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Birmingham, Alabama 35294

  • Multiple Myeloma

Purpose:

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.


Study summary:

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.


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.


Study is Available At:


Original ID:

BMTCTN1302


NCT ID:

NCT02440464


Secondary ID:

U01HL069294-05


Study Acronym:


Brief Title:

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


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)


Overall Status:

Active, not recruiting


Study Phase:

Phase 2


Genders:

N/A


Minimum Age:

18 Years


Maximum Age:

70 Years


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

National Heart, Lung, and Blood Institute (NHLBI)


Oversight Authority:

  • United States: Institutional Review Board
  • United States: Food and Drug Administration


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

2


Number of Groups:

0


Total Enrollment:

57


Enrollment Type:

Actual


Overall Contact Information

Official Name:Mary Horowitz, MD
Study Director
Center for International Blood and Marrow Transplant Research

Study Dates

Start Date:August 2015
Completion Date:March 2023
Completion Type:Anticipated
Primary Completion Date:March 2021
Primary Completion Type:Anticipated
Verification Date:December 2019
Last Changed Date:December 18, 2019
First Received Date:May 7, 2015

Study Outcomes

Outcome Type:Primary Outcome
Measure:Progression-Free Survival
Time Frame:2 years post-randomization
Safety Issues:False
Description: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.
Outcome Type:Secondary Outcome
Measure:Incidence of Acute GVHD (Grades II-IV)
Time Frame:2 years post-randomization
Safety Issues:False
Description:Cumulative incidence of acute GVHD grades II-IV from randomization will be compared between treatment arms.
Outcome Type:Secondary Outcome
Measure:Incidence of Acute GVHD (Grades III-IV)
Time Frame:2 years post-randomization
Safety Issues:False
Description:Cumulative incidence of acute GVHD grades III-IV from randomization will be compared between treatment arms.
Outcome Type:Secondary Outcome
Measure:Incidence of Chronic GVHD
Time Frame:2 years post-randomization
Safety Issues:False
Description:Cumulative incidence of cGVHD from randomization will be compared between treatment arms.
Outcome Type:Secondary Outcome
Measure:Disease Progression
Time Frame:2 years post-randomization
Safety Issues:False
Description:The cumulative incidence of myeloma progression will be compared between treatment arms.
Outcome Type:Secondary Outcome
Measure:Treatment-Related Mortality (TRM)
Time Frame:2 years post-randomization
Safety Issues:False
Description: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.
Outcome Type:Secondary Outcome
Measure:Incidence of Grade ≥ 3 toxicity
Time Frame:2 years post-randomization
Safety Issues:False
Description: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
Outcome Type:Secondary Outcome
Measure:Incidence of Infections
Time Frame:2 years post-randomization
Safety Issues:False
Description: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
Outcome Type:Secondary Outcome
Measure:Overall Survival (OS)
Time Frame:2 years post-randomization
Safety Issues:False
Description:Overall survival (OS) from randomization will be compared between the treatment arms.
Outcome Type:Secondary Outcome
Measure:Health-Related Quality of Life (QoL)
Time Frame:2 years post-randomization
Safety Issues:False
Description: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 tre
Outcome Type:Secondary Outcome
Measure:Best response to Treatment after Randomization
Time Frame:2 years post-randomization
Safety Issues:False
Description: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 separa

Study Interventions

Intervention Type:Procedure
Name:Allogeneic HSCT
Description: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.
Arm Name:Ixazomib Maintenance
Other Name:Allogeneic hematopoietic stem cell transplant
Intervention Type:Drug
Name:Fludarabine
Description:Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3.
Arm Name:Ixazomib Maintenance
Other Name:Fludara
Intervention Type:Drug
Name:Melphalan
Description:Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3.
Arm Name:Ixazomib Maintenance
Other Name:Alkeran
Intervention Type:Drug
Name:Bortezomib
Description:Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3.
Arm Name:Ixazomib Maintenance
Other Name:Velcade®
Intervention Type:Drug
Name:Ixazomib
Description: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.
Arm Name:Ixazomib Maintenance
Other Name:MLN9708
Intervention Type:Drug
Name:Placebo
Description: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.
Arm Name:Placebo
Other Name:sugar pill

Study Arms

Study Arm Type:Experimental
Arm Name:Ixazomib Maintenance
Description:Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance
Study Arm Type:Placebo Comparator
Arm Name:Placebo
Description:Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance.

Study Agencies

Agency Class:NIH
Agency Type:Lead Sponsor
Agency Name:National Heart, Lung, and Blood Institute (NHLBI)
Agency Class:Other
Agency Type:Collaborator
Agency Name:Blood and Marrow Transplant Clinical Trials Network

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: April 03, 2020

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