Converting Novel Therapeutic Models into Early Phase Clinical Trials

Transcription

1 Converting Novel Therapeutic Models into Early Phase Clinical Trials James H. Doroshow, M.D. Deputy Director for Clinical and Translational Research National Cancer Institute, NIH IOM National Cancer Policy Summit New Opportunities & Challenges in Cancer Research and Care Washington, D.C. November 4, 2013

2 100 Years of Cancer Research Models Radical Mastectomy Radiation Rx First chemotherapy agents: Nitrogen mustard, aminopterin, 6-mercaptopurine Human tumor Xenografts (nu/nu mice) First large scale In vitro human tumor cell drug screening PDXs CTCs Phase 0 Biomarker-driven therapy NCI Est d Patient Focused Combo chemotherapy of ALL and lymphoma from murine leukemia studies Model Focused GEMM s The Cancer Genome Atlas Individualized Patient Models

3 Emerging Human-Centered Preclinical Strategies in Drug Discovery/Development Patient- Derived Xenografts (PDX) & Conditionally Reprogrammed Cell Lines GEM- Derived Allografts (GDA) Tumorigenesis Tumor/patient heterogeneity Transplantation into syngeneic immunocompetent mice Create reprogrammed cell lines Transplantation into NSG mice Molecularly characterize, treat/screen mice bearing transplants & cells with relevant drugs Pre-clinical trials driven by molecular diagnostic tools: NCI Preclinical Models Consortium & PDX Repository Genetically- Engineered Mice (GEM) Tumorigenesis Made in wild type mice or using the Collaborative Cross Treat with best available drugs

4 Histology Over Multiple Generations: , Colorectal Cancer Patient No H&E Patient not delinked PDX Sample obtained from DTC clinic (06-C-0213) Considered a PDX tumor model as a sample has not yet been frozen and re-established in mice In vitro cell culture with Rho Kinase inhibitor and fibroblastconditioned F-media, not on mouse feeder layer. P0, Biopsy Material P0, CTC Material Biopsy Date: 5/1/2013 Blood Draw Date: 5/1/2013 In Vitro Growth: Primary Cell, Mixed Population Cultures Biopsy Date: 5/1/2013 Biopsy Date: 5/22/2013 Blood Draw Date: 5/1/2013 4

5 P1 (BL0293F-563P1) Jax- BL0293F Mouse Xenografts Patient Derived Xenograft BL-0293F563M672 Cell Strain BL0293F-Patient Rho Kinase-cell culture derived mouse xenografts are similar in morphology as noted in BL0293 patient derived Urothelial Cancer Xenografts Cell Strain Derived Xenograft 10X 20X 5

6 MPACT Assay 4 Drug Protocols, 3 Pathways, 22 Targeted Genes (amoi) Pathway Treatment Protocol RAS/RAF/MEK Trametinib DMSO; MEK Inhibitor AKT/PI3K Everolimus; mtor Inhibitor DNA Repair ABT Temozolomide; PARP Inhibitor MK Carboplatin; Wee1 Inhibitor Gain of Function Mutations BRAF KRAS NRAS HRAS AKT1 AKT2 AKT3 PIK3CA mtor Loss of Function Mutations NF1 PTEN FBXW7 ATM ATR ERCC1 MLH1 MSH2 NBN RAD51 PARP1 PARP2 TP53 6

7 BLADDER CANCER PDX WITH P53 Mutation Everolimus Control Trametinib qd x 28 Trametinib Control ABT-888 Control MK1775 Control Everolimus qd x 28d MK Carboplatin bid x 5 d ABT TMZ bid x 14 d Rx

8 NCI s M-PACT Clinical Trial: Study Design Arm A Assign treatment identified to target mutation Tumor biopsy from all patients for sequencing Mutation detected OR Mutation not detected RANDOMIZATION Arm B DISEASE PROGRESSION Assign treatment NOT identified to target mutation Off-Study Fresh tumor biopsy on-study and at progression Primary endpoint response (CR + PR) and 4-month PFS improved for agents chosen on the basis of specific mutations Crossover from Arm B (non-mutation directed) to Arm A (mutation-directed) treatment at progression Trial open across NCI s Phase I/II network (>30 NCI-designated Cancer Centers) Accrual expected to begin Q

9 Human Tumor Tissue Based Experimental Therapeutics *Clinical observations: Clinical response Patients eligible for early or late phase clinical trials Patient-derived preclinical models for targets PK Analysis of tumor and other tissues for pathway activation or resistance * Translational research with clinical models Sequencing Functional imaging Patient assigned to trial based on molecular characterization of tumor Methylation Tumor and normal tissue PD markers CTCs, CECs Tumor-initiating cells Patient monitoring Patient monitoring: post-treatment molecular re-analysis * * * FISH IHC Expression array

10 Optimizing Patient-Centric Models for Therapeutic Cancer Research Can we change the preclinical-clinical paradigm to: Develop individual preclinical, patientcentric, predictive therapeutic models using PDX or other systems derived from molecularly-characterized tumor biopsies, CTCs, or circulating DNA? Perform proof-of-mechanism clinical trials that incorporate specific, individualized data at treatment initiation and at the time of disease progression based on these preclinical models? Collaborate sufficiently to apply these new models to speed drug development?