A randomized phase III multicenter trial assessing efficacy and toxicity of a combination of Rituximab and Lenalidomide (R2) vs Rituximab alone as maintenance after chemoimmunotherapy with Rituximab-chemotherapy (R-CHT) for relapsed/refractory FL patients not eligible for autologous transplantation (ASCT)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Italiana Linfomi Ets

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

15 May 2014 → ongoing

Decision date (initial)

2025-01-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Celgene Corporation (a Bristol Myers Squibb company)

External identifiers

EU CT number

2024-511640-11-00

EudraCT number

2012-003392-18

ClinicalTrials.gov

NCT02390869

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To evaluate in patients responsive to induction whether the R2-MANT program may improve progression-free survival (PFS) compared to patients treated with R-MANT.

Secondary objectives 5

1. To compare in patients respondents to induction the R2-MANT vs the R-MANT program for: - Safety, in terms of rate of grade III-IV adverse events. - Efficacy, in terms of OS.
2. To evaluate the activity of maintenance program on minimal residual disease (MRD) assessed in terms of: rate of conversion to molecular remission, rate of molecular relapse, disease kinetics by real time PCR in the bone marrow (BM) and peripheral blood (PB).
3. To assess the prognostic impact of molecular persistence and molecular relapse on PFS and OS.
4. To assess quality of life (QoL) at study entry and to compare QoL between study arms at the end of induction and at 6, 12 and 24 months of maintenance, using the EORTC QLQ-C30C questionnaire.
5. To compare the cost-effectiveness of treatment arms by performing a detailed analysis of direct medical costs including chemotherapy, lenalidomide, patient monitoring, management of side effects and relapses through the evaluation of total healthcare costs and Quality Adjusted Life Years (QALYs) using Euro-Qol (EQ-5D) questionnaire.

Conditions and MedDRA coding

Follicular lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Follicular lymphoma grade I, II and IIIa according to the WHO classification. Re-biopsy at study entry is strongly encouraged but mandatory only in case of suspected transformation (elevated LDH or rapidly-growing disease or unusual relapse presentation)
2. First or second relapse or progression following R-chemotherapy (Rituximab maintenance and IF radiotherapy are not considered treatment lines).
3. Previous treatment with Bendamustine can be considered eligible if relapse occurred after ≥ 24 months.
4. Age >18 years
5. Patients not eligible for high dose chemotherapy and ASCT because of: age ≥ 65 years, impaired PS or organ function due to major heart, lung, liver, kidney or other comorbidities or relapsed or refractory disease after previous ASCT.
6. stage II, III or IV according to Ann Arbor at relapse.
7. Need of treatment according to SIE-SIES-GITMO guidelines for follicular lymphoma: stage II-IV with systemic symptoms, high tumor burden (i.e. >3 lymph nodes measuring >3 cm or a single lymph node >7 cm), extranodal disease, cytopenia due to marrow involvement, spleen involvement (≥16 cm by CT), leukemic phase, serious effusion, symptomatic or life endangering organ involvement, rapid lymphoma progression, consistently increased LDH levels.
8. Must be able to adhere to the study visit schedule and other protocol standards.
9. ECOG performance status ≤ 2 (except when PS impairment is related to lymphoma).
10. Be willing and able to comply with the protocol for the duration of the study.
11. Absolute neutrophil count (ANC) ≥ 1.5 x 10 9/L unless due to marrow involvement by lymphoma; and platelets count ≥ 75 x 109/L unless due to marrow involvement by lymphoma
12. Calculated creatinine clearances ≥ 40 ml/min.
13. All patients must agree to be using effective contraception for the entire treatment period according to standard guidelines for patients receiving lenalidomideFemales of childbearing potential (FCBP) must: - Have a negative medically supervised pregnancy test prior to starting of study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices complete and continued sexual abstinence. - Either commit to continued abstinence from heterosexual intercourse (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy.  Male subjects must: - Agree to use a condom during sexual contact with a FCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and for 28 days after discontinuation of study therapy. - Agree to not donate semen during study drug therapy and for 28 days after discontinuation of study drug therapy.  All subjects must: - Have an understanding that the study drug could have a potential teratogenic risk. - Agree to abstain from donating blood while taking study drug therapy and for 28 days after discontinuation of study drug therapy. - Agree not to share study medication with another person. - Agree to be counselled about pregnancy precautions and risk of fetal exposure.

Exclusion criteria 18

1. Any lymphoma subtype other than FL including transformed FL
2. Grade 3b follicular lymphoma
3. Radiotherapy within 3 months prior to study entry
4. Major surgery (excluding lymph node biopsy) within 28 days prior to registration.
5. HIV positive serology. HBV and HCV positive patients will be not excluded from the study if the hepatic enzymes are within the ranges later defined. HBV occult carriers patients will be given lamivudine as prophylaxis starting one week before chemotherapy. HbsAg, HBcAb, HBV-DNA and HCV-RNA levels will be monitored twice every month in HCV or HBV positive patients.
6. Life expectancy < 6 months
7. Known sensitivity or allergy to murine products
8. Prior history of malignancies, other than follicular lymphoma, unless the subject has been free of the disease for > 3 years with the exception of adequately cured localized non-melanoma skin cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast or incidental histological finding of prostate cancer (TNM stage of T1a or T1b)
9. Prior use of lenalidomide.
10. Neuropathy > Grade 1.
11. Myocardial infarction within the last 6 months
12. Presence or history of CNS involvement by lymphoma
13. Subjects who are at a high risk for a thromboembolic event and are not willing to take venous thromboembolic (VTE) prophylaxis.
14. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) > 3x upper limit of normal (ULN), except in subjects with documented liver involvement by lymphoma
15. Total bilirubin > 2.0 mg/dl (34 umol/L) except in cases of Gilberts Syndrome and documented liver involvement by lymphoma
16. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
17. Pregnant or lactating females
18. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study, or which confounds the ability to interpret data from the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint will be the Progression-free Survival. PFS will be measured from the date of randomization to the date of documented first occurrence of disease progression or relapse or to the date of death from any cause. Patients without events considered and patients who are lost to follow up will be censored at their last assessment date.

Secondary endpoints 6

1. OS will be measured from the date of randomization and from enrolment to the date of death from any cause. Patients who have not died at the time of the final analysis will be censored at the date of the last contact.
2. Toxicity will be classified according to definitions of Common Terminology Criteria for Adverse Event latest version (CTCAE). It will be determined by the incidence of severe, life- threatening (CTCAE grade 3, 4 and 5) and/or serious adverse events (Infusion-related reactions).
3. Rate of molecular remission will be defined as the proportion of patients PCR negative for Bcl-2/IgH at different time-points including those achieving continuous MR in two or more consecutive time-points.
4. Rate of molecular conversion will be defined as the proportion of patients from baseline PCR-positivity to PCR-negativity.
5. Rate of molecular relapse will be defined as the proportion of patients from PCR-negativity to PCR-positivity.
6. QoL will be measured at the baseline, the end of induction and at 6, 12 and 24 months of maintenance through the EORTC QLQ-C30 questionnaire.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Italiana Linfomi Ets

Sponsor organisation

Fondazione Italiana Linfomi Ets

Address

Piazza Filippo Turati 5

City

Alexandria

Postcode

15121

Country

Italy

Scientific contact point

Organisation

Fondazione Italiana Linfomi Ets

Contact name

Barbara Botto, MD

Public contact point

Organisation

Fondazione Italiana Linfomi Ets

Contact name

Barbara Botto, MD

Locations

1 EU/EEA country · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications