Clinical Trials /

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

NCT02440464

Description:

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.

Related Conditions:
  • Multiple Myeloma
  • Plasma Cell Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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)

Clinical Trial IDs

  • ORG STUDY ID: BMTCTN1302
  • SECONDARY ID: U01HL069294-05
  • NCT ID: NCT02440464

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
FludarabineFludaraIxazomib Maintenance
MelphalanAlkeranIxazomib Maintenance
BortezomibVelcade®Ixazomib Maintenance
IxazomibMLN9708, NinlaroIxazomib Maintenance
Placebosugar pillPlacebo

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Ixazomib MaintenanceExperimentalAllogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance
  • Fludarabine
  • Melphalan
  • Bortezomib
  • Ixazomib
PlaceboPlacebo ComparatorAllogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance.
  • Fludarabine
  • Melphalan
  • Bortezomib
  • Placebo

Eligibility 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.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-Free Survival
Time Frame:2 years post-randomization
Safety Issue:
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.

Secondary Outcome Measures

Measure:Incidence of Acute GVHD (Grades II-IV)
Time Frame:2 years post-randomization
Safety Issue:
Description:Cumulative incidence of acute GVHD grades II-IV from randomization will be compared between treatment arms.
Measure:Incidence of Acute GVHD (Grades III-IV)
Time Frame:2 years post-randomization
Safety Issue:
Description:Cumulative incidence of acute GVHD grades III-IV from randomization will be compared between treatment arms.
Measure:Incidence of Chronic GVHD
Time Frame:2 years post-randomization
Safety Issue:
Description:Cumulative incidence of cGVHD from randomization will be compared between treatment arms.
Measure:Disease Progression
Time Frame:2 years post-randomization
Safety Issue:
Description:The cumulative incidence of myeloma progression will be compared between treatment arms.
Measure:Treatment-Related Mortality (TRM)
Time Frame:2 years post-randomization
Safety Issue:
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.
Measure:Incidence of Grade ≥ 3 toxicity
Time Frame:2 years post-randomization
Safety Issue:
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 ≥ 3 toxicity will be compared between treatment arms at 6, 12 and 18 months post-randomization.
Measure:Incidence of Infections
Time Frame:2 years post-randomization
Safety Issue:
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 a competing event, will be compared between the two treatment arms at 6, 12 and 18 months post randomization.
Measure:Overall Survival (OS)
Time Frame:2 years post-randomization
Safety Issue:
Description:Overall survival (OS) from randomization will be compared between the treatment arms.
Measure:Health-Related Quality of Life (QoL)
Time Frame:2 years post-randomization
Safety Issue:
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 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.
Measure:Best response to Treatment after Randomization
Time Frame:2 years post-randomization
Safety Issue:
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 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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Heart, Lung, and Blood Institute (NHLBI)

Trial Keywords

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

Last Updated