Report from IUCC Associate Director for Clinical Research

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Report from IUCC Associate Director for Clinical
Research

• Presentation to External Advisory Committee
  Sept 25, 2006

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OUTLINE

• EDT Program Overview
• Memberships
• Publications
• Funding
• Accrual to EDT Therapeutic Trials
• Activities
• Responsibilities of Co-Leaders
• EDT Scientific Themes and Goals
• Themes and Goals
• Intra- and inter-programmatic interactions
• Highlights of interactions
• EDT Scientific Accomplishments
• Future Plans

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The Goals of the IUCC

• Vision
• To be a leading, national comprehensive cancer
  center based on our scientific investigation,
  health care delivery, and education.
• Mission
• IUCC seeks to reduce the burden of cancer through
  innovation and dissemination
• Goals
• 1. Foster excellence in interdisciplinary
  translational research through established and
  developing research programs.
• 2. Provide the highest quality patient care
  through interdisciplinary clinical programs.
• 3. Develop nationally recognized
  interdisciplinary graduate and post-graduate
  education and training programs.
• 4. Facilitate the development and implementation
  of a statewide cancer control program.

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The IUCCs Comprehensive Approach to the Cancer
Continuum
Diagnosis Treatment
Terminal Care
Early Detection
Prevention
Cancer Prevention and Control
Healthy Behaviors
Risk Factor Behaviors
Early Detection
Survivor- ship
End of Life Support
Follow-up
EDT - Breast Cancer H,M I
Optimizing Therapeutic Efficacy
Biomarker Identification
Minimizing Toxicity
Drug Discovery
Chemoprevention
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IUCC Organization Structure to Enhance Clinical
Trial Conduct for All Disciplines
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Clinical Research Committee

• Representatives from all disciplines
• ? Medical Oncology ? Pediatrics
• ? Behavioral ? Hoosier Oncology Group
• ? Surgery ? Vice Chancellor for Research
• ? Urology ? Clinical Pharmacology
• Radiation Oncology ? Radiology
  (incl.Interventional)
• Monthly Meeting (minutes provided)
• SRC Chair (Croop)
• CTMC and Minority Accrual (Clark, Selbe)
• CRO (Lee, Bridges, Abonour, Fallon)

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Clinical Research Committee- Chaired by AD for
Clinical Research

• Roles/Responsibilities1)   Facilitate and
  oversee conduct of clinical research for all
  disciplines represented in the IUCC
• 2)   Review recommendations of the SRC and CTMC
  and determine policy with input based from broad
  membership
• 3) Monitor and enhance Minority Accrual
• 4)   To promote multidisciplinary clinical and
  translational investigations among laboratory,
  clinical, and behavioral investigators 5)   To
  promote consistent protocol development and
  uniform reporting to track accrual, adverse
  events, and continuing review6)   To allocate
  Cancer Center resources
• - CCSG protocol specific research or other
  Cancer Center funds to investigator initiated
  pilot or Phase I studies based upon scientific
  merit and contribution to the mission of the
  Cancer Center
• - Clinical Research Office services

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Clinical Research and IUCC

• GOAL 1 Foster excellence in interdisciplinary
  translational research through established and
  developing research programs.
• Objective 1
• Recruit key investigators (basic and clinical)
  to develop comprehensive disease based research
  groups
• Objective 2
• Increase number and quality of investigator
  initiated trials with a focus on R21 Quick Trials
• Objective 3
• Make protocol development and review process
  more efficient for all cancer-related disciplines

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Foster excellence in interdisciplinary
translational research

• Recent key clinical recruits to enhance clinical
  trial accrual
• Brian Schneider, MD Breast Cancer, Clin Pharm
• Gabi Chiorean, MD GI and Phase 1
• Sherif Farag, MBBS, PhD BMT Director
• Noah Hahn, MD - GU
• Daniela Matei, MD Ovarian Cancer
• John Turchi, PhD Lung Cancer translational
  research

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• Fostering excellence in interdisciplinary
  translational research with initiatives to
• 1) maximize the quality of investigator
  initiated trials
• 2) streamline protocol development process for
  investigators

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Process for IUCC Support of Investigator
Initiated Trials
Clinical Trials as Part of Indiana University
Cancer Center Translational Initiative (ITRAC)
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Clinical Trials as Part of ITRAC
Clinical
Candidate
Product
Preclinical Discovery
Development
Launch
Preclinical Discovery
Target ID
-
Target ID
-
Assay Development,
Candidate
Lead
High Impact Clinical Trials
Target/Disease
Target/Disease
Selection
Optimization
Validation
Validation
Target ID
Drug Discovery, In Vitro Data
In Vivo Data
Clinical
Trials
Continuous PSR RFA on website, advertised in IUCC
newsletter (monthly deadline, 3 pages limit,
overview of concept)
IUCC Investigator Initiated Concept Assessment
Panel (subcommittee of CRC)
Protocol specific research
Non PSR IIT

• Access to support for writing protocol and grant
  application
• data-base development, CRS, RN, biostats,
  protocol development
• Clinical core usage (imaging, PG, proteomics,
  genomics, PK)
• Protocol Development Approved

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Clinical Trials as Part of ITRAC
Clinical
Candidate
Product
Preclinical Discovery
Development
Launch
Preclinical Discovery
Target ID
-
Target ID
-
Assay Development,
Candidate
Lead
High Impact Clinical Trials
Target/Disease
Target/Disease
Selection
Optimization
Validation
Validation
Target ID
Drug Discovery, In Vitro Data
In Vivo Data
Clinical
Trials

• Submission of protocol to SRC
• Scored (science, potential for NCI funding, phase
  2)
• Budget for complete protocol developed

Notification to investigator of amount of support
from IUCC
Activation of trial

• Progress report of start-up portion
• Overview of science (conduct of trial, data)
• Progress to extramural funding (R21 working group
  participation, submission)

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PSR Requirements

• A.      Nursing and CRS support to conduct and
  complete innovative or proof-of-principle
  clinical trials originating from IUCC
• B.      Early phase testing of candidate drug or
  device to prevent, treat, diagnose or detect
• C.      Short duration (less than one year)
• D.      Basis for future grant support or lead to
  phase II or III
• E.      Document oversight of budget by leadership

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Resources Available to Facilitate Investigator
Initiated Clinical Trials

• Oncore
• Development of electronic case report forms
• Tracking accrual, SAEs, communication with IRB,
  SRC, ePRMS
• Illumina translational genomics facility
• RNA profiling from paraffin embedded tissue (far
  less cumbersome than frozen samples)
• Research Related Imaging
• dceMRI, novel PET tracers
• Clinical Pharmacology and Pharmacogenetics
• HPLC-MS/MS, DNA extraction and analysis
• Proteomic Facilities
• MALDI/TOF, SELDI, Glycoproteomics (IU-B),
  Metabolomics (PU)

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Increasing Number of R21 Quick Trials

• R21 Quick Trials Working Group
• NCI funding opportunity to cover cost of
  translational clinical trials
• Implemented August 2006
• In conjunction with PSR mechanism
• Core group of investigators meet to put grant
  together
• Templates for required sections
• Peer review

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Clinical Research and IUCC

• GOAL 2 Provide the highest quality patient care
  through interdisciplinary clinical programs.
• Objective 1
• Mapping project to maximize the clinical trial
  activity for the disease spectrum for all
  diseases
• Objective 2
• Develop a disease and discipline based advocate
  program to facilitate communication across the
  IUCC
• Objective 3
• Disseminate clinical trial activity and quality
  patient care to the community by integration of
  clinical programs with the Hoosier Oncology Group

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Mapping Clinical Research at IUCC

• Purpose
• Collate all clinical research in a uniform web
  accessible format to document research efforts
  along the continuum of the cancer process
• Recognize the importance of all clinical research
  from prevention to palliation
• Identify strengths and weaknesses
• Identify opportunities for collaborations
• Format to map out comprehensive programs from the
  lab to the clinic

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IUCC Prostate Cancer Program
Prevention
Supportive / Correlative
Localized
Metastatic
Biochemical
Measurable
Tx Naïve
Local Relapse
Low Risk
Int. Risk
High Risk
HSPC
AIPC
HSPC
AIPC
E3805 ADT /- Doc (Dr. Sweeney)
0102-35 HIFU (Dr. Koch)
RTOG 0521 XRT ADT /- Doc (Dr. McGarry)
RTOG 0126 70 v 79 Gy (Dr. McGarry)
No Trials
CALGB 90401 Doc /- Bev (Dr. Sweeney)
AMG 20040138 AMG162 (Dr. Sweeney)
Astra-Zeneca KC ZD6474 (Dr. Hahn)
0052 Strength Traiining (Dr. Damush)
No Trials
SWOG 9921 ADT /- MP (Dr. Sweeney)
E9802 Prostvac-V/F GMCSF (Dr. Hahn)
CALGB 90202 ADT /- Zom (Dr. Sweeney)
D9902 Provenge (Dr. Gardner)
0121 Functional CT (Dr. Akisik)
HOG 03-67 Pemtxd 2nd line (Dr. Sweeney)
0165 PC-GRACE (Dr. Hahn)
RTOG 0518 XRT ADT /- Zometa (Dr. McGarry)
0501-03B AA PC Screening (Dr. Sweeney)
ME-CLN-006 Panzem 2nd line (Dr. Hahn)
In Development
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Disease and Discipline Based Clinical Research
Advocates

• Process to Map All Research
• Co-ordinate SRC submission process
• Disease-based advocate
• GI Hematology
• GU Pediatrics
• Breast Thoracic
• Discipline-based advocates
• Radiation Oncology
• Radiology
• Behavioral
• Gastroenterology

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Mapping Clinical Research at IUCC

• Roles and Responsibilities of Advocates
• Sign off on all SRC submissions and provide
  annual progress report on accrual to studies and
  accomplishments in prior year
• Ensure trials that cross disciplines trials have
  been reviewed by all relevant disciplines prior
  to submission and that a letter of support is
  provided by all relevant parties
• eg behavioral survivorship study in colorectal
  cancer will require support letter from
  colorectal and behavioral research advocates
  respectively
• eg a study requiring chemotherapy with a
  surgical intervention will require a surgeon and
  medical oncology sign-off.
• Update the appropriate disease based mapping

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Clinical Research and IUCC

• GOAL 2 Provide the highest quality patient care
  through interdisciplinary clinical programs.
• Objective 1
• Mapping project to maximize the clinical trial
  activity for the disease spectrum for all
  diseases
• Objective 2
• Develop a disease and discipline based advocate
  program to facilitate communication across the
  IUCC
• Objective 3
• Disseminate clinical trial activity and quality
  patient care to the community by integration of
  clinical programs with the Hoosier Oncology Group

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Dissemination of clinical trials into the
community

• Hoosier Oncology Group
• 12 staff to help write and conduct clinical
  trials
• Chairman Christopher Sweeney, MBBS
• Chief Medical Officer Lawrence Einhorn, MD
• Conduct trials in community 30 sites accrue
• Centralized IRB established
• gt 200 patients per year on trial
• All investigator initiated 10 open at anyone
  time 2.5M per year in Investigator Initiated or
  Federal Support
• HOG publications
• Since 1983 101 manuscripts and 44 ASCO
  abstracts
• 1/04 - 9/06 10 manuscripts and 13 ASCO
  abstracts

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Hoosier Oncology Group

• Lung Cancer
• Randomized phase III trial led by Hanna and
  Einhorn
• A Phase III Trial of Cisplatin/Etoposide/Radiother
  apy With or Without Consolidation Docetaxel in
  Patients with Inoperable Locally Advanced Stage
  III Non-Small Cell Lung Cancer (NSCLC) Hoosier
  Oncology Group LUN01-24
• The interim efficacy findings of the formal DSMB
  indicate that there is a very small probability
  that this study will ever establish a significant
  difference favoring either of the two arms.
• Implications for the management of NSCLC

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Hoosier Oncology Group

• Integration of Emerging Technologies
• Clinical specimen collection for Sledge 10M DOD
  Center of Excellence grant to study proteomics
  and pharmacogenetics as predictor of response
• Clinical specimen collection and management of
  NCI sponsored CPTAC grant (validate different
  proteomic platforms)
• 7M grant in collaboration with Purdue Cancer
  Center

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Glycoproteins as biomarkers of response in HOG
Study - Serum of Prostate Cancer Patients
Baseline
24 weeks Treatment
Peak Area
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Glycan Number
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Major Accomplishments

• Clinical Trial Accrual
• HOG
• gt 200 patients per year accrued
• IUCC Investigator Initiated Trials
• Summary 3 16 (470 of 3010 patients)
• Does not include compassionate use, roll-overs,
  reviewed to not incude correlative studies
• Expanding Phase I Clinical Trial Activity
• 11 First into Human Phase 1 trial (Jan 04 to
  Sept 06)
• gt 100 patients accrued to phase 1 trials
• Leadership in ECOG
• Sledge Chairman Breast Committee
• Miller PI of two randomized phase III breast
  cancer trials
• Sweeney PI of randomized phase III prostate
  cancer trial
• Hanna PI of phase II mesothelioma trial

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Major Accomplishments

• Pediatric Trial Accrual
• Year Analytical Cases Accrued
• 2004 148 84 (57)
• 2005 161 66 (41)
• Riley Top five of all 260 COG centers
• Therapeutic accrual
• 275,000 NCI support annually

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Major AccomplishmentsBiomarker Development and
Cancer Prevention
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csPCNA Antibody in IHC Detects Cancer Cells
Specifically in Tissue
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Prevention

• Cancer prevention and Control
• Tailored efforts to improve colorectal cancer,
  breast cancer screening
• Tailored efforts for increasing smoking cessation
  
• Tailored efforts to minimize viral mediated
  cancers by modifying risky behaviors

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AccomplishmentsNew Drug Discovery and
Development-Implementation of ITRAC
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Validation of c-kit as a target for
Neurofibromatosis (HMI)
Before After 3 months imatinib
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Other New Drugs

• HMI
• JNK Inhibition in AML (Boswell, Cripe)
• First in human
• AML1-FOG and GATA1 in MDS (Chan, Cripe)
• Phase 2 HOG study
• Novel techniques for stem cell mobilization to
  enhance transplantation (Broxmeyer)

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Other New Drugs

• EDT
• Parthenolide Analogues
• RAID supported projected
• Completed preclinical toxicology
• APE Inhibitors
• Collaboration with Purdue University
• ABCG2 Inhibitors

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Breast Cancer Development of bevacizumab plus
paclitaxel as a therapy for breast cancer from
bench validation to leading randomized phase 3
trial
E2100 Bevacizumab paclitaxel prolongs DFS
versus paclitaxel alone
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AccomplishmentsTailoring therapy and improving
cancer care and quality of life
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• Pharmacogenetics to tailor therapy
• CYP2D6 in tamoxifen
• (JNCI, 2005)
• ABCG2 and hormone refractory prostate cancer
• (Clin Canc Res 2006)
• Erlotinib and CYP3A4, ABCG2
• ASCO 2006
• Etoposide in TCC, Vinorelbine in Br Ca and
  Vincristine in Peds

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Poor metabolizers of tamoxifen have a worse
breast cancer survival (based on CYP2D6)
n115
EM
2-year RFS EM 98 IM 92 PM 68 Log Rank P0.009

n40
IM
PM
n16
Years after randomization
Breast cancer recurrence or death
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Possible Role of ABCG2 in HRPC
Basis for correlative studies in NCI Sponsored
Phase 3 Prostate Cancer Trials