Phase 1Primary objective- To determine the maximum tolerated dose (MTD) and recommended phase 2 dose level (RDL) of lenalidomide administered during 21 days of a 4 week cycle, combined with continuous cyclophosphamide and prednisone. See paragraph…
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase 1
Primary endpoint
- Dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended
phase 2 dose (RDL) of lenalidomide, cyclophosphamide, combined with prednisone
(REP).
Phase 2
Primary endpoint
- Overall response rate. In this analysis we will consider the best response
obtained during treatment
Secondary outcome
Phase 1
Secondary endpoints
- Toxicity, especially myelosuppression, polyneuropathy and thrombosis
Phase 2
Secondary endpoints
- Toxicity, especially myelosuppression, polyneuropathy and thrombosis
- Progression free survival (PFS; i.e. time from registration to progression or
death from any
cause, whichever comes first
- Overall survival measured from registration. Patients still alive or lost to
follow up are
censored at the date they were last known to be alive
- Prognostic factors for response and survival
- Immunomodulatory effects of lenalidomide by evaluation of T cell subsets and
cytokine analysis
Background summary
Rationale
We have shown that the combination of lenalidomide, cyclophosphamide, and
prednisone was feasible and effective in heavily pre-treated myeloma patients
(19). However, the optimal dose of lenalidomide with continuous
cyclophosphamide and prednisone has not yet been defined. The aims of this
study were to develop a safe cyclophosphamide, lenalidomide and prednisone
combination suitable for clinical use and evaluation in subsequent randomized
clinical trials. To this end, the maximum tolerated dose (MTD) and toxicity
profile of lenalidomide, cyclophosphamide, and prednisone (REP) was determined
for patients with relapsed refractory disease, who were already exposed to
lenalidomide.
Study objective
Phase 1
Primary objective
- To determine the maximum tolerated dose (MTD) and recommended phase 2 dose
level (RDL) of lenalidomide administered during 21 days of a 4 week cycle,
combined with continuous cyclophosphamide and prednisone. See paragraph 10 for
definitions of MTD and RDL.
Secondary objective
- To evaluate toxicity.
Phase 2
Primary objective
- To investigate the efficacy of lenalidomide administered during 21 days of a
4 week cycle, combined with continuous cyclophosphamide and prednisone at the
RDL, as determined by the (s)CR+VGPR+PR rate.
Secondary objectives
- To evaluate toxicity.
- To evaluate progression-free survival
- To evaluate overall survival
- To evaluate prognostic factors for response and survival
- To evaluate the immunomodulatory effects of lenalidomide by using flow
cytometric and cytokine analysis
Study design
This is a prospective, non-randomized, open label, phase 1/2 study.
Details of all treatments (dose and schedule) are given in section 5 of the
protocol. All eligible patients will be registered (see section 11) and treated
with REP chemotherapy at different dose-levels (phase 1 part) or at the
recommended dose level (RDL) in the phase 2 part of the study.
Intervention
Treatment with lenalidomide, endoxan and prednisone.
Study burden and risks
Until now the number of different treatment modalities for multiple myeloma is
limited, which indicates the need for new treatment regimens. The REP regimen
is active in patients with heavily pretreated myeloma including those with
lenalidomide-refractory disease (van de Donk, BJH 2010). The most optimal
dosing schedule of REP is currently unknown, and therfore this study is
initiated.
Besides potential beneficial effects such as response and therefore increased
survival, it is possible that REP chemotherapy (lenaliomide, endoxan and
prednisone) induces cytopenias with associated risk of infections and
bleeding. Other side effects of these drugs are described on the protocol and
patient information letter.
De Boelelaan 1117
Amsterdam 1081 HV
NL
De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
• Multiple myeloma/Salmon & Durie stage II/III A or B
• Previous lenaliomide- refractory disease (refractory to prior treatment indicates progressive disease on last prior therapy, best response of stable disease (not CR, VGPR, PR or PD) to last prior therapy, or progressive disease within 3 months (International Uniform Response Criteria for Multiple Myeloma)) is required in both the phase 1 and 2 part of the study1
• * 1 previous line of treatment
• Age * 18 years
• WHO performance 0, 1, 2, or 3
• Measurable disease i.e. serum M-protein (>10 g/l), or urinary light-chain excretion (>200 mg/24 h), or proven plasmacytoma by biopsy
• Life expectancy at least 3 months
• Written informed consent
• Patient commits to pregnancy prevention program (for detailed information see section 10.1)
•Negative pregnancy tests before inclusion if female of child baring potential;
Sexually active women of child bearing potential must agree to use 2 reliable forms of adequate contraception while on study drug (and 4 weeks before and after study drug) (for detailed information see section 10.1)
Men must agree not to father a child and to use a condom if his partner is of childbearing potential
1) A therapy-free interval or other lines of therapy between prior lenalidomide therapy and REP is allowed
Exclusion criteria
• Non-secretory myeloma
• Known hypersensitivity to lenalidomide
• Inadequate marrow reserve as defined by a platelet count <100 x 109/L or an absolute neutrophil count <1.5 x 109/L
• Systemic AL amyloidosis
• Uncontrolled or severe cardiovascular disease (NYHA class III or IV heart failure; myocardial infarction within the last 6 months of study entry); unstable angina; unstable cardiac arrythmias; clinically significant pericardial disease)
• Significant hepatic dysfunction (total bilirubin * 3 times normal value or transaminases * 3 times normal value), unless related to myeloma
• Creatinine clearance <30 mL/min
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, etc.)
• Patients known to be HIV-positive
• History of active malignancy during the past 5 years, except basal carcinoma of the skin or stage 0 cervical carcinoma
• Unable or unwillingness to comply with the pregnancy prevention program (for detailed information see section 10.1)
• Not able and/or willing to use adequate contraception
• Pregnant or lactating females
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-023577-20-NL |
| ClinicalTrials.gov | NCT01352338 |
| CCMO | NL34649.041.11 |