Lymphoma CommitteeAlliance for Clinical Trials in

Oncology2016 Beijing International Lymphoma Conference

April 9, 2016David J. Straus, M.D.

Memorial Sloan Kettering Cancer CenterNew York, NY

USA

CALGB/Alliance

• Cancer and Leukemia Group B (CALGB)– Founded in 1956– Multidisciplinary, multimodality– Funded by National Cancer Institute (US)– Former Lymphoma Chairs

• Arlen Gottlieb, Bruce Peterson, Dan Longo, George Canellos, Bruce Cheson (2003-2013), John Leonard (2013-present)

• Alliance for Clinical Trials in Oncology– Founded 2011– Merger of CALGB, NCCTG, ACOSOG– 10,000 specialist members US/Canada– NCI National Clinical Trials Network

Alliance for Clinical Trials in Oncology

Purpose: to reduce the impact of cancer by uniting a broad community of scientists and clinicians from many disciplines, committed to discovering, validating and disseminating effective strategies for the prevention and treatment of cancer

Alliance achieves this purpose by conducting high quality multidisciplinary cancer control, prevention,

and treatment trials that engage a comprehensive research network;

furthering our understanding of the biological basis of the cancer process and its treatment, from discovery, to validation, to clinical practice;

providing a scientific and operational infrastructure for innovative clinical and translational research in academic and community settings

Leukemia LymphomaRespiratoryGenito-urinary

Gastro-intestinalBreast MyelomaNeuro-

Oncology

Surgical Oncology, Medical Oncology, Radiation Oncology, Pathology, Imaging, Oncology Nursing, Clinical Research Associates, Biostatistics, Bioinformatics, Information Systems, Pharmacology, Pharmacogenomics, Patient Advocates,

Health Outcomes, Symptom Intervention, Experimental Therapeutics, Community Oncology, Research Ethics, Laboratory Medicine, Regulatory Affairs,

Cancer Prevention, Special Populations Research

395 committee members

31 scientific committees16 administrative committees

NCI National Clinical Trials

Network

Alliance Foundation

Trials

NCTN logo

Study Design by Scientific and

Modality Committees

Study Operations

National Clinical Trials NetworkNCTN logo

National Clinical Trials Network

3,100 Institutions

14,000 Investigators

Member Institutions136 Main Members 927 Affiliates/Components

NCI National Clinical Trials

Network

Alliance Foundation

Trials

NCTN logo

Study Design by Scientific and

Modality Committees

Study Operations

Alliance for Clinical Trials in Oncology Foundation

Not-for-Profit Corporation created to enhance and expand the ability of Alliance members* to conduct cancer clinical research

• 501(c)3: tax exempt• Governance and operations structure

separate from the AllianceAlliance Foundation Trials, LLC (AFT)

• Subsidiary organization created to conduct cancer clinical research involving partners other than the National Cancer Institute

Alliance Foundation: Contract Categories

Alliance Foundation support of NCI studies• Contracts between Alliance Foundation and outside parties

for work in collaboration with NCI-funded initiatives• Example: Contract with industry partner to fund correlative

science projects for an NCI-funded trial

Alliance Foundation Trials (AFT)• Contracts between Alliance Foundation Trials, LLC and

outside parties for work that does not involve NCI studies or NCI resources

• Examples: PCORI awards (Patient-Centered Outcomes Research Institute), Investigator-initiated industry-sponsored trials

Alliance Lymphoma CommitteeLeadership

• Chair – John Leonard (Cornell) - 2013

• Bruce Cheson (Georgetown) 2003-2013

• Vice Chair – Nancy Bartlett (Washington U)

• Pathology/Lymphoma Translational Science – Eric Hsi (Cleveland Clinic)

• Imaging– Heiko Schoder (MSKCC)– Lale Kostakoglu (Mt. Sinai)

Alliance Lymphoma Committee Members

• Jeremy Abramson – MGH• Anne Beaven - Duke• Kristie Blum – Ohio State• Bruce Cheson - Georgetown• Sean Collins – Georgetown• Steven Horwitz - MSKCC• Anthony Jaslowski -

Community• Lawrence Kaplan – UCSF• Lale Kostakoglu – Mt. Sinai• Ann LaCasce - Dana

Farber/Partners• Frederick Lansigan –

Datmouth• Brian Link – U of Iowa

• Kami Maddocks – Ohio State• Ben Marchello – Community• Benjamin Marchello _

Montana CC• Peter Martin - Cornell• Vicki Morrison - U of

Minnesota• Heiko Schoder - MSKCC• Thomas Shea - U of North

Carolina• Sonali Smith – U of Chicago• David Straus – MSKCC• Chaitra Ujjani – Georgetown• Andrew Zelenetz - MSKCC

Alliance Lymphoma Trials Open to Accrual

Protocol Number Study TitleCALGB 50801 Phase II trial of response-adapted therapy based on

positron emission tomography (PET) for bulky stage I and stage II classical Hodgkin lymphoma (HL)

CALGB 50904 A randomized phase II trial of ofatumumab and bendamustine vs. ofatumumab, bortezomib and bendamustine in patients with untreated follicular

lymphoma

CALGB 51101 A randomized phase II trial of myeloablative versus non-myeloablative consolidation chemotherapy for

newly diagnosed primary CNS B-cell lymphoma

CALGB 150905 Natural killer cell KIR and HLA genotypes may predict response to antibody therapy in follicular lymphoma

Selected research highlights

US cooperative group risk-adapted Hodgkin Lymphoma clinical trials

CALGB 50604 (non-bulky stage I/II) Intergroup: ASH abstract 2015AVBD x 2 cycles → PET scan

