentResponse BreastPIK3CAExon 9BRCA2 +PD BreastPIK3CAExon 9PD MelanomaPIK3CAExon 20 ColonPIK3CAExon patients had CNA blood samples drawn, 4 positive for PIK3CA mutations

21 21 Anti-Tumor Activity of MK mg QOD dose level

22 Anti-tumor Activity of MK-2206: CA125 Ovarian Cancer Patients (3/3) TumorDose CA 125 Baseline CA 125 NadirComment Ovarian DLT off study Ovarian DLT off study Ovarian Continues 22

23 23 Conclusions The MTD of oral MK-2206 QOD is 60 mg –Predominant toxicities at MTD were mild to moderate skin rash, GI symptoms, fatigue, and hyperglycemia –Severe toxicity of skin rash above the MTD Dose proportional PK pAkt inhibition in whole blood and tumor Early indications of anti-tumor activity

24 Acknowledgments The study investigators would like to thank the patients for participating in this trial as well as the nurses and clinical research associates who contributed to the implementation of this study. START (Southern Texas Accelerated Research Therapeutics) Dr. Amita Patnaik Ms. Cally Claiborne Ms. Brianne Kaiser Mr. James Agnew Ms. Rachel Pesek Royal Marsden Hospital and The Institute of Cancer Research Ms. Lauren BrittonMs Samantha Costigan Ms. Sue Chen Ms. Liz SheridanMr. Shaun Decordova Ms. Joana Moreira Dr. Michelle GarrettMs. Philippa Grainger Ms. Juliet Dukes Mr. Simon HeatonDr. Nina Tunariu H. Lee Moffitt Cancer Center & Research Institute Dr. Dan Sullivan Mr. Rich Lush Ms. Michelle Mintz


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