Clinical Trials /

Ixazomib & Rituximab After Stem Cell Transplant in Treating Patients With Mantle Cell Lymphoma in Remission

NCT02632396

Description:

This phase I/II trial studies the side effects and best dose of ixazomib citrate (ixazomib) when given together with rituximab and to see how well they work after stem cell transplant in treating patients with mantle cell lymphoma that are no longer showing signs or symptoms of cancer. Ixazomib may stop the growth of cancer cell by blocking enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Giving ixazomib together with rituximab after transplant may help prevent the cancer from coming back.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ixazomib & Rituximab After Stem Cell Transplant in Treating Patients With Mantle Cell Lymphoma in Remission
  • Official Title: A Phase I/II Study of MLN9708 as Post-Transplant Maintenance for Patients With Mantle Cell Lymphoma Undergoing Autologous Stem Cell Transplant in First Remission

Clinical Trial IDs

  • ORG STUDY ID: IRB00076016
  • SECONDARY ID: NCI-2015-01943
  • SECONDARY ID: X16058
  • SECONDARY ID: Winship2839-15
  • NCT ID: NCT02632396

Conditions

  • Mantle Cell Lymphoma

Interventions

DrugSynonymsArms
IxazomibNinlaro, MLN9708, Ixazomib CitrateTreatment (ixazomib, rituximab)
RituximabRituxan, MabThera, Chimeric Anti-CD20 AntibodyTreatment (ixazomib, rituximab)

Purpose

This phase I/II trial studies the side effects and best dose of ixazomib citrate (ixazomib) when given together with rituximab and to see how well they work after stem cell transplant in treating patients with mantle cell lymphoma that are no longer showing signs or symptoms of cancer. Ixazomib may stop the growth of cancer cell by blocking enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Giving ixazomib together with rituximab after transplant may help prevent the cancer from coming back.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the recommended phase II dose and assess the safety of ixazomib when
      administered as post-transplant maintenance in mantle cell lymphoma and to evaluate the
      safety of rituximab in combination with the recommended phase II dose (RP2D) of ixazomib.
      (Phase I)

      II. To assess preliminary evidence of efficacy of ixazomib in combination with rituximab when
      administered as post-transplant maintenance in mantle cell lymphoma. (Phase II)

      SECONDARY OBJECTIVES:

      I. To evaluate for preliminary evidence of efficacy of ixazomib (+/- rituximab) maintenance
      therapy in patients with mantle cell lymphoma undergoing autologous stem cell transplant in
      first partial or complete remission. (Phase I)

      II. To evaluate for preliminary evidence of efficacy of ixazomib (+/- rituximab) maintenance
      therapy in patients with mantle cell lymphoma who have a complex karyotype and other
      high-risk cytogenetic or clinical markers. (Phase I)

      III. To evaluate toxicities associated with prolonged administration of ixazomib maintenance
      therapy in patients with mantle cell lymphoma (MCL). (Phase I)

      IV. To evaluate the rate of minimal residual disease (MRD) in patients who have completed an
      autologous transplant for mantle cell lymphoma and to assess the impact of MRD on outcomes
      for patients receiving maintenance therapy. (Phase I)

      V. To evaluate efficacy of ixazomib with rituximab maintenance therapy in patients with MCL
      who undergo autologous stem cell transplantation in first remission who have a complex
      karyotype and/or additional high risk cytogenetic or clinical features at diagnosis. (Phase
      II)

      VI. To further evaluate safety and toxicity of prolonged administration of ixazomib. (Phase
      II)

      VII. To evaluate long-term disease-related and survival outcomes for patients with MCL who
      receive post-transplant maintenance therapy with ixazomib with rituximab. (Phase II)

      VIII. To evaluate the rate of minimal residual disease (MRD) in patients who have completed
      an autologous transplant for mantle cell lymphoma and to assess the impact of MRD on outcomes
      for patients receiving maintenance therapy. (Phase II)

      TERTIARY OBJECTIVES:

      I. To evaluate the prognostic value of pre-transplant positron emission tomography
      (PET)/computed tomography (CT) in mantle cell lymphoma.

      II. To evaluate the ability of the single nucleotide polymorphism (SNP) array to identify
      high-risk cytogenetic features in patients with MCL.

      III. To evaluate the impact of ixazomib maintenance (+/- rituximab) on immunoglobulin levels
      for patients completing autologous stem cell transplantation for mantle cell lymphoma.

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

      Beginning between 70-180 days after stem cell transplant, patients receive ixazomib orally
      (PO) on days 1, 8, and 15, and rituximab intravenously (IV) (or subcutaneously [SC] after
      first dose if deemed appropriate) on day 1 of courses 1, 3, 5, 7, and 9. Treatment repeats
      every 28 days for up to 10 courses in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up every 6 months for up to 2
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ixazomib, rituximab)ExperimentalBeginning between 70-180 days after stem cell transplant, patients receive ixazomib PO on days 1, 8, and 15, and rituximab IV (or SC after first dose if deemed appropriate) on day 1 of courses 1, 3, 5, 7, and 9. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.
  • Ixazomib
  • Rituximab

Eligibility Criteria

        Inclusion Criteria:

          -  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.

          -  Female patients who:

               -  Are postmenopausal for at least 1 year before the screening visit, OR

               -  Are surgically sterile, OR

               -  If they are of childbearing potential, 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

               -  Agree to practice true abstinence when this is in line with the preferred and
                  usual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation,
                  symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
                  of contraception).

          -  Male patients, even if surgically sterilized (ie, 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; (periodic abstinence (eg, calendar, ovulation,
                  symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
                  of contraception).

          -  Patients must have a diagnosis of mantle cell lymphoma confirmed at diagnosis by one
             of the following:

               -  t(11;14) detected by fluorescence in situ hybridization (FISH), conventional
                  cytogenetics, or other molecular evaluation

               -  Expression of cyclin D1 confirmed by immunohistochemistry.

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

          -  Patients must have completed an autologous stem cell transplant after their first
             course of treatment; patients who have relapsed or progressed at any time prior to
             transplant are not eligible.

          -  Patients must not have experienced confirmed progressive disease since the time of
             their transplant.

          -  Absolute neutrophil count (ANC) ≥ 1,000/mm³ and platelet count ≥ 75,000/mm³. Platelet
             transfusions to help patients meet eligibility criteria are not allowed within 3 days
             before study enrollment. Patients may receive growth factor support prior to
             initiating therapy but must remain off of growth factor for at least 7 days before
             starting therapy and must meet eligibility on cycle 1, day 1. Patients who complete
             the consent process but do not meet hematologic eligibility within 30 days may be
             re-consented and enrolled on study if they ultimately do meet eligibility requirements
             before day +180. No patients may initiate therapy after day +180 and they must meet
             all remaining eligibility criteria.

          -  Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN) except for
             previously documented Gilbert's disease, defined as a mild unconjugated
             hyperbilirubinemia with no other identifiable cause and bilirubin values < 6 mg/dL;
             patients with hyperbilirubinemia secondary to presumed Gilbert's disease who are being
             considered for enrollment in the study MUST have a fractionated bilirubin included in
             their screening labs when determining eligibility.

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN.

          -  Calculated creatinine clearance ≥ 30 mL/min using Cockcroft-Gault formula.

          -  Note: Patients are expected to initiate therapy as close to day +100 as possible. No
             patient may initiate therapy before day +70 and initiation of therapy beyond day +130
             is allowed ONLY for patients who meet all eligibility criteria except for hematologic
             parameters, in which case patients may be delayed until their hematologic laboratories
             meet criteria but no later than day +180. Regardless of the time of therapy
             initiation, patients must meet all eligibility criteria and must have completed all
             consent documentation and screening procedures within the specified window.

        Exclusion Criteria:

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

          -  Failure to have fully recovered (ie, ≤ grade 1 toxicity) from the reversible effects
             of prior chemotherapy, except for laboratory abnormalities which are addressed above.

          -  Major surgery within 14 days before enrollment.

          -  Radiotherapy within 14 days before enrollment; if the involved field is small, 7 days
             will be considered a sufficient interval between treatment and administration of the
             ixazomib.

          -  Central nervous system involvement with lymphoma at any time in the patient's history;
             intrathecal prophylaxis during induction is allowed as long as active disease has not
             been identified.

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

          -  Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
             hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
             unstable angina, or myocardial infarction within the past 6 months; patients
             experiencing an isolated cardiac complication at the time of transplant who have been
             evaluated by cardiology and remained stable for at least 60 days are eligible.

          -  Systemic treatment, within 14 days before the first dose of ixazomib, with strong
             cytochrome P450, family 3, subfamily A (CYP3A) inducers (rifampin, rifapentine,
             rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort.

          -  Ongoing or active systemic infection, active hepatitis B or C virus infection, or
             known human immunodeficiency virus (HIV) positive. Patients who have previously tested
             positive for hepatitis B core antibody may be eligible if they are confirmed to NOT
             have active disease and are on appropriate anti-viral therapy. No additional hepatitis
             or HIV testing is required for patients who have been evaluated during their induction
             and/or pre-transplant work-up and have had no clinical evidence of HIV, hepatitis B or
             hepatitis C since their last evaluation.

          -  Any serious medical or psychiatric illness that could, in the investigator's opinion,
             potentially interfere with the completion of treatment according to this protocol.

          -  Known allergy to any of the study medications, their analogues, or excipients in the
             various formulations of any agent. Patients with a prior reaction to rituximab are
             permitted if the investigator feels that this reaction is manageable with standard
             supportive care measures and would otherwise be comfortable administering rituximab
             outside of the clinical trial setting.

          -  Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
             absorption or tolerance of ixazomib including difficulty swallowing; patients with
             known GI involvement with mantle cell lymphoma who have no clinical evidence of active
             disease at the time of enrollment are eligible.

          -  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, carcinoma in situ of any type, or low
             risk cervical cancer are not excluded if they have undergone complete resection and
             are deemed free of disease by their treating physician; patients with low risk
             prostate cancer who are under observation are eligible if their urologist or
             oncologist does not expect them to require therapy within 1 year.

          -  Patient has ≥ grade 3 peripheral neuropathy, or grade 2 with pain on clinical
             examination during the screening period.

          -  Receipt of therapy on a clinical trial, including investigational and
             non-investigational agents not included in this trial, within 30 days of the start of
             this trial and throughout the duration of this trial; participation on non-therapeutic
             clinical studies is allowed, and patients who participated on a clinical trial for
             induction and/or transplant but who have completed the prescribed therapy course for
             that study and have been off therapy for at least 30 days are eligible.

          -  Prior exposure to ixazomib; however, prior bortezomib exposure is allowed.

          -  Patients with any history of relapsed/refractory disease, or who have progressed at
             any time since beginning induction therapy are not eligible; patients who have
             evidence of residual disease by FISH, cytogenetics, SNP array, or flow cytometry
             without any measurable nodal disease or morphologic evidence of disease in the bone
             marrow or peripheral blood are eligible.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose of ixazomib, defined as the dose where 1 or fewer of 6 treated patients experience a dose limiting toxicity graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (Phase I)
Time Frame:28 days
Safety Issue:
Description:Determined using the Kaplan-Meier method.

Secondary Outcome Measures

Measure:Conversion rate from MRD positive to MRD negative during therapy (Phase I & II)
Time Frame:Up to 10 months (10 courses of treatment)
Safety Issue:
Description:
Measure:Incidence of adverse events graded according to CTCAE version 4.03 (Phase I & II)
Time Frame:Up to 30 days after administration of the last dose of study treatment
Safety Issue:
Description:Adverse events will be tabulated across all patients who received any treatment with a focus on severe (grade 3-5) adverse events and toxicities as well as commonly encountered lower grade adverse events. All adverse events will be reported in tabular form, and as, possible, identification of adverse events possibly, probably, or definitely related to study therapy will be noted.
Measure:Median OS (Phase II)
Time Frame:Up to 2 years
Safety Issue:
Description:The relationship between cytogenetic variables and OS will be explored using the Kaplan-Meier method.
Measure:Median PFS (Phase II)
Time Frame:Up to 2 years
Safety Issue:
Description:The relationship between cytogenetic variables and PFS will be explored using the Kaplan-Meier method.
Measure:Overall survival (OS) (Phase II)
Time Frame:1 year
Safety Issue:
Description:The relationship between cytogenetic variables and OS will be explored using the Kaplan-Meier method.
Measure:PFS for all patients and for those patients with a complex karyotype and other high-risk clinical or cytogenetic features (Phase I)
Time Frame:1 year
Safety Issue:
Description:The relationship between cytogenetic variables and PFS will be explored using the Kaplan-Meier method.
Measure:PFS for patients with a complex karyotype and other high risk clinical or cytogenetic features (Phase II)
Time Frame:1 year
Safety Issue:
Description:The relationship between cytogenetic variables and PFS will be explored using the Kaplan-Meier method.
Measure:Rate of MRD positivity (Phase I & II)
Time Frame:Baseline
Safety Issue:
Description:
Measure:Rate of patients maintaining MRD negativity from study entry to completion of therapy (Phase I & II)
Time Frame:Up to 10 months (10 courses of treatment)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Emory University

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