Clinical Trials /

Pomalidomide and Dexamethasone With or Without Ixazomib in Treating Patients With Relapsed Multiple Myeloma

NCT02004275

Description:

This randomized phase I/II trial studies the side effects and best dose of pomalidomide and ixazomib when given together with dexamethasone and to see how well pomalidomide and dexamethasone with or without ixazomib works in treating patients with multiple myeloma that has come back. Biological therapies, such as pomalidomide and dexamethasone, may stimulate the immune system in different ways and stop cancer cells from growing. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether pomalidomide and dexamethasone are more effective with or without ixazomib in treating multiple myeloma.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pomalidomide and Dexamethasone With or Without Ixazomib in Treating Patients With Relapsed Multiple Myeloma
  • Official Title: A Phase I/II Study of Pomalidomide, Dexamethasone and Ixazomib vs. Pomalidomide and Dexamethasone for Patients With Multiple Myeloma Relapsing on Lenalidomide as Part of First Line Therapy

Clinical Trial IDs

  • ORG STUDY ID: A061202
  • SECONDARY ID: NCI-2013-01702
  • SECONDARY ID: U10CA031946
  • NCT ID: NCT02004275

Conditions

  • Multiple Myeloma in Relapse

Interventions

DrugSynonymsArms
pomalidomidePomalyst®Arm I (pomalidomide, dexamethasone)
ixazomibMLN9708Arm II (pomalidomide, dexamethasone, ixazomib)
dexamethasoneArm I (pomalidomide, dexamethasone)

Purpose

This randomized phase I/II trial studies the side effects and best dose of pomalidomide and ixazomib when given together with dexamethasone and to see how well pomalidomide and dexamethasone with or without ixazomib works in treating patients with multiple myeloma that has come back. Biological therapies, such as pomalidomide and dexamethasone, may stimulate the immune system in different ways and stop cancer cells from growing. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether pomalidomide and dexamethasone are more effective with or without ixazomib in treating multiple myeloma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To establish the maximum tolerated dose (MTD) for combination therapy
      pomalidomide/dexamethasone/ixazomib. (Phase I) II. To assess whether the combination of
      pomalidomide/dexamethasone/ixazomib improves progression-free survival (PFS) relative to
      pomalidomide/dexamethasone. (Phase II)

      SECONDARY OBJECTIVES:

      I. To determine dose-limiting toxicities (DLTs). (Phase I) II. To analyze type and grade of
      all serious adverse events (SAEs). (Phase I) III. To analyze type and grade of all adverse
      events (AEs). (Phase I) IV. To analyze the reason for and incidence of dose
      modifications/omissions/delays. (Phase I) V. To assess preliminary evidence of clinical
      efficacy. (Phase I) VI. To assess whether the overall response rate (ORR), partial response
      (PR), very good partial response (VGPR), complete response (CR) or stringent CR (sCR) rate
      differ with respect to treatment regimen. (Phase II) VII. To assess the clinical benefit rate
      (CBR: minimal response [MR] + ORR) for pomalidomide/dexamethasone/ixazomib compared to
      pomalidomide/dexamethasone. (Phase II) VIII. To assess the disease control rate (DCR: stable
      disease [SD] + CBR) for pomalidomide/dexamethasone/ixazomib compared to
      pomalidomide/dexamethasone. (Phase II) IX. For those patients achieving a PR or better, we
      will assess whether the combination of pomalidomide/dexamethasone/ixazomib increases the
      duration of response (DOR) compared to pomalidomide/dexamethasone. (Phase II) X. To assess
      whether the combination of pomalidomide/dexamethasone/ixazomib improves overall survival (OS)
      compared to those taking pomalidomide/dexamethasone alone. (Phase II) XI. To assess time to
      next treatment (TNT) for patients taking pomalidomide/dexamethasone/ixazomib compared to
      those on pomalidomide/dexamethasone. (Phase II) XII. To evaluate the safety of
      pomalidomide/dexamethasone/ixazomib compared with pomalidomide/dexamethasone. (Phase II)
      XIII. For patients on the pomalidomide/dexamethasone arm who opt to cross-over to the
      pomalidomide/dexamethasone/ixazomib arm, assessment of response rate (ORR, CBR, DCR), DOR,
      TNT, PFS and OS will be evaluated from date of cross-over. (Phase II) XIV. To determine if
      baseline level of perceived fatigue and overall quality of life (QOL) is associated with OS.
      (Phase II)

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

      After completion of study treatment, patients are followed up every 4 weeks until disease
      progression and then every 3 months for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (pomalidomide, dexamethasone)ExperimentalPatients receive pomalidomide PO QD on days 1-21 and dexamethasone PO QD on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients achieving disease progression may cross over to Arm II.
  • pomalidomide
  • dexamethasone
Arm II (pomalidomide, dexamethasone, ixazomib)ExperimentalPatients receive pomalidomide, dexamethasone, and ixazomib as in Phase I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • pomalidomide
  • ixazomib
  • dexamethasone

Eligibility Criteria

        -  Histologically confirmed diagnosis of symptomatic multiple myeloma; relapsed disease
             is myeloma that has previously responded to prior therapy (MR or better) and
             subsequently progressed

          -  Patient must have measurable disease or non-measurable disease, defined as one or more
             of the following holding true:

               -  Measurable disease:

                    -  Serum M-protein >= 1.0 g/dL (>= 0.5 g/dL for IgA or IgM myeloma) and/or

                    -  Urine M-protein >= 200 mg/24 hours and/or

                    -  Involved serum free light chain level >= 10 mg/dL AND an abnormal serum free
                       light chain ratio

               -  For non-measurable disease:

                    -  Baseline marrow burden of myeloma of at least 30%

          -  Progression on lenalidomide as part of first line therapy (lenalidomide-refractory
             disease)

             * Lenalidomide-refractory disease is defined as disease progression on or progression
             within 60 days of the last dose of a lenalidomide-based treatment; patients should
             have received at least 2 cycles of a lenalidomide-based regimen to be evaluable for
             refractoriness; examples: 1) progression on lenalidomide maintenance therapy after
             initial induction +/- consolidation; 2) initial response followed by progression on
             continuous lenalidomide-dexamethasone +/- elotuzumab or daratumumab

          -  Pomalidomide naive disease

          -  Proteasome inhibitor naive or sensitive disease; proteasome inhibitor sensitive
             disease is defined as a PR or better to prior proteasome inhibitor-based therapy that
             is maintained for >= 60 days from the last dose of the proteasome inhibitor

             * A patient who receives induction therapy with lenalidomide, bortezomib and
             dexamethasone and achieves a PR or better but subsequently progresses on continued
             lenalidomide or lenalidomide-dexamethasone would be eligible provided the progression
             occurs 60 days or more after discontinuation of the bortezomib; similarly, ixazomib
             exposure is allowed provided they meet the definition of proteasome inhibitor
             sensitive disease

          -  1 prior line of systemic therapy for multiple myeloma, where a line of therapy for
             myeloma is defined as 1 or more planned cycles of single agent or combination therapy,
             as well as a planned series of treatment regimens administered in a sequential manner
             (e.g. lenalidomide, bortezomib and dexamethasone induction therapy for 4 cycles
             followed by autologous stem cell transplantation and then lenalidomide maintenance
             therapy would be considered 1 line of prior therapy); a new line of therapy begins
             when a planned therapy is modified to include other treatment agents (alone or in
             combination) as a result of disease progression, disease relapse or treatment-related
             toxicity (e.g. a patient is progressing in the face of lenalidomide maintenance
             therapy and has bortezomib and dexamethasone added into their regimen); a new line of
             therapy also begins when a planned treatment-free interval is interrupted by the need
             to start treatment due to disease relapse/progression (e.g. a patient with relapsed
             myeloma achieves a partial response after a planned 8 cycles of cyclophosphamide,
             bortezomib and dexamethasone, enjoys an 8-month period off therapy but then
             experiences disease progression requiring re-initiation of therapy)

          -  Allogeneic stem cell transplantation is allowed provided the patient is >= 1 year from
             transplant at time of registration, is not on immunosuppressive therapy to
             treat/prevent graft-versus-host disease, has no evidence of active graft versus host
             disease, and no evidence of active infection

          -  No other chemotherapy or radiation therapy within 14 days prior to registration

          -  No investigational therapy within 14 days prior to registration

          -  No major surgery within 28 days prior to registration

          -  No G-CSF (filgrastim) or GM-CSF (sargramostim) within 7 days of registration or
             pegfilgrastim within 14 days of registration to meet eligibility criteria

          -  No platelet transfusions within 7 days of registration to meet eligibility criteria;
             Note: red blood cell transfusions are allowed at any time

          -  A female of childbearing potential is a sexually mature female who: 1) has not
             undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
             postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in
             the preceding 24 consecutive months)

               -  Women of childbearing potential:

                    -  Must have a negative serum or urine pregnancy test with a sensitivity of at
                       least 25 mlU/ml no more than 14 days prior to registration and must agree to
                       repeat this test within 24 hours of starting pomalidomide

                    -  Must either commit to complete abstinence from heterosexual contact or begin
                       TWO acceptable methods of birth control, one highly effective method and one
                       additional effective (barrier) method, AT THE SAME TIME, before starting
                       pomalidomide

                    -  Must agree to ongoing pregnancy testing

                    -  Must agree to not become pregnant or breast feed a child during treatment on
                       this protocol

               -  Men must practice complete abstinence or agree to use a condom during sexual
                  contact with a female of childbearing potential, even if they have had a
                  successful vasectomy

               -  Note: All participants must be counseled at a minimum of every 28 days about
                  pregnancy precautions and risks of fetal exposure

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

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

          -  Platelet count >= 50 x 10^9/L

          -  Calculated (Calc.) creatinine clearance >= 30 mL/min; calculated utilizing the
             Cockcroft-Gault formula or 24-hour urine collection

          -  Total bilirubin < 1.5 x upper limits of normal (ULN)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper
             limits of normal (ULN)

          -  Note: G-CSF and platelet transfusions cannot be used to increase counts to meet
             eligibility criteria

          -  Patients cannot have:

               -  Central nerve system involvement

               -  Primary refractory multiple myeloma, where primary refractory multiple myeloma is
                  defined as disease that is nonresponsive - patients who have never achieved a
                  minimal response (MR) or better - with any therapy over the course of their
                  disease; it includes patients who never achieve MR or better in whom there is no
                  significant change in M-protein and no evidence of clinical progression as well
                  as patients who meet criteria for true progressive disease (PD)

               -  Primary or secondary plasma cell leukemia

               -  Light-chain (AL) amyloidosis or polyneuropathy, organomegaly, endocrinopathy,
                  monoclonal gammopathy, and skin changes (POEMS) syndrome

               -  Known active hepatitis C based on:

                    -  +hepatitis C virus (HCV) antibody (confirmed)

                    -  +HCV RNA

                    -  Liver disease with history of positive serology

                    -  Note: patients with a prior history of hepatitis C that has been
                       successfully eradicated with antiviral therapy are eligible

               -  Known hepatitis B surface antigen positivity

               -  Previous hypersensitivity to any of the components of the study treatment

               -  Prior history of erythema multiforme with thalidomide or lenalidomide treatment

          -  =< grade 2 peripheral neuropathy

          -  Adequate cardiac function, defined as:

               -  No electrocardiogram (EKG) evidence of acute ischemia

               -  No EKG evidence of active, clinically significant conduction system abnormalities

               -  No EKG evidence of > grade 2 (> 480 ms) corrected QT (QTc) prolongation

               -  Prior to study entry, any EKG abnormality at screening not felt to put the
                  patient at risk has to be documented by the investigator as not medically
                  significant

               -  No uncontrolled angina or severe ventricular arrhythmias

               -  No clinically significant pericardial disease

               -  No history of myocardial infarction within 6 months prior to registration

               -  No class 3 or higher New York Heart Association congestive heart failure

          -  No strong inducers of cytochrome P450 (CYP) 3A4 or CYP1A2 or strong inhibitors of
             CYP3A4 or CYP1A2 within 14 days prior to registration

               -  Note: Ixazomib is a substrate of CYP3A4 and CYP1A2

          -  Patients with human immunodeficiency virus (HIV) infection are eligible, provided they
             meet the following:

               -  No history of acquired immunodeficiency syndrome (AIDS)-defining conditions or
                  other HIV related illness

               -  Cluster of differentiation (CD)4+ cells nadirs > 350/mm^3 within 28 days prior to
                  registration

               -  Treatment sensitive HIV and, if on anti-HIV therapy, HIV viral load < 50
                  copies/mm^3 within 28 days prior to registration

               -  Note: HIV+ patients who enroll on this study and are assigned to treatment with
                  ixazomib may need to modify their anti-retroviral therapy prior to receiving
                  protocol therapy if they are on strong inducers or potent inhibitors of
                  cytochrome P450 3A4

          -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Patients randomized to Arm 1 may opt to
             switch to the 3-drug regimen following disease progression; these patients must be
             re-registered to the study and meet the eligibility criteria below

          -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Patient must have measurable disease or
             non-measurable disease after progression on pomalidomide + dexamethasone, defined as
             one or more of the following holding true:

             * Measurable disease:

               -  Serum M-protein >= 0.5 g/dL and/or

               -  Urine M-protein >= 200 mg/24 hours and/or

               -  Involved serum free light chain level >= 10 mg/dL AND an abnormal serum free
                  light chain ratio

                  * For non-measurable disease:

               -  Marrow burden of myeloma of at least 30%

          -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2):

               -  Women of childbearing potential:

                  ** Must have a negative serum or urine pregnancy test within 72 hours prior to
                  re-registration

                  ** Must either commit to complete abstinence from heterosexual contact or begin
                  TWO acceptable methods of birth control, one highly effective method and one
                  additional effective (barrier) method, AT THE SAME TIME, before starting
                  pomalidomide

                  ** Must agree to ongoing pregnancy testing

                  ** Must agree to not become pregnant or breast feed a child during treatment on
                  this protocol

               -  Men must practice complete abstinence or agree to use a condom during sexual
                  contact with a female of childbearing potential, even if they have had a
                  successful vasectomy

               -  Note: All participants must be counseled at a minimum of every 28 days about
                  pregnancy precautions and risks of fetal exposure

          -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): ECOG performance status 0-2

          -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Absolute neutrophil count (ANC) >= 1.0
             x 10^9/L

          -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Platelet count >= 50 x 10^9/L

          -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Calc. creatinine clearance >= 30 mL/min

             * Calculated utilizing the Cockcroft-Gault formula or 24-hour urine collection

          -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Total bilirubin < 1.5 x upper limits of
             normal (ULN)

          -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): AST and ALT < 2.5 x upper limits of
             normal (ULN)

          -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Note: G-CSF and platelet transfusions
             cannot be used to increase counts to meet eligibility criteria

          -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): =< grade 2 peripheral neuropathy

          -  RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): No strong inducers of cytochrome P450
             (CYP) 3A4 or CYP1A2 or strong inhibitors of CYP3A4 or CYP1A2 * Note: Ixazomib is a
             substrate of CYP3A4 and CYP1A2
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of pomalidomide and ixazomib, determined according to incidence of dose limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Incidence and type of dose limiting toxicities (DLTs), serious adverse events, and adverse events, graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I)
Time Frame:Up to 4 weeks post study treatment
Safety Issue:
Description:
Measure:Incidence of dose reductions/delays (Phase I)
Time Frame:Up to 4 weeks post-study treatment
Safety Issue:
Description:
Measure:Overall response rate (ORR), defined as partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) according to International Myeloma Working Group (IMWG) Uniform Response Criteria (Phase II)
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Clinical benefit rate (CBR), defined as minimal response (MR) and better according to International Myeloma Working Group (IMWG) Uniform Response Criteria (Phase II)
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Disease control rate (DCR), defined as stable disease (SD) and better according to International Myeloma Working Group (IMWG) Uniform Response Criteria (Phase II)
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Duration of response (DOR), calculated for all patients achieving an objective response, partial response (PR) or better (Phase II)
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Overall survival (OS) (Phase II)
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Time to next treatment (TNT) (Phase II)
Time Frame:Up to 3 years post-registration
Safety Issue:
Description:
Measure:Incidence, type and severity of adverse events, graded according to National Cancer Institute (NCI) Common Terminology Criteria Adverse Events (CTCAE) version 4.0 (Phase II)
Time Frame:Up to 4 weeks post-study treatment
Safety Issue:
Description:
Measure:Response rates (overall response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) for all patients on the pomalidomide/dexamethasone arm at the time of cross-over to pomalidomide/dexamethasone/ixazomib (Phase II)
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Progression free survival (PFS) for all patients on the pomalidomide/dexamethasone arm at the time of cross-over to pomalidomide/dexamethasone/ixazomib (Phase II)
Time Frame:Up to 3 years post-registration (at crossover)
Safety Issue:
Description:
Measure:Baseline level of perceived fatigue and QOL, assessed using the Registration Fatigue/Uniscale Assessment form (Phase II)
Time Frame:baseline
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Alliance for Clinical Trials in Oncology

Last Updated

November 19, 2019