Main info

Identifier:

HO110 FL

Sponsor:

HOVON

Working group party:

Lymphoma

Stage:

2nd Line

Echelon:

Level C-HIC&C-SCT

Included patients:

110

(of 174)

Active sites:

50

(of 55)

Title:

ReBeL study: a randomized phase I/II trial of lenalidomide and rituximab with or without bendamustine in patients ≥ 18 years with relapsed follicular lymphoma A HOVON/GLSG/NCRI study.

Timeline

News

Details

Phase:

Prospective randomized Phase I/II study

Monitoring Type:

Not any more

Objectives:

For the phase I part of the study:

• To determine the feasibility and recommended dose level (RDL) of the combination of lenalidomide, rituximab, and bendamustine in a 28 day schedule.

For the phase II part of the study:

• To study the efficacy and toxicity of the two arms of the study (LR: lenalidomide and rituximab, and LRB: lenalidomide, rituximab, and bendamustine) in patients with relapsed follicular lymphoma, and to identify the most promising of these two treatment arms.
• To determine the value of PET-CT scanning in response assessment of FL patients
• To identify predictive factors for response. For this purpose, in the non-chemotherapy-based lenalidomide-rituximab regimen and in the chemotherapy-based lenalidomide-rituximab-bendamustine regimen, various tissue–associated markers will be explored both on tumor cells and on non-malignant cells of the tumor microenvironment using tissue microarrays or primary lymphoma biopsy samples. 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 treatment with the non-chemotherapy-based lenalidomide-rituximab regimen or from the chemotherapy-based lenalidomide-rituximab-bendamustine regimen.
• To specifically explore treatment-induced alterations in non-malignant immune cell populations. For this purpose, alterations during treatment in these populations in the peripheral blood and at the tissue level of involved lymph nodes will be performed. For the latter analysis sequential fine needle aspirations and biopsies will be performed in a selection of patients. The sequential biopsies will also be used to study the biological mechanisms of tumor cell kill.

Eligibility

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 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 (unless bone marrow infiltration), 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 Risk Management Plan;
• Written informed consent

Exclusion Criteria:

• Rituximab-refractory patients (definition: progression during or within 6 months after rituximab containing immunochemotherapy. Patients relapsing under rituximab maintenance treatment are eligible, if at biopsy or FNA CD20 positivity is confirmed);
• Clinical or histologic signs of transformation. Patients with a prior 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 occurred >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 equivalent 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);
• 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

Registration Details

Participating Sites

= Active hospitals

= Inactive hospitals