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

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ClinicalTrials.gov Identifier: NCT02004275
Recruitment Status : Recruiting
First Posted : December 9, 2013
Last Update Posted : June 20, 2018
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Celgene Corporation
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Multiple Myeloma in Relapse Drug: pomalidomide Drug: ixazomib Drug: dexamethasone Phase 1 Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 73 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 2014
Estimated Primary Completion Date : December 2018


Arm Intervention/treatment
Experimental: Arm I (pomalidomide, dexamethasone)
Patients 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.
Drug: pomalidomide
given PO
Other Name: Pomalyst®

Drug: dexamethasone
given PO

Experimental: Arm II (pomalidomide, dexamethasone, ixazomib)
Patients receive pomalidomide, dexamethasone, and ixazomib as in Phase I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: pomalidomide
given PO
Other Name: Pomalyst®

Drug: ixazomib
given PO
Other Name: MLN9708

Drug: dexamethasone
given PO




Primary Outcome Measures :
  1. 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 ]
  2. Progression free survival (PFS) (Phase II) [ Time Frame: Up to 3 years post-registration ]

Secondary Outcome Measures :
  1. 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 ]
  2. Incidence of dose reductions/delays (Phase I) [ Time Frame: Up to 4 weeks post-study treatment ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. Overall survival (OS) (Phase II) [ Time Frame: Up to 3 years ]
  8. Time to next treatment (TNT) (Phase II) [ Time Frame: Up to 3 years post-registration ]
  9. 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 ]
  10. 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 ]
  11. 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) ]
  12. Baseline level of perceived fatigue and QOL, assessed using the Registration Fatigue/Uniscale Assessment form (Phase II) [ Time Frame: baseline ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02004275


Contacts
Contact: Peter Voorhees, MD 919 966-5879

  Show 278 Study Locations
Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
Celgene Corporation
Millennium Pharmaceuticals, Inc.
Investigators
Study Chair: Peter Voorhees, MD University of North Carolina, Chapel Hill

Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT02004275     History of Changes
Other Study ID Numbers: A061202
NCI-2013-01702 ( Registry Identifier: Clinical Trial Reporting Program )
U10CA031946 ( U.S. NIH Grant/Contract )
First Posted: December 9, 2013    Key Record Dates
Last Update Posted: June 20, 2018
Last Verified: June 2018

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Pomalidomide
Ixazomib
Thalidomide
BB 1101
Glycine
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists