Clinical Trials /

Ixazomib in Treating Patients With Relapsed Multiple Myeloma That Is Not Refractory to Bortezomib

NCT01415882

Description:

This randomized phase II trial studies how well ixazomib (ixazomib citrate) works in treating patients with multiple myeloma that has returned after a period of improvement but is not resistant to bortezomib. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ixazomib in Treating Patients With Relapsed Multiple Myeloma That Is Not Refractory to Bortezomib
  • Official Title: Phase 2 Trial of Ixazomib Combinations in Patients With Relapsed Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: MC1181
  • SECONDARY ID: NCI-2011-02303
  • SECONDARY ID: 11-001516 00
  • SECONDARY ID: Mod11-001516-50
  • SECONDARY ID: MC1181
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT01415882

Conditions

  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Arm D (ixazomib citrate, dexamethasone, and cyclophosphamide)
DexamethasoneAacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, VisumetazoneArm A (ixazomib citrate and dexamethasone, closed to accrual)
Ixazomib CitrateMLN-9708, MLN9708, NinlaroArm A (ixazomib citrate and dexamethasone, closed to accrual)

Purpose

This randomized phase II trial studies how well ixazomib (ixazomib citrate) works in treating patients with multiple myeloma that has returned after a period of improvement but is not resistant to bortezomib. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the confirmed overall response rate (>= partial response [PR]) of MLN9708
      (ixazomib citrate), used as a single agent in patients with relapsed multiple myeloma, who
      are proteasome inhibitor naïve (including bortezomib) naive OR have received less than 6
      cycles of therapy with bortezomib and had a better than PR with no progression at the time of
      discontinuation. (Arm A - Permanently closed to accrual as of Addendum 5) II. To determine
      the confirmed overall response rate (>= PR) of MLN9708 at a 4 mg dose level in combination
      with dexamethasone in patients with relapsed multiple myeloma, who are proteasome inhibitor
      naïve (including bortezomib) naïve OR have received less than 6 cycles of therapy with
      bortezomib and had a better than PR with no progression at the time of discontinuation. (Arm
      B) III. To determine the confirmed overall response rate (>= PR) of MLN9708 at a 5.5 mg dose
      level in combination with dexamethasone in patients with relapsed multiple myeloma, who are
      proteasome inhibitor naïve (including bortezomib) naïve OR have received less than 6 cycles
      of therapy with bortezomib and had a better than PR with no progression at the time of
      discontinuation. (Arm C) IV. To determine the confirmed overall response rate (>= PR) of
      MLN9708 in combination with cyclophosphamide and dexamethasone in patients with relapsed
      multiple myeloma, who are proteasome inhibitor naive (including bortezomib) naïve OR have
      received less than 6 cycles of therapy with bortezomib and had a better than PR with no
      progression at the time of discontinuation. (Arm D)

      SECONDARY OBJECTIVES:

      I. To determine the overall response rate of MLN9708 in combination with dexamethasone, when
      dexamethasone is added to MLN9708 for lack of response or for progression. (Arm A) II. To
      determine the event free survival and overall survival among patients with relapsed myeloma
      following treatment with MLN9708 with dexamethasone added for lack of response or
      progression. (Arm A) III. To determine the event free survival and overall survival among
      patients with relapsed myeloma following treatment with MLN9708 at two different doses, in
      combination with dexamethasone. (Arms B and C) IV. To determine the event free survival and
      overall survival among patients with relapsed myeloma following treatment with MLN9708 in
      combination with cyclophosphamide and dexamethasone. (Arms D)

      OUTLINE: Patients are randomized to 1 of 3 treatment arms (Arm A permanently closed to
      accrual as of Addendum 5).

      ARM A: Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15. Patients with lack
      of minor response by the end of the second course or lack of partial response by the end of
      the fourth course also receive dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Courses
      repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive ixazomib citrate PO on days 1, 8 and 15 and dexamethasone PO on days
      1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      ARM C: Patients receive higher dose of ixazomib citrate PO on days 1, 8, and 15 and
      dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      ARM D: Patients receive ixazomib citrate PO on days 1, 8, and 15, cyclophosphamide PO and
      dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of
      disease progression or unacceptable toxicity.

      ARM E: Patient receive isazomib citrate PO on days 1,8 and 15, cyclophosphamide PO on days
      1,8,15 and 22. Daratumumab IV Days 1, 8, 15, 22 for cycles 1-2; Days 1, 15 for cycles 3-6;
      and Day 1 for subsequent cycles. Courses repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      Dexamethasone IV (PO only if IV unavailable) days 1,8,15 and 22. *Dexamethasone is started
      Day 1 Cycle 1

      **Dexamethasone should be given IV (PO only if IV is unavailable), approximately 1 hour or
      less prior to daratumumab infusion. On days when subjects receive this dose of dexamethasone
      in the clinic, dexamethasone will not be self-administered at home. On days when daratumumab
      is not scheduled, PO may be taken at home.

      After completion of study treatment, patients are followed up every 6 or 12 months for 2
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (ixazomib citrate and dexamethasone, closed to accrual)ExperimentalPatients receive ixazomib citrate PO on days 1, 8, and 15. Patients with lack of minor response by the end of the second course or lack of partial response by the end of the fourth course also receive dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Dexamethasone
  • Ixazomib Citrate
Arm B (ixazomib citrate and dexamethasone)ExperimentalPatients receive ixazomib citrate PO on days 1, 8 and 15 and dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Dexamethasone
  • Ixazomib Citrate
Arm C (higher-dose ixazomib citrate and dexamethasone)ExperimentalPatients receive higher doses of ixazomib citrate PO on days 1, 8, and 15 and dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Dexamethasone
  • Ixazomib Citrate
Arm D (ixazomib citrate, dexamethasone, and cyclophosphamide)ExperimentalPatients receive ixazomib citrate PO on days 1, 8, and 15, cyclophosphamide PO and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cyclophosphamide
  • Dexamethasone
  • Ixazomib Citrate
Arm E (Ixazomib, cyclophosphamide, daratumab, dexaExperimentalPatient receive ixazomib citrate PO on days 1, 8 &15, cyclophosphamide PO on days 1, 8,15,& 22 (Discontinue after 12 cycles), Daratumumab IV on days 1,8,15 & 22 for cycles 1-2; days 1,15 for cycles 3-6; day 1 for subsequent cycles, Dexamethasone PO on days 1,8,15 & 22.
  • Cyclophosphamide
  • Dexamethasone
  • Ixazomib Citrate

Eligibility Criteria

        Inclusion Criteria:

          -  Calculated creatinine clearance (using Cockcroft-Gault equation) >= 30 mL/min

          -  Absolute neutrophil count >= 1000/mL

          -  Untransfused platelet count >= 75000/mL

          -  Hemoglobin >= 8.0 g/dL

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

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN

          -  Patients with relapsed multiple myeloma who have already received one or more standard
             treatment regimens

          -  Measurable disease of multiple myeloma as defined by at least ONE of the following:

               -  Serum monoclonal protein >= 1.0 g/dL

               -  >= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis

               -  Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum
                  immunoglobulin kappa to lambda free light chain ratio

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

          -  Patients should be proteasome inhibitor naïve (including bortezomib and carfilzomib)
             OR have received less than 6 cycles of therapy with a bortezomib or carfilzomib
             containing regimen and were not refractory to the bortezomib or carfilzomib based
             regimen (less than a PR or progression on or within 60 days of discontinuation)

          -  Provide informed written consent

          -  Negative pregnancy test done =< 7 days prior to registration, for women of
             childbearing potential only

          -  Willing to return to consenting Mayo Clinic institution for follow-up during the
             Active Monitoring Phase of the study; Note: during the Active Monitoring Phase of a
             study (i.e., active treatment and observation), participants must be willing to return
             to the consenting institution for follow-up

          -  Recovered (i.e., < grade 1 toxicity) from the reversible effects of prior
             antineoplastic therapy

        Exclusion Criteria:

          -  Recent prior chemotherapy:

               -  Alkylators (e.g. melphalan, cyclophosphamide) =< 14 days prior to registration

               -  Anthracyclines =< 14 days prior to registration

               -  High dose corticosteroids, immune modulatory drugs (thalidomide or lenalidomide)
                  =< 7 days prior to registration

          -  Prior therapy with any proteasome inhibitor other than bortezomib or carfilzomib

          -  Concomitant high dose corticosteroids other than what is part of treatment protocol
             (concurrent use of corticosteroids); EXCEPTION: patients may be on chronic steroids
             (maximum dose 20 mg/day prednisone equivalent) if they are being given for disorders
             other than myeloma, i.e., adrenal insufficiency, rheumatoid arthritis, etc

          -  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

          -  Any of the following:

               -  Pregnant women or women of reproductive ability who are unwilling to use 2
                  effective methods of contraception from the time of signing the informed consent
                  form through 90 days after the last dose of study drug

               -  Nursing women

               -  Men who are unwilling to use a condom (even if they have undergone prior
                  vasectomy) while having intercourse with any women, while taking the drug and for
                  30 days after stopping treatment

          -  Other co-morbidity which would interfere with patient's ability to participate in
             trial, e.g. uncontrolled infection, uncompensated heart or lung disease

          -  Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered
             investigational; NOTE: bisphosphonates are considered to be supportive care rather
             than therapy, and are thus allowed while on protocol treatment

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

          -  Major surgery within 14 days before study registration

          -  Systemic treatment with strong inhibitors of cytochrome P450, family 1, subfamily A
             (CYP3A) inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin,
             phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before the
             first dose of study treatment

          -  Evidence of current uncontrolled cardiovascular conditions, including cardiac
             arrhythmias, congestive heart failure, angina, or myocardial infarction within the
             past 6 months; Note: prior to study entry, any electrocardiogram (ECG) abnormality at
             screening must be documented by the investigator as not medically relevant

          -  Known human immunodeficiency virus (HIV) positive

          -  Known hepatitis B surface antigen-positive status, or known or suspected active
             hepatitis C infection

          -  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

          -  Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
             absorption or tolerance of MLN9708 including difficulty swallowing

          -  Diarrhea > grade 1, based on the National Cancer Institute (NCI) Common Terminology
             Criteria for Adverse Events (CTCAE) grading, in the absence of antidiarrheals
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of confirmed responses with ixazomib citrate alone (Arm A only-closed to accrual as of addendum 5), ixazomib citrate with dexamethasone (Arms B + C), or ixazomib citrate with dexamethasone and cyclophosphamide (Arm D)
Time Frame:Up to 2 years
Safety Issue:
Description:A confirmed response is defined as stringent complete response, CR, very good partial response, or PR noted as the objective status on 2 separate evaluations while receiving ixazomib citrate with or without dexamethasone. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. 95% confidence intervals for the true success proportion will be calculated by the exact binomial method.

Secondary Outcome Measures

Measure:Confirmed response rate with the addition of dexamethasone (Arm A only)
Time Frame:Up to 2 years
Safety Issue:
Description:Estimated by the number of patients who achieve a confirmed response at any time (with single agent ixazomib citrate or ixazomib citrate plus dexamethasone) divided by the number of evaluable patients. 95% confidence intervals for the true confirmed response rate will be calculated by the exact binomial method.
Measure:Event-free survival
Time Frame:From registration to disease progression while receiving ixazomib citrate and dexamethasone, death due to any cause, or subsequent treatment for multiple myeloma, assessed up to 2 years
Safety Issue:
Description:Date of progression will be defined as the date that the criteria for progressive disease were first met after initiation of dexamethasone. The distribution of event-free survival will be estimated using the method of Kaplan-Meier.
Measure:Incidence of adverse events, graded according to NCI CTCAE version 3.0
Time Frame:Up to 30 days after the last day of study drug treatment
Safety Issue:
Description:The maximum grade for each type of adverse event, regardless of causality, will be recorded and reported for each patient, and frequency tables will be reviewed to determine adverse event patterns.
Measure:Overall survival
Time Frame:From registration to death due to any cause, assessed up to 2 years
Safety Issue:
Description:The distribution of survival time will be estimated using the method of Kaplan-Meier.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mayo Clinic

Last Updated

May 20, 2019