• PET-→ 2 more ABVD cycles • PET+ → 2 cycles escalated BEACOPP + IF RT

CALGB 50801 (bulky stage I/II): AccruingABVD x 2 cycles → PET scan

• PET - → 4 more ABVD cycles• PET+ → 4 cycles escalated BEACOPP + IF RT

S0816 (stage III/IV) Intergroup: J Clin Oncol, in press, 2016ABVD x 2 cycles → PET scan

• PET - → 4 more ABVD cycles• PET+ → 6 more escalated BEACOPP cycles

CALGB 50604 Progression Free SurvivalPost cycle 2 ABVD PET- and PET+ Patients

Years from Study Entry

Prob

abilit

y pr

ogre

ssio

n fre

e

0 1 2 3 4

0.0

0.2

0.4

0.6

0.8

PET-negativePET-positive

N= 131N= 13

Events= 8Events= 4

p-value= 0.0008

Est. 3-yr PFS Hazard RatioPET - 92% (84%-96%) 6.04 (1.82-20.08)

PET + 66% (32%-86%)

Follow-up timeMedian: 2.1 yearsRange: < 1month – 4.3 years1 Death (Suicide – PET +)

0%

20%

40%

60%

80%

100%

0 12 24 36 48

Months After Registration

PET-negativePET-postive

At Risk27755

Failed3916

2-year Estimate79%61%

S0816 PFS by PET2 Result

Arm 1: Continued ABVD

Arm 1: eBEACOPP

All Patients at Risk Failed 2-Year Estimate

PET negative 277 39 79%

PET positive 55 16 61%

DLBCLComparison of CHOP-R and EPOCH-R

*Doses increased or decreased based on degree of neutropenia.

Rituximab 375 mg/m2 d1Etoposide 50 mg/m2/d CI d1-4*

Doxorubicin 10 mg/m2/d CI d1-4*Vincristine 0.4 mg/m2/d CI d1-4

Cyclophosphamide 750 mg/m2 d5*Prednisone 60 mg/m2 bid d1-4

G-CSF 5 μg/kg d6-ANC recoveryq3w × 6

Rituximab 375 mg/m2 d1Cyclophosphamide 750 mg/m2 d1

Doxorubicin 50 mg/m2 d1Vincristine 1.4 mg/m2 (2 mg cap) d1

Prednisone 40 mg/m2 d1-5

q3w × 6

R-CHOP DA*-R-EPOCH

CALGB:50303 Phase III Randomized Study of R-CHOP v. DA-EPOCH-R with Microarray

Randomization

ARM A: R-CHOP

ARM B: DA-EPOCH-R

C1 C2 C3 C4 C5 C6

C1 C2 C3 C4 C5 C6

Stage Stage

Treatmentcompleted

Treatmentcompleted

if no change C5 to C7 staging

0 3 6 9 12 15 18 21 25

Time Line (weeks)

Tumor BiopsyBlood Samples

• Gene Expression Profiling• GCB v ABC DLBCL Analysis • Discovery

• Whole Genome Sequencing • Germ line and Tumor• Discovery

50303 status• Completed accrual 5/2013• Case review complete• Assessing timeline for final clinical analysis• “Upgrading” molecular profiling technology

- High priority for NCI (Lou Staudt)- Resolving consent/ethical issues

• Many components (clinical, correlative, PET)• Will probably be presented at ASH 2016 but

need to confirm feasibility

A051301 Molecular profiling-based therapy in recurrent DLBCL

Ibrutinib x 12 months

Placebo x 12 months

Follow Up Follow Up

RandomizationStratify by time to relapse,

conditioning regimen

Arm A Arm B

Relapsed/Refractory DLBCL-ABCSalvage ≥PR, stem cells collected

ASCT: CBV or BEAM+ Ibrutinib 560 mg

ASCT: CBV or BEAM

Upfront FL studies Focus on non-chemotherapy regimens

• Published- 50402 (Czuczman) – Phase II R + Galiximab (anti-CD80)- 50701 (Grant) – Phase II R + Epratuzumab (anti-CD22)

• Under analysis- 50401 (Martin) – Phase II R + Lenalidomide

• Celgene has completed accrual of phase III vs standard chemoimmunotherapy

- 50901 (Rosenbaum) – Phase II Ofatumumab (anti-CD20)

• Accruing- 50904 (Blum) Phase II – Benda/Ofatumumab +/- Bortezomib with

maintenance R/RBort

Other areas• A51101 (Batchelor) – Primary CNS lymphoma – Ph II myeloablative vs

non-myeloablative (accruing slowly)• A051301 (Andreadis/Shea) – Ibrutinib with auSCT in DLBCL• Alliance Foundation (Martin/Leonard/Smith) - Azacitidine + R-CHOP in

DLBCL• Alliance Foundation (Maddocks) – Ibrutinib + palbociclib (CKI)• Imaging

- PET adapted therapy in Hodgkin Lymphoma- PET as surrogate for outcome in DLBCL, FL

• Correlative science- Molecular profiling in DLBCL (50303, 51301)- FcR polymorphisms with rituximab in FL (Byrd)- IHC markers in FL (Chadburn)- Serum markers in Hodgkin lymphoma (Hsi)

Plans and priorities• Better assess and manage timelines of analysis and reporting

of completed and companion studies (with data/statistical, translational, imaging and other team members)

• Collaborate effectively via LYSC and SWOG/ECOG members- High risk FL, High risk DLBCL, upfront MCL may be priorities- Advance initiatives in HL, T cell as opportunities allow- Focus on precision therapy, biomarkers, surrogates- Navigate intergroup collaborations

• Optimize industry partnerships- Capitalize on AFT mechanism

• Advance promising translational sciences (MRD, profiling)• Continue to engage committee members and participating

individuals, particularly junior investigators