Shortening the Cancer Drug Development Timeline: Role of Molecular Pharmacodynamics

Transcription

1 Shortening the Cancer Drug Development Timeline: Role of Molecular Pharmacodynamics James H. Doroshow, M.D. Deputy Director for Clinical & Translational Research National Cancer Institute, NIH Bladder Cancer Think Tank Charlotte, NC August 6, 2015

2 Causes of Phase II Failures: Nature Rev. Drug Discov. 10: 1, 2011

3 Avoiding Phase II Failures 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Ph III Success POM + /Effective Walk away confidently POM+ /Ineffective Inadequate test of hypothesis POM nd/ineffective Pfizer s 3 pillars of survival Required exposure shown at site of action Hits [binds] the target with required kinetics Relevant downstream pharmacology(pd) at site of action 44 NME programs across therapeutic areas Drug Discov. Today 17: 419, 2012

4 Lack of Molecular Markers with Proven Clinical Utility Follows Lack of Clinically-Demonstrable POM Drug Class Clinical POM Biomarker Anti-estrogens Yes ER, PR, genomic signature Trastuzumab Yes Her2 FISH, IHC EGFR small molecule inhibitors Yes Mutation status B-Raf, ALK inhibitors Yes Mutation status Topo I & II Inhibitors No?? Platinums No?? Alkylating Agents No?? C-Met inhibitors No?? IGF-I receptor antagonists No?? Src inhibitors No?? HDAC/DNMT inhibitors No?? VEGF/VEGFR +/-??

5 Standard Drug Development Pipeline: Re-envisioned Hypothesis Generation Clinical Candidate Development Commercialization Drugs Assays Trials Risk $1200 MM Cumulative Investment Target Validation $ MM Target/ Molecule Discovery Assay Development Lead Optimization Preclinical Development Phase Phase I II Phase III Registration Global Launch Global Optimization Lead Generation $ MM $20-60 MM Risk GOAL: Time: 5-6 Years Time: Years

6 Increasing the Impact of Early Trials in Cancer Drug Development Development of PD assays; critical prelude to clinical biomarker Pharmacology, Toxicology, Formulation First-in-Human Clinical Trials Prospective biomarker validation clinical trial FDA Preclinical efficacy Parallel track imaging agent development Early combination & combined modality trials

7 Should We Perform Early Phase Trials Without Generating Evidence Supporting Proof-of-Mechanism Patient by Patient? Background: Recent cancer small molecule development has been characterized by both high profile successes and failures; successes were rapid and resulted from molecular stratification; failure associated with lack of clear demonstration of P-of-M early in clinical development. Feasibility:Should we only develop agents that can be brought to the clinic under conditions that demonstrate P-of-M? Should resources be refocused around this paradigm with a consequent decrease in the number of trials performed and drugs evaluated? Implications for success: Fewer costly, late stage development failures; improved understanding of actual mechanism of action or resistance in the clinic.

8 Proof of Mechanism in Early Trials Demonstrate drug action on intended tumor target (proof of mechanism) in a human malignancy early in development evaluate hypotheses surrounding mechanism of action per se evidence of target modulation in the clinic assists decision to move agent forward, or not... evaluate relationship of drug schedule and systemic exposure to target effects; examine relevance of marker chosen to represent target modulation examine the value of non-invasive markers prior to expectation of efficacy Potential to investigate molecular effects of the agent in non-malignant tissues relevance of surrogate tissues genetic toxicology NOT: predictive of clinical benefit only later stage (larger) trials can define relevance of target modulation to tumor growth inhibition Eur. J. Cancer 45:

9 Shortening Timelines with P-O-M Studies: Critical Issues Developing the right assay for the target Is the target suitable to drive drug development? Tissue acquisition and handling Assay validation and clinical readiness Tumor heterogeneity Comprehensive approach to proof-of-mechanism (did you hit the target?) and proof-of-concept (did hitting the target affect growth-controlling pathways?) Understanding the relationship between dose, schedule, target inhibition, and efficacy: essential for testing targeted combinations Multiplex approach to PD assay development 2015 model for cancer drug development

