| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer in the lymph nodes. |
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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 | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003903 |
| E.1.2 | Term | B-cell lymphoma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003902 |
| E.1.2 | Term | B-cell lymphoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
To determine the efficacy and rate of severe toxicity of the two arms of the randomised trial (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 overall response rate, molecular response rate, event free survival, progression free survival, and overall survival rate.
To determine the time to the next anti-lymphoma treatment and relative dose intensity of Lenalidomide and, if applicable, Bendamustine. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The UK is participating in three translational research aspects of the study:
1)To identify tissue-based predictive factors for response
2)To study longitudinally the effect of lenalidomide versus lenalidomide-bendamustine on T cell subsets and NK cells in peripheral blood and at the tissue level
3)To evaluate the clinical utility of PET-CT scanning in FL
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|
| E.3 | Principal inclusion criteria |
Relapsed FL grade 1, 2, 3a;
Ann Arbor stage II-IV at relapse;
A biopsy or FNA to show CD20 postivity 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 three 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:
1)Only one prior treatment (with a maximum of 6 cycles) with bendamustine is
allowed
2)Patients must have had a PR or CR following prior use of bendamustine
3)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 (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). Patients must be able to adhere to the requirements of the Lenalidomide Pregnancy Prevention
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 or rituximab maintenance treatment);
Clinical or histologic signs of transformation or prior transformed phase of FL;
Prior allogeneic SCT;
Prior autologous SCT less than one year ago;
Any prior use of lenalidomide;
Concurrent use of other anti-cancer agents or treatments;
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);
Active fungal, bacterial, and/or viral infection;
Recent vaccination for yellow fever (within 4 weeks before registration)
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);
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 skin, 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) |
Primary endpoints
-complete remission rate (based on the revised Cheson criteria)
-rate of severe toxicity.
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The number and percentage of patients who achieve disease response (Complete Response) will be assessed at end of treatment (approximately 6 months after randomisation).Number of patients who suffer grade 3 or 4 toxicity will be assessed throughout treatment (up to 6 months). |
|
| 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 induction).
- 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-overall response rate and molecular response rate will be determined at end of treatment (approximately 6 months after randomisation).
- Event free survival will be determined 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 induction).(Approximately 6 months plus the maintenance phase.
- Progression free survival will be determined time from registration to disease progression, relapse or death, whichever occurs first.
- For disease free survival until progression, relapse, death or next antilymphoma treatment.
- overall survival from registration until death.
- Relative dose will be determined after the induction period.
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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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 20 |
| 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 | No |
| 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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| The end of the trial will be when last patient has completed their 8 year follow up visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 14 |
| 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 | 20 |
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