Paul Nguyen, MD

Associate Professor of Radiation OncologyDana-Farber/Brigham and Women’s

Harvard Medical School

Radiation Oncology Clinical Trials:

The US Perspective

Disclosures

• Advisory Boards:– Medivation– Genome Dx

• MOVEMBER

• Founded in Australia

• >$550 million raised for prostate and testicular cancer since 2003

• $109,000 raised by Harvard Hospitals in 2013

“Random Task” from theAustin Powers movie

Outline

• Brief History of the RTOG

• Other NCI Cooperative Groups

• Trial Group Consolidations

• Current Climate for US Collaborative Trials In Radiation Oncology

1955

• US establishes the cancer cooperative group network structure, recognizing the need for large-scale studies

1968

1968

Dr. Simon Kramer establishes RTOG

Faculty at Thomas Jefferson in Philadelphia

Rad-Onc not yet a recognized specialty

1968

RTOG’s first randomized trial:

Radiation +/- Methotrexate for SCC of Head and Neck

Only 3 Chairs Since ThenLuther Brady Jim Cox Wally Curran

Continuous NIH Funding for Over 40 Years

Several Major Trials Helping to Establish Standards of Care

RTOG 92-02 (Long-course ADT for locally advanced prostate CA)

RTOG 94-08 (Short-course ADT for intermediate-risk PCa)

RTOG 95-08 (WBRT+SRS boost for single brain metastasis)

Development of Cores Within RTOG

• Statistical

• Pathology

• Translational/Tissue Bank

• Quality of Life

• Health economics

Focus Areas

• GU

• Head and Neck

• GI

• Brain

• Lung

Strong AccrualLarge Canadian and Private Practice Participation

• 800-1400 patients accrued to GU protocols per year

• Canada Represents 1/3 of Accrual to GU Trials

• Community Practice Represents 1/3 of Accrual to GU trials

Jones PI of RTOG 94-08

International Outreach

International Outreach:

-Member sites added in Israel, South Korea, China, Australia

Running Trials With Good Equipoise

Meta-analysis of 57 RTOG Phase III trials 1968-2002

JAMA. 2005;293(8):970-978.

WHAT ABOUT OTHER GROUPS?

NSABP

National Surgical Adjuvant Breast and Bowel Project

Major Breast RT trials:

-NSABP B-06 (PI: Fisher – Surgery)

-NSABP B-18 (PI: Fisher – Surgery)

-NSABP B-27 (PI: Mamounas – Surgery)

SWOG

Southwest Oncology Group

SWOG 8794 – Adjuvant RT vs. Observation After Prostatectomy

-PI Ian Thompson (Urology)

CALGB

Cancer and Leukemia Group B

-Leukemia, Lymphoma, Breast, GI, GU, Lung, Melanoma

CALGB 9343: Lumpectomy + Tam +/- RT in women over age 70

-PI: Hughes (Surgery)

GOG

Gynecologic Oncology Group

-Med Oncs, Surgeons, and Rad Oncs

GOG-99: RT for “high intermediate risk” Endometrial Cancer

PI Keyes – Rad Onc

www.cancer.gov/clinicaltrials/nctn

Problems with Groups

• Redundancy in disease sites and focus

• Expensive duplication of core functions and administration

Sequestration

• Automatic federal spending cuts enacted in 2013

Sequestration and NCI Budget

Flat budget averaging $4.9 Billion from 2005-2013 (was $4.8 Billion in 2013)

Sequestration cut all research funding by 5.1-7.3% in 2013 and mandated that it stay flat through 2021

National failure to see research as an investment rather than an expense

NCI’s Goals of Cooperative Group Reorganization

1) Save money

2) Reduce Redundancies

3) Improve prioritization

4) Focus on precision medicine

www.cancer.gov/clinicaltrials/nctn

The Artist Formerly Known as “Prince”

“NRG Oncology”

NSABP – Breast, GI

RTOG – GU, GI, H&N, CNS, Lung

GOG - Gyn

www.nrgoncology.org

www.nrgoncology.org

www.cancer.gov/clinicaltrials/nctn

Major Directional Changes• Drop in annual enrollment onto NCI trials from

21,000 a year to mandated 17,000 a year cap

• More support for community participation– NCORP (Community Onc Research Program)

• Focus on precision medicine trials– Less likely to fund 2000 patient prostate trials

NCI website: To effectively treat cancer with targeted

therapies, the molecular signature of an individual’s tumor must first be diagnosed with sophisticated genetic techniques; only then can an appropriate therapy be selected.

