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

NCT02440464 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: BMT CTN 1302U01HL069294-05
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 15

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.

Conditions

Multiple Myeloma

Keywords

Multiple Myeloma; Allogeneic Transplant; Maintenance Therapy; Anti-Myeloma Agents; Hematologic Disorders

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Progression-Free Survival

  The primary endpoint compares progression-free survival as a time to event endpoint from randomization between patients randomized to ixazomib and placebo maintenance in high risk multiple myeloma. Participants are considered a failure of the primary endpoint if they die or suffer from disease progression or if they initiate non-protocol anti-myeloma therapy. Disease progression was evaluated using the International Uniform Response Criteria. Participants must meet one of the criteria for disease progression specified in the protocol. The time to this event is the time from randomization to progression, death, or initiation of non-protocol anti myeloma therapy whichever comes first. The Kaplan-Meier estimator was used to estimate progression-free survival during the 2 year post-transplant follow-up period. Participants who were event-free at two years post-transplant are censored at that time.

  12 months and 21 months post-randomization

Secondary Outcomes (13)

• Percentage of Participants With Acute GVHD (Grades III-IV)

  100 days post-randomization

• Percentage of Participants With Chronic GVHD

  12 months and 21 months post-randomization

• Percentage of Participants With Best Response to Treatment After Randomization

  2 years post-transplant

• Percentage of Participants With Response to Treatment

  18 months and 24 months post-transplant

• Percentage of Participants With Disease Progression

  12 months and 21 months post-randomization

Study Arms (2)

Ixazomib Maintenance

EXPERIMENTAL

Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance

Procedure: Allogeneic HSCT; Drug: Fludarabine; Drug: Melphalan; Drug: Bortezomib; Drug: Ixazomib

Placebo

PLACEBO COMPARATOR

Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance.

Procedure: Allogeneic HSCT; Drug: Fludarabine; Drug: Melphalan; Drug: Bortezomib; Drug: Placebo

Interventions

Allogeneic HSCT PROCEDURE

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.

Also known as: Allogeneic hematopoietic stem cell transplant

Ixazomib Maintenance; Placebo

Fludarabine DRUG

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

Also known as: Fludara

Ixazomib Maintenance; Placebo

Melphalan DRUG

Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3.

Also known as: Alkeran

Ixazomib Maintenance; Placebo

Bortezomib DRUG

Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3.

Also known as: Velcade®

Ixazomib Maintenance; Placebo

Ixazomib DRUG

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.

Also known as: MLN9708, Ninlaro

Ixazomib Maintenance

Placebo DRUG

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.

Also known as: sugar pill

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 hematopoietic cell transplantation (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 free light chain (FLC) levels from baseline (time of progression/relapse).
• ii. In patients with immunoglobulin G (IgG) kappa multiple myeloma (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.
• Patients must have a related or unrelated peripheral blood stem cell donor that meet one of the following criteria:
• A sibling donor who is a 6/6 match at HLA-A and -B (intermediate or higher resolution) and -DR Beta 1 (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
• 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
• 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.
• Cardiac function: Ejection fraction \> 40%
• Estimated creatinine clearance greater than 40 mL/minute (using the Cockcroft-Gault formula and actual body weight)
• Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 40% (adjusted for hemoglobin) and forced expiratory volume in one second (FEV1) ≥ 50%
• 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).

You may not qualify if:

• Karnofsky Performance Score \< 70%
• Prior allogeneic HCT
• Patient with purely non-secretory multiple myeloma \[absence of monoclonal protein (M protein) in serum as measured by electrophoresis and immunofixation and the absence of Bence Jones protein in the urine defined by the use of conventional electrophoresis and immunofixation techniques and the absence of involved serum free light chain \> 100 mg/L\].
• Planned pre-emptive/prophylactic administration of donor lymphocytes (as per section 2.5.2)
• Central Nervous System (CNS) involvement with multiple myeloma defined as cerebrospinal fluid (CSF) positivity for plasma cells or a parenchymal CNS plasmacytoma
• Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
• Presence of fluid collection (ascites, pleural, or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated.
• Patients seropositive for the human immunodeficiency virus (HIV).
• Patient with active Hepatitis B or C determined by serology and/or nucleic acid amplification test (NAAT).
• Patients with hypersensitivity to bortezomib, boron or mannitol.
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 (ixazomib) including difficulty swallowing.
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
• Patients with ≥ grade 2 sensory peripheral neuropathy.
• 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.
• Female patients who are lactating or pregnant

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead
• Blood and Marrow Transplant Clinical Trials Network: collaborator
• National Cancer Institute (NCI): collaborator
• National Marrow Donor Program: collaborator

Study Sites (15)

University of Alabama

Birmingham, Alabama, 35294, United States

Location

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

H. Lee Moffitt Cancer Center

Tampa, Florida, 33624, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

BMT Northside

Atlanta, Georgia, 30342, United States

Location

Loyola University Medical Center

Maywood, Illinois, 60153, United States

Location

University of Kentucky

Lexington, Kentucky, 40536, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

Ohio State/Arthur G. James Cancer Hospital

Columbus, Ohio, 43210, United States

Location

University of Texas /MD Anderson CRC

Houston, Texas, 77030, United States

Location

West Virginia University

Morgantown, West Virginia, 26506, United States

Location

University of Wisconsin Hospital & Clinics

Madison, Wisconsin, 53792, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53211, United States

Location

Related Publications (1)

• Bashir Q, Nishihori T, Pasquini MC, Martens MJ, Wu J, Alsina M, Anasetti C, Brunstein C, Dawson P, Efebera Y, Gasparetto C, Geller N, Giralt S, Hall AC, Koreth J, McCarthy P, Scott E, Stadtmauer EA, Vesole DH, Hari P. A Multicenter Phase II, Double-Blind, Placebo-Controlled Trial of Maintenance Ixazomib After Allogeneic Transplantation for High-Risk Multiple Myeloma: Results of the Blood and Marrow Transplant Clinical Trials Network 1302 Trial. Transplant Cell Ther. 2023 Jun;29(6):358.e1-358.e7. doi: 10.1016/j.jtct.2022.07.007. Epub 2022 Jul 12.

  PMID: 35840087 RESULT

MeSH Terms

Conditions

Multiple Myeloma; Hematologic Diseases

Interventions

fludarabine; fludarabine phosphate; Melphalan; Bortezomib; ixazomib; Sugars

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Carbohydrates

Results Point of Contact

• Title: Adam Mendizabal, PhD
• Organization: The Emmes Company

amendizabal@emmes.com

(301) 251-1161

Study Officials

• Mary Horowitz, MD

  Center for International Blood and Marrow Transplant Research

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 7, 2015
• First Posted: May 12, 2015
• Study Start: August 1, 2015
• Primary Completion: October 1, 2020
• Study Completion: October 1, 2020
• Last Updated: January 4, 2023
• Results First Posted: January 21, 2022

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Within 6 months of official study closure at participating sites.
• Access Criteria: Available to the public

Locations

US (15)