Clinical Trials /

R-ICE and Lenalidomide in Treating Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma

NCT02628405

Description:

This phase I/II trial studies the side effects and best dose of lenalidomide when given together with rituximab-ifosfamide-carboplatin-etoposide (R-ICE) and to see how well they work in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement and that has not responded to previous treatment. Drugs used in chemotherapy, such as rituximab, ifosfamide, carboplatin, etoposide, and lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving lenalidomide with R-ICE may be a better treatment for patients with diffuse large B-cell lymphoma.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Primary Mediastinal B-Cell Lymphoma
  • Transformed Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: R-ICE and Lenalidomide in Treating Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma
  • Official Title: Phase I/II, Open-Label Study of R-ICE (Rituximab-Ifosfamide-Carboplatin-Etoposide) With Lenalidomide-R-ICE (R2-ICE) in Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Clinical Trial IDs

  • ORG STUDY ID: RU051417I
  • SECONDARY ID: NCI-2015-01990
  • SECONDARY ID: ACCRU RU051417I
  • SECONDARY ID: RU051417I
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT02628405

Conditions

  • Diffuse Large B-Cell Lymphoma
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma
  • Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma
  • Transformed Recurrent Non-Hodgkin Lymphoma

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplat, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboTreatment (R2-ICE)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Treatment (R2-ICE)
IfosfamideAsta Z 4942, Asta Z-4942, Cyfos, Holoxan, Holoxane, Ifex, IFO, IFO-Cell, Ifolem, Ifomida, Ifomide, Ifosfamidum, Ifoxan, IFX, Iphosphamid, Iphosphamide, Iso-Endoxan, Isoendoxan, Isophosphamide, Mitoxana, MJF 9325, MJF-9325, Naxamide, Seromida, Tronoxal, Z 4942, Z-4942Treatment (R2-ICE)
LenalidomideCC-5013, CC5013, CDC 501, RevlimidTreatment (R2-ICE)
RituximabBI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab Biosimilar BI 695500, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, RTXM83Treatment (R2-ICE)

Purpose

This phase I/II trial studies the side effects and best dose of lenalidomide when given together with rituximab-ifosfamide-carboplatin-etoposide (R-ICE) and how well they work in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement and that has not responded to previous treatment. Biological therapies, such as lenalidomide, may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as R-ICE, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving lenalidomide with R-ICE may be a better treatment for patients with diffuse large B-cell lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the safety and maximum tolerated dose (MTD) of the addition of lenalidomide to
      the R-ICE chemoimmunotherapy regimen
      (lenalidomide-rituximab-ifosfamide-carboplatin-etoposide [R2ICE]) for the treatment of
      primary-refractory/first-relapse B-cell lymphoma. (Phase I) II. To determine if the addition
      of lenalidomide (based on dose determination from phase I) to the R-ICE chemoimmunotherapy
      regimen (R2-ICE) would lead to clinically meaningful improvement in the overall response
      rates (ORR) for patients with first-relapse/refractory diffuse large B-cell lymphoma
      (DLBCL). (Phase II)

      SECONDARY OBJECTIVES:

      I. To evaluate the effect of the addition of lenalidomide to RICE on the number (percentage)
      of patients proceeding to stem cell transplant (SCT).

      II. To evaluate the effect of the addition of lenalidomide to RICE on other surrogate
      outcome measures including complete metabolic response (CMR) rate and overall survival.

      TERTIARY OBJECTIVES:

      I. ORR based on germinal center B-cell-like (GCB) versus non-GCB subtypes. II. Role of
      positron emission tomography (PET)/computed tomography (CT) scans. III. Minimal residual
      disease (MRD) detection and quantification. IV. Future tissue and blood based studies.

      OUTLINE: This is a phase I, dose-escalation study of lenalidomide followed by a phase II
      study.

      Patients receive lenalidomide orally (PO) daily on days 1-14, rituximab intravenously (IV)
      on day 1, ifosfamide IV over 24 hours on day 2, carboplatin IV over 1-2 hours on day 2, and
      etoposide IV over 1 hour on days 1-3. Treatment repeats every 21 days for 2 courses in the
      absence of disease progression or unacceptable toxicity. Patients achieving CMR, partial
      metabolic response (PMR), or no metabolic response (NMR) may receive 2 more courses per
      physician discretion. After completion of 2 cycles of R2ICE treatment, patients achieving
      objective status of CMR, PMR or NMR may proceed to SCT during the event monitoring phase.

      After completion of study treatment, patients are followed up every 3 months for 3 years and
      then yearly for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (R2-ICE)ExperimentalPatients receive lenalidomide PO daily on days 1-14, rituximab IV on day 1, ifosfamide IV over 24 hours on day 2, carboplatin IV over 1-2 hours on day 2, and etoposide IV over 1 hour on days 1-3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CMR, PMR, or NMR may receive 2 more courses per physician discretion. After completion of 2 cycles of R2ICE treatment, patients achieving objective status of CMR, PMR or NMR may proceed to SCT during the event monitoring phase.
  • Carboplatin
  • Etoposide
  • Ifosfamide
  • Lenalidomide

Eligibility Criteria

        Inclusion Criteria:

          -  Histological confirmation of expressing cluster of differentiation (CD)20 antigen as
             determined by pathology at the respective institution and central pathology review at
             Mayo Clinic Rochester; Note: for phase I, all types of B-cell lymphomas would be
             allowed to participate; for phase II, only DLBCL patients are allowed; patients with
             transformed lymphoma, primary mediastinal large B-cell lymphoma (PMLBCL) and
             primary-refractory lymphoma are also allowed to participate in both phases of the
             study; Note: central pathology review is mandatory but is retrospective in nature;
             slides should be submitted within 30 days of enrollment; patients can be enrolled
             prior to submission of slides

          -  Measurable disease (at least 1 lesion >= 1.5 cm in diameter) as detected by PET/CT

          -  Only 1 line of previous anti-lymphoma therapy is allowed and not currently receiving
             any other agent that would be considered as a treatment for the lymphoma; patients
             must be >= 2 weeks from prior anti-lymphoma therapy; the use of steroids and/or
             rituximab up to 1 week prior to registration for management of symptoms is allowed

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

          -  Absolute neutrophil count (ANC) >= 1500/mm^3

          -  Platelet count >= 75,000/mm^3

          -  Total bilirubin =< 2 × upper limit of normal (ULN) (unless related to lymphoma or
             Gilbert's disease) OR =< 5 × ULN for subjects with documented or suspected Gilbert's
             disease, or related to involvement of the liver by the lymphoma

          -  Aspartate transaminase (AST) and alanine aminotransferase (ALT) (serum glutamate
             pyruvate transaminase [SGPT]) =< 3 x ULN unless evidence of the direct liver and/or
             bone involvement by lymphoma, then =< 5 x ULN

          -  PHASE I: Subjects must have calculated creatinine clearance >= 60 ml/min by
             Cockcroft-Gault formula

          -  PHASE II: Subjects must have calculated creatinine clearance >= 30 ml/min by
             Cockcroft-Gault formula

          -  Negative pregnancy test done =< 14 days prior to registration, for women of
             childbearing potential only

          -  Provide informed written consent

          -  Willing to return to enrolling institution for follow-up (during the active
             monitoring phase of the study [i.e. active treatment and observation])

          -  Willing to provide blood samples for correlative research purposes

          -  Considered transplant-eligible, as determined by the opinion of the investigator at
             the participating institution; the participating institution does not need to be a
             transplant center but patients can be referred to a transplant center if needed

          -  Willing and able to register into and comply with the mandatory requirements of
             Celgene's REVLIMID (lenalidomide) Risk Evaluation and Mitigation Strategies (REMS™)
             program

          -  Females of reproductive potential are willing and able to adhere to the scheduled
             pregnancy testing as required by Celgene's REVLIMID REMS™ program

          -  Willing and able to take aspirin (81 mg) daily as prophylactic anticoagulation
             (patients intolerant to acetylsalicylic acid [ASA] may use warfarin or low molecular
             weight heparin)

        Exclusion Criteria:

          -  Pregnant women

          -  Nursing women

          -  Men or women of childbearing potential who are unwilling to employ adequate
             contraception

               -  NOTE: patients unwilling or unable to do any of the following are also excluded:

                    -  Men must agree to use a latex condom during sexual contact with a female of
                       child-bearing potential even if they have had a successful vasectomy

                    -  Women of child bearing potential must agree to use 2 methods of reliable
                       contraception simultaneously

                    -  All patients must be counseled at a minimum of every 21 days about
                       pregnancy precautions and risks of fetal exposure

          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the
             judgment of the investigator, would make the patient inappropriate for entry into
             this study or interfere significantly with the proper assessment of safety and
             toxicity of the prescribed regimens including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Immunocompromised patients and patients known to be human immunodeficiency virus
             (HIV) positive and currently receiving antiretroviral therapy; NOTE: patients known
             to be HIV positive, but without clinical evidence of an immunocompromised state, are
             eligible for this trial; patients with HIV on antiretroviral therapy other than
             zidovudine (AZT) and/or stavudine and without prior acquired immunodeficiency
             syndrome (AIDS) defining conditions and adequate CD4 count (> 400) are eligible

          -  History of myocardial infarction =< 180 days prior to registration or congestive
             heart failure requiring use of ongoing maintenance therapy for life-threatening
             ventricular arrhythmias

          -  Receiving any other investigational agent which would be considered as a treatment
             for the primary neoplasm; patients must be >= 2 weeks from prior anti-lymphoma
             therapy; the use of steroids and/or rituximab up to 1 week prior to registration for
             management of symptoms is allowed

          -  Other active malignancy =< 3 years prior to registration; EXCEPTIONS: non-melanotic
             skin cancer, carcinoma-in-situ of the cervix, or any cancer that, in the judgment of
             the investigator, has been treated with curative intent and will not interfere with
             the study treatment plan and response assessment; NOTE: if there is a history of
             prior malignancy, they must not be receiving other specific treatment such as
             radiation, chemotherapy, or immunotherapy for their cancer

          -  Unable or unwilling to take any prophylaxis; patients with history of or new/active
             deep vein thrombosis/embolism/thrombophilia are allowed to participate if they are on
             appropriate therapeutic anticoagulation during the treatment on the trial; these
             patients would not need the aspirin with the lenalidomide unless clinically
             indicated; therefore, patients must be able and willing to receive anticoagulation
             (prophylaxis versus therapeutic as clinically indicated)

          -  No history of radiation therapy to >= 25% of the bone marrow for other diseases

          -  Receiving erythroid stimulating agents (epoetin alfa [EPO]: Procrit, Aranesp)

          -  Patients with active or prior central nervous system (CNS) lymphoma or cerebrospinal
             fluid involvement with malignant lymphoma cells; NOTE: these patients are usually
             treated with CNS directed therapy; screening for cerebrospinal fluid (CSF)/CNS
             involvement is NOT required but can be performed per treating medical doctor (MD)
             discretion

          -  Active hepatitis B as defined by seropositivity for hepatitis B surface antigen
             (HBsAg); subjects with positive hepatitis B core antibody titers and normal liver
             transaminases are allowed provided that antiviral prophylaxis is administered per
             institutional guidelines; NOTE: subjects with hepatitis C antibody will be eligible
             provided that they do not have elevated liver transaminases or other evidence of
             active hepatitis
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (%) as assessed by PET/CT scans after 2 cycles of therapy
Time Frame:21 days
Safety Issue:
Description:The number and severity of all adverse events (overall and by dose-level) will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion. This will provide an indication of the level of tolerance for this treatment combination in this patient group.

Secondary Outcome Measures

Measure:Percentage of Adverse Events (%) categorized based on severity using CTCAE system/organ/class criteria
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The frequency and percentage of patients experiencing a particular grade/severity of adverse event would be aggregated and combined data reported.
Measure:Overall proportion of patients (%) proceeding to stem cell transplant
Time Frame:At 42 days of treatment
Safety Issue:
Description:Estimated by the number of patients who proceed to transplant divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Academic and Community Cancer Research United

Last Updated

April 18, 2017