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Allogeneic Hematopoietic Stem Cell Transplantation With Ixazomib for High Risk Multiple Myeloma (BMT CTN 1302)

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ClinicalTrials.gov Identifier: NCT02440464
Recruitment Status : Active, not recruiting
First Posted : May 12, 2015
Last Update Posted : October 5, 2018
Sponsor:
Collaborators:
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Information provided by (Responsible Party):
National Heart, Lung, and Blood Institute (NHLBI)

Brief Summary:
This study is designed to compare progression-free survival (PFS) from randomization among patients randomized on the BMT CTN 1302 protocol, "Multicenter Phase II, Double-blind Placebo Controlled Trial of Maintenance Ixazomib after Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Multiple Myeloma". It is hypothesized that Ixazomib maintenance therapy will result in improved PFS in patients with high-risk multiple myeloma following Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) compared to placebo.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Procedure: Allogeneic HSCT Drug: Fludarabine Drug: Melphalan Drug: Bortezomib Drug: Ixazomib Drug: Placebo Phase 2

Detailed Description:
The study is designed as a Phase II, multi-center double-blind trial that randomizes patients with high risk Multiple Myeloma to Ixazomib maintenance or placebo 60-120 days after allogeneic HSCT. The primary objective of this randomized trial is to compare progression free survival from randomization as a time to event endpoint between patients randomized to Ixazomib maintenance or placebo. Secondary objectives are to describe for each treatment arm: rates of grade II-IV and III-IV Graft-Versus-Host-Disease (GVHD), chronic GVHD, best disease response rates, disease progression, transplant related mortality, overall survival, rates of Grade ≥ 3 toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, incidence of infections, and health-related quality of life.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 57 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Multicenter Phase II, Double-blind Placebo Controlled Trial of Maintenance Ixazomib After Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Multiple Myeloma (BMT CTN #1302)
Study Start Date : August 2015
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: Ixazomib Maintenance
Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance
Procedure: Allogeneic HSCT
Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11.
Other Name: Allogeneic hematopoietic stem cell transplant

Drug: Fludarabine
Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3.
Other Name: Fludara

Drug: Melphalan
Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3.
Other Name: Alkeran

Drug: Bortezomib
Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3.
Other Name: Velcade®

Drug: Ixazomib
Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.
Other Names:
  • MLN9708
  • Ninlaro

Placebo Comparator: Placebo
Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance.
Procedure: Allogeneic HSCT
Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11.
Other Name: Allogeneic hematopoietic stem cell transplant

Drug: Fludarabine
Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3.
Other Name: Fludara

Drug: Melphalan
Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3.
Other Name: Alkeran

Drug: Bortezomib
Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3.
Other Name: Velcade®

Drug: Placebo
Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Other Name: sugar pill




Primary Outcome Measures :
  1. Progression-Free Survival [ Time Frame: 2 years post-randomization ]
    Progression-free survival from randomization will be compared between patients randomized to the Ixazomib maintenance and placebo maintenance arms as a time to event analysis.


Secondary Outcome Measures :
  1. Incidence of Acute GVHD (Grades II-IV) [ Time Frame: 2 years post-randomization ]
    Cumulative incidence of acute GVHD grades II-IV from randomization will be compared between treatment arms.

  2. Incidence of Acute GVHD (Grades III-IV) [ Time Frame: 2 years post-randomization ]
    Cumulative incidence of acute GVHD grades III-IV from randomization will be compared between treatment arms.

  3. Incidence of Chronic GVHD [ Time Frame: 2 years post-randomization ]
    Cumulative incidence of cGVHD from randomization will be compared between treatment arms.

  4. Disease Progression [ Time Frame: 2 years post-randomization ]
    The cumulative incidence of myeloma progression will be compared between treatment arms.

  5. Treatment-Related Mortality (TRM) [ Time Frame: 2 years post-randomization ]
    Treatment-related mortality is defined as death occurring in a patient from causes other than disease relapse or progression. Cumulative incidence of treatment-related mortality from randomization will be compared between treatment arms.

  6. Incidence of Grade ≥ 3 toxicity [ Time Frame: 2 years post-randomization ]
    Grade ≥ 3 toxicities will be tabulated by grade for each treatment arm, by type of toxicity as well as the peak grade overall. Toxicity frequencies will be described for each time interval as well as cumulative over time. The cumulative incidence of Grade ≥ 3 toxicity will be compared between treatment arms at 6, 12 and 18 months post-randomization.

  7. Incidence of Infections [ Time Frame: 2 years post-randomization ]
    The number of infections and the number of patients experiencing infections will be tabulated by type of infection, severity, and time period after randomization. The cumulative incidence of severe, life-threatening, or fatal infections, treating death as a competing event, will be compared between the two treatment arms at 6, 12 and 18 months post randomization.

  8. Overall Survival (OS) [ Time Frame: 2 years post-randomization ]
    Overall survival (OS) from randomization will be compared between the treatment arms.

  9. Health-Related Quality of Life (QoL) [ Time Frame: 2 years post-randomization ]
    Health quality of life will be described from time of pre-transplant to time prior to randomization utilizing the FACT-BMT self-report, transplant-specific questionnaire, and the generic quality of life tool, the SF-36. Comparisons between maintenance treatment groups will be performed prior to maintenance, 6 months after start of maintenance and at 24 months after transplant. Only English and Spanish speaking patients are eligible to participate in the HQL component of this trial.

  10. Best response to Treatment after Randomization [ Time Frame: 2 years post-randomization ]
    Best response (sCR, CR, VGPR, or PR) after randomization will be compared between treatment groups using a chi-square test. Additionally, responses at 12 months and 18 months post-randomization will be assessed in each arm. These will be summarized separately for patients in CR at the time of randomization vs. those who were in less than a CR. Best response at Day 60 (prior to randomization) will be reported for all transplanted patients



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must meet one of the following disease criteria:

    a. Patients with high risk multiple myeloma in partial response (PR) or better with no prior progression and are ≤ 24.0 months after autologous HCT (single or planned tandem), or are ≤ 24.0 months after initiation of systemic anti-myeloma therapy for patients without prior autologous HCT; or

    i. High risk is defined by the presence of any one of the following detected at any time prior to enrollment: deletion of chromosome 13 by conventional cytogenetics, hypodiploidy, abnormality in chromosome 1(1q amplification or 1p deletion), t(4;14), t(14;16), t(14;20) or deletion of 17p by fluorescence in situ hybridization (FISH) or conventional karyotyping; high risk criteria based on commercially available gene expression profiling (GEP)

    b. Patients with high risk multiple myeloma (see criterion 2.a.i. above) in very good partial response (VGPR) or better with 1 prior progression which occurred ≤ 24.0 months after autologous HCT (single or planned tandem), or ≤ 24.0 months after initiation of systemic anti-myeloma therapy for patients without prior autologous HCT; or

    i. Patients with one prior progression without measurable monoclonal paraprotein at the time of disease progression or relapse (< 1.0 g/dl in serum or < 200 mg/24hrs in urine) may be considered to have met VGPR criteria if < 5% plasma cells in bone marrow and ≥ 90% decrease in the difference between involved and uninvolved FLC levels from baseline (time of progression/relapse).

    ii. In patients with IgG kappa MM receiving daratumumab: International Myeloma Working Group criteria for VGPR may not be achieved since daratumumab is known to increase the IgG kappa spike. In such cases the FLC and marrow may be used to establish VGPR, as above, with prior approval from the protocol co-chairs.

    c. Patients with standard risk multiple myeloma in VGPR or better (see criteria 2.b.i. and 2.b.ii. above) at the time of enrollment with 1 prior progression ≤ 24.0 months from single or planned tandem autologous HCT; or d. Patients with primary plasma cell leukemia in VGPR or better with no prior disease progression and are ≤ 18.0 months after autologous HCT, or are ≤ 18.0 months after initiation of anti-myeloma therapy without prior autologous HCT.

  2. Patients must have a related or unrelated peripheral blood stem cell donor that meet one of the following criteria:

    1. A sibling donor who is a 6/6 match at HLA-A and -B (intermediate or higher resolution) and -DRB1 (at high resolution using DNA-based typing) and must be willing to donate peripheral blood stem cells and meet institutional criteria for donation OR
    2. A related donor (other than sibling) who is a 8/8 match for HLA-A, -B, -C (at intermediate or higher resolution) and -DRB1 (at high resolution using DNA-based typing) and must be willing to donate peripheral blood stem cells and meet institutional criteria for donation OR
    3. An unrelated donor who is an 8/8 match at HLA-A, -B, -C, and -DRB1 (at high resolution using DNA-based typing) and must be willing to donate peripheral blood stem cells and meet institutional criteria for donation.
  3. Cardiac function: Ejection fraction > 40%
  4. Estimated creatinine clearance greater than 40 mL/minute (using the Cockcroft-Gault formula and actual body weight)
  5. Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 40% (adjusted for hemoglobin) and forced expiratory volume in one second (FEV1) ≥ 50%
  6. Liver function: total bilirubin < 2x the upper limit of normal and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5x the upper normal limit (Patients with Gilbert's Disease are permitted to exceed the defined bilirubin value of 2x the upper limit of normal, however measurements of direct bilirubin should be done to confirm this diagnosis).
  7. Female subjects (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two (2) effective methods of contraception at the same time, 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) through 90 days after the last dose of maintenance therapy (see Section 2.6.2 for definition of postmenopausal).
  8. Male subjects (even if surgically sterilized) must agree to one of the following: practice effective barrier contraception (see Section 2.6.4.1 for list of barrier methods), or 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 from the time of signing the informed consent through 90 days after last dose of maintenance therapy.
  9. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
  10. Able to comply with the study visit schedule and other protocol requirements.

Exclusion Criteria:

  1. Karnofsky Performance Score < 70%
  2. Prior allogeneic HCT
  3. Patient with purely non-secretory multiple myeloma [absence of monoclonal protein (M protein) in serum as measured by electrophoresis and immunofixation and the absence of Bence Jones protein in the urine defined by the use of conventional electrophoresis and immunofixation techniques and the absence of involved serum free light chain > 100 mg/L].
  4. Planned pre-emptive/prophylactic administration of donor lymphocytes (as per section 2.5.2)
  5. Central Nervous System (CNS) involvement with multiple myeloma defined as CSF positivity for plasma cells or a parenchymal CNS plasmacytoma
  6. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
  7. Presence of fluid collection (ascites, pleural, or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated.
  8. Patients seropositive for the human immunodeficiency virus (HIV).
  9. Patient with active Hepatitis B or C determined by serology and/or NAAT.
  10. Patients with hypersensitivity to bortezomib, boron or mannitol.
  11. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 (ixazomib) including difficulty swallowing.
  12. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
  13. Patients with ≥ grade 2 sensory peripheral neuropathy.
  14. Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure (see Appendix D), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
  15. Female patients who are lactating or pregnant
  16. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent < 5 years, which is in remission, will be reviewed on a case-by-case basis by the Protocol Officer or one of the Protocol Chairs.
  17. Patients with multi-organ involvement by amyloidosis or evidence of amyloidosis related organ dysfunction.
  18. Failure to have fully recovered (i.e., no toxicities > Grade 1 by CTCAE version 4.0) from the reversible effects of prior chemotherapy.
  19. Patient with serious medical of psychiatric illness likely to interfere with participation on this clinical study
  20. Participation in clinical trials with other investigational agents not included in this trial, ≤ 14.0 days of enrollment on this trial and throughout its duration.
  21. Patients who have received radiation therapy within 3 weeks before transplant. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.
  22. Patients unable or unwilling to adhere to the study assessment schedule.

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): NCT02440464


Locations
United States, Alabama
University of Alabama
Birmingham, Alabama, United States, 35294
United States, California
City of Hope National Medical Center
Duarte, California, United States, 91010
United States, Florida
H. Lee Moffitt Cancer Center
Tampa, Florida, United States, 33624
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
BMT Northside
Atlanta, Georgia, United States, 30342
United States, Illinois
Loyola University Medical Center
Maywood, Illinois, United States, 60153
United States, Kentucky
University of Kentucky
Lexington, Kentucky, United States, 40536
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27705
United States, Ohio
Ohio State/Arthur G. James Cancer Hospital
Columbus, Ohio, United States, 43210
United States, Texas
University of Texas /MD Anderson CRC
Houston, Texas, United States, 77030
United States, West Virginia
West Virginia University
Morgantown, West Virginia, United States, 26506
United States, Wisconsin
University of Wisconsin Hospital & Clinics
Madison, Wisconsin, United States, 53792
Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53211
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Investigators
Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research

Additional Information:
Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT02440464     History of Changes
Other Study ID Numbers: BMTCTN1302
U01HL069294-05 ( U.S. NIH Grant/Contract )
First Posted: May 12, 2015    Key Record Dates
Last Update Posted: October 5, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Time Frame: Within 6 months of official study closure at participating sites.
Access Criteria: Available to the public
URL: https://biolincc.nhlbi.nih.gov/home/

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Heart, Lung, and Blood Institute (NHLBI):
Multiple Myeloma
Allogeneic Transplant
Maintenance Therapy
Anti-Myeloma Agents
Hematologic Disorders

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
Fludarabine
Fludarabine phosphate
Ixazomib
Bortezomib
Melphalan
Vidarabine
Glycine
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents