| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016905 |
| E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
For the phase I part of the study: to determine the dose limiting toxicity (DLT) and recommended dose level (RDL) of lenalidomide and bendamustine given in combination with rituximab for the phase II part of the study
For the phase II of the study: to determine the efficacy and toxicity of the two arms of the study (arm A: lenalidomide and rituximab, and arm B: lenalidomide, rituximab and bendamustine) in patients with relapsed follicular lymphoma (FL)
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| E.2.2 | Secondary objectives of the trial |
• to determine the value of PET-CT scanning in response assessment of FL patients
• To identify predictive factors for response. For this purpose, various tissue–associated markers will be explored both on tumor cells and on non-malignant cells of the tumor microenvironment. These studies will be supported by gene expression profiling in a selection of the patients. Results will be correlated to clinical outcome as well as PET-CT results and circulating subsets of T cells and NK cells. An exploratory analysis will be performed to identify putative covariates that might indicate which patient populations would benefit most from protocol treatment.
• To specifically explore treatment-induced alterations in non-malignant immune cell populations. The sequential biopsies will also be used to study the biological mechanisms of tumor cell kill.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Relapsed FL grade 1, 2, 3a, see protocol appendix A;
• Ann Arbor stage II-IV at relapse, see protocol appendix B;
• A biopsy or FNA to show CD20 positivity is required. A biopsy/FNA performed at any time since the most recent therapy is acceptable as long as this shows FL and there is no clinical concern for transformation at the time of study entry. In case clinically transformation is suspected, a biopsy should be obtained at the time of study entry to exclude transformation.
• A maximum of five prior systemic treatment regimens (patients who have had a prior allogeneic SCT are excluded; prior autologous SCT (if > 1 year ago) is allowed);
• Prior bendamustine is allowed, under the following conditions:
- Only one prior treatment (with a maximum of 6 cycles) with bendamustine is allowed
- Patients must have had a PR or CR following prior use of bendamustine
- Prior treatment with bendamustine must have taken place ≥24 months ago (measured from the start of prior bendamustine treatment, i.e. approximately 18 months from the end of prior bendamustine treatment);
• Subjects must have an indication for treatment based on one or more of the following criteria:
- Involvement of at least 3 nodal sites, each with a diameter > 3 cm
- Symptomatic splenomegaly
- Bulky disease at study entry according to the GELF criteria: nodal or extranodal mass (except spleen) > 7 cm in its greatest diameter
-B-symptoms (absence or presence of fever and/or night sweats and/or unexplained loss of 10% of body weight or more in the 6 months preceding diagnosis)
- Hb < 10 g/dl (6.2 mmol/l) (if caused by bone marrow infiltration and not otherwise explained)
- thrombocytopenia: platelets < 100x109/l) caused by bone marrow infiltration
- Organ compression syndrome (e.g. hydronephrosis caused by lymphadenopathy)
- Pleural/peritoneal effusion
- Symptomatic extranodal manifestations;
• Measurable disease as defined in appendix C (patients with only bone marrow involvement are therefore not eligible);
• Age ≥ 18 years;
• Able to adhere to the study visit schedule and other protocol requirements;
• WHO performance status of 0-2;
• Laboratory test results within these ranges: absolute neutrophil count ≥ 1.5x 109/l, platelet count ≥ 100x 109/l (unless bone marrow infiltration), creatinine clearance ≥ 50 ml/min, total bilirubin ≤ 30 µmol/l (1,75 mg/dl), AST & ALT ≤ 3x ULN;
• Females of childbearing potential must have a negative serum or urine pregnancy test within 10 - 14 days prior to and again within 24 hours of starting lenalidomide treatment;
• Patients must be willing and capable to use adequate contraception during and after the therapy (all men, all pre-menopausal women; see protocol chapter 10.2 and 12.5). Patients must be able to adhere to the requirements of the Lenalidomide Pregnancy Prevention Risk Management Plan;
• Written informed consent.
