Clinical Trials /

Lenalidomide, Ixazomib, and Rituximab as Front-Line Therapy for High Risk Indolent B-Cell Lymphoma

NCT02898259

Description:

A Phase IB/II Trial of Lenalidomide (Revlimid®), Ixazomib and Rituximab (RIXAR) as Front-line Therapy for High Risk Indolent B cell Lymphoma

Related Conditions:
  • Follicular Lymphoma
  • Lymphoblastic Lymphoma
  • Marginal Zone Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Lenalidomide, Ixazomib, and Rituximab as Front-Line Therapy for High Risk Indolent B-Cell Lymphoma
  • Official Title: A Phase IB/II Trial of Lenalidomide (Revlimid®), Ixazomib and Rituximab (RIXAR) as Front-line Therapy for High Risk Indolent B Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: CASE1414
  • NCT ID: NCT02898259

Conditions

  • B Cell Lymphoma
  • Lymphoma

Interventions

DrugSynonymsArms
IxazomibLenalidomide + Ixazomib + Rituximab
LenalidomideRevlimidLenalidomide + Ixazomib + Rituximab
RituximabRituxanLenalidomide + Ixazomib + Rituximab

Purpose

A Phase IB/II Trial of Lenalidomide (Revlimid®), Ixazomib and Rituximab (RIXAR) as Front-line Therapy for High Risk Indolent B cell Lymphoma

Detailed Description

      Primary:

      To determine the maximum tolerated dose and toxicity of the combination of oral ixazomib and
      lenalidomide plus rituximab in patients with previously untreated low-grade B cell lymphoma
      having high tumor burden by GELF criteria or FLIPI 3-5

      Secondary:

        -  To determine overall response rate in an expanded cohort at the MTD for follicular
           lymphoma and for non-follicular low-grade B cell lymphoma

        -  Duration of response, time to progression, progression free survival, time to treatment
           failure and overall survival

        -  Create tissue microarray from paraffin embedded tissue for future studies.

        -  Assessment of baseline lymphocyte subsets as prognostic markers.

      Overview of Study Design:

      This study combines three classes of agents that have non-overlapping mechanisms of action
      and toxicity profiles, with each pair having demonstrated clinical evidence of benefit
      without unexpected toxicity. We use the lenalidomide-rituximab backbone, feasible and active
      in lymphoma, and add a novel oral proteasome inhibitor to potentially enhance efficacy,
      minimize toxicity and limit patient visits for treatment.

      Patients with previously untreated low-grade B cell lymphoma having high tumor burden by GELF
      criteria or FLIPI 3-5 will be treated with the combination of oral ixazomib + lenalidomide +
      rituximab.

      The primary objective is to determine the maximum tolerated dose and toxicity of this
      regimen. The study will use a standard 3 + 3 design for determination of MTD during cycle 1.
      There will be three dose levels for escalation, followed by two expansion cohorts of 12
      patients each at the MTD, one cohort with follicular lymphoma and one cohort with
      non-follicular low-grade lymphoma (SLL, marginal zone, lymphoplasmacytic).
    

Trial Arms

NameTypeDescriptionInterventions
Lenalidomide + Ixazomib + RituximabExperimentalIxazomib will be orally administered with a starting dose of 2.0mg. Lenalidomide will be administered orally with a starting dose of 20mg. Rituximab will be administered intravenously at the standard dose of 375mg/m2. The study will use a standard 3 + 3 design for determination of MTD during cycle 1. There will be three dose levels for escalation, followed by two expansion cohorts of 12 patients each at the MTD, one cohort with follicular lymphoma and one cohort with non-follicular low-grade lymphoma (SLL, marginal zone, lymphoplasmacytic). Patients will be treated for 12 cycles of 4 week duration.
  • Ixazomib
  • Lenalidomide
  • Rituximab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed, low-grade B-lymphocyte Non-Hodgkin's
             Lymphoma (NHL) by the World Health Organization Classification:

               -  Follicular lymphoma grades 1, 2, and 3a

               -  Marginal zone B-cell lymphoma, including extranodal (MALT), nodal and splenic.
                  Excluding: Small lymphocytic lymphoma Lymphoplasmacytic lymphoma/Waldenström's
                  macroglobulinemia (WM)

               -  Lymphoplasmacytic lymphoma (including Waldenström's macroglobulinemia (WM))

          -  Must have stage 2, 3 or 4 disease, with either high tumor burden by Groupe d'Etude des
             Lymphomes Folliculaires (GELF) criteria and/or Follicular Lymphoma International
             Prognostic Index (FLIPI) 3-5

               -  To meet GELF criteria, patient must have at least one criterion:

                    -  Nodal or extranodal mass > 7 cm

                    -  At least 3 nodal masses: each > 3.0 cm in longest dimension

                    -  Systemic symptoms due to lymphoma or B symptoms

                    -  Splenomegaly with spleen > 16 cm by Computed Tomography (CT) scan

                    -  Evidence of compression syndrome (e.g., ureteral, orbital, gastrointestinal)
                       or pleural or peritoneal serous effusion due to lymphoma (irrespective of
                       cell content)

                    -  Leukemic presentation (> 5.0 x 10^9/L malignant circulating follicular or
                       lymphoma cells)

                    -  Cytopenias (absolute neutrophil count < 1.0 X 10^9/L, hemoglobin < 10 gm/dL,
                       and/or platelets <100 x 10^9/L).

               -  AND/OR To meet FLIPI criteria, patient must have at least 3 out of the following
                  5 criteria:

                    -  Age > 60 years

                    -  Ann Arbor stage III-IV

                    -  Hemoglobin level < 12 mg/dL

                    -  ≥ 5 nodal areas

                    -  Serum Lactate Dehydrogenase (LDH) level above normal

          -  Must have previously untreated lymphoma. A short (< 2 week) course of steroids for
             symptom palliation is permitted. Prior involved field radiotherapy for symptom
             palliation is permitted as long as there is measurable disease outside the radiation
             port. If radiotherapy has been given, there should be at least 7 days between last
             treatment and beginning of protocol therapy.

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.

          -  Patients must have adequate hematologic, hepatic, and renal function as defined below:

               -  Absolute neutrophil count (ANC) ≥ 1,000/mcL

               -  Platelet count ≥ 75,000/mcL

               -  Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN)

               -  Aspartate Aminotransferase (AST) (SGOT) ≤ 3 x institutional upper limit of normal

               -  Alanine Aminotransferase (ALT) (SGPT) ≤ 3 x institutional upper limit of normal

               -  Calculated creatinine clearance ≥ 30 mL/min/1.73 m^2

          -  Participants must agree to ongoing anticoagulation as prophylaxis against deep vein
             thrombosis (DVT) using aspirin (81 or 325 mg) daily, warfarin or low molecular weight
             heparin, or a patient already taking another oral anticoagulant (e.g. direct thrombin
             inhibitors for atrial fibrillation) may continue that agent.

          -  All study participants must be willing to register with the mandatory RevAssist
             program and be willing to comply with its requirements.

          -  All study participants must be registered into the mandatory Revlimid REMS® program,
             and be willing and able to comply with the requirements of the REMS® program.

          -  A woman of childbearing potential must agree to practice:

               -  2 effective methods of contraception, at the same time, from the time of signing
                  the informed consent form through 90 days after the last dose of study drug, OR

               -  True abstinence when this is in line with the preferred and usual lifestyle of
                  the subject.

               -  A woman of childbearing potential must have a negative serum or urine pregnancy
                  test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and
                  again within 24 hours of starting therapy with Revlimid®. Females of reproductive
                  potential must adhere to the scheduled pregnancy testing as required in the
                  Revlimid REMS® program.

          -  Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree
             to one of the following:

               -  Agree to practice effective barrier contraception during the entire study
                  treatment period and through 90 days after the last dose of study drug, OR

               -  Agree to practice true abstinence when this is in line with the preferred and
                  usual lifestyle of the subject.

          -  Subjects must have the ability to understand and the willingness to sign a written
             informed consent document and HIPAA consent document. Voluntary written consent must
             be given before performance of any study related procedure not part of standard
             medical care, with the understanding that consent may be withdrawn by the patient at
             any time without prejudice to future medical care.

        Exclusion Criteria:

          -  Patients who are receiving any other investigational agents.

          -  Female patients who are lactating or have a positive serum pregnancy test during the
             screening period.

          -  Major surgery within 14 days before enrollment.

          -  Radiotherapy within 14 days before enrollment. If the involved field is small (single
             nodal area), 7 days will be considered a sufficient interval between treatment and
             beginning of protocol therapy.

          -  Known central nervous system involvement.

          -  Infection requiring systemic antibiotic therapy or other serious infection within 14
             days before study enrollment.

          -  Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
             cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or
             myocardial infarction within the past 6 months.

          -  Systemic treatment, within 14 days before the beginning of protocol therapy, with
             CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin,
             phenobarbital), or use of St. John's wort.

          -  Known allergy to any of the study medications, their analogues, or excipients in the
             various formulations of any agent. Specifically, prior desquamating rash or erythema
             nodosum during prior thalidomide or other similar agents.

          -  Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
             absorption or tolerance of ixazomib or lenalidomide including difficulty swallowing.

          -  Diagnosed or treated for another malignancy within 2 years before study enrollment or
             previously diagnosed with another malignancy and have any evidence of residual
             disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are
             not excluded if they have undergone complete resection.

          -  Patient has ≥ Grade 2 peripheral neuropathy on clinical examination during the
             screening period.

          -  Participation in other clinical trials, including those with other investigational
             agents not included in this trial, within 30 days of the start of this trial and
             throughout the duration of this trial.

          -  Any prior use of Revlimid® or Velcade®.

          -  Known seropositivity for, or active viral infection with, Human Immunodeficiency Virus
             (HIV), Hepatitis B Virus (HBV) (unless due to vaccination), or Hepatitis C Virus
             (HCV). HIV-positive patients on combination antiretroviral therapy are ineligible
             because of the potential for pharmacokinetic interactions with lenalidomide and
             ixazomib. In addition, these patients are at increased risk of lethal infections when
             treated with marrow suppressive therapy. Appropriate studies will be undertaken in
             patients receiving combination antiretroviral therapy when indicated.

          -  Pregnant or breastfeeding women are excluded from this study because lenalidomide has
             known teratogenic effects. Because there is an unknown, but potential risk for adverse
             events in nursing infants secondary to treatment of the mother with lenalidomide,
             breastfeeding should be discontinued if the mother is treated with lenalidomide. These
             potential risks may also apply to other agents used in this study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:maximum tolerated dose of oral ixazomib
Time Frame:Up to 15 months after beginning treatment
Safety Issue:
Description:To determine the maximum tolerated dose and toxicity of the combination of oral ixazomib and lenalidomide plus rituximab in patients with previously untreated low-grade B cell lymphoma having high tumor burden by GELF criteria or FLIPI 3-5

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:Up to 15 months after beginning treatment
Safety Issue:
Description:These criteria are based on the Revised Response Criteria for Malignant Lymphoma and include the following categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Relapse and Progression (PD).
Measure:Duration of response
Time Frame:Up to 15 months after beginning treatment
Safety Issue:
Description:Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented.
Measure:Time to progression
Time Frame:Up to 15 months after beginning treatment
Safety Issue:
Description:Duration of time from start of treatment to time of progression.
Measure:Progression free survival
Time Frame:Up to 15 months after beginning treatment
Safety Issue:
Description:progression free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
Measure:Time to treatment failure
Time Frame:Up to 15 months after beginning treatment
Safety Issue:
Description:Time to treatment failure (event-free survival) is defined as the time from study entry to first event of disease progression, discontinuation of treatment for any reason, initiation of new treatment, or death.
Measure:Overall survival
Time Frame:Up to 15 months after beginning treatment
Safety Issue:
Description:Overall survival is defined as the date of study entry to the date of death.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Brian Hill, MD, PhD

Trial Keywords

  • Lenalidomide
  • Ixazomib
  • Rituximab

Last Updated

November 12, 2019