Clinical Trials /

Idasanutlin, Ixazomib Citrate, and Dexamethasone in Treating Patients With Relapsed Multiple Myeloma

NCT02633059

Description:

This phase I/II trial studies the side effects and best dose of idasanutlin and ixazomib citrate when given together with dexamethasone in treating patients with multiple myeloma that has returned after a period of improvement. Drugs used in chemotherapy, such as idasanutlin and 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. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving idasanutlin, ixazomib citrate, and dexamethasone together may work better in treating patients with multiple myeloma.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Idasanutlin, Ixazomib Citrate, and Dexamethasone in Treating Patients With Relapsed Multiple Myeloma
  • Official Title: Phase 1 / 2 Trial of Idasanutlin in Combination With Ixazomib and Dexamethasone in Patients With 17p Deleted, Relapsed Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: MC1582
  • SECONDARY ID: NCI-2015-02155
  • SECONDARY ID: NP29909
  • SECONDARY ID: X16066
  • SECONDARY ID: MMRC-061
  • SECONDARY ID: MC1582
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT02633059

Conditions

  • Recurrent Plasma Cell Myeloma

Interventions

DrugSynonymsArms
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, VisumetazoneTreatment (ixazomib citrate, idasanutlin, dexamethasone)
IdasanutlinRG-7388, RG7388, RO-5503781, RO5503781Treatment (ixazomib citrate, idasanutlin, dexamethasone)
Ixazomib CitrateMLN-9708, MLN9708, NinlaroTreatment (ixazomib citrate, idasanutlin, dexamethasone)

Purpose

This phase I/II trial studies the side effects and best dose of idasanutlin and ixazomib citrate when given together with dexamethasone in treating patients with multiple myeloma that has returned after a period of improvement. Drugs used in chemotherapy, such as idasanutlin and 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. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving idasanutlin, ixazomib citrate, and dexamethasone together may work better in treating patients with multiple myeloma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated doses (MTD) of idasanutlin and ixazomib (ixazomib
      citrate) to be used in combination with dexamethasone in patients with relapsed or
      refractory multiple myeloma with TP53 (17p) deletion. (Phase I) II. To evaluate the
      confirmed response rate of ixazomib and idasanutlin used in combination with dexamethasone
      in patients with relapsed or refractory multiple myeloma with TP53 (17p) deletion. (Phase
      II)

      SECONDARY OBJECTIVES:

      I. To describe the toxicities and the confirmed response rate associated with the
      combination of idasanutlin, ixazomib and dexamethasone. (Phase I) II. To describe the
      toxicities associated with the combination of idasanutlin, ixazomib and dexamethasone.
      (Phase II) III. To describe the complete response (CR) and very good partial response (VGPR)
      rates. (Phase II) IV. To assess progression-free and overall survival. (Phase II)

      TERTIARY OBJECTIVES:

      I. Assess murine double minute 2 (MDM2) inhibition in bone marrow plasma cells. II. Identify
      potential biomarkers associated with response. III. To explore the pharmacodynamic effects
      of idasanutlin.

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

      Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15 and idasanutlin PO once
      daily (QD) on days 1-5 every 28 days in the absence of disease progression or unacceptable
      toxicity. Patients also receive dexamethasone PO on days 1, 8, 15, and 22 every 28 days for
      12 courses at the discretion of the treating physician.

      After completion of study treatment, patients are followed up for 30 days, every 3 months,
      and then every 6 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ixazomib citrate, idasanutlin, dexamethasone)ExperimentalPatients receive ixazomib citrate PO on days 1, 8, and 15 and idasanutlin PO QD on days 1-5 every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive dexamethasone PO on days 1, 8, 15, and 22 every 28 days for 12 courses at the discretion of the treating physician.
  • Dexamethasone
  • Idasanutlin
  • Ixazomib Citrate

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of multiple myeloma (MM) with deletion 17p (del17p) or monosomy 17 by
             fluorescence in situ hybridization (FISH) who have received at least one line of
             therapy

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

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0
             x upper limit of normal (ULN)

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

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

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

          -  Hemoglobin >= 8.0 g/dL

          -  NOTE: white blood count and platelet count criteria must be met without any
             transfusion or growth factor support

          -  Patients with measurable disease defined as at least one of the following:

               -  Serum monoclonal protein >= 1.0 g/dL by protein electrophoresis

               -  > 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 or 2

          -  Ability to understand the purpose and risks of the study and provide signed and dated
             informed consent and authorization to use protected health information

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

          -  Willing to follow strict birth control measures as suggested below

               -  Female patients: if they are of childbearing potential (except if postmenopausal
                  for at least 1 year before the screening visit, OR are surgically sterile),
                  agree to one of the following:

                    -  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)

          -  Willing to return to enrolling institution for follow-up (during the Active
             Monitoring Phase of the study)

          -  Willing to provide bone marrow and blood samples for correlative research purposes

        Exclusion Criteria:

          -  Other malignancy requiring active therapy

               -  EXCEPTIONS: Non-melanoma skin cancer, ductal carcinoma in situ (DCIS) or
                  carcinoma-in-situ of the cervix

               -  NOTE: if there is a history of prior malignancy, they must not be receiving
                  other specific treatment for their cancer

          -  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 2 peripheral neuropathy, or grade 1 with pain on clinical
             examination during the screening period

          -  Major surgery =< 14 days before study registration

          -  All CYP2C8 inhibitors, inducers, and substrates should be discontinued >= 7 days
             prior to registration; systemic treatment with CYP2C8 inhibitors (anastrozole,
             montelukast, quercetin, trimethoprim, gemfibrozil, rosiglitazone, pioglitazone),
             inducers (carbamazepine, phenytoin, rifabutin, rifampin), or substrates (amiodarone,
             repaglinide, rosiglitazone, sorafenib, torsemide) should be discontinued >= 7 days
             prior to registration

          -  Systemic treatment with strong inhibitors of CYP3A4 (clarithromycin, telithromycin,
             itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A4
             inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital,
             Gingko biloba, St. John's wort) are not allowed =< 14 days before registration

          -  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

          -  Corrected QT (QTc) > 470 milliseconds (msec) on a 12-lead ECG obtained during the
             Screening period

               -  Note: If a machine reading is above this value, the ECG should be reviewed by a
                  qualified reader and confirmed on a subsequent ECG

          -  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 ixazomib or idasanutlin including difficulty
             swallowing

          -  Diarrhea > grade 1, based on the National Cancer Institute (NCI) Common Terminology
             Criteria for Adverse Events (CTCAE) grading, or currently taking antidiarrheals

          -  Need for ongoing therapeutic anticoagulation

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

          -  Patients that have previously been treated with ixazomib, or who participated in a
             blinded study with ixazomib (whether treated with ixazomib or not)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Adverse events profile graded according to NCI CTCAE version 4.03 (Phase I)
Time Frame:Up to 30 days after last dose of study treatment
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.

Secondary Outcome Measures

Measure:Incidence of adverse events graded according to NCI CTCAE version 4.03 (Phase II)
Time Frame:Up to 6 months
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.
Measure:Overall survival (Phase II)
Time Frame:Time from registration to death due to any cause, assessed up to 6 months
Safety Issue:
Description:The distribution of overall survival will be estimated using the method of Kaplan-Meier.
Measure:Progression free survival (Phase II)
Time Frame:Time from registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 6 months
Safety Issue:
Description:The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.
Measure:Rate of CR (Phase II)
Time Frame:Up to 6 months
Safety Issue:
Description:The rate of CR will be estimated by the number of patients with an sCR or CR or divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportions will be calculated.
Measure:Rate of PR (Phase II)
Time Frame:Up to 6 months
Safety Issue:
Description:The rate of PR will be estimated by the number of patients with a VGPR or PR divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportions will be calculated.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mayo Clinic

Last Updated

March 16, 2017