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| E.4 | Principal exclusion criteria |
• Rituximab-refractory patients (definition: progression during or within 6 months after rituximab containing immunochemotherapy. Patients relapsing under rituximab containing maintenance treatment are eligible, if at biopsy or FNA CD20 positivity is confirmed);
• Clinical or histologic signs of transformation. Patients with a proir transformed phase of FL are eligible IF there are currently no signs of transformation and there is histologic proof that the current phase is not transformed AND the transformed phase occured >2 years ago
• Prior allogeneic SCT;
• Prior autologous SCT less than one year ago;
• Any prior use of an immunomodulatory agents such as lenalidomide pomalidomide or CC-122
• Concurrent use of other anti-cancer agents or treatments;
• the use of prednisolone for any other indication than lymphoma treatment is allowed at a maximum dose of or equivilant to 20 mg prednisolone;
• Concurrent use of allopurinol, e.g. because of gout. Patients with gout are advised to switch to another anti-gout medication, because of the risk of Stevens-Johnson Syndrome observed in patients using bendamustine and allopurinol;
• Use of any other experimental drug or therapy within 28 days of baseline;
• Hepatitis B (including HBcAb) positive, Hepatitis C positive and/or HIV positive patients;
• Patients with uncontrolled autoimmune hemolytic anemia (AIHA) or autoimmune thrombocytopenia (ITP);
• Recent vaccination for yellow fever (within 4 weeks before registration)
• Active fungal, bacterial, and/or viral infection;
• Pregnant or breast-feeding females (lactating females must agree not to breast feed while taking lenalidomide);
• Known hypersensitivity and/or serious adverse reactions to lenalidomide or similar drugs;
• Intolerance of exogenous protein administration, or known allergy to murine products;
• Uncontrolled hyperthyroidism or hypothyroidism;
• Neuropathy ≥ grade 2 at time of inclusion;
• Clinically symptomatic severe cardiac dysfunction (NYHA III-IV, see protocol appendix G);
• Clinically symptomatic severe pulmonary dysfunction;
• Severe neurologic or psychiatric diseases;
• Concurrent severe and / or uncontrolled medical condition (e.g. uncontrolled diabetes, infection);
• History of active malignancy during the past 5 years with the exception of basal carcinoma of the dkin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, prostate cancer (TNM stage of T1a or T1b);
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I
• dose limiting toxicity
• recommended dose level of lenalidomide and of bendamustine in combination with rituximab (for arm B of the phase II of the study)
Phase II
• complete remission rate (based on the revised Cheson criteria60)
• rate of severe toxicity.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For phase I of the study:
After every 3 patients have completed cycle 1 in each dose level of phase I of the study, a safety analysis of dose-limiting toxicity (DLT) is performed to determine whether patients can be included in the next dose level. Another analysis will be performed when all data of cycles 1 and 2 are available, in order to determined the recommended dose level (RDL) for the phase II part
For phase II of the study:
as soon as all data regarding induction treatment for all patients are available and have been validated |
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| E.5.2 | Secondary end point(s) |
• Overall response rate following induction treatment and at the end of maintenance rituximab
• Molecular response rate.
• Event free survival (EFS; i.e. time from registration to induction failure, progression, relapse or death, whichever occurs first). A patient counts as induction failure if no PR or CR was achieved after induciton.
• progression free survival (PFS; i.e. time from registration to disease progression, relapse or death, whichever occurs first);
• disease free survival (DFS; i.e. time from CR to relapse or death, whichever comes first)
• time to next antilymphoma treatment
• overall survival (O.S.; i.e. time from registration until death)
•relative dose intensity of lenalidomide and, if applicable, bendamustine
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Additional analyses will be performed when for all patients the data on maintenance treatment have been evaluated, and also when complete follow up until 8 years from registration is available for all patients |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| No direct comparison between the two treatment arms will be performed. |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 32 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 11 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 11 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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