Reduce Intensity Conditioning Donor Stem Cell Transplant for the Treatment of Relapsed Multiple Myeloma
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| ClinicalTrials.gov Identifier: NCT04205240 |
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Recruitment Status :
Recruiting
First Posted : December 19, 2019
Last Update Posted : March 22, 2021
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Sponsor:
Srinivas Devarakonda
Information provided by (Responsible Party):
Srinivas Devarakonda, Ohio State University Comprehensive Cancer Center
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Brief Summary:
This phase II trial studies how well a reduced intensity conditioning regimen after donor stem cell transplant works in treating patients with multiple myeloma that has come back (relapsed). Drugs used in chemotherapy, such as cyclophosphamide, tacrolimus, and mycophenolate mofetil, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as daratumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving a reduce intensity conditioning regimen consisting of cyclophosphamide, tacrolimus, mycophenolate mofetil, and daratumumab after donor stem cell transplant may improve survival and reduce the risk of multiple myeloma coming back.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Recurrent Plasma Cell Myeloma | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Cyclophosphamide Biological: Daratumumab Drug: Fludarabine Drug: Melphalan Drug: Mycophenolate Mofetil Drug: Tacrolimus | Phase 2 |
PRIMARY OBJECTIVE:
I. To determine the 2-year progression-free survival (PFS) for haploidentical, matched or mismatched, related or unrelated reduce intensity allogenic hematopoietic stem cell transplantation (allo HSCT) in relapsed multiple myeloma (MM) patients.
SECONDARY OBJECTIVES:
I. To determine 2 year overall survival (OS). II. To determine the cumulative incidence of grade II-IV acute-graft-versushost-disease (aGVHD) at day 100 and 180.
III. To determine the 100 days, 1 year and 2 year cumulative incidence of treatment-related mortality (TRM).
IV. To assess one-year GVHD-free relapse-free survival (GRFS). V. To determine the cumulative incidence of chronic graft-versus-hostdisease (cGVHD) Va. To assess overall and best response rates 100 days after allo HCT, 3 months, 6 months and every 6 months thereafter until end of daratumumab maintenance.
VI. To determine rate of relapse after allo HSCT followed by maintenance. VII. To determine rate of minimal residual disease (MRD) negativity using next generation sequencing (Food and Drug Administration [FDA] approved) in patients achieving a very good partial response (VGPR) or better.
CORRELATIVE OBJECTIVE:
I. To determine immune reconstitution pattern on days +30, +100, +180 and +365 following allo HSCT.
OUTLINE:
Patients receive fludarabine intravenously (IV) on days -5 to -2 and melphalan IV on days -3 to -2, then undergo stem cell transplantation on day 0. Patients receive cyclophosphamide on days 3 and 4, tacrolimus orally (PO) or twice daily (BID) or IV starting on day 5, and mycophenolate mofetil IV or PO three times daily (TID) on days 5 to 35. Patients also receive daratumumab IV starting between day 90-150 for up to 1 year. Treatment continues in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically for up to 2 years post stem cell transplantation.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 20 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Reduce Intensity Conditioning (RIC) Allogenic Hematopoietic Stem Cell Transplantation (Allo HSCT) for Patients With Relapsed Multiple Myeloma: A Pilot Study |
| Actual Study Start Date : | May 27, 2020 |
| Estimated Primary Completion Date : | December 31, 2022 |
| Estimated Study Completion Date : | December 31, 2022 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Multiple myeloma
MedlinePlus related topics:
Multiple Myeloma
| Arm | Intervention/treatment |
|---|---|
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Experimental: Treatment (conditioning regimen, stem cell transplant)
Patients receive fludarabine IV on days -5 to -2 and melphalan IV on days -3 to -2, then undergo stem cell transplantation on day 0. Patients receive cyclophosphamide on days 3 and 4, tacrolimus PO BID or IV starting on day 5, and mycophenolate mofetil IV or PO TID on days 5 to 35. Patients also receive daratumumab IV starting between days 90-150 for up to 1 year. Treatment continues in the absence of disease progression or unacceptable toxicity.
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Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic hematopoietic stem cell transplantation
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Biological: Daratumumab Given IV
Other Names:
Drug: Fludarabine Given IV
Other Name: Fluradosa Drug: Melphalan Given IV
Other Names:
Drug: Mycophenolate Mofetil Given IV or PO
Other Names:
Drug: Tacrolimus Given PO or IV
Other Names:
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Primary Outcome Measures :
- 2-year progression-free survival (PFS) [ Time Frame: From the date of transplant until the date of relapse or date of death from any cause, assessed at 2 years ]Patients who do not relapse or die will be censored at the date of last clinical assessment. Kaplan-Meier curves will be generated to estimate the PFS rates at 2 years posttransplant. To evaluate the potential association between patient characteristics and PFS, the log-rank test will be used to compare the PFS curves and Cox proportional hazard regression model will be used to estimate the hazard ratio.
Secondary Outcome Measures :
- Incidence of adverse events [ Time Frame: Up to 2 years post-transplant ]Adverse events by grade will be summarized. The occurrence of grade 3+ adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) will be summarized as well. Adverse events will initially be reviewed regardless of attribution, but also according to whether adverse events are possibly, probably, or definitely related to treatment.
