Re-Engineering Early Phase Cancer Drug Development: Decreasing the Time from Novel Target to Novel Therapeutic

16th Annual Drug Discovery Symposium Robert H. Lurie Comprehensive Cancer Center & Center for Molecular Innovation & Drug Discovery

Northwestern University Chicago, IL

October 12, 2011

Re-Engineering Early Phase Cancer Drug Development: Decreasing the Time from

Novel Target to Novel Therapeutic

James H. Doroshow, M.D. Deputy Director for Clinical & Translational Research

National Cancer Institute, NIH

Most Drugs Fail in Late Stages of Development: Particularly in Oncology

Rates of success for compounds entering first in man that progress to subsequent phase

Kola & Landis; Nature Reviews Drug Discovery 2004

• 70% of oncology drugs that enter Phase 2 fail to enter Phase 3

• 59% of oncology drugs that enter Phase 3 fail

• Late stage failure leads to enormous risk

• Failure is primarily due to lack of efficacy>toxicity

All indications

Standard Drug Development Pipeline: Re-envisioned

Clinical Candidate Development

Hypothesis Generation

Risk

Risk

Cumulative Investment

Preclinical Development Phase

I Phase

II Phase

III Regis- tration

Global Launch

Global Optimization

Commercialization

Lead Optimization

Target Validation

Assay Development

Lead Generation

Target/ Molecule Discovery

Time: 6-8 Years Time: 12-15 Years

GOAL:

$1200 MM

$500-600 MM

$200-300 MM

$20-60 MM

Drugs Assays Trials

Therapeutics Discovered / Developed by NCI from Preclinical Stage Approved by FDA Past Decade

Year Agents Role of NCI Mechanism of Support

2011

18F-NaFluoride (PET Bone Scans)

Produced agent; filed first-ever NDA from an NIH Institute: developed distribution system after NDA approved; bone scans absent 99Tc

DCTD Frederick personnel; extramural contracts; DCTD regulatory support

2010 Eribulin Natural product discovery; screening; clinical formulation; efficacy testing; clinical candidate selection; first-in-human trials by NCI

DCTD/DTP Frederick labs; analytical, formulation, PK, toxicology contracts; RO1 grant; U01 grant

2009 Pralatrexate RAID project; NCI produced GMP bulk drug DCTD contract resources for production of GMP quality bulk drug

2009 Romidepsin (Depsipeptide)

Developed safe human dosing schedule in large animals; PK and Tox; produced drug for clinical trials; conducted first-in-human trials in NIH CC

DCTD/DTP pharmacology and toxicology and drug production contracts; Frederick animal facilities

2004 Cetuximab Produced first lots for imaging; chimeric clones; NCI Drug Development Group Grantee

Frederick Biologics Contracts; Coop. Drug Discovery Grant

2004 5-Azacytidine Pre-clinical molecular pharmacology; produced pre-clinical and clinical drug supply; conducted pivotal trial

DTP Contracts; Frederick Labs; U01 Grants

2003

Bortezomib

Extensive analog screening; MOA and PD studies; PK & Tox; clinical formulation

DCTD/DTP Frederick labs; formulation, PK, Tox contracts

2000 Temozolomide Scale up synthesis and clinical formulation DCTD/DTP bulk drug and formulation contracts

NCI’s Approach to Discovering & Developing More Anticancer Drugs

•  Provide better discovery and development tools ü  Public availability of screening data from approved &

investigational agents ü  Targeted combinations—in vitro and in vivo

•  Facilitate academic discovery per se •  Provide structured resources to transition from

R01 target discovery to the clinic

US FDA Approved Anticancer Agents Activity in the NCI 60 panel: Potency in µM

Name NSC # Mean GI50 Mean TGI50 Mean LC50 Signaling agents Bortezomib 681239 0.00051 0.0063 3.6 Dasatinib 732517 0.33 8.9 51 Erlotinib 718781 5.5 59 >90 Everolimus 733504 0.095 14 56 Gefitinib 715055 3.2 19 49 Imatinib 743414 15 43 81 Lapatinib 745750 2.9 20 61 Nilotinib 747599 2.9 13 49 Sorafenib 747971 1.9 6.0 30 Sunitinib 750690 2.2 9.6 31 Temsirolimus 683864 0.038 51 >100 Romidepsin 630176 0.00025 0.0081 0.038 Vorinostat 701852 0.94 17 70

Molec. Cancer Ther. 9: 1451-1460, 2010

Plated Drug Sets: Dilution Series

http://dtp.cancer.gov/branches/dscb/oncology_drugset_explanation.html

8

The NCI Experimental Therapeutics (NExT) Pipeline:

Target discovery through early stage clinical trials

Exploratory Screen

Development

Screening/ Designed Synthesis

Lead Development

Candidate Seeking

Clinical Candidate

Phase 0 / I Trials

Early Phase II Trials

Drug Discovery Early Development

CB

C C

reat

ed

Transformation of the NCI Therapeutics Pipeline

Imaging/IDG RAID Intramural

Cancer Centers

SPORE

Roadmap

DDG

RO1/PO1 Biotech & Small Pharma

Created NCI Experimental Therapeutics Program (NExT): Unified Discovery & Development utilizing NCI Frederick

as a Critical Resource

Targets Therapeutics INCLUDES • Investigational drugs and biologics

• Investigational imaging agents and theranostics

• Academic & Biotech & Pharma projects

• Includes Phase 0, I and II Programs

A single pipeline for all therapeutic development resources: One Pipeline, Many Points of Entry

Where Did We Need to Go? Rapid translation of discoveries into public health benefits

NExT Program Coop Grps

Goals of the NExT Program

• Develop  treatments  for  unmet  medical  needs  (e.g,  rare  cancers  and  pediatric  tumors)    • Provide  resources  for  natural  product  development  and  the  development  of  high  risk  targets    • Move  discoveries  from  TCGA  into  drug  discovery    •   Support  development  of  biological  agents    • Develop  qualified  PD  and  predicEve  molecular  markers  for  the  clinic  

• Focus  on  discovery  and  development  projects  from  academic  invesEgators  and  small  biotechs    

11

NCI Chemical Biology Consortium (CBC)

•  Mission: Dramatically increase flow of early stage drug candidates into NCI therapeutics pipeline

•  Vision: •  Develop integrated network of chemists, biologists,

and molecular oncologists, with synthetic chemistry support ü  Active management by NCI and external

advisory boards ü  Unify discovery with NCI pre-clinical and

clinical development ü  Linked to other NCI initiatives; NCI Intramural

chemistry integral partner •  Focus on unmet needs in therapeutics: “undruggable”

targets, under-represented malignancies •  Enable a clear, robust pipeline all the way from target

discovery through clinical trials for academic, small biotech, and pharma investigators

FRONT END: NCI’s Experimental Therapeutics Platform

Biotech

Big Pharma

Market Risk

Dis

cove

ry R

isk

NCI

Chemical Biology Consortium Vision

•  Builds on >50 yrs of NCI experience in cancer drug development

•  Not intended to replicate Pharma •  CBC members will submit own

projects and take on those of other investigators

•  Focus on bringing academic targets and molecules to patients

•  Will not shy away from difficult targets

•  Longer time horizon •  NCI committed to supporting CBC

projects from inception through proof-of-concept, PD-driven clinical trials if milestones achieved: Only NCI could do this

•  Inclusive involvement of CBC members in shared projects developed in parallel across consortium

Why is CBC different?

NCI Chemical Biology Consortium (CBC)

Model Development and Target Validation

Target identification

Parallel medicinal chemistry

Optimal potency/

selectivity

Efficacy in pivotal in vivo

models Primary HTS

Small Animal Imaging Center

Multiple Entry Points into the NExT

Exploratory Screen Development

Screening/ Designed Synthesis

Lead Development Candidate Seeking

Clinical    Candidate  

Early Stage Pharmacodynamics

Later Stage Assay Validation

Therapeutics Discovery & Development Support Provided by NCI (NExT)

• Medicinal  chemistry,  HTS,  lead  op7miza7on  • Enhanced  synthesis  of  small  molecules  and  pep7des  • Scale-­‐up  produc7on  of  small  molecules,  biologicals,  &  imaging  agents  • Isola7on  and  purifica7on  of  naturally  occurring  substances  • Development  of  early  stage,  clinical  pharmacodynamic  assays  • Exploratory  toxicology  studies  and  pharmacokine7c  evalua7on  • PK/PD/efficacy/ADME  studies  (bioanaly7cal  method  development)  • Development  of  suitable  formula7ons  • Range-­‐finding  ini7al  toxicology  and  IND-­‐directed  toxicology  • Product  development  planning  and  advice  in  IND  prepara7on  • Later-­‐stage  preclinical  development  of  monoclonal  an7bodies,          recombinant  proteins,  and  gene  therapy  agents  • Manufacture  of  drug  supplies  • Analy7cal  methods  development  for  bulk  material;  formula7on  • CLIA-­‐grade  clinical  assay  development  for  later  trials  • Produc7on  of  clinical  dosage  forms  • Stability  tes7ng  of  clinical  dosage  forms  • Regulatory  support  and  early  phase  trials  

How Does An Extramural Investigator Access NCI’s Drug Discovery and

Development Resources?

NCI Experimental Therapeutics

Extramural scientists may propose targets, screens, or molecules for entry into the NExT pipeline; 3 receipt dates

per year https://dctd.cancer.gov/nextapp or

https://dctd.cancer.gov/nextregistration

NExT Application Process

NExT Pipeline: Oversight and Decision Support

Anticipate ~20-30 projects in the pipeline per year

Prioritization Process Used To Ascertain Which Compounds To Move Forward?

•  This selection is based on the following criteria. –  Scientific Merit –  Feasibility –  NCI Mission –  Novelty –  Clinical Need

•  A Stage Gate evaluation process to benchmark the progress and priority of projects within the portfolio

•  This evaluation process is also to provide guidance about the priority utilization of the capacity – based resources provided by NCI

Scoring:

1 = Exceptional

3 = Excellent

6 = Satisfactory

9 = Poor

265 NExT Applications Received in Cycles 1-8

Source of NExT Applications

LDHA: Therapeutic Target in Cancer

•  The proto-oncogene c-myc can drive glutamine as well as glucose metabolism. In cancer, c-myc deregulation can result in the added uptake of glucose and its conversion to lactate, thereby contributing to the “Warburg Effect”.

•  ChIP sequencing confirmed that Lactate Dehydrogenase A (LDHA), an enzyme that converts lactate to pyruvate, is a direct downstream target of Myc.

•  Knockdown of LDHA decreased colony formation and reduced the growth of tumors in breast and lung cancer xenografts.

•  Japanese families that completely lack LDHA are otherwise normal except for exertional myopathy.

•  FX11 is a selective, small molecule, active site LDHA inhibitor identified from a malarial LDH screen that provides proof-of-concept for targeting cancer metabolism in human lymphoma and pancreatic cancer models.

FX11 Treatment Leads to Regression of Tumors in Lymphoma and Pancreatic Xenograft Models

Pancreas

FX11

Lymphoma

NCGC: hit validation/med chemistry

Primary uHTS Co-crystallization with HTS “hits”

NIH Chemical Genomics Center Secondary biochemical

and cell-based screens Dang Lab

Screen development and high-throughput screening

Hit to Lead Lead Optimization Candidate Seeking

FX11 Lead Compound Ki 4 uM

LDHA : Next Steps

ü HTS screen to identify new scaffolds ü Co-crystallization with FX11 ü Optimize SAR for lead compound FX11, increase potency and improve solubility

Portfolio Stratified by Agent Class

Projects that are closed or awaiting resourcing are not included

Small  Molecule  57%  

Biologic  35%  

Natural  Product  5%  

Imaging  3%  

Interim Project Evaluation

§  Results Not Replicated §  Reproducible §  Not applicable

64%  

33%  

3%  

33%  

67%  

§  Results Not Replicated §  Did Not Meet Milestones

Bayer  Healthcare  In-House Target Validation

Nat.  Rev.  Drug  Discov.  10:  643-­‐644,  2011  

Projects  Closed  by  NExT  (Including  Legacy  Projects  from  RAID)  

ASSAYS: 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 –  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

Clin. Cancer Res. 14: 3658-3663, 2008

Developing the ‘Right’ Assay Tools

for Early Stage Proof of Mechanism Studies

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!

Cryobiopsy: Freeze

Excisional Biopsy Cryobiopsy: Excise

Standard 18 gauge Bx

pAKT Settings Min 20.0 Max 75.0 1 min exp.

phospho-AKT (Cell Signaling #9271)

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60 kDa

β-Actin Actin Settings

Min 20.0 Max 3000.0 30 sec exp.

Comparing Effect of Four Tumor Harvest Methods on phosphoAKT Levels

Separated on an 8% Tris-Gly Gel

Indenoisoquinolines

•  Unique, non-camptothecin Topo I inhibitors; chemically stable

•  Prolonged Topo I-Drug-DNA complex formation

•  Unique patterns of DNA cleavage •  Not substrates for ABCG2 efflux pump •  Produce dose- and time-dependent

DNA double strand cleavage demonstrable as phosphorylation of the H2AX histone

•  Low cross-resistance with camptothecin analogs (irinotecan; topotecan)

•  Discovered by Yves Pommier (NCI intra- mural program); developed by DCTD

•  FIH Randomized NCI Phase I trial of NSC 724998 vs 725776

Develop comprehensive PD package for proof of mechanism evaluation

PRIOR to first-in-human studies

Y

YY

Top1

HRPY

Y = MAH IgM MAb C21 (BD) capture AbY = RAH pAb Ab28432 (AbCam) primary AbY-HRP= GAR-HRP-XSA secondary Ab

(XSA =extra serum absorbed)

