Successful practice changing development

plans: Rituximab in Burkitt lymphoma

Véronique Minard-Colin, MD, PhD

Pediatric and Adolescent Oncology

Gustave Roussy, Villejuif, France

No disclosure

CD20 immunotherapy question in

childhood B-NHL

High survival rates ~ 90%

Rituximab may have unexpected/severe toxicity in

children

Two rituximab phase 2 trials in children

BFM single agent upfront window study

COG pilot study of LMB chemo + rituximab

No randomized trial in Burkitt except one in adults in

France

LeBien, Tedder Blood 2008; Meinhardt, JCO 2010; Goldman, Leukemia 2013 and BJH 2014; Barth, BJH 2014

There was a necessity to demonstrate

effectiveness of rituximab in childhood B-NHL

“Fluctuations” over time

Trial design: Historical comparison?

Group C - CNS negative - EFS

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LMB89

LMB96 standard

LMB96 reduced

LMB01

At risk

logrank : p = 0.03

NHL-BFM 95

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MTX 4h : 77%

MTX 24h : 92%

Standard during RCT : 71%

Standard after RCT : 86%

At risk

MTX 24h non R : 71%

MTX 24h after R: 86%

Need for controled/randomised studies

R

5

Who are the “high risk” patients”

who may benefit for rituximab?

BFM R3, R4, trt std,

LMB SFOP St III LDH>2N, group C

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BFM 95&04 : 85%

SFOP 96&01 : 87%

At risk

St III high LDH, st IV and B-AL

Randomized

Phase 3 trial

EFS 84% 92%

301 pts/arm

2009

R-combo

With

LMB or BFM

To make a long story short…

2010 2011

JAN2009

Budapest

APR2009

BFM/GPOH

proposal

NOV2009

Wroclaw

A comprehensive

Burkitt Programm

With 7 risk groups

JAN 2010

IGR approval

for sponsorship

MAY2010

Amsterdam

A Phase III

In high-risk

A phase II

In PLMLB

A Phase III

In high-risk

A phase II

In PLMLB

A common

LMB-based

protocol

APR2010

BFM/GPOH

Stepped down

MAR2011

COG

approval

AUG2011

NCI/CTEP

approval

NCI will support

the Ritux study only

NOV2011

Paris

Investigator

meeting

Nov28th

1st center

opening

Dec2008

PHRC

USA

Canada

Australia

Partner

INTERGROUP COLLABORATION

ACADEMIC STUDY with an “EXPERIMENTAL DRUG” and

a Pediatric Investigation Plan required by EMA (EMEA-000308-PIP01-08-M02)

Inter-B-NHL Ritux 2010

Sponsors

12 countries292 sites

Inter-B-NHL Ritux 2010: Model of academic study

with industry partnership

Opportunity to develop a trial with efficacy and safety data

Intergroup Collaboration (12 countries – 292 sites)

3 continents

New countries on board (Poland, HK)

Common backbone chemotherapy: LMB

High quality of care and analysis

Two separate databases (GR and COG) fused in GR for analysis

All events reviewed by an international SC

An active Independent Data Monitoring Committee

To make a long story short…

First patient Dec 2011 (France)

May 2012 (USA)

July 2014 (UK)

Nov 2016 (Poland)

Results of the randomized intergroup trial Inter-B-NHL ritux 2010

for children and adolescents with high risk B-cell non Hodgkin’s

lymphoma and mature acute leukemia: Evaluation of rituximab

efficacy in addition to standard LMB chemotherapy regimen.

Minard-Colin V, Aupérin A, Pillon M, Burke A, Anderson J, Barkauskas D,

Wheatley K, Delgado RF, Alexander S, Uyttebroeck A, Bollard C, Zsíros J,

Csoka M, Goma G, Tulard A, Patte C, and Gross T

Sponsors: Gustave Roussy and COG

N°EudraCT: 2010-019224-31

ClinicalTrials.gov Identifier: NCT01516580

July 2015: 1st Interim analysis

155 101 71 36 21 7 1

155 89 56 33 18 6

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Months since randomization

Event Free Survival

With Rituximab

Without Rituximab

At risk

94.2% (88.5%-97.2%)81.5% (73.0%-87.8%)

1-year EFS (95%CI)

HR=0.33

Minard-Colin ASCO 2016

First Interim Analysis - Decisions

- March 2016: Study re-open with a single-arm rituximab

for 120 additional patients

To answer to the secondary objectives:

Safety/Immunity status/Ancillary studies

March,1, 2017: 92/120 patients included

- Following IDMC recommendation, sponsors decided to halt

the randomization in Nov 2015 and continue follow-up to

have mature data for all randomized patients

Final analysis in progress, 49/332 pts follow-up < 1 year

Future of childhood B-NHL treatment?

Standard Risk (40-45% pts; Stages I/II/III LDH<2N)*

Current EFS 97-98% - Survival 99%

Acute toxicity of CT but no expected long term side

effects

The use of rituximab is questionable?

High Risk: Backbone chemotherapy + Rituximab

Inter-B-NHL results will change our clinical practice

Patte C, SIOP 2010 *n=291 pts from LMB96 (SFOP) and LMB2001

Refractory/relapsed B NHL

Rare (< 5 patients / year in France)

Clonal heterogeneity and resistance to CD20 mAb

International Phase 1/2 in progress: Backbone

chemotherapy + rituximab +/-ibrutinib

New drugs: CAR CD19 - anti PD1/PDL1 (DLBCL) –

BiTE - anti CD79 - EZH2 (DLBCL)- PI3K/Akt/mTOR

How to develop new drugs?

Need international and adult collaborations

Conclusion

InterB NHL 2010:

-Initiated by Academic: Medical need in childhood

-Conducted on 3 different continents

-A success of Academic/Pharma collaboration and

PIP development

> 95% of children with B NHL are now cured

A few challenges remain ahead: new drugs

development in rare refractory/relapse disease and cure

of Burkitt in less privileged countries

Inter-B-NHL Ritux 2010: a Successfull Academic study with

International and Transatlantic collaboration and Pharma support

Steering Committee: Anne Aupérin, Amos Burke,

Angelo Rosolen, Marta Pillon, Jim Anderson, Don

Barkauskas, Keith Wheatley, Tom Gross and

Catherine Patte

Independent Data Monitoring Committee: Richard

Sposto, François Pein, Robert Marcus, and Ross

Pinkerton

Treating Physicians, Nurses, Pharmacists and

Research Staff

Patients and their Families

Sponsors: Gilles Vassal and Peter Adamson

F. Hoffmann-La Roche

Programme Hospitalier de

Recherche Clinique

(PHRC, INCa France)

U10CA180899 and U10

CA98548 (NCI, USA)

Cancer Research UK

Acknowledgement and Funding

Roche Team