1 / 24

Abstract #3503

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

haruko
Download Presentation

Abstract #3503

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

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 2Royal Marsden Hospital and The Institute of Cancer Research, Sutton, Surrey, UK , 3Merck & Co., Inc., North Wales, PA

  2. MK-2206, a novel oral, potent, allosteric inhibitor of AKT PDK 1 PH N PDK 2 MK-2206 T308 P S473 P ATP C PH Kinase N 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 LNCaP (prostate) A2780 (Ovarian) 0 14 41 123 370 1111 3333 10000 MK-2206 (nM) 0 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 • 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 †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

  12. Dose Escalation Phase

  13. Hematologic Toxicity: Dose Escalation and Expansion Phase

  14. Non-Hematologic Toxicity: Dose Escalation and Expansion Phase

  15. Skin Rash

  16. Non-Hematologic Toxicity: Dose Escalation and Expansion Phase

  17. Non-Hematologic Toxicity: Dose Escalation and Expansion Phase

  18. Preliminary PK Summary of MK-2206

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

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

  22. Anti-tumor Activity of MK-2206: CA125Ovarian Cancer Patients (3/3)

  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 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

More Related