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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Alliance for Clinical Trials in Oncology
Sponsor:
Collaborators:
Celgene Corporation
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier:
NCT02004275
First received: November 26, 2013
Last updated: March 19, 2014
Last verified: March 2014
  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 refractory multiple myeloma. Biological therapies, such as pomalidomide and dexamethasone, may stimulate the immune system in different ways and stop tumor cells from growing. Ixazomib may stop the growth of tumor 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 Intervention Phase
Multiple Myeloma in Relapse
Drug: pomalidomide
Drug: ixazomib
Drug: dexamethasone
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: 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 Refractory to Lenalidomide and Proteasome Inhibitor-Based Therapy

Resource links provided by NLM:


Further study details as provided by Alliance for Clinical Trials in Oncology:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
  • Progression free survival (PFS) (Phase II) [ Time Frame: Up to 3 years post-registration ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
  • Incidence of dose reductions/delays (Phase I) [ Time Frame: Up to 4 weeks post-study treatment ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Overall survival (OS) (Phase II) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Time to next treatment (TNT) (Phase II) [ Time Frame: Up to 3 years post-registration ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • Baseline level of perceived fatigue and QOL, assessed using the Registration Fatigue/Uniscale Assessment form (Phase II) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 132
Study Start Date: February 2014
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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. Patients receive pomalidomide (dose determined in phase I) oral on days 1-21, ixazomib (dose determined in phase I) oral on days 1, 8 and 15 and dexamethasone oral on days 1, 8, 15 and 22. Courses repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of patient consent.
Drug: pomalidomide
given PO
Other Name: Pomalyst®
Drug: ixazomib
given PO
Other Name: MLN9708
Drug: dexamethasone
given PO

Detailed Description:

This is a phase I, dose-escalation study of pomalidomide, dexamethasone and ixazomib followed by a phase II study. The primary purpose of the Phase I portion of the study is to establish the maximum tolerated dose for combination therapy pomalidomide/dexamethasone/ixazomib. Patients receive pomalidomide orally (PO) once daily (QD) on days 1-21, dexamethasone PO QD on days 1, 8, 15, and 22, and ixazomib PO QD on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. About 24 patients will take part in this portion of the study.

The primary purpose of the Phase II portion of the study is to assess whether the combination of pomalidomide/dexamethasone/ixazomib improves progression free survival relative to pomalidomide/dexamethasone. Please see the "Arms" section below for a detailed description of the treatment arms for Phase II of the study. The dose for pomalidomide and ixazomib will be determined in phase I of the study. About 108 patients will take part in this portion of the study. The secondary objectives are listed below.

Secondary Phase I Objectives:

  1. To determine dose-limiting toxicities (DLTs)
  2. To analyze type and grade of all serious adverse events (SAEs)
  3. To analyze type and grade of all adverse events (AEs)
  4. To analyze the reason for and incidence of dose modifications/omissions/delays
  5. To assess preliminary evidence of clinical efficacy

Secondary Phase II Objectives:

  1. To evaluate the overall response rate (ORR), partial response (PR), very good partial response (VGPR), complete response (CR) and stringent CR (sCR) rate for pomalidomide/dexamethasone/ixazomib compared to pomalidomide/dexamethasone
  2. To assess the clinical benefit rate (CBR: minimal response (MR) + ORR) for pomalidomide/dexamethasone/ixazomib compared to pomalidomide/dexamethasone
  3. To assess the disease control rate (DCR: stable disease (SD) + CBR) for pomalidomide/dexamethasone/ixazomib compared to pomalidomide/dexamethasone
  4. 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.
  5. To assess whether the combination of pomalidomide/dexamethasone/ixazomib improves overall survival (OS) compared to those taking pomalidomide/dexamethasone alone.
  6. To assess time to next treatment (TNT) for patients taking pomalidomide/dexamethasone/ixazomib compared to those on pomalidomide/dexamethasone.
  7. To evaluate the safety of pomalidomide/dexamethasone/ixazomib compared with pomalidomide/dexamethasone.
  8. 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.
  9. To determine if baseline level of perceived fatigue and overall quality of life (QOL) is associated with OS.

Patients are followed up every 4 weeks until disease progression, death or the withdrawal of informed consent.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Eligibility Criteria:

  1. Documentation of Disease:

    Histologically confirmed diagnosis of symptomatic multiple myeloma.

  2. Measurable disease:

    1. Serum M-protein ≥ 1.0 g/dL and/or
    2. Urine M-protein ≥ 200 mg/24 hours and/or
    3. Involved serum free light chain level ≥ 10 mg/dL and an abnormal serum free light chain ratio and/or
    4. Baseline marrow burden of myeloma of at least 30%
  3. Prior Treatment:

    1. Previously treated symptomatic multiple myeloma
    2. Lenalidomide and proteasome inhibitor-refractory multiple myeloma (dual refractory disease)

      • Lenalidomide and proteasome inhibitor-refractory disease is defined as disease progression on or progression within 60 days of the last dose of a lenalidomide and proteasome inhibitor-based treatment.
      • Patients should have received at least 2 cycles of a lenalidomide or proteasome inhibitor-based regimen at standard doses to be evaluable for refractoriness.
      • Patients can be refractory to either bortezomib or carfilzomib they do not need to be refractory to both.
      • Patients can be refractory to lenalidomide and proteasome inhibitors given sequentially as part of different lines of therapy or therapy that includes a combination of lenalidomide and a proteasome inhibitor.
    3. At least 2 or more prior lines of systemic therapy for multiple myeloma

      • 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).
    4. Allogeneic stem cell transplantation is allowed provided the patient is ≥ 1 year from transplant, is not on immunosuppressive therapy to treat/prevent graft-versus-host disease, has no evidence of active graft versus host disease, no evidence of active infection and meets all other criteria for participation.
    5. No other chemotherapy or radiation therapy within 14 days prior to registration
    6. No investigational agent within 21 days prior to registration
    7. Pomalidomide naïve and pomalidomide sensitive disease are allowed during phase I and phase II

      • Sensitivity to pomalidomide is defined as an MR or better to prior pomalidomide-based therapy that is maintained for ≥60 days from the last dose of therapy.
    8. No concurrent investigational therapy
    9. No major surgery within 28 days prior to registration
    10. Patients cannot have received G-CSF (Filgrastim) or GM-CSF (Sargramostim) within 1 week of screening or Pegfilgrastim within 2 weeks of screening to meet eligibility criteria
  4. Non-pregnant and non-nursing:

    A female of childbearing potential is a sexually mature female who has not undergone a hysterectomy or bilateral oophorectomy or 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).

    1. 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 therapy and repeated again within 24 hours of starting pomalidomide
    2. Women of childbearing potential 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
    3. Females of childbearing potential must agree to ongoing pregnancy testing.
    4. 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.
    5. All participants must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
    6. Participating women cannot be pregnant or nursing
  5. ≥18 years of age
  6. Eastern Cooperative Oncology Group (ECOG) Performance status 0-2
  7. Required Initial Laboratory Values:

    1. Absolute Neutrophil Count (ANC) ≥ 1.0 x 10^9/L
    2. Platelet Count ≥ 50 x 10^9/L
    3. Calculated Creatinine Clearance* ≥ 50 mL/min
    4. Total Bilirubin < 1.5 x upper limits of normal (ULN)
    5. AST and ALT < 2.5 x upper limits of normal (ULN)

      • Calculated utilizing the Cockcroft-Gault formula or 24-hour urine collection
  8. Intercurrent or Recent Illness:

    1. No central nervous system involvement
    2. No primary refractory multiple myeloma

      • 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
      • primary refractory multiple myeloma also includes patients who never achieve minimal response (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)
    3. No primary or secondary plasma cell leukemia
    4. No amyloid light-chain (AL) amyloidosis or polyneuropathy, organomegaly, endocrinopathy, monoclonal, gammopathy and skin changes (POEMS) syndrome
    5. No known active hepatitis C based on +HCV antibody (confirmed), +HCV ribonucleic acid (RNA) and liver disease with history of positive serology
    6. No known hepatitis B surface antigen positivity
    7. No previous hypersensitivity to any of the components of the study treatment
    8. No prior history of erythema multiforme with thalidomide or lenalidomide treatment
  9. Peripheral Neuropathy ≤ Grade 2
  10. Adequate cardiac function defined as:

    1. No electrocardiography (EKG) evidence of acute ischemia
    2. No EKG evidence of active, clinically significant conduction system abnormalities
    3. No EKG evidence of >Grade 2 (>480 ms) quantum tunnelling composite (QTc) prolongation
    4. 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
    5. No uncontrolled angina or severe ventricular arrhythmias
    6. No clinically significant pericardial disease
    7. No history of myocardial infarction within the last 6 months
    8. No Class 3 or higher New York Heart Association Congestive Heart Failure
  11. Concomitant Treatment - Patients cannot be on strong inducers of cytochrome P450 (CYP) 3A4 or CYP1A2 or strong inhibitors of CYP3A4 or CYP1A2.

    • Ixazomib is a substrate of CYP3A4 and CYP1A2. For additional information about potential drug-drug and drug-food interactions with ixazomib, please see the protocol.
    • Strong CYP3A4 inducers prohibited (examples):

      • phenytoin
      • carbamazepine
      • rifampin
      • rifabutin
      • rifapentin
      • phenobarbital
      • St. John's Wort
    • Strong CYP3A4 inhibitors are prohibited:

      • boceprevir
      • indinavir
      • nelfinavir
      • lopinavir
      • saquinavir
      • telaprevir
      • ritonavir
      • clarithromycin
      • conivaptan
      • itraconazole
      • ketoconazole
      • mibefradil
      • nefazodone
      • posaconazole
      • voriconazole
      • telithromycin
    • Strong CYP1A2 inhibitors are prohibited:

      • fluvoxamine
      • ciprofloxacin
  12. Human Immunodeficiency virus (HIV) infection - Patients with HIV infection are eligible, provided they meet the following:

    1. No history of Acquired Immune Deficiency Syndrome (AIDS)-defining conditions or other HIV related illness
    2. CD4+ cells nadirs > 350/mm^3
    3. Treatment sensitive HIV and, if on anti-HIV therapy, HIV viral load < 50 copies/mm^3

Please 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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02004275

Locations
United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Peter Voorhees, M.D.    919-966-5879      
Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
Celgene Corporation
Millennium Pharmaceuticals, Inc.
Investigators
Study Chair: Peter Voorhees, M.D. University of North Carolina, Chapel Hill
  More Information

No publications provided

Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT02004275     History of Changes
Other Study ID Numbers: A061202, NCI-2013-01702, U10CA031946
Study First Received: November 26, 2013
Last Updated: March 19, 2014
Health Authority: United States: Food and Drug Administration
United States: Central Institutional Review Board

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
Dexamethasone 21-phosphate
Pomalidomide
Thalidomide
BB 1101
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids

ClinicalTrials.gov processed this record on September 18, 2014