www.cancer.gov/clinicaltrials/nctn

Harold VarmusNCI Director

Biomarker-directed studiesAssume this agent quintuples survival in pts w/target

Stewart et al. J Clin Oncol 2010Courtesy of Brian Alexander, MD

Unselected populationN=668, but only 10% have relevant target, p=0.16

Selected populationN=16, but all have target, p=0.02

Biomarker enrichment strategies

Tajik et al. Clin Cancer Res 2013;19:4578-4588Courtesy of Brian Alexander, MD

“Bucket” or “Basket” trials

• Good for signal finding in early development

• Example: NCI MATCH

Courtesy of Brian Alexander, MD

NCI MATCH• Mutation defined groups across tumor types

– ~25% from non-breast/lung/colon/prostate

• Primary endpoint response rate

www.dcdt.cancer.gov

“Bucket” or “Basket” trials

• Good for strong biomarker hypotheses supported by prior clinical data

• Will not determine predictive value of M

• Example: Lung MAP

Courtesy of Brian Alexander, MD

Lung MAP• Lung Master Protocol for squamous cell

• Mutations define what sub-trial to enroll on

www.lung-map.orgCourtesy of Brian Alexander, MD

Agnostic approach

• Generates predictive marker data• Good for weaker or competing biomarker

hypotheses

Less Likely to See Classic Large RT Studies

RTOG 99-10: 1489 pts intermediate risk PCa

4mos vs. 9mos ADT. Negative study

(ASTRO Plenary 2013)

RTOG 0126: 1532 pts intermediate risk PCa. 79.2Gy vs. 70.2Gy, no OS difference

(ASTRO Plenary 2014)

Challenges Getting Concepts Approved Through CTEP

CTEP Disease site x:

-5 rad onc

-15 med onc

- 4 surg onc

- NCI staff

- Patient advocate

CTEP Disease site x:

-1 non-RTOG rad onc

-15 med onc

- 4 surg onc

- NCI staff

- Patient advocate

RTOG-affiliated rad oncs excluded from deliberation on RTOG proposals

Tighter Control on Archival Tissue

• New proposals to use old tissue must go through CTEP.

• No more “pet” single biomarker studies

• High-throughput analysis yielding large amounts of data for tissue are favored.

RTOG 92-02 Single Marker Studies on Biopsy Tissue

Marker Prognostic? PI/Paper

p16 YES Chakravarti, JCO

pKA YES Pollack, Clin Cancer Research

MDM2 YES Khor, JCO

Ki67 YES Khor, JCO

Bcl2/Bax YES Khor, Clin Cancer Research

Good results, but tissue rapidly depleted

RTOG 92-02 Single Marker Studies on Biopsy Tissue

Marker Prognostic? PI/Paper

p16 YES Chakravarti, JCO

pKA YES Pollack, Clin Cancer Research

MDM2 YES Khor, JCO

Ki67 YES Khor, JCO

Bcl2/Bax YES Khor, Clin Cancer Research

p27 NO!

RTOG 92-02 Single Marker Studies on Biopsy Tissue

Marker Prognostic? PI/Paperp16 YES Chakravarti, JCO

pKA YES Pollack, Clin Cancer Research

MDM2 YES Khor, JCO

Ki67 YES Khor, JCO

Bcl2/Bax YES Khor, Clin Cancer Research

p27 NO!

Current RTOG 92-02 Proposal to CTEPHigh-Density Arrays to Analyze Remaining Tissue

• 5.5 million probes on array

• 1.4 million RNA transcripts

• Includes all known protein-coding genes and non-coding transcripts

• Assay performed in a CLIA-certified laboratory

The Future For US Rad-Onc Trials• Harder to get large trials funded

• NCI-funded trials will need biomarker component

• Courting industry funding to operate trial outside of NCI funding mechanism

• Greater International Collaboration

ENZARADTROG 14.01/ANZUP 1303

Enzalutamide (24 months) + GnRH (24 months)+ 78Gy/39 fractions RT

EligibilityHigh-Risk Prostate Cancer

Screening Randomisation 1:1

NSAA (6months)+ GnRH (24 months)+78Gy/39 fractions RT

StratificationGleason Score 8-10T3-4 diseasePSA ≥ 20ng/mlStudy site

Co Chairs: Scott Williams and Paul Nguyen

N=800, Primary Endpoint = Overall SurvivalParticipants: ANZUP, TROG, Dana-Farber, ICORG, UK

Lewiston Tribune, Idaho Dec 2007, page 1

“Michael Millhouse giving the windows some holiday spirit with a Christmas greeting”