Clinical Trials /

Lenalidomide With or Without Ixazomib Citrate and Dexamethasone in Treating Patients With Residual Multiple Myeloma After Donor Stem Cell Transplant

NCT02389517

Description:

This randomized phase II trial studies how well lenalidomide alone compared to lenalidomide, ixazomib citrate, and dexamethasone work in treating patients with multiple myeloma that remains (residual) after donor stem cell transplant. Lenalidomide may help the immune system kill abnormal blood cells or cancer cells and may also prevent the growth of new blood vessels that are needed for cancer growth. Ixazomib citrate may stop the growth of cancer cells by interfering with proteins necessary for cell growth. Drugs used in chemotherapy, such as dexamethasone, 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. It is not yet known whether lenalidomide is more effective with or without ixazomib citrate and dexamethasone in treating residual multiple myeloma.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Lenalidomide With or Without Ixazomib Citrate and Dexamethasone in Treating Patients With Residual Multiple Myeloma After Donor Stem Cell Transplant
  • Official Title: Phase II Randomized Trial of Continuation of Post-Transplant Maintenance With Single-Agent Lenalidomide vs. Consolidation/Maintenance With Ixazomib-Lenalidomide-Dexamethasone in Patients With Residual Myeloma

Clinical Trial IDs

  • ORG STUDY ID: IRB14-0899
  • SECONDARY ID: NCI-2015-00138
  • SECONDARY ID: X16047
  • SECONDARY ID: 14-0899
  • SECONDARY ID: IRB14-0899
  • SECONDARY ID: P30CA014599
  • NCT ID: NCT02389517

Conditions

  • Plasma Cell Myeloma
  • Residual Disease

Interventions

DrugSynonymsArms
Ixazomib CitrateMLN-9708, MLN9708, proteasome inhibitor MLN9708Arm I (ixazomib citrate, lenalidomide, dexamethasone)
LenalidomideCC-5013, CC5013, CDC 501, IMiD-1Arm I (ixazomib citrate, lenalidomide, dexamethasone)
DexamethasoneDMArm I (ixazomib citrate, lenalidomide, dexamethasone)

Purpose

This randomized phase II trial studies how well lenalidomide alone compared to lenalidomide, ixazomib citrate, and dexamethasone work in treating patients with multiple myeloma that remains (residual) after donor stem cell transplant. Lenalidomide may help the immune system kill abnormal blood cells or cancer cells and may also prevent the growth of new blood vessels that are needed for cancer growth. Ixazomib citrate may stop the growth of cancer cells by interfering with proteins necessary for cell growth. Drugs used in chemotherapy, such as dexamethasone, 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. It is not yet known whether lenalidomide is more effective with or without ixazomib citrate and dexamethasone in treating residual multiple myeloma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the rate of minimal residual disease (MRD)-negative disease by
      multiparameter-flow cytometry at 12 months after randomization.

      SECONDARY OBJECTIVES:

      I. Evidence of response as demonstrated by the improvement of the depth of response by at
      least one category according to International Myeloma Working Group (IMWG) response criteria.

      II. Progression free survival (PFS). III. Overall survival (OS). IV. Duration of MRD-negative
      disease. V. Safety and tolerability of experimental arm (ixazomib citrate, lenalidomide, and
      low dose dexamethasone [IRd]) vs. control arm (lenalidomide [Rd]).

      TERTIARY OBJECTIVES:

      I. Determination of markers of response based on pre-treatment characteristics using methods
      described in correlative research.

      II. Evaluation of MRD by gene sequencing method using the Sequenta platform (LymphoSIGHT®) in
      parallel with multi-parameter flow cytometry (MFC).

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      ARM I: Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15, lenalidomide PO
      once daily (QD) on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22 (of courses 1-4
      only).

      ARM II: Patients receive lenalidomide PO as in Arm I.

      In both arms, treatment repeats every 28 days for 12 courses in the absence of disease
      progression or unacceptable toxicity.

      After the completion of treatment, patients are followed up at 30 days and then every 3
      months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (ixazomib citrate, lenalidomide, dexamethasone)ExperimentalPatients receive ixazomib citrate PO on days 1, 8, and 15, lenalidomide PO QD on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22 (of courses 1-4 only).
  • Ixazomib Citrate
  • Lenalidomide
  • Dexamethasone
Arm II (lenalidomide)Active ComparatorPatients receive lenalidomide PO as in Arm I.
  • Lenalidomide

Eligibility Criteria

        Inclusion Criteria:

          -  Patients who completed induction treatment followed by autologous stem cell transplant
             as initial therapy for symptomatic myeloma as per IMWG criteria and initiated Revlimid
             (lenalidomide) maintenance

               -  Patients must have initiated lenalidomide maintenance at approximately 3 months
                  post autologous stem transplant (preferably 70-90 but not more than 120 days)

               -  Patients must be receiving lenalidomide 10 mg or 15 mg and be able to tolerate
                  dose escalation to 25 mg daily

               -  Patients must have received lenalidomide maintenance for 3 months (+1 month
                  window for a maximum of 4 months lenalidomide prior to enrollment)

          -  No evidence of progressive disease on lenalidomide

          -  Any measurable residual disease at the time of screening for the study documented in
             at least one of the following ways:

               -  Serum protein electrophoresis (SPEP)/immunofixation studies (IFIX) positive
                  disease

               -  Freelite only positive disease

               -  SPEP/IFIX - negative and Freelite- negative but MRD-positive disease is allowed

          -  Evidence of MRD at the time of screening for this study by multi-color flow cytometry
             (bone marrow procedure at screening required)

          -  Bone marrow specimen will be required at study entry; available deoxyribonucleic acid
             (DNA) sample will be used for calibration step for MRD evaluation by gene sequencing

          -  Life expectancy of more than 3 months

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

          -  Bilirubin =<1.5 x upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN

          -  Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

          -  Hemoglobin >= 8 g/dL

          -  Platelet count >= 75 x 10^9/L

          -  Calculated creatinine clearance (by Cockroft-Gault) >= 50 ml/min or serum creatinine
             below 2 g/dL

          -  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 [e.g., calendar, ovulation,
                  symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
                  of contraception)

          -  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; (periodic abstinence [e.g., calendar, ovulation,
                  symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
                  of contraception)

        Exclusion Criteria:

          -  Evidence of progressive disease on lenalidomide maintenance as per IMWG criteria

          -  Patients who have already started or received multi-drug consolidation regimen
             post-transplant expect for lenalidomide maintenance

          -  Diarrhea > grade 1 in the absence of anti-diarrheals

          -  Central nervous system involvement

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

          -  History of allergy to mannitol

          -  Major surgery within 14 days before enrollment

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

          -  Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
             cardiac conditions such as hypertension, or cardiac arrhythmias, or New York Heart
             Association stage III and IV congestive heart failure, or unstable angina or
             myocardial infarction within the past 6 months

          -  Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead
             electrocardiogram (ECG) during screening

          -  Uncontrolled diabetes

          -  Acute infection requiring systemic anti-infectives, antivirals, or antifungals within
             two weeks prior to first dose

          -  Systemic treatment, within 14 days before the first dose of ixazomib, with strong
             inhibitors of cytochrome P450 family 3, subfamily A, polypeptide 2 (CYP1A2)
             (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450 family 3,
             subfamily A CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole,
             ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin,
             rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo
             biloba or St. John's wort

          -  Ongoing or active systemic infection, active hepatitis B or C virus infection, or
             known human immunodeficiency virus (HIV) positive

          -  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

          -  Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
             absorption or tolerance of ixazomib 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 nonmelanoma skin cancer or carcinoma in situ of any type are
             not excluded if they have undergone complete resection

          -  Patient has >= grade 3 peripheral neuropathy, or grade 2 with pain 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of MRD between the two arms, as measured by flow cytometry and sequencing
Time Frame:At 12 months
Safety Issue:
Description:The comparison will be made using a one sided test at the 10% significance level. This comparison will be performed using a Cochran Mantel-Haenszel (CMH) test stratified by very good partial response (VGPR) status and risk factors vs. no risk factors.

Secondary Outcome Measures

Measure:Overall response rate defined as an improvement from very good partial response (VGPR) to near complete response (nCR) or better than nCR including conversion from complete response (CR) to MRD negative disease according to IMWG criteria
Time Frame:At 6 months
Safety Issue:
Description:The rate of overall response will be reported along with its exact 95% binomial confidence interval.
Measure:Overall response defined as an improvement from VGPR to nCR or better than nCR including conversion from CR to MRD negative disease according to IMWG criteria
Time Frame:At 12 months
Safety Issue:
Description:The rate of overall response will be reported along with its exact 95% binomial confidence interval.
Measure:Duration of response (MRD-negative disease)
Time Frame:From the date of the clinical examination, which confirmed the response, until the date of disease progression, or censoring at the date of last clinical follow-up, assessed up to 2 years
Safety Issue:
Description:Duration of response will be assessed conditionally upon achieving at least a partial response.
Measure:Time to progression
Time Frame:Up to 2 years
Safety Issue:
Description:Time to event will be estimated using the product-limit method of Kaplan and Meier.
Measure:Estimated PFS
Time Frame:From the date of randomization until the date of documented disease progression or death, assessed up to 2 years
Safety Issue:
Description:Time to event will be estimated using the product-limit method of Kaplan and Meier. MRD status will be correlated with PFS.
Measure:Estimated OS
Time Frame:Up to 2 years
Safety Issue:
Description:Time to event will be estimated using the product-limit method of Kaplan and Meier.
Measure:Incidence, intensity, and type of adverse events as graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:Safety variables will be tabulated and presented for all patients in the study. Exposure to study drug and reasons for discontinuation of study treatment will be tabulated. Group comparisons will be performed using chi-square or Fisher's exact test.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Chicago

Last Updated

April 29, 2019