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Abstract #3503 A Phase I Study of MK-2206, an Oral Potent Allosteric Akt Inhibitor in Patients with Advanced Solid Tumors Anthony W. Tolcher,1 Timothy.

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Presentation on theme: "Abstract #3503 A Phase I Study of MK-2206, an Oral Potent Allosteric Akt Inhibitor in Patients with Advanced Solid Tumors Anthony W. Tolcher,1 Timothy."— Presentation transcript:

1 Abstract #3503 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 Bono2 1START (South Texas Accelerated Research Therapeutics), San Antonio, TX Royal Marsden Hospital and The Institute of Cancer Research, Sutton, Surrey, UK , 3Merck & Co., Inc., North Wales, PA

2 (Incapable of membrane localization)
MK-2206, a novel oral, potent, allosteric inhibitor of AKT PDK 1 PH N PDK 2 MK-2206 P T308 S473 P ATP C N PH Kinase Kinase Active AKT Inhibited AKT (Incapable of membrane localization) 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 IC50 for AKT1 = 5 nM; AKT2 = 12 nM; AKT3 = 65 nM May be less vulnerable to feedback activation on Akt compared to ATP-competitive inhibitors 2

3 MK-2206 Inhibits pAKT & Downstream Signaling Pathways in Human Tumor Cells
A2780 (Ovarian) LNCaP (prostate) 14 41 123 370 1111 3333 10000 MK-2206 (nM) 14 41 123 370 1111 3333 10000 pAkt(T308) pAkt(S473) Akt pTSC(T1462) pPRAS40(T246) pS6 (S235,236) 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) IC50 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

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 Major Eligibility Criteria
Test Level 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 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 †Upper limits of normal

7 Treatment Schema Oral MK-2206 administered in 28-day treatment cycles
7-Day Drug Holiday Cycles 2 - 6† Schedule Days Days Days MK QOD Dose QOD beginning Day 1 Off Drug Dose QOD beginning Day 36 †Patients permitted to continue beyond 6 cycles

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 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 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 Patient Demographics Characteristics: Number of patients 34
Age, median (range) 56 (25 to 84) Male, n (%) 19 (56) ECOG PS, n (%) 1 12 (35) 22 (65) Prior chemotherapy regimens, n (%) 2 3 2 (6) 3 (9) 29 (85) Diagnosis: Tumor Type Number of Patients Breast Melanoma Neuroendocrine Prostate Ovarian Colorectal Parotid 7 4 3 2 Other: lung, pancreatic, GIST, Kaposi’s sarcoma, renal cell, DSRCT, pheochromocytoma, synovial cell sarcoma, squamous cell carcinoma transitional of urothelium 10

12 Dose Escalation Phase Dose (mg) No. of Patients No. of Cycles DLTs
Enrolled Dose Reduced 30 QOD 60 QOD 90 QOD 75 QOD 3 6 (12+) 7 6 10 13 9 4 2

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 1 2 ANC Thrombocytopenia

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 4 2 3 1 Mucosal inflammation

15 Skin Rash

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 3 1 2 Pruritus 3 Diarrhea

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 2 1 2 Nausea 3 Fatigue

18 Preliminary PK Summary of MK-2206

19 Preliminary PD Summary of MK-2206 60 mg QOD – Tumor
~ 90% tumor pAkt inhibition in 5 out of 7 patients 0.000 2.000 4.000 6.000 8.000 10.000 12.000 14.000 16.000 18.000 Cycle 1 Baseline Cycle 1 D15 (normalized to total protein) pAkt unit 1 2 3 4 5 6 7 Patient Pt 1 – Kaposi sarcoma Pt 2 – DSRCT sarcoma Pt 3 – Pheochromocytoma Pt 4 – Breast Pt 5 – Breast Pt 6 – Melanoma Pt 7 – Breast 0.000 0.050 0.100 0.150 0.200 0.250 Cycle 1 Screening Cycle 1 D15 Pt 1 * * C1D15 pAKT value was below LLOD 19

20 Circulating Nucleic Acid PIK3CA Mutations
7 patients had CNA blood samples drawn, 4 positive for PIK3CA mutations Tumor Gene Exon Comment Response Breast PIK3CA Exon 9 BRCA2 + PD Melanoma Exon 20 Colon

21 Anti-Tumor Activity of MK-2206
30 mg QOD dose level

22 Anti-tumor Activity of MK-2206: CA125 Ovarian Cancer Patients (3/3)
Dose CA 125 Baseline CA 125 Nadir Comment Ovarian 90 1572 534 DLT off study 1729 1142 60 225 155 Continues

23 Conclusions The MTD of oral MK-2206 QOD is 60 mg Dose proportional PK
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 Britton Ms Samantha Costigan Ms. Sue Chen Ms. Liz Sheridan Mr. Shaun Decordova Ms. Joana Moreira Dr. Michelle Garrett Ms. Philippa Grainger Ms. Juliet Dukes Mr. Simon Heaton Dr. Nina Tunariu H. Lee Moffitt Cancer Center & Research Institute Dr. Dan Sullivan Mr. Rich Lush Ms. Michelle Mintz


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