Y

YY

Top1

HRPYHRPY

Y = MAH IgM MAb C21 (BD) capture AbY = RAH pAb Ab28432 (AbCam) primary AbY-HRP= GAR-HRP-XSA secondary Ab

(XSA =extra serum absorbed)

R2 = 0.6915

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ELISAWB

A375 Melanoma

Correlation of Topo I mRNA (Array) to Protein (ELISA) in NCI 60 Cell Panel

Molec. Cancer Ther. 8: 1878-1884, 2009

Comparison of Topo I Protein by Western Blot to Protein (ELISA)

Effect of Topotecan on Topo I Activity in vitro (ELISA)

Topo I ELISA

Development of a Validated ELISA for Topo I Quantitation: Indenoisoquinoline First-in-Human Trial

Topoisomerase I Levels in Xenograft Extracts

AAXR2-18, YKR2-39, YPR2-2, AAYR2-17 Treated with Topotecan or Vehicle Control

+

Vehicle Controls Solid red line = Avg vehicle control

Dashed red line = Avg ± 1 and 2 SD Black line = Dose Response

NSC 724998 (mg/kg)

Topo

1 (

ng/m

l/µg

ptn)

Vehicle Control 4h Topotecan (15 MG/KG) treated

Effect of NSC 724998 on Topo I Levels in A375 Xenografts

Topoisomerase I Inhibition and Correlation with Efficacy In Vivo Using Topo I ELISA

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; qualify outside labs for testing, and

prepare qualifying sample sets and analytes to disseminate technology

N=30 N=300 N=3000

Phase I Phase II Phase III

Current Stages of Therapeutics Development: Trials

FDA

Match the Technology to the Task

N=10-60 N=200-300 N=600-800

Target Development Qualify Assays

Initial Proof of Mechanism “Phase 0”

Target Assessment Preliminary estimate accuracy of measurement

of drug effect on target Downstream molecular interactions

Early read on efficacy Understanding toxicity

Target Validation Comparative benefit of target inhibition

Association of MOA with efficacy Minimum data to define safety

Improving the Impact of Early Clinical Trials

FDA Supporting assays in model systems

OptimizeAssay

Target Inhibition as the Endpoint of a Phase II Trial: Proof of Concept Study of Oral Topotecan in Advanced

Solid Neoplasms Expressing HIF-1α

• Eligibility: HIF-1α +ve solid tumors of any histology (>10% of tumor cells by IHC)

• Treatment: Oral chronic topotecan (1.2 mg/m2 PO daily x 5 days x 2 wks q28 days)

• Primary endpoint: Inhibition of HIF-1α expression in tumor • Schema:

NCI-05-C-0186: Giovanni Melillo, MD PI

D1 D8 D29

Biopsy PET DCE-MRI

PET DCE-MRI

Biopsy PET DCE-MRI CT

D36

CT

Cycle 1 Cycle 2

PD endpoints: •  IHC (MVD, Glut-1) •  mRNA expression (HIF-1 target genes,

VEGF, PGK-1, CAIX) •  serum/plasma markers (VEGF, osteopontin) •  CEP (circulating endothelial precursor cells)

HIF-1α staining in patient #4 (breast cancer)

Baseline Biopsy After 2 Cycles of Topotecan

ü Accrual: 16 patients •  12 evaluable: 1 melanoma, 1 bladder, 1 breast, 2 ovarian ca., 1 SCLC,

1 bladder, 1 H/N, 4 CRC [PRs in SCLC, Ovarian cancer] •  4 not evaluable: 1 ASPS, 1 adrenal, 1 colon, 1 pancreas

ü Toxicities: myelosuppression, diarrhea (first 2 pts., at 1.6 mg/m2), well tolerated at 1.2 mg/m2

Pilot Study of Oral Topotecan in Advanced Solid Neoplasms Expressing HIF-1α

Clin. Cancer Res. 17: 5123-5131, 2011

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mRNA Expression of HIF-1α Downstream Targets After Topotecan

Clin. Cancer Res. 17: 5123-5131, 2011

•  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 non-

specific 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

Evolution of the Oncologic Drug Development Paradigm

1991 2011

Accelerating Cancer Diagnosis and Drug Development

DCTD Division of Cancer Treatment and Diagnosis

v  Developmental Therapeutics

Jerry Collins Joe Tomaszewski Melinda Hollingshead Ralph Parchment Robert Kinders Tom Pfister Myrtle Davis Bev Teicher Shivaani Kummar v  Center for Cancer

Research Yves Pommier Lee Helman Bob Wiltrout William Bonner

v  DCTD Jason Cristofaro Barbara Mrochowski v  CTEP Jamie Zweibel Jeff Abrams v  Cancer Imaging Paula Jacobs v  Cancer Diagnosis Barbara Conley Mickey Williams