Clinical Trials /

Pembrolizumab, Ixazomib Citrate, and Dexamethasone in Treating Participants With Relapsed Multiple Myeloma

NCT03506360

Description:

This phase II trial studies how well pembrolizumab works when given together with ixazomib citrate and dexamethasone in treating participants with multiple myeloma that has come back. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Ixazomib citrate may stop the growth of tumor cells by blocking some of the enzymes needed 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. Giving pembrolizumab together with ixazomib citrate and dexamethasone may work better in treating participants with multiple myeloma.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab, Ixazomib Citrate, and Dexamethasone in Treating Participants With Relapsed Multiple Myeloma
  • Official Title: Phase 2 Trial of Pembrolizumab, Ixazomib, and Dexamethasone for Relapsed Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: MC1782
  • SECONDARY ID: NCI-2018-00590
  • SECONDARY ID: MC1782
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03506360

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, pembrolizumab, dexamethasone)
Ixazomib CitrateMLN-9708, MLN9708, NinlaroTreatment (ixazomib citrate, pembrolizumab, dexamethasone)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (ixazomib citrate, pembrolizumab, dexamethasone)

Purpose

This phase II trial studies how well pembrolizumab works when given together with ixazomib citrate and dexamethasone in treating participants with multiple myeloma that has come back. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Ixazomib citrate may stop the growth of tumor cells by blocking some of the enzymes needed 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. Giving pembrolizumab together with ixazomib citrate and dexamethasone may work better in treating participants with multiple myeloma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the overall response rate (>= partial response [PR]) of pembrolizumab in
      combination with standard doses of ixazomib citrate (ixazomib) and dexamethasone, in patients
      with relapsed symptomatic multiple myeloma (MM).

      SECONDARY OBJECTIVES:

      I. To determine the ? very good partial response (VGPR) and complete response (CR) rate of
      pembrolizumab added to standard doses of ixazomib and dexamethasone in relapsed myeloma.

      II. To determine the progression free survival and overall survival among patients with
      relapsed MM following treatment with the combination of pembrolizumab, ixazomib and
      dexamethasone.

      III. To determine the toxicities associated with pembrolizumab added to standard doses of
      ixazomib and dexamethasone in patients with relapsed MM.

      CORRELATIVE RESEARCH:

      I. PDL-1 expression on myeloma cells and non-tumor cell compartments from the bone marrow
      will be assessed at baseline.

      II. Measures of T-cell activation / exhaustion will be assessed at baseline and after cycle 1
      and cycle 3.

      III. Natural killer (NK) cell function and numbers will be evaluated at baseline and after
      cycle 1 and cycle 3.

      OUTLINE:

      Participants receive ixazomib citrate orally (PO) on days 1, 8, 15, 29, 36, 43, 57, 64, and
      71 and pembrolizumab intravenously (IV) over 30 minutes on days 1, 22, 43, 64. Participants
      also receive dexamethasone PO on days 1, 8, 15, 29, 36, 43, 57, 64, and 71. Courses with
      dexamethasone repeat every 84 days for up to 1 year and courses with ixazomib citrate and
      pembrolizumab repeat every 84 days for up to 2 years in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months until
      progressive disease, and then every 6 months for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ixazomib citrate, pembrolizumab, dexamethasone)ExperimentalParticipants receive ixazomib citrate PO on days 1, 8, 15, 29, 36, 43, 57, 64, and 71 and pembrolizumab IV over 30 minutes on days 1, 22, 43, 64. Participants also receive dexamethasone PO on days 1, 8, 15, 29, 36, 43, 57, 64, and 71. Courses with dexamethasone repeat every 84 days for up to 1 year and courses with ixazomib citrate and pembrolizumab repeat every 84 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Dexamethasone
  • Ixazomib Citrate
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of relapsed, symptomatic multiple myeloma by International Myeloma Working
             Group (IMWG) diagnostic criteria for multiple myeloma

          -  Obtained ? 14 days prior to registration: Calculated creatinine clearance (using
             Cockcroft-Gault equation below) ? 30 mL/min

          -  Obtained ? 14 days prior to registration: Absolute neutrophil count (ANC) ? 1000/mm^3

          -  Obtained ? 14 days prior to registration: Platelet count ? 75000/mm^3; Note: Platelet
             transfusion is not allowed ? 3 days prior to registration

          -  Obtained ? 14 days prior to registration: Hemoglobin ? 8.0 g/dL

          -  Obtained ? 14 days prior to registration: Total bilirubin ? 1.5 x upper limit of
             normal (ULN)

          -  Obtained ? 14 days prior to registration: Alanine aminotransferase (ALT) and aspartate
             aminotransferase (AST) ? 2.5 x ULN

          -  Must have relapsed or refractory disease after treatments including three therapies:
             proteasome inhibitors, immunomodulatory imide drugs (IMiDs), and anti-CD38 antibody

          -  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, or 1

          -  Provide informed written consent

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

          -  Willing to follow strict birth control measures;

               -  Female patients: If they are of childbearing potential, 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 120 days after the last
                       dose of study drug, AND must also adhere to the guidelines of any
                       treatment-specific pregnancy prevention program, if applicable, 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 (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 120 days after the last dose of study drug, OR

                    -  Must also adhere to the guidelines of any treatment-specific pregnancy
                       prevention program, if applicable, 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 planned research

        Exclusion Criteria:

          -  Myeloma disease that is refractory to ixazomib treatment

          -  Has a known additional malignancy that is progressing or requires active treatment;
             exceptions include early stage cancers (carcinoma in situ or stage 1) treated with
             curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially
             curative therapy

          -  Any of the following:

               -  Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception

          -  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, or any ancillary therapy considered investigational ?
             14 days prior to study registration; NOTE: Bisphosphonates are considered to be
             supportive care rather than therapy, and are thus allowed while on protocol treatment

          -  Peripheral neuropathy ? grade 3 on clinical examination or grade 2 with pain during
             the screening period

          -  Major surgery ? 14 days prior to study registration

          -  Radiotherapy ? 14 days prior to registration; NOTE: If the involved field is small, 7
             days will be considered a sufficient interval between treatment and administration of
             study drugs

          -  Participation in any other clinical trials with other investigational agents not
             included in this trial ? 21 days prior to registration

          -  Has active autoimmune disease that has required systemic treatment ? 2 years prior to
             study registration (i.e. with use of disease modifying agents, corticosteroids or
             immunosuppressive drugs);

               -  NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic
                  corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.)
                  is not considered a form of systemic treatment

          -  Has a history of (non-infectious) pneumonitis that required steroids or current
             pneumonitis

          -  Has a known history of interstitial lung disease

          -  Has an active infection requiring systemic therapy

          -  Has a history of current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject?s
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

          -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

          -  Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
             hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
             detected)

          -  Has a known history of active TB (Bacillus tuberculosis)

          -  Has received a live vaccine ? 30 days prior to study registration

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis

          -  Allogeneic hematopoietic stem cell transplant

          -  Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin,
             carbamazepine, phenytoin, phenobarbital), or use of St. John?s wort ? 14 days prior to
             registration

          -  Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
             absorption or tolerance of ixazomib including difficulty swallowing
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate defined as a partial response or better noted as the objective status on two consecutive evaluations
Time Frame:Up to 2 years
Safety Issue:
Description:The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.

Secondary Outcome Measures

Measure:? Very good partial response (VGPR) response rate with pembrolizumab added to ixazomib citrate and dexamethasone
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated by the number of patients who achieve a VGPR, complete response (CR), or stringent complete response (sCR) at any time divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success rate will be calculated.
Measure:Complete response rate with pembrolizumab added to ixazomib citrate and dexamethasone
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated by the number of patients who achieve a CR or sCR at any time divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success rate will be calculated.
Measure:Survival time
Time Frame:From date of first treatment 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.
Measure:Progression-free survival
Time Frame:From date of first treatment to the earliest date of documentation of disease progression or death due to any cause, assessed up to 2 years
Safety Issue:
Description:The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.
Measure:Incidence of adverse events graded according National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 2 years
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.

Details

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

Last Updated

April 16, 2020