Therapy of Non-Hodgkin-Lymphoma by Combination of Lenalidomide + Rituximab, Dexa, High-dose ARA-C and CisP

Open-label, Multicenter Phase I/II Study: Salvage Therapy of Progressive and Relapsed Aggressive Non-Hodgkin-Lymphoma by Combination of Lenalidomide (Revlimid®) With Rituximab, Dexamethason, High-dose ARA-C and Cisplatinum (R²-DHAP)

The goal of this study is to evaluate efficacy and safety of the combination of lenalidomide, an immunomodulatory drug (IMiD) with a standard immunochemotherapy treatment, called R-DHAP. R-DHAP consists of a monoclonal antibody called Rituximab and chemotherapy consisting of Dexamethasone, high dose Cytarabine, often called Ara-C, and platinum based chemotherapy, either cisplatinum, or, if treatment with cisplatinum is contraindicated, carboplatinum.

This is a phase 1/2 study to evaluate the efficacy and safety of lenalidomide added to a standard chemotherapy regime of R-DHAP (Rituximab, Dexamethasone, high-dose Cytarabine, Cis/Carboplatinum) in the treatment of relapsed or refractory high-grade B-cell non-hodgkin-lymphoma (NHL).

The study hypothesis is that the combination of lenalidomide with standard immunochemotherapy will lead to an overall response rate of at least 60%. In this study, 3 rounds of immunochemotherapy in combination with lenalidomide will be administered. After the first or second round of therapy, peripheral hematopoetic stem cells will be harvested. Consolidation treatment with autologous or allogenic peripheral blood stem cell transplantation is recommended in all patients suitable, but is not part of the study.

In phase 1, up to six cohorts of at least 6 patients each will be treated with the study therapy, with lenalidomide in increasing dosages, to determine the maximum tolerated dose (MTD).

In phase 2, 50 patients will be treated with the MTD. Efficacy and safety will be evaluated.

Inclusion Criteria:

Age: 18-70

Risk groups: All risk groups

histology: diagnosis or a recurrent or primary progressive aggressive b-cell non-hodgkin lymphoma, in particular

• follicular lymphoma grade III
• diffuse large b-cell lymphoma
• burkitt lymphoma
• mantle cell lymphoma, blastoid variant
• aggressive marginal zone lymphoma

Performance status: ECOG 0-2

Criteria for women of childbearing potential:

Women of childbearing potential have to:

• understand the teratogenic risk associated with the study therapy, especially lenalidomide
• understand the need of reliable, uninterrupted birth control from 4 weeks prior to the start of the study drug, during the duration of the study treatment, and 4 weeks after completion of study treatment, and be able to reliably use birth control, except if the patient commits to absolute sexual abstinence, confirmed on a monthly basis

The following are effective methods of contraception:

• implant
• levonorgestrel-releasing intrauterine system (IUS)
• medroxyprogesterone acetate depot
• tubal sterilisation
• sexual intercourse with a vasectomised male partner only, vasectomy must be confirmed by two negative semen analyses
• ovulation-inhibitory progesterone-only pills If not established on effective contraception, the female subject must be referred to an appropriately trained health care professional for contraceptive advice in order that contraception can be initiated.
• Understand that even if she has amenorrhea, she must follow all the advice on effective contraception
• Understand the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy.
• Agree to have a medically supervised pregnancy test with a minimum sensitivity of 25 mIU/ml on the day of the study visit or in the 3 days prior to the study visit once the subject has been on effective contraception for at least 4 weeks. This requirement also applies to women of childbearing potential who practice complete and continued abstinence. The test should ensure the subject is not pregnant when she starts treatment.
• Agree to have a medically supervised pregnancy test every 4 weeks including 4 weeks after the end of study treatment, except in the case of confirmed tubal sterilization. These pregnancy tests should be performed on the day of the study visit or in the 3 days prior to the study visit. This requirement also applies to women of childbearing potential who practice complete and continued abstinence.

Male patients have to:

• Agree to use condoms throughout study drug therapy, during any dose interruption and for one week after cessation of study therapy if their partner is of childbearing potential and has no contraception.
• Agree not to donate semen during study drug therapy and for one week after end of study drug therapy.

All patients have to:

• Agree to abstain from donating blood while taking study drug therapy and for one week following discontinuation of study drug therapy.
• Agree not to share study medication with another person and to return all unused study drug to the investigator

Patients must be able to take low molecular weight heparin as prophylactic anticoagulation

Written informed consent is necessary

Exclusion Criteria:

• pregnant or lactating females
• already initiated salvage lymphoma therapy (except prephase as specified in this study)
• serious accompanying disorder or impaired organ function causing significant clinical problems and reduced lyfe expectancy, in particular: heart: angina pectoris CCS>2 cardiac failure NYHA>2 and/or EF<45% lungs: FeV1<60%, diffusion capacity <50% of the reference values kidneys: creatinine>2 times the upper reference limit liver: bilirubin >2 times the upper reference limit
• platelets <80000/mm³, leukocytes <2500/³
• CNS involvement of lymphoma
• known hypersensitivity to the medications to be used
• known HIV-positivity
• suspicion that patient compliance will be poor, especially that rules for effective contraception will not be followed
• simultaneous participation in other treatment studies
• non-conformity to eligibility criteria