10 Developing the Right AssayTools for Early Stage Proof of Mechanism Studies

11 Standards for Validated PD Assays: Preparation Required for Intended Use Selection of assay format and platform; adequate instrumentation Production of assay controls (QC Samples) Selection of standards and the standards matrix Will the standards matrix be a cell or tissue extract? How will that affect stability of the standards? Concentration-response relationships for agent on growth and target modulation in culture Assay sensitivity for multiple determinations on same clinical specimen Minimizing replicate variability Specific optimization of handling by specimen type Validation Issues: Use common reagents (Master Lot) Precision Validation (Operator, Day, Instrument) Accuracy Validation (Dilution Linearity, Spike Recovery) Assay Transfer between sites SOPs in place?

12 Pharmacodynamic Assay Development Conceptp Feasibility & Development Validation Launch Target Application Platform Feasibility Development γ-h2ax Protein (tumor) γ-h2ax Protein (tumor) DNA Damaging Agents DNA Damaging Agents Analytical Validation Biopsy Assays Preclinical Modeling Specimen SOPs Assay Transfer ELISA P P P P P l Clinical Validation Support NCI Clinical Trials Transfer to Scientific Community qifa P P P P P P P P l Top 1 Protein TOPO Inhibitors ELISA P P P P P P P l pmet TK domain and Grb2 Docking Site MET TK domain and Grb2 Docking Site PARG mrna PARP 1 mrna PARP 1,2 Activity (PAR levels) PARP 2 mrna Stem Cell Proteins -ALDH 1A1 -OCT 3/4 -NANOG -CD44v6 DNA Methylation Me-CpG LINE1 Kinase Inhibitors ELISA P P P P l Kinase Inhibitors PARP Inhibitors PARP Inhibitors PARP Inhibitors PARP Inhibitors Tumor Stem Cell Inhibitors Methylation Inhibitors IFA Custom Reagents P l RT-qPCR P P P P P P P R RT-qPCR P P P P P P P R IA P P P P P P P l l RT-qPCR P P P P P P P R IFA P l H l Pyrosequence P P P P P P l KEY: l In Progress P Completed X Dropped l Delayed CA Commercially Available NA/UIN Not Applicable or Uninformative l Technical Difficulty H On Hold R Ready

13 Target Suitability for PD-Driven Early Phase Trials Clin. Cancer Res. 14:

14 Clinical Qualification of PD Assay: Humanizing Preclinical Models Clinical Readiness of PD Assay: Therapeutically relevant in preclinical model: Replicate the clinical setting in which the assay will be practiced: Clinical procedures for sample acquisition and handling Storage requirements and transferability Time frames achievable in clinical setting Inter- and intratumoral variability Stability of baseline Minimum doses required for target effect; does target inhibition correlate with altered tumor growth or toxicity in vivo Suitability of surrogate tissues Actually works when you do a DRY RUN Now You Can Start!

15 Development of pmet Immunoassay Assay Flow Chart Add Standards, Biopsy Extracts & Controls Incubate 1-hour Wash Add Reporter Antibody Incubate 1-hour Wash Add Tracer (Poly-HRP Streptavidin) Incubate 30-minutes Wash & Read Chemiluminescence [Total Assay Time = 2.5 Hours]

16 Efficacy and pmet Inhibition by Crizotinib in GTL16 Human Gastric Cancer Xenografts

17 Effect of Ischemia Time on Stability of Met and pmet in SNU5 Human Gastric Cancer Xenografts 0 min = Flash frozen 18G needle biopsy; 1-60 min = tumor quarters; N=5; Tumor either kept at room temperature or at 37 o C for indicated times and then flash frozen

18 Mechanism of Action of AZD1775 AZD1775 IC 50 = 5 nm in vitro Cell Cycle 12: , 2013

19 Phase I Trial of AZD1775 AZD1775 was administered orally BID for 2.5 days 21-day cycle; > 18 yrs; normal organ function 3+ 3 design; DLT cycle 1; progressive solid tumors

20 Patient Characteristics and Adverse Events Patient No. 18 Median Age (range) 54 (22-78) Male/Female 8/10 ECOG Performance Status Prior Rx (mean; range) 4 (1-7) Tumor Sites # of patients Sarcoma 10 NSCLC 2 H & N SCC 2 Other 4 Adverse Event Gr 2 Gr 3 Gr4 Leucopenia Neutropenia Lymphopenia Anemia 1 3 Thrombocytopenia 3 1 Febrile neutropenia Nausea 5 Vomiting 3 Abdominal pain 1 1 J. Clin. Oncol. 2015

21 Mean Plasma Concentrations of AZD1775 Following Multiple Dosing at 225 mg and 300 mg MK-1775 Plasma Concentration (nm) Time (hr) Day Time (Day) AM Pre-dose Mean ± SD (n=3, 300 mg MK-1775) Mean ± SD (n=17, 225 mg MK-1775) Time (hr) Day 3 15 patients received 225 mg BID dosing Plasma concentrations increased after each dose to an average Cmaxof 1650 nm after the 5 th dose; target 1000 nm Total AUC on day 3 was 2-3 X higher than on D1

22 Lung Adenocarcinoma: 53 Year Old Female (EGFR wt; ALK neg; biopsies of subcutaneous tumor nodule; multiple prior chemorx s) H & E ptyr15cdk gh2ax Post dose 5; (week one) Pre-dose

23 Leiomyosarcoma: 42 Year Old Female (Gluteal mass biopsies; multiple prior chemorx s) H & E ptyr15cdk gh2ax Post dose 5; (week one) Pre-dose

24 Confirmed PR: Metastatic SCC H& N with BRCA1 Germline Mutation Baseline After 2 cycles After 4 cycles

25 Combination AKT and MEK Inhibition AZD6244 * MK-2206 Feedback compensation for single agents Clearly enhanced efficacy for combination MEK-AKT inhibition in xenograft models Modest efficacy in standard dose-escalation phase I associated with increased toxicity: rash, retinal abnl s, LFT increase

26 NCI Protocol 8868 Pilot Study of MK-2206 (AKT Inhibitor) + AZD6244 (a MEK Inhibitor) in Patients with Advanced CRC Drug administration: Weekly AKTi (90 mg po) + Daily MEKi (75 mg po) Pre- and post-treatment analysis for: DNA based analysis pakt, perk and multiplexed phospho-proteins in the MAPK and PI3K pathways; new, sensitive Elisa s; sampling, tissue handling, and prestabilization of analytes > 70% inhibition of both phosphoproteins required for optimal efficacy of the combination Goals: Examine the degree and duration of target inhibition Perturbation of cross-talk/feedback loops Correlation with clinical outcome

27 Effect of Combined MEK/AKT Inhibition on Levels of p-erk and p-akt in Tumor % Inhibition of Phosphorylation Patient p-erk p-akt Course 1; Day1 Kras mutant Course 1; Day 1 Kras wild type Course 1; Day Accurate, sensitive PD markers needed to determine if dosing compromised

28 Match the Technology to the Task

29 Multiplex Pharmacodynamic Assay Development Concept Feasibility & Development Validation Launch Target Application Platform Exploratory/ Feasibility Development Analytical Validation Biopsy Assays Fit for Purpose Specimen SOPs Assay Transfer Clinical Readiness Support NCI Trials/QAP Transfer Community/ Licensing Certif Marking Apoptosis Panel Priority #1: Caspase 3, ciap1/2, gh2ax Priority #2: SMAC, Bcl-xl, Bcl- 2, BAD, BAX, FADD/pro- Caspase 8, DR4/DR5, XIAP, other IAPs, Mcl-1 Multiple IFA multiple x l l l l l l l l l Autophagy (LC3-II, Annexin V, Nuclear apobodies, ATG4β, Mitochondria) Multiple & Autoph. Inhibitors IFA multiple x l DNA Damage Repair Priority #1: NBS1, ERCC1, gh2ax) Priority #2: Chk1, BRCA, ATR Multiple IA multiple x l l l l l l l l l EMT/Stem Cell Proteins Weinberg/CPTC: FOXQ1, LBX1, SLUG, SNAIL, ZEB1, ZEB2, FOXC2, GSC, SOC9, CD133, FOX03, NANOG DCTD/SAIC: ALDH 1A1, OCT 3/4, NANOG, CD44v6 Stem Cell Inhibitors IFA multichannel l l l l Glycolysis Control Priority #1: GSK3, HK2, PFK1, PDK1, PKM2, LDH-A Priority #2: AXIN, βcatenin, PKA, LKB1, AMPK, PKCβ, AKT2, ULK1, GYS1, PDH-A1, PDP-1, BIM1 Multiple IA multiple x l l

30 Goal : Develop Multiplex IFA to Determine DNA Repair Response to Treatment Multiple multiplex IFA panels being developed, to be used in parallel on serial sections (FFPE). Each panel will be based on clinically relevant targets Ultimate goal: design method to determine the global DNA repair protein profile (activation, inactivation) of tissue biopsies in response to a variety of cytotoxic treatments Panel 3 Panel 2 Panel

31 Developing Multiplex Assays Require PD assays prior to clinical trials: Establish Proof-of-Mechanism Multiplex platforms - Evaluate multiple targets and downstream effectors - Build on successful γh2ax quantitative IFA - Focus on DNA damage/repair & apoptosis Define tissue handling, background levels, time course, calibrators High priority agents for NCI trials: ATRi; combinations from ALMANAC study; XIAP inhibitors DNA Damage/Repair Panel Apoptosis Panel

32 Multiplex Assays: Understanding Combination MOAs NCI ALMANAC: A Large Matrix of Anti-Neoplastic Agent Combinations

33 Multiplex Assays: Correlating Efficacy with MOA Bortezomib DNA Damage Panel Clofarabine Control Clofarabine+ Bortezomib HCT-116 Colon Xenograft

34 Pharmacodynamic Assay Development for Proof of Mechanism Early Phase Trials: A Resource Intensive Enterprise REQUIRES Develop FDA-quality assays for target status, downstream effects, and toxicity markers Relate drug effect markers to tumor effect and drug exposure in preclinical models of Phase 0/1 target lesions Develop procedures for biopsies of tumor and normal tissues using clinical instruments that provide samples available for biomarker assay development that mimic what is available in the clinic Formalize biopsy, specimen handling, and analytical assays as SOPs Implement PD assay SOPs in clinical arena of operations Conduct laboratory analysis of clinical specimens Laboratory QA/QC; prepare qualifying sample sets and analytes Initiate training program to disseminate technology and qualify extramural labs for testing

35 Improving the Impact of Early Clinical Trials Target Assessment Preliminary estimate accuracy of measurement of drug effect on target Downstream molecular interactions Early read on efficacy Understanding toxicity Supporting assays in model systems N=10-60 N= N= FDA Optimize Assay Target Development Qualify Assays Initial Proof of Mechanism Phase 0 Nature Rev. Cancer 7: , Target Validation Comparative benefit of target inhibition Association of MOA with efficacy Minimum data to define safety

36 Evolution of the Oncologic Drug Development Paradigm Develop estimates of response rates and characterize side effects in a non-randomized fashion For minimally pretreated patients with measurable disease after standard therapy In a specific tumor type With a drug (that has a nonspecific mechanism of action) Perform flexible evaluations of therapeutic activity and toxicity over a broad range of continuous endpoints For a wide variety of: acceptable subjects, prior treatments, extent and evaluability of disease and performance status In a wide range of genotypically, rather than histologically, specific diseases, under conditions that allow assessment of the biochemical effect of an intervention in tumor and normal tissue With one or more molecules that produce specific effects on defined targets (as well as possible off-target interactions) Using the minimum necessary data set to assure the safety and efficacy of a novel therapy

37 DCTD Division of Cancer Treatment and Diagnosis Accelerating Cancer Diagnosis and Drug Development Developmental Therapeutics Jerry Collins Joe Tomaszewski Melinda Hollingshead Ralph Parchment Robert Kinders Deb Wilsker Tom Pfister Myrtle Davis Bev Teicher Shivaani Kummar Center for Cancer Research Yves Pommier Lee Helman Bob Wiltrout William Bonner Peter Choyke DCTD Jason Cristofaro Barbara Mrochowski Michael Difilippantonio CTEP Jamie Zweibel Jeff Abrams Cancer Imaging Paula Jacobs Cancer Diagnosis Barbara Conley Mickey Williams