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Clinical Trial Results:
A phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of the efficacy and safety of lenalidomide (Revlimid®) as maintenance therapy for high-risk patients with chronic lymphocytic leukemia following first-line therapy

Summary
EudraCT number	2011-004698-98
Trial protocol	DE AT IT ES NL
Global end of trial date	14 Jan 2021

Results information
Results version number	v1(current)
This version publication date	13 Dec 2021
First version publication date	13 Dec 2021
Other versions

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

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Sponsor protocol code

CLLM1

ISRCTN number

US NCT number

NCT01556776

WHO universal trial number (UTN)

Other trial identifiers

Celgene Protocol Number: RV-CLL-GCLLSG-0725

Sponsor organisation name

University of Cologne

Sponsor organisation address

Albertus-Magnus-Platz, Cologne, Germany, 50923

Public contact

CLLM1-Help Desk, Deutsche CLL-Studiengruppe, 49 22147888220, cllstudie@uk-koeln.de

Scientific contact

CLLM1-Help Desk, Deutsche CLL-Studiengruppe, 49 22147888220, cllstudie@uk-koeln.de

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

14 Jan 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

14 Jan 2021

Global end of trial reached?

Yes

Global end of trial date

14 Jan 2021

Was the trial ended prematurely?

Main objective of the trial

Primary Objective: • To compare the efficacy of lenalidomide versus placebo maintenance therapy. The primary efficacy objective of this study is to investigate if lenalidomide maintenance therapy is superior to placebo maintenance therapy in prolonging progression free survival (PFS), for subjects with a high risk of early progression following first-line treatment. All subjects, including both subjects who do and do not achieve MRD negativity will be treated up to disease progression with maintenance therapy. Secondary Objective: • To evaluate the prolongation of overall survival (OS) of lenalidomide versus placebo maintenance therapy • To evaluate the safety of lenalidomide versus placebo maintenance therapy.

Protection of trial subjects

Prophylaxis for TLS, thromboembolism and infection and treatment of tumor flare reaction (TFR) In subjects with bulky disease (at least one lymph node >5cm in the largest diameter) TLS prophylaxis, comprising of oral hydration and allopurinol 300 mg/day will be initiated 3 days prior to starting maintenance therapy and for a minimum of the first treatment cycle at each dose level. Subjects with bulky disease and a known allergy to allopurinol will be excluded from the study. Subjects should be closely monitored for evidence of arterial and venous thromboembolic events while on study drug. Modifiable risk factors for thromboembolic events should be managed wherever possible (eg, smoking cessation; control of hypertension and hyperlipidaemia). Medicines that may increase the risk of thromboembolism, such as oestrogens and erythropoietic agents, should be used with caution during lenalidomide treatment. In case of hospitalization the subject should receive appropriate antithrombotic medication during the duration of the hospitalization. The investigator may use appropriate anti coagulation prophylactic therapies (i.e. LMW heparin, fondaparinux, warfarin, etc.) at their discretion based on the subjects pre-disposing risk factors for thromboembolism (i.e. subjects with a history of a thromboembolic event and/or taking a concomitant medication associated with an increased risk for a thromboembolic event and/or known hypercoagulable state regardless of thromboembolic history). In case of contraindications for prophylactic anti coagulation medication, compression stockings are recommended. Subjects with no history of DVT or arterial thromboembolic events within the past 12 months, no clear indication or contraindication for antiplatelet or anticoagulant therapy, with no active bleeding, and who are not considered to be at high risk of bleeding should receive low dose aspirin (75 mg to 100 mg) as prophylactic anti-thrombotic treatment while on study drug

Background therapy

Published analyses revealed that subjects with a median progression free survival (PFS) of < 24 months after randomization showed a significantly shorter overall survival (OS) compared with subjects achieving a PFS of ≥ 24 months. 15 % of these subjects were characterized by both, the presence of 17p deletions and TP53 gene mutations, another 7.5% by TP53 mutation alone. Interestingly, the majority of subjects with a poor prognosis could not be defined by a mutation of TP53 or del(17p). An analysis showed that a combination of minimal residual disease (MRD) levels of ≥10-2 or a combination of MRD levels of ≥10-4 to <10-2 plus at least one of the three parameters (del(17p) or TP53 mutation or an unmutated IGHV-status) defined a group of subjects at high risk of early progression (HR). The median PFS of HR subjects was 22 months, the median PFS for subjects defined as low risk (LR; n=103) was 69 months. HR subjects had a 6.4 fold increased risk for progression (HR 6.4, 95% CI: 3.970-10.347; p<0.0001) and a 5.7 fold increased risk for death, with a median OS of only 57 months (assessed from the beginning of FCR therapy). In contrast, median OS was not reached in the LR group at the time point of the analyses (HR 5.758, 95% CI: 2.799-11.844, p<0.0001). The combined use of genetic markers and an MRD assessment two months after the completion of first line treatment (final restaging) allows the identification of CLL subjects with a very poor prognosis after FCR therapy. The high risk group identified by this approach should be treated within clinical trials using novel strategies including maintenance protocols.

Evidence for comparator

Although maintenance therapy has been established in recent years for the treatment of a subset of subjects with Non-Hodgkin’s Lymphoma (NHL), it is a novel concept in the management of CLL. It is not regularly used and only a limited number of small studies have been conducted evaluating consolidation/maintenance therapy for limited periods of time with alemtuzumab or rituximab. Based on the limited amount of available data, it appears that maintenance therapy may improve the quality of remission in CLL subjects and prolong progression-free survival (PFS). A large phase 3 trial investigating lenalidomide as maintenance following response to second line therapy is ongoing. However, a large well-controlled study had not been conducted to investigate the beneficial effect of maintenance therapy following front line therapy; specifically in subjects with aggressive disease. This phase 3 study will evaluate whether lenalidomide maintenance therapy will prolong PFS in CLL subjects with a high risk of early progression following first line treatment.

Actual start date of recruitment

01 May 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country