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Reduce Intensity Conditioning Donor Stem Cell Transplant for the Treatment of Relapsed Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT04205240
Recruitment Status : Recruiting
First Posted : December 19, 2019
Last Update Posted : March 22, 2021
Sponsor:
Information provided by (Responsible Party):
Srinivas Devarakonda, Ohio State University Comprehensive Cancer Center

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

Detailed Description:

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.

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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 related topics: Multiple Myeloma

Arm Intervention/treatment
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.
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic hematopoietic stem cell transplantation
Other Names:
  • Allogeneic Hematopoietic Cell Transplantation
  • Allogeneic Stem Cell Transplantation
  • HSC
  • HSCT
  • Stem Cell Transplantation, Allogeneic

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamide Monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Biological: Daratumumab
Given IV
Other Names:
  • Anti-CD38 Monoclonal Antibody
  • Darzalex
  • HuMax-CD38
  • JNJ-54767414

Drug: Fludarabine
Given IV
Other Name: Fluradosa

Drug: Melphalan
Given IV
Other Names:
  • Alanine Nitrogen Mustard
  • CB-3025
  • L-PAM
  • L-Phenylalanine mustard
  • L-Sarcolysin
  • L-Sarcolysin Phenylalanine mustard
  • L-Sarcolysine
  • Melphalanum
  • Phenylalanine Mustard
  • Phenylalanine Nitrogen Mustard
  • Sarcoclorin
  • Sarkolysin
  • WR-19813

Drug: Mycophenolate Mofetil
Given IV or PO
Other Names:
  • Cellcept
  • MMF

Drug: Tacrolimus
Given PO or IV
Other Names:
  • FK 506
  • Fujimycin
  • Hecoria
  • Prograf
  • Protopic




Primary Outcome Measures :
  1. 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 :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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:
  1. 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.



Information from the National Library of Medicine

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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
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Contact: The Ohio State University Comprehensive Cancer Center 1-800-293-5066 OSUCCCClinicaltrials@osumc.edu

Locations
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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
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Principal Investigator: Srinivas Devarakonda, M.D. Ohio State University Comprehensive Cancer Center
Additional Information:
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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

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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