- Cumulative incidence of grade II-IV acute graft-versus host disease (GvHD (aGVHD) [ Time Frame: Up to 6 weeks ]The event will be onset of grade II-IV aGvHD and time to aGvHD will be defined as the period of time from transplantation to the event of aGvHD. Death and early relapse without aGvHD will be competing risks. Cumulative incidence rate of aGVHD with 95% confidence intervals will be estimated from the cumulative incidence curves. To evaluate the association between patient characteristics and aGVHD, the Gray's test accounting for competing risks will be used to compare the cumulative incidence curves and a proportional hazards model for the sub distribution of competing risks will be used to estimate the hazard ratio. The cumulative incidence of chronic GVHD (cGVHD) will be similarly analyzed.
- Rate of relapse [ Time Frame: From the date of transplant to relapse treating death from any cause as a competing risk, assessed up to 2 years ]Patients without relapse or death will be censored at last clinical assessment date. The similar analysis approach used for outcome of aGVHD will be applied.
- Overall survival (OS) [ Time Frame: From the date of transplant to death or last contact date if no death, assessed up to 2 years ]A similar analysis approach described above for PFS will be applied for the OS analysis.
- 1- year GVHD-free Relapse-free Survival (GRFS) [ Time Frame: From the date of transplant until the date of grade II-IV acute GVHD, chronic GVHD, disease relapse or progression, or death from any cause, whichever occurs first, assessed at 1 year ]Patients who do not experience an event will be censored at the date of last clinical assessment. A similar analysis approach described above for PFS will be applied for the GRFS analysis.
- 100-day cumulative incidence of treatment-related mortality (TRM) [ Time Frame: From the date of transplant to date of death, assessed up to 100 days ]The event will be death due to reasons other than disease. The competing risk for non relapsed mortality (NRM) will be death due to disease. The cumulative incidence curve accounting competing risks will be generated to estimate the cumulative incidence rate at various time points.
- 1-year cumulative incidence TRM [ Time Frame: From the date of transplant to date of death, assessed at 1 year ]The event will be death due to reasons other than disease. The competing risk for NRM will be death due to disease. The cumulative incidence curve accounting competing risks will be generated to estimate the cumulative incidence rate at various time points.
- 2-year cumulative incidence of TRM [ Time Frame: From the date of transplant to date of death, assessed at 2 years ]The event will be death due to reasons other than disease. The competing risk for NRM will be death due to disease. The cumulative incidence curve accounting competing risks will be generated to estimate the cumulative incidence rate at various time points.
- Overall response rate [ Time Frame: Up to 2 years post-transplant ]The proportion of each type of response with a 95% confidence interval (CI) will be reported for all evaluable patients, assuming a binomial distribution.
- Best response rate [ Time Frame: Up to 2 years post-transplant ]The proportion of each type of response with a 95% CI will be reported for all evaluable patients, assuming a binomial distribution.
Other Outcome Measures:
- Rate of minimal residual disease-negativity [ Time Frame: Baseline up to 365 days post-transplant ]Will be defined as the proportion of patients who achieved minimal residual disease-negative status at the respective time point, in accordance with the International Myeloma Working Group criteria. Minimal residual disease was evaluated by next-generation sequencing using ClonoSEQ Assay.
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| Ages Eligible for Study: | 18 Years to 75 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Patients with a partial response (PR) or better prior to allo-transplantation
- Relapsed MM with chemo sensitivity disease, with or without prior autologous HSCT
- First allogenic transplant
- Donors can be haploidentical, mismatch or matched related or unrelated. Stem cell source will be peripheral blood except for haploidentical where stem cell source will be bone marrow
- Ejection fraction >= 45%
- Estimated creatinine clearance greater than 40 mL/minute
- Diffusion capacity of the lung for carbon monoxide (DLCO) >= 40% (adjusted for hemoglobin)
- Forced expiratory volume in 1 second (FEV1) >= 50%
- Total bilirubin < 2 x the upper limit of normal
- Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5 x the upper normal limit
- Signed informed consent
Exclusion Criteria:
- Patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS), Waldenstrom macroglobulinemia
- Uncontrolled bacterial, viral or fungal infection
- Patients with prior malignancies < 3 years except resected basal cell/squamous cell carcinoma, treated carcinoma in-situ. Other cancers treated with curative intent < 3 years previously will not be allowed unless approved by the principal investigator
- Female patients who are pregnant or breastfeeding. A negative pregnancy test will be required for all women of child bearing potential
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): NCT04205240
Contacts
| Contact: The Ohio State University Comprehensive Cancer Center | 1-800-293-5066 | OSUCCCClinicaltrials@osumc.edu |
Locations
| United States, Ohio | |
| Ohio State University Comprehensive Cancer Center | Recruiting |
| Columbus, Ohio, United States, 43210 | |
| Contact: Kristyn Glover 614-366-7102 Kristyn.Glover@osumc.edu | |
| Principal Investigator: Srinivas Devarakonda, MD | |
Sponsors and Collaborators
Srinivas Devarakonda
Investigators
| Principal Investigator: | Srinivas Devarakonda, M.D. | Ohio State University Comprehensive Cancer Center |
Additional Information:
| Responsible Party: | Srinivas Devarakonda, Principal Investigator, Ohio State University Comprehensive Cancer Center |
| ClinicalTrials.gov Identifier: | NCT04205240 |
| Other Study ID Numbers: |
OSU-19190 NCI-2019-07892 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) |
| First Posted: | December 19, 2019 Key Record Dates |
| Last Update Posted: | March 22, 2021 |
| Last Verified: | March 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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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 Mycophenolic Acid |
Cyclophosphamide Melphalan Mechlorethamine Nitrogen Mustard Compounds Fludarabine Daratumumab Tacrolimus Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents |