investigator training program march 9, 2010 - research

SUNY Upstate Medical University

Investigator Training ProgramInvestigator Training ProgramMarch 9, 2010March 9, 2010

Can I do this study? Considerations for Can I do this study? Considerations for Conducting Studies at UpstateConducting Studies at Upstate


Why are we at Upstate?Why are we at Upstate?Goals of an Academic Medical Goals of an Academic Medical

CenterCenterPatient CarePatient Care–– Tertiary careTertiary care–– Care for patients without concern for Care for patients without concern for

insuranceinsuranceTeachingTeaching–– Stimulating environmentStimulating environment

ResearchResearch–– Basic research versus clinical researchBasic research versus clinical research


Clinical ResearchClinical Research

Can we further the field and contribute Can we further the field and contribute to to generalizablegeneralizable knowledge (research)?knowledge (research)?Can we contribute to the practice of Can we contribute to the practice of evidenceevidence--based medicine?based medicine?


YES!!YES!!


J National Cancer InstituteJ National Cancer Institute1996;88:12101996;88:1210--12151215


J Clinical OncologyJ Clinical Oncology2005;23:1902005;23:190--196196


What are the Strengths of Upstate What are the Strengths of Upstate Medical University?Medical University?

Only medical school in a large geographic Only medical school in a large geographic areaareaActive clinical staff (excellent Active clinical staff (excellent clinicians/teachers)clinicians/teachers)Multidisciplinary capabilitiesMultidisciplinary capabilities–– Examples: Examples: JoslinJoslin Diabetes Center, Thoracic Diabetes Center, Thoracic

Oncology ProgramOncology ProgramExcellent DepartmentsExcellent Departments


What are our Weaknesses?What are our Weaknesses?

We are a smaller universityWe are a smaller universityClinicians are very busyClinicians are very busy–– Lack of protected time to conduct researchLack of protected time to conduct research–– Emphasis on Emphasis on ““productivityproductivity””–– Lack of mentorsLack of mentors

Difficult to balance the basic versus the Difficult to balance the basic versus the clinical missionsclinical missionsBudget constraintsBudget constraints


Where to Start?Where to Start?Institutional ResourcesInstitutional Resources

Clinical Trials Office (CTO)Clinical Trials Office (CTO)Contracts (Research Foundation)Contracts (Research Foundation)Institutional Review Board (IRB)Institutional Review Board (IRB)Quality Assurance and Improvement Quality Assurance and Improvement Program (QAIP)Program (QAIP)PharmacyPharmacyClinical Research Associates (Clinical Research Associates (CRAsCRAs))


Where to Start?Where to Start?Ingredients for Clinical ResearchIngredients for Clinical Research

TimeTime–– Set goals and be protective of that protected timeSet goals and be protective of that protected time

MentorsMentors–– Where to start?Where to start?–– Use that experienceUse that experience–– Get trainees involved (Fellows, students)Get trainees involved (Fellows, students)

Clinical Research AssociatesClinical Research Associates–– Key expertiseKey expertise


Where to Start?Where to Start?Ingredients for Clinical ResearchIngredients for Clinical Research

Do I have the patients?Do I have the patients?Is it an important question?Is it an important question?Do I have the time?Do I have the time?Is the budget adequate?Is the budget adequate?Are my colleagues on board?Are my colleagues on board?Do I have the support necessary?Do I have the support necessary?


CLINICAL RESEARCH CLINICAL RESEARCH ASSOCIATES (CRA)ASSOCIATES (CRA)

IRB submissions, RegulatoryIRB submissions, RegulatoryAssist in placing patients onAssist in placing patients on--study study -- assure assure eligibility requirements, preeligibility requirements, pre--study testingstudy testingMaintain protocolsMaintain protocols--availability, accurate, availability, accurate, updatesupdatesAbstract information from charts to flow Abstract information from charts to flow sheets, send data to data management centersheets, send data to data management centerCommunicate with affiliatesCommunicate with affiliatesPrepare for audits, Administrative functionsPrepare for audits, Administrative functions


TYPES OF CLINICAL TYPES OF CLINICAL TRIALSTRIALS

Cooperative Group Studies (CALGB, SWOG, Cooperative Group Studies (CALGB, SWOG, ECOG, COG, GOG)ECOG, COG, GOG)Drug company studiesDrug company studies-- investigator or investigator or company initiatedcompany initiatedInIn--house studies house studies -- investigator initiated or investigator initiated or consortiums of institutionsconsortiums of institutionsPromising institutional studies can lead to Promising institutional studies can lead to cooperative group studies (pilot studies)cooperative group studies (pilot studies)Rare diseasesRare diseases


What is the right mix of studies?What is the right mix of studies?

NIH/NCI sponsored trialsNIH/NCI sponsored trials–– Tend to ask paradigm questions, that define Tend to ask paradigm questions, that define

standard of carestandard of care–– DonDon’’t pay as wellt pay as well

Pharmaceutical TrialsPharmaceutical Trials–– Goal may be to position a drug or device for marketGoal may be to position a drug or device for market–– Many excellent studies available, but be criticalMany excellent studies available, but be critical–– Meet with Scientific LiaisonsMeet with Scientific Liaisons–– May pay more, butMay pay more, but……..


CANCER AND LEUKEMIA CANCER AND LEUKEMIA GROUP B (CALGB)GROUP B (CALGB)

one of three adult oncology one of three adult oncology multidisciplinary cooperative treatment multidisciplinary cooperative treatment groups funded by the National Cancer groups funded by the National Cancer InstituteInstituteothers are Southwest Oncology Group others are Southwest Oncology Group (SWOG) and Eastern Cooperative (SWOG) and Eastern Cooperative Oncology Group (ECOG)Oncology Group (ECOG)


CALGB ORGANIZATIONCALGB ORGANIZATION

Central Office of the ChairmanCentral Office of the Chairman--University of Chicago, Dr. Richard University of Chicago, Dr. Richard Schilsky, ChairmanSchilsky, ChairmanStatistical CenterStatistical Center--Duke UniversityDuke UniversityData Management CenterData Management Center--Duke Duke UniversityUniversityFortyForty--six Institutions and Their Affiliates six Institutions and Their Affiliates (>200)(>200)SUNYSUNY--Upstate Medical UniversityUpstate Medical University


CALGB COMMITTEESCALGB COMMITTEES

GIGIGUGUBREASTBREASTMELANOMAMELANOMA

LEUKEMIALEUKEMIALYMPHOMALYMPHOMARESPIRATORYRESPIRATORY


CALGB MODALITY CALGB MODALITY COMMITTEESCOMMITTEES

Cancer ControlCancer ControlCorrelative SciencesCorrelative Sciences--Leuk/Lymphoma Leuk/Lymphoma and Solid Tumorand Solid TumorData ManagementData ManagementOncology NursingOncology NursingPathologyPathology

Pharmacy and Pharmacy and Experimental Experimental Therapeutics (PET)Therapeutics (PET)PsychoPsycho--OncologyOncologyRadiation OncologyRadiation OncologySurgerySurgeryTransplantTransplant


MAIN MEMBER: SUNY MAIN MEMBER: SUNY UPSTATE MEDICAL UPSTATE MEDICAL

UNIVERSITYUNIVERSITYCoordinating CenterCoordinating CenterData ManagementData ManagementIRB IssuesIRB IssuesQuality AssuranceQuality AssuranceNetworkNetwork--Affiliates (Affiliates (FaxtonFaxton, VA), VA)PI PI -- Dr. Arlan Gottlieb (1976Dr. Arlan Gottlieb (1976--1989), 1989), David Duggan (1989David Duggan (1989--1994), Stephen 1994), Stephen Graziano (1994Graziano (1994--present)present)


INSTITUTIONAL GOALSINSTITUTIONAL GOALS

Maintain High Maintain High Accrual Rate Accrual Rate (>100 Patients Per (>100 Patients Per Year)Year)Timely Timely Submission Of Submission Of Accurate, High Accurate, High Quality DataQuality Data

Contribute To Contribute To Group Science Group Science And LeadershipAnd LeadershipIncrease Increase Participation By Participation By SurgeonsSurgeons--become become Truly MultiTruly Multi--disciplinarydisciplinary


HOW ARE WE FUNDED?HOW ARE WE FUNDED?

Infrastructure Support from CALGB for Lead CRA, Infrastructure Support from CALGB for Lead CRA, PI Salary Support and travelPI Salary Support and travelPer case accrual ($2,000/treatment accrual)Per case accrual ($2,000/treatment accrual)–– pays for data management (CRA salaries)pays for data management (CRA salaries)–– Office (Mailing, Computer Support)Office (Mailing, Computer Support)

CALGB Foundation (Pharmaceutical Funds)CALGB Foundation (Pharmaceutical Funds)CCOP Program (Community Clinical Oncology CCOP Program (Community Clinical Oncology Program)Program)VA/NCI Initiative, CTSUVA/NCI Initiative, CTSU–– $2,000 per patient placed on a treatment trial$2,000 per patient placed on a treatment trial


WHAT IS A CANCER WHAT IS A CANCER CLINICAL TRIAL?CLINICAL TRIAL?

a study conducted with cancer patients, a study conducted with cancer patients, usually to evaluate a new treatmentusually to evaluate a new treatmenteach study is designed to answer a each study is designed to answer a scientific question scientific question


WHY ARE CLINICAL WHY ARE CLINICAL TRIALS IMPORTANT?TRIALS IMPORTANT?

help us to steadily improve treatment, help us to steadily improve treatment, discard ineffective treatmentdiscard ineffective treatmentfind less toxic treatmentsfind less toxic treatmentsnew treatments must prove to be safe and new treatments must prove to be safe and effective before they become widely effective before they become widely availableavailabletodaytoday’’s standard treatment were s standard treatment were research studies in the pastresearch studies in the past


WHY WOULD A PATIENT WHY WOULD A PATIENT BE INTERESTED IN A BE INTERESTED IN A

CLINICAL TRIAL?CLINICAL TRIAL?hope for best treatment for themselveshope for best treatment for themselveshope for a longer time to live, a cure, a hope for a longer time to live, a cure, a way to feel betterway to feel bettercontribute to research that may help contribute to research that may help othersothersparticipating patients may be among the participating patients may be among the first to receive a new therapy before it is first to receive a new therapy before it is widely availablewidely available


TYPES OF CLINICALTYPES OF CLINICALTRIALSTRIALS

PHASE IPHASE IPHASE IIPHASE IIPHASE IIIPHASE III


PHASE I TRIALPHASE I TRIALGOALSGOALS

to determine the relation between toxicity to determine the relation between toxicity and doseand dose--schedule of treatmentschedule of treatmentto determine the maximumto determine the maximum--tolerated tolerated dose of therapydose of therapyto define toxicity is the primary objective, to define toxicity is the primary objective, efficacy is of secondary importanceefficacy is of secondary importancesmall cohorts, escalating doses of drugs to small cohorts, escalating doses of drugs to define dosedefine dose--limiting toxicity limiting toxicity


PHASE II STUDYPHASE II STUDYGOALSGOALS

identify tumor types for which the identify tumor types for which the treatment appears promisingtreatment appears promisingto define effectivenessto define effectivenessoften done in 2 stagesoften done in 2 stagesusually 35usually 35--40 patients to define response 40 patients to define response raterate


PHASE III STUDYPHASE III STUDYGOALSGOALS

to determine the effects of a treatment to determine the effects of a treatment relative to the natural history of the relative to the natural history of the diseasediseaseto determine whether a new treatment is to determine whether a new treatment is more effective than a standard therapymore effective than a standard therapyto determine whether a new treatment is to determine whether a new treatment is as effective as a standard therapy but is as effective as a standard therapy but is associated with less morbidityassociated with less morbiditylarge numbers of patients requiredlarge numbers of patients required


CALGB GOALSCALGB GOALS

MultiMulti--institutional cooperative research institutional cooperative research group dedicated to the systematic group dedicated to the systematic planning, conduct, analysis, and planning, conduct, analysis, and reporting of research as applied to the reporting of research as applied to the therapy of patients with malignancytherapy of patients with malignancyTranslate the most recent advances and Translate the most recent advances and therapies to large groups of patients in therapies to large groups of patients in Central New YorkCentral New York


Selected Landmark StudiesSelected Landmark Studies

Dose and dose intensity of adjuvant Dose and dose intensity of adjuvant chemotherapy for stage II, nodechemotherapy for stage II, node--positive breast positive breast cancercancerIntensive post remission chemotherapy in Intensive post remission chemotherapy in adults with acute myeloid leukemiaadults with acute myeloid leukemiaSequential Chemotherapy followed by Sequential Chemotherapy followed by Radiotherapy for unresectable stage III nonRadiotherapy for unresectable stage III non--small cell lung cancersmall cell lung cancerRole of cytogenetics in predicting outcome in Role of cytogenetics in predicting outcome in acute myelogenous leukemiaacute myelogenous leukemia


Problems and ChallengesProblems and ChallengesOnly 2Only 2--3% of adult cancer patients are enrolled 3% of adult cancer patients are enrolled on Clinical Trialson Clinical TrialsFunding Funding -- NCI versus PharmaceuticalNCI versus PharmaceuticalInsurance Coverage Insurance Coverage –– Medicare, VAMedicare, VA–– Costs of Clinical Trials versus standard careCosts of Clinical Trials versus standard care

Pressures on Institutional Review BoardsPressures on Institutional Review Boards–– Duke, Johns HopkinsDuke, Johns Hopkins

Pressure on Academic PhysiciansPressure on Academic PhysiciansNew Privacy LawsNew Privacy Laws


ASCO Presidential SymposiumASCO Presidential Symposium20002000

Despite significant barriers, more that 80% of Despite significant barriers, more that 80% of oncologists participate in clinical trials!!oncologists participate in clinical trials!!Large reservoir of + feelings toward Large reservoir of + feelings toward cooperative group trialscooperative group trialsCost factors direct increased participation in Cost factors direct increased participation in industry supported trialsindustry supported trialsInsurers and Medicare pay for the clinical care Insurers and Medicare pay for the clinical care costs of clinical trialscosts of clinical trialsClinical research is a Clinical research is a ““labor of lovelabor of love””


Clinical Trials and the Public Clinical Trials and the Public TrustTrust

Virtually all of the advances in cancer Virtually all of the advances in cancer therapy during the last 40therapy during the last 40--50 years have 50 years have come from the randomized clinical trialcome from the randomized clinical trialMost have been conducted by US Cancer Most have been conducted by US Cancer Cooperative GroupsCooperative GroupsFDA requires evidence from wellFDA requires evidence from well--conducted clinical trials for licensing of conducted clinical trials for licensing of new agents new agents


CLINICAL RESEARCH IS CLINICAL RESEARCH IS GOOD CLINICAL CAREGOOD CLINICAL CARE


Treatment of NonTreatment of Non--small Cell small Cell Lung CancerLung Cancer

Stage Treatment of Choice I Surgery II Surgery IIIA Surgery for T3 lesions

Surgery/RT + chemotherapy IIIB RT + chemotherapy IV Palliative chemotherapy, RT or

supportive care

SUNY Upstate Medical UniversityWinton T et al. N Engl J Med 2005;352:2589-2597

Kaplan-Meier Estimates of Survival among Patients Who Received Adjuvant Vinorelbine plus Cisplatin and Those Who Underwent Observation Alone


J Clinical OncologyJ Clinical Oncology2008;26:50432008;26:5043--50515051


CALGB 9633CALGB 9633RCT OF ADJUVANT CHEMOTHERAPY IN STAGE IB NSCLCRCT OF ADJUVANT CHEMOTHERAPY IN STAGE IB NSCLC

T2N0MOstage IB NSCLC

COMPLETESURGICAL RESECTION

ADJUVANT CHEMOTHERAPY

Paclitaxel, 200 mg/m2

Carboplatin, AUC=6 mg/ml x min4 cycles over 12 weeks

OBSERVATIONrandomization within 4-8 wks of resection

STRATIFIEDsquamous vs. otherpoorly differentiated vs. othermediastinoscopy: yes vs. no


Survival: Patients with Tumor Survival: Patients with Tumor ≥≥ 4.0 cm4.0 cm

0 2 4 6 8

S u rviva l T im e (Y e a rs )

0.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty

O b se rva tio nC h e m o

0 1 2 3 4 5 6 7 8 90 1 2 3 4 5 6 7 8 9

HR=0.66; 90% CI: 0.45-0.97; p=0.04

N=97

N=99



Palliative chemotherapy, RT or Palliative chemotherapy, RT or supportive caresupportive care

Stage IVStage IVRT +/RT +/-- chemotherapychemotherapyStage IIIBStage IIIB

Surgery for T3 lesionsSurgery for T3 lesions + Chemo+ ChemoRT/Surgery + chemotherapyRT/Surgery + chemotherapy

Stage IIIAStage IIIASurgery Surgery + Chemotherapy+ ChemotherapyStage II Stage II Surgery Surgery + Chemotherapy+ ChemotherapyStage IBStage IBSurgerySurgeryStage IAStage IATreatment of ChoiceTreatment of ChoiceStageStage


Can We Ask Paradigm Questions?Can We Ask Paradigm Questions?

Examples in Lung Cancer:Examples in Lung Cancer:–– CALGB 8433CALGB 8433–– CALGB 9663CALGB 9663–– CALGB 9795 (JBR.10)CALGB 9795 (JBR.10)–– CALGB 9730CALGB 9730–– Interest TrialInterest Trial–– ATLAS TrialATLAS Trial–– DocetaxelDocetaxel vsvs PemetrexedPemetrexed


Potential Therapeutic Targets

1. Growth factors and growth-factor receptors (eg, EGFR

family, VEGF-R)

2. Signal transduction pathways (eg, RAS, raf, MAPK, MEK, ERK, PI3K,

protein kinase C)

4. Proteasome

5. Cell survival pathways (eg, mTOR, cyclin-dependent kinases, p53, Bcl-2)

6. Extracellular matrix / Angiogenic pathways

(eg, MMP, VEGF, integrins)

1

2

3

4

56

Adapted from Ullrich. Oncology. 2002;63(Suppl 1):1-5.

3. Vaccine Tumor-associated antigens or

markers (eg, gangliosides)


Current Clinical Trials for Current Clinical Trials for NSCLCNSCLC

Stage IAStage IA--B (Surgical) CALGB 30506: Phase III trial of CT B (Surgical) CALGB 30506: Phase III trial of CT vsvs ObsObs for for early stage NSCLCearly stage NSCLCStage IBStage IB--IIIA IIIA –– E1505: CT +/E1505: CT +/-- bevacizumabbevacizumabStage IIIA/IIIB Stage IIIA/IIIB unresectableunresectable–– RTOG 0617: CT/RT +/RTOG 0617: CT/RT +/-- cetuximabcetuximab to 6000 to 6000 cGycGy vsvs 7400 7400 cGycGy–– CALGB 30605: PS 2 or PS 0CALGB 30605: PS 2 or PS 0--1 with 1 with >>10% weight loss, CT 10% weight loss, CT RT + RT +

cetuximabcetuximabStage IV Stage IV –– CALGB 30607: maintenance CALGB 30607: maintenance sunitinibsunitinib/placebo p 4 cycles of CT/placebo p 4 cycles of CT–– BoehringerBoehringer--IngelheimIngelheim, For EGFR Mutation +: BI2292 , For EGFR Mutation +: BI2292 vsvs

chemotherapy chemotherapy –– 22ndnd lineline-- CALGB 30704: CALGB 30704: pemetrexedpemetrexed vsvs sunitinibsunitinib vsvs bothboth–– 22ndnd lineline--Pfizer trial of PF for ALK+ patientsPfizer trial of PF for ALK+ patients–– Merck: Phase III study of Merck: Phase III study of docetaxeldocetaxel +/+/-- ASA404 for secondASA404 for second--line line

treatment of NSCLCtreatment of NSCLC”” ((GajraGajra))


Clinical Trials for SCLCClinical Trials for SCLC

Limited Stage SCLCLimited Stage SCLC–– CALGB 30610: Intergroup trial of 3 radiation CALGB 30610: Intergroup trial of 3 radiation

therapy schedules (Dr. Bogart)therapy schedules (Dr. Bogart)

Extensive stage SCLCExtensive stage SCLC–– CALGB 30504: Platinum/CALGB 30504: Platinum/etoposideetoposide +/+/-- sunitinibsunitinib

maintenancemaintenance–– CelgeneCelgene: : AmrubicinAmrubicin versus versus topotecantopotecan for 2for 2ndnd line line

therapy (Dr. Shah)therapy (Dr. Shah)



Palliative chemotherapy, RT or Palliative chemotherapy, RT or supportive caresupportive care

Stage IVStage IVRT +/RT +/-- chemotherapychemotherapyStage IIIBStage IIIB

Surgery for T3 lesionsSurgery for T3 lesions + Chemo+ ChemoRT/Surgery + chemotherapyRT/Surgery + chemotherapy

Stage IIIAStage IIIASurgery Surgery + Chemotherapy+ ChemotherapyStage II Stage II Surgery Surgery + Chemotherapy+ ChemotherapyStage IBStage IBSurgerySurgeryStage IAStage IATreatment of ChoiceTreatment of ChoiceStageStage


How to Be EffectiveHow to Be Effective

Be Passionate!Be Passionate!Decide on mix of studies, prioritiesDecide on mix of studies, prioritiesKnow the study (attend the investigator Know the study (attend the investigator meeting)meeting)Watch the budgets (personnel may be on Watch the budgets (personnel may be on ““softsoft””monies)monies)Talk to Scientific Liaisons from IndustryTalk to Scientific Liaisons from IndustryTalk to colleagues at other Talk to colleagues at other insitutionsinsitutions–– Consortiums can be effective (examples: Roswell Consortiums can be effective (examples: Roswell

Park, Duke, Rhode Island)Park, Duke, Rhode Island)


How to Be EffectiveHow to Be Effective

Communicate within your Division/SectionCommunicate within your Division/Section–– Regular Conferences to discuss study detailsRegular Conferences to discuss study details–– Eligibility Criteria, Treatment specifics, ProblemsEligibility Criteria, Treatment specifics, Problems–– Physicians, NPPhysicians, NP’’s, Nursess, Nurses

Meet with Meet with CRACRA’’ss on a regular basison a regular basisCommunicate with PharmacyCommunicate with PharmacyCommunicate with IRB, QAIPCommunicate with IRB, QAIP


CLINICAL RESEARCH IS CLINICAL RESEARCH IS GOOD CLINICAL CAREGOOD CLINICAL CARE

investigator training program march 9, 2010 - research

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