Clinical Development for Patients with Cancer

Transcription

1 OMP 59R5: a Novel Therapeutic Antibody in Clinical Development for Patients with Cancer Jakob Dupont, MD, MA Chief Medical Officer and Senior Vice President OncoMed Pharmaceuticals Inc. Adjunct Clinical Assistant Professor Medical Oncology Stanford University Medical Center

2 Disclosure I am employed by OncoMed Pharmaceuticals.

3 Cancer Stem Cells: Driving Tumor Growth and Metastasis Isolation of Cancer Stem Cells from Patient-Derived Colon Tumor

4 Signaling Pathways in Cancer OncoMed Area of Focus Self-Renewal/ CSC Pathways Modulate Differentiation and Differentiation Self-Renewal New Pathways OncoMed Validated (e g RSPO-LGR) (e.g. RSPO LGR) Notch Notch1-4 DLL4 Jagged Wnt FZD1-10 Wnt Ligands Reduce CSC Frequency Traditional Growth Factor Growthy Pathways RTKs Her2 EGF IGF Met ALK Angiogenesis VEGF No effect on CSC Frequency

5 Cancer Stem Cells (CSCs) and the Notch Pathway Cancer Stem Cells (CSCs) CSCs first demonstrated in leukemia 1 Clarke et al. were the first to identify tumor initiating cells in solid tumors 2 CSCs now demonstrated in numerous malignancies and associated with chemoresistance and metastasis The Notch Pathway The Notch pathway mediates CSC self-renewal and proliferation Therapeutic objective: Inhibit CSC self renewal and/or force differentiation Self-renewal Activation of Notch2 and/or Notch3 has been implicated in several tumor types: lung, pancreatic, ovarian, and breast cancers 1 Bonnet and Dick, Nature Med 3, Al-Hajj et al PNAS 100,

6 Signal Transduction by the Notch Pathway Notch Pathway: Ligands DLL1, 3, 4, JAG1, 2 Receptors Notch 1, 2, 3, 4 Targets for OMP-59R5

7 OMP 59R5: Anti Notch 2/3 OMP-59R5 Targets Notch2 and Notch3 and Blocks Ligand Dependent Signaling OMP-59R5 is a fully human OMP-59R5 is a fully human antibody - originally identified by binding Notch2 and subsequently found to also bind Notch3

8 Preclinical Data: OMP 59R5 (Anti Notch2/3) Patient Derived Pancreatic Adenocarcinoma Anti Notch2/3 Delays Tumor Recurrence After Gemcitabine Treatment in PN8 Tumors Anti Notch 2/3 Decreases Tumorigenicity Of CD44 + ; PROCR + Cells in NOD/SCID mice ) tumor vo olume (mm Gem+Abs Abs alone 59R5: 5 20 mg/kg, g, weekly Gemcitabine: 20 mg/kg, weekly olume, mm 3 Tumorigenicity (101 Days Post Cell Injection) Control Ab +Gemcitabine Anti-Notch2/ Gem Tumor Vo Days Gem + OMP-59R5 OMP-59R5 Gem + control Ab control Ab 0 Control mab Anti-Notch2/3 Gemcitabine Combination

9 Ph1a Study of OMP 59R5 in Solid Tumor Patients Study 59R5 001 University of Michigan Cancer Center, Ann Arbor, MI David C Smith, Rashmi Chugh, Villette Thorpe The START Center for Cancer Care, San Antonio, TX Anthony Tolcher, Amita Patnaik, Kyri Papadopoulos, Glenda Chambers OncoMed Pharmaceuticals Inc., Redwood City, CA Lu Xu, Ann M Kapoun, Jakob Dupont

10 Objectives: Study 59R5 001: Objectives and Design Primary: Safety Secondary: Pharmacokinetics, immunogenicity, efficacy Exploratory: Biomarkers Design: Repeating dose safety study in subjects with advanced solid tumors with DLT window first 28 days on study. 3+3 design with 6 additional subjects at MTD Weekly (QW): 0.5, 1, 2.5, and 5 mg/kg Every Other Week (Q2W): 5, 7.5, 10mg/kg g Every Three Weeks (Q3W): 7.5mg/kg PD assessments: Whole blood RNA, Plasma, Hair Follicles, Tumor Response assessment: Day 56, then every 8 weeks withcontinued treatment until progression of disease or unacceptable toxicity

11 Key Eligibility Criteria: Key Eligibility Criteria and DLT Definition Advanced, refractory solid tumor patients No uncontrolled Grade 1 diarrhea ECOG PS <2 > 18 years of age DLT dfiii definition Any Grade 3 or greater adverse event Except for: Grade 3 infusion reactions that resolve within 24hrs Grade 3 diarrhea, nausea, and/or vomiting that responds to standard medical treatment within 48hrs Grade 3 electrolyte disturbances that correct within 24hrs

12 Patient Demographics Number of Patients Enrolled 39 Median Age (range) 59 (28 90) Gender N (%) M: 20 (51%) F: 19 (49%) Tumor Types (N) Colorectal Cancer (10) Breast Cancer (5) Adenoid Cystic Cancer (3) Pancreatic Cancer (3) Chondrosarcoma (2) Liposarcoma (2) Prostate Cancer (2) Other (11)

