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Clinical Trial Results:
A PHASE IB/II STUDY OF ESCALATING DOSES OF REVLIMID IN ASSOCIATION WITH R-CHOP (R2-CHOP) IN THE TREATMENT OF B-CELL LYMPHOMA

Summary
EudraCT number	2007-007698-22
Trial protocol	FR
Global end of trial date	23 Nov 2015

Results information
Results version number	v1(current)
This version publication date	14 Jan 2018
First version publication date	14 Jan 2018
Other versions
Summary report(s)	CSR Synopsis

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

R2-CHOP

ISRCTN number

US NCT number

NCT00901615

WHO universal trial number (UTN)

Sponsor organisation name

LYSARC

Sponsor organisation address

CH Lyon Sud – Secteur Sainte Eugénie – Pav 6D, PIERRE-BENITE Cedex, France, 69495

Public contact

Yvain ROBREAU, LYSARC, 33 4 72 66 93 33,

Scientific contact

Prof Hervé TILLY, LYSA, 33 2 32 08 22 00,

Sponsor organisation name

Centre Henri Becquerel

Sponsor organisation address

rue d'Amiens, ROUEN, France, 76038

Public contact

Yvain ROBREAU, LYSARC CH Lyon Sud – Secteur Sainte Eugénie – Pav 6D - 69495 PIERRE-BENITE Cedex - France, +33 4 72 66 93 33,

Scientific contact

Prof. Hervé TILLY, LYSA CH Lyon Sud - Service d’Hématologie – Bâtiment 1 F 69495 PIERRE-BENITE Cedex , +33 2 32 08 22 00,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

23 Nov 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

23 Nov 2015

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the Phase Ib part of the study is to determine the recommended dose (RD) of lenalinomide (Revlimid) when administered in association with R-CHOP. The primary objective of the Phase II part of the study is to assess the efficacy of the association of Revlimid and R-CHOP in a population of patients with follicular lymphoma as measured by the response rate at the end of treatment.

Protection of trial subjects

salavge therapy if necessary

Background therapy

Evidence for comparator

Actual start date of recruitment

06 Jan 2009

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy, Scientific research

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 108

Worldwide total number of subjects

108

EEA total number of subjects

108

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

108

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Fom 06-Jan-2009 to 25-Jan-2012

Screening details

• Phase IB: Patients with one of the following B-cell Lymphoma, CD 20 positive: o Mantle cell, Marginal zone, follicular o Histological transformation from low grade to high grade o Diffuse large B cell • Phase II: Patients with follicular lymphoma, WHO grade 1, 2 or 3a with at least one of the following signs requiring initiation of treatment

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

R2-CHOP

Arm description

Arm type

Experimental

Investigational medicinal product name

Revlimid

Investigational medicinal product code

Lenalidomide

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

2.5 mg, 5 mg and 10 mg strengths. All patients were treated with R2-CHOP at a three-week interval for 6 cycles.

Number of subjects in period 1	R2-CHOP
Started	108
Completed	101
Not completed	7
Consent withdrawn by subject	2
Adverse event, non-fatal	1
concurrent illness	2
Protocol deviation	1
Lack of efficacy	1

Baseline characteristics

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Reporting group title

Overall trial

Reporting group description

Reporting group values	Overall trial	Total
Number of subjects	108	108
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	108	108
From 65-84 years	0	0
85 years and over	0	0
Age continuous
Units: years
median (full range (min-max))	59 (24 to 77)	-
Gender categorical
Units: Subjects
Female	52	52
Male	56	56

Subject analysis set title

Phase I part

Subject analysis set type

Full analysis

Subject analysis set description

Subjects included in Phase I part

Subject analysis set title

Phase II part

Subject analysis set type

Full analysis

Subject analysis set description

Subjects included in phase II part

Subject analysis sets values	Phase I part	Phase II part
Number of subjects	28	80
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	28	80
From 65-84 years	0	0
85 years and over	0	0
Age continuous
Units: years
median (full range (min-max))	58 (24 to 77)	60 (29 to 71)
Gender categorical
Units: Subjects
Female	12	40
Male	16	40

End points

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Reporting group title

R2-CHOP

Reporting group description

Subject analysis set title

Phase I part

Subject analysis set type

Full analysis

Subject analysis set description

Subjects included in Phase I part

Subject analysis set title

Phase II part

Subject analysis set type

Full analysis

Subject analysis set description

Subjects included in phase II part

Primary: Complete Response Rate at the End of Treatment According to Cheson 99

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End point title

Complete Response Rate at the End of Treatment According to Cheson 99 ^[1]

End point description

End point type

Primary

End point timeframe

end of treatment

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Included in figure

End point values	R2-CHOP	Phase II part
Number of subjects analysed	0 ^[2]
Units: Subjects with CR or CRu
CR or CRu		59
Other		21

Notes
[2] - Not applicable

No statistical analyses for this end point

Primary: Dose limiting toxicities (DLT)

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End point title

Dose limiting toxicities (DLT) ^[3]

End point description

End point type

Primary

End point timeframe

End of cycle 2

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis

End point values	R2-CHOP	Phase I part
Number of subjects analysed	0 ^[4]
Units: Subject presenting DLT
with DLT		6
without DLT		21

Notes
[4] - Not applicable

No statistical analyses for this end point

Secondary: Overall Response Rate at the End of Treatment

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End point title

Overall Response Rate at the End of Treatment

End point description

End point type

Secondary

End point timeframe

End of treatment

End point values	R2-CHOP	Phase II part
Number of subjects analysed	0 ^[5]
Units: Subjects with response
response (CR, CRu, PR)		75
Other (SD, PD)		5

Notes
[5] - Not applicable

No statistical analyses for this end point

Secondary: Progression free survival

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End point title

Progression free survival

End point description

End point type

Secondary

End point timeframe

60 months

End point values	R2-CHOP	Phase II part
Number of subjects analysed	0 ^[6]
Units: Subjects presenting event
Event		18
Censored		62

Attachments

Untitled (Filename: PFS.png)

Notes
[6] - Not applicable

No statistical analyses for this end point

Secondary: Overall survival

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End point title

Overall survival

End point description

End point type

Secondary

End point timeframe

60 months

End point values	R2-CHOP	Phase II part
Number of subjects analysed	0 ^[7]
Units: Deaths
Dead		4
Censored		76

Attachments

Untitled (Filename: OS.png)

Notes
[7] - Not applicable

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Overall study

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Phase I

Reporting group description

Reporting group title

Phase II

Reporting group description

Serious adverse events	Phase I	Phase II
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 27 (25.93%)	21 / 80 (26.25%)
number of deaths (all causes)	0	4
number of deaths resulting from adverse events	0	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified
subjects affected / exposed	1 / 27 (3.70%)	6 / 80 (7.50%)
occurrences causally related to treatment / all	1 / 1	6 / 6
deaths causally related to treatment / all	0 / 0	1 / 1
Vascular disorders
Vascular disorders
subjects affected / exposed	0 / 27 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
General disorders and administration site conditions
subjects affected / exposed	2 / 27 (7.41%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Immune system disorders (
subjects affected / exposed	1 / 27 (3.70%)	0 / 80 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Reproductive system and breast disorders
subjects affected / exposed	0 / 27 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders
subjects affected / exposed	1 / 27 (3.70%)	3 / 80 (3.75%)
occurrences causally related to treatment / all	1 / 1	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Investigations
subjects affected / exposed	0 / 27 (0.00%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications
subjects affected / exposed	0 / 27 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiac disorders
subjects affected / exposed	0 / 27 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Nervous system disorders
subjects affected / exposed	0 / 27 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Blood and lymphatic system disorders
subjects affected / exposed	2 / 27 (7.41%)	5 / 80 (6.25%)
occurrences causally related to treatment / all	1 / 2	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Eye disorders
subjects affected / exposed	0 / 27 (0.00%)	1 / 80 (1.25%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal disorders
subjects affected / exposed	0 / 27 (0.00%)	3 / 80 (3.75%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders
subjects affected / exposed	1 / 27 (3.70%)	2 / 80 (2.50%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Renal and urinary disorders (
subjects affected / exposed	0 / 27 (0.00%)	4 / 80 (5.00%)
occurrences causally related to treatment / all	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Infections and infestations
subjects affected / exposed	2 / 27 (7.41%)	6 / 80 (7.50%)
occurrences causally related to treatment / all	2 / 2	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Phase I	Phase II
Total subjects affected by non serious adverse events
subjects affected / exposed	27 / 27 (100.00%)	68 / 80 (85.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)
subjects affected / exposed	0 / 27 (0.00%)	7 / 80 (8.75%)
occurrences all number	0	7
Vascular disorders
VASCULAR DISORDERS
subjects affected / exposed	2 / 27 (7.41%)	4 / 80 (5.00%)
occurrences all number	2	7
Surgical and medical procedures
SURGICAL AND MEDICAL PROCEDURES
subjects affected / exposed	0 / 27 (0.00%)	1 / 80 (1.25%)
occurrences all number	0	1
General disorders and administration site conditions
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
subjects affected / exposed	3 / 27 (11.11%)	2 / 80 (2.50%)
occurrences all number	3	2
Immune system disorders
IMMUNE SYSTEM DISORDERS
subjects affected / exposed	1 / 27 (3.70%)	0 / 80 (0.00%)
occurrences all number	1	0
Reproductive system and breast disorders
REPRODUCTIVE SYSTEM AND BREAST DISORDERS
subjects affected / exposed	0 / 27 (0.00%)	1 / 80 (1.25%)
occurrences all number	0	1
Respiratory, thoracic and mediastinal disorders
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
subjects affected / exposed	3 / 27 (11.11%)	3 / 80 (3.75%)
occurrences all number	3	4
Investigations
INVESTIGATIONS
subjects affected / exposed	0 / 27 (0.00%)	4 / 80 (5.00%)
occurrences all number	0	5
Injury, poisoning and procedural complications
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
subjects affected / exposed	0 / 27 (0.00%)	1 / 80 (1.25%)
occurrences all number	0	2
Cardiac disorders
CARDIAC DISORDERS
subjects affected / exposed	1 / 27 (3.70%)	2 / 80 (2.50%)
occurrences all number	1	3
Nervous system disorders
NERVOUS SYSTEM DISORDERS
subjects affected / exposed	3 / 27 (11.11%)	7 / 80 (8.75%)
occurrences all number	3	8
Blood and lymphatic system disorders
BLOOD AND LYMPHATIC SYSTEM DISORDERS
subjects affected / exposed	27 / 27 (100.00%)	68 / 80 (85.00%)
occurrences all number	88	420
Eye disorders
EYE DISORDERS
subjects affected / exposed	0 / 27 (0.00%)	2 / 80 (2.50%)
occurrences all number	0	3
Gastrointestinal disorders
GASTROINTESTINAL DISORDERS
subjects affected / exposed	0 / 27 (0.00%)	8 / 80 (10.00%)
occurrences all number	0	12
Hepatobiliary disorders
HEPATOBILIARY DISORDERS
subjects affected / exposed	2 / 27 (7.41%)	1 / 80 (1.25%)
occurrences all number	2	1
Skin and subcutaneous tissue disorders
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
subjects affected / exposed	1 / 27 (3.70%)	4 / 80 (5.00%)
occurrences all number	1	5
Renal and urinary disorders
RENAL AND URINARY DISORDERS
subjects affected / exposed	0 / 27 (0.00%)	4 / 80 (5.00%)
occurrences all number	0	4
Infections and infestations
INFECTIONS AND INFESTATIONS
subjects affected / exposed	14 / 27 (51.85%)	29 / 80 (36.25%)
occurrences all number	14	42
Metabolism and nutrition disorders
METABOLISM AND NUTRITION DISORDERS
subjects affected / exposed	6 / 27 (22.22%)	3 / 80 (3.75%)
occurrences all number	6	3

More information

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Were there any global substantial amendments to the protocol? Yes

15 Oct 2008

The first one concerns form corrections in the research protocol (mainly harmonizations between the synopsis and the text of the protocol and corrections of translation errors of measurement units), the submission of a patient booklet which was be distributed to the participants in the study and aimed at ensuring compliance with the test treatment, the collection of safety data (version 1 of 15 October 2008) and the modification of the investigator coordinator of the study, Professor Bertrand COIFFIER, by Professor Hervé TILLY and the modification of the principal investigator of the René Huguenin center of St Cloud, Dr. Maud JANVIER, by Dr. Carole SOUSSAIN. These modifications has been implemented in Protocol version 3 dated October 15, 2008.

01 Oct 2009

Second amendment concerns the addition of a dose level in Phase IB at 25 mg (indeed, the initially planned maximum level of 20 mg was well tolerated in the trial as in other trials studying the combination of Lenalidomide and Rituximab) and the addition of a cut-off date concerning the analysis of the primary criterion of Phase IB prior to that concerning the analysis of secondary criteria due to the earlier availability of data. These modifications has been implemented in Protocol version 4 dated October 1st, 2009.

27 Oct 2010

Third amendment concerns: 1. The transfer of the trial promotion to the Centre Henri Becquerel (Rouen, France). 2. Following the inclusion of all patients in Phase I, the primary endpoint data were analyzed. The Research Monitoring Committee recommended the 25 mg dose for Phase II with a schedule of dose adjustments for toxicity. 3. Five search locations are added and another has changed address. 4. In order to take into account the evolution of the practices, the protocol plan foreseen two cycles of rituximab alone for the end of the induction treatment and recommended the establishment of a maintenance treatment for the answering patients. 5. The PET-scan exam was added to the efficacy evaluation criteria as it now corresponds to the usual care of the patients involved in the research. 6. The safety information of the investigational drug was updated following the updating of the Investigator's Brochure. These modifications has been implemented in Protocol version 5 dated October 27, 2010.

30 Aug 2011

Fourth amendment concerns 1. The conditions for reporting secondary malignancies and the conditions for reviewing the data by the DSMC following the recommendations of the AFSSAPS concerning the suspicion of risk of occurrence of secondary cancers dear to patients receiving lenalidomide. 2. The change of principal investigators in three research sites: the Principal Investigator of the Nancy Center, that of Paris St Louis and that of the Institut Curie have been modified. 3. The safety information of the investigational drug has been updated following updates to the Investigator Brochure version 14 and RCP version 20 of Revlimid. These modifications has been implemented in Protocol version 6 dated August 30, 2011.

16 Dec 2011

Last amendment to the protocol concerns the updating of the product's safety information following the transmission of the new version of Investigator's Brochure No. 15 and RCP 22 by the product owner. For this purpose, a supplement of information leaflet of the patients has been written. These modifications has been implemented in Protocol version 6.2 dated December 16, 2011.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/22733106

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Clinical trials

Clinical Trial Results:
A PHASE IB/II STUDY OF ESCALATING DOSES OF REVLIMID IN ASSOCIATION WITH R-CHOP (R2-CHOP) IN THE TREATMENT OF B-CELL LYMPHOMA

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Complete Response Rate at the End of Treatment According to Cheson 99

Primary: Complete Response Rate at the End of Treatment According to Cheson 99

Primary: Dose limiting toxicities (DLT)

Primary: Dose limiting toxicities (DLT)

Secondary: Overall Response Rate at the End of Treatment

Secondary: Overall Response Rate at the End of Treatment

Secondary: Progression free survival

Secondary: Progression free survival

Secondary: Overall survival

Secondary: Overall survival

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: A PHASE IB/II STUDY OF ESCALATING DOSES OF REVLIMID IN ASSOCIATION WITH R-CHOP (R2-CHOP) IN THE TREATMENT OF B-CELL LYMPHOMA

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Complete Response Rate at the End of Treatment According to Cheson 99

Primary: Complete Response Rate at the End of Treatment According to Cheson 99

Primary: Dose limiting toxicities (DLT)

Primary: Dose limiting toxicities (DLT)

Secondary: Overall Response Rate at the End of Treatment

Secondary: Overall Response Rate at the End of Treatment

Secondary: Progression free survival

Secondary: Progression free survival

Secondary: Overall survival

Secondary: Overall survival

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A PHASE IB/II STUDY OF ESCALATING DOSES OF REVLIMID IN ASSOCIATION WITH R-CHOP (R2-CHOP) IN THE TREATMENT OF B-CELL LYMPHOMA