13 Dose Limiting Tox (DLT) & Maximum Tolerated Dose (MTD) Schedule* Dose (mg/kg) Enrolled(N) DLTs (N) DLT description Weekly Gr3 hypokalemia (Gr3 diarrhea) 2. Gr3 diarrhea Every 2 Week Gr3 diarrhea 2. Gr3 diarrhea Every 3 Weeks TOTAL 41 4 All diarrhea related ltddlts

14 Related Adverse Events: All Grades (>5%) All Grades Related AEs ( 5%) 0.5QW (N=3) CTCAE Version QW (N=3) OMP 59R5 doselevel (mg/kg) (N=36) 2.5QW (N=6) 5QW (N=9) 5QoW (N=6) 10QoW (N=3) 7.5Q3W (N=6) Diarrhea (58%) Fatigue (28%) Nausea (22%) Decreased Appetite (14%) Vomiting (11%) Dehydration (8%) Dizziness (8%) Increased ALT (8%) Hypokalemia 3 3 (8%) Abdominal pain (8%) Anemia (8%) Thrombocytopenia (8%) Hypersensitivity (6%) Urticaria 1 1 2(6%) Increased AST 2 2 (6%) Constipation (6%) Hypercalcemia (6%) ALL (%)

15 Related Adverse Events: All Grades 3 5 CTCAE Version 4.02 All Grade 3 AEs. No Grade 4 or 5 related AEs OMP 59R5 dose level (mg/kg) (N=36)** All Grades Related AEs ( 5%) 0.5QW 1QW 2.5QW 5QW 5QoW 10QoW 7.5Q3W ALL (N=3) (N=3) (N=6) (N=9) (N=6) (N=3) (N=6) (%) Diarrhea (14%) Anemia (3%) Fatigue 1 1 (3%) Increased ALT 1 1 (3%) Hypokalemia 1 1 (3%) Significant ifi Correlation Between Diarrhea Grade and Dose of OMP 59R5 4 # of pts Grade 0 Grade 1 Grade 2 Grade QW 1QW 2.5QW 5QW 5Q2W 10Q2W 7.5Q3W Correlation between diarrhea grade & dose for weekly dosing: p-value = * * Cochran-Armitage trend test

16 Pharmacokinetics and Immunogenicity Fast nonlinear clearance suggests target mediated drug disposition Apparent T1/2= 47 ± mg/kg Q3Wdosing ofomp 59R5 provides a period of drug wash out Anti drug antibody formation (18 %, 5/28) did not affect PK Symbol: group mean and SD; Line: model fit

17 Study 59R5-001: Days on Study* Triple Negative Breast Cancer (Jag1 Amp): 7.5mg/kg Q3wk Liposarcoma: 10mg/kg Q2wk Sub bjects (N=39 9) Adenoid cystic ca: 5mg/kg Q2wk Rectal ca: 5mg/kg Qwk Kaposi s s Sarcoma: 5mg/kg Qwk Adenoid cystic ca: 2.5mg/kg Qwk DLT Window Tumor Tumor Days on Study Assessment Assessment ongoing * Four patients currently on study

18 Pharmacodynamic Data Gene Expression in Blood Blood RNA: HES1 Gene Expression Baseline to d28, d56, d112 Blood RNA: HES1 Gene Expression Baseline to d28 by Dose Weekly OMP-59R5 dosing PD samples taken prior to next tdosing HES1 HES1

19 Pharmacodynamic Data Serial Tumor Biopsies OMP-59R5 Down-regulated Notch3 PD Biomarker in Tumor Biopsies OMP-59R5 Up-Regulated mir150, Target of the NOTCH Pathway in Tumor Biopsies mir150: expression T cell Notch3 Pt14 KS 5 QW Pt27 PC 10QoW Pt28 CRC 5QoW Pt29 CRC 5QoW Pt14 KS 5 QW Pt27 PC 10QoW Pt28 CRC 5QoW Pt29 CRC 5QoW

20 Conclusions OMP 59R5 (Anti Notch2/3) is well tolerated in patients with advanced solid tumor Dose limiting iti toxicity: it diarrhea Maximum tolerated doses (MTDs) were: 2.5mg/kg QW, 7.5mg/kg Q3W. Q2WMTD stillbeing determined Pharmacokinetics: Fast, nonlinear clearance Pharmacodynamics: Modulation of Notch pathway at 1mg/kg, sustained 1 week in surrogate tissues and tumor biopsies. Prolonged stable disease in some patients at doses 2.5mg/kg Ph1b/2 studies in solid tumors including pancreatic cancer

21 Antibody Therapy In Ph1b/2 Study in FL Pancreatic Cancer First-Line Pancreatic Cancer Investigating anti-notch Efficacy and safety Ph1b: Safety Run-In First-line Metastatic Pancreatic Ca (Tissue Required) 1:1 Gemcitabine* + Anti-Notch2/3 Gemcitabine* + Placebo Study is ongoing ALPINE OMP-59R5 in Pancreatic Cancer * Gemcitabine: 1000mg/m 2 weekly for 3 weeks, 1 week rest ALPINE OMP-59R5 in Pancreatic Cancer

22 Acknowledgements Patients, their families, and care givers University of Michigan David Smith, MD Rashmi Chugh, MD Terri O Neill Neill, RN Kim Feldhaus, RN Villete Thorpe Elaine Granch START Anthony Tolcher, MD Kyri Papadopoulos, MD Amita Patnaik, MD Glenda Chambers OncoMed Dawn Hill Ann Kapoun, PhD Lu Xu, PhD