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Combination Chemotherapy and Donor Stem Cell Transplant Followed by Ixazomib Citrate Maintenance Therapy in Treating Patients With Relapsed High-Risk Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT02504359
Recruitment Status : Recruiting
First Posted : July 21, 2015
Last Update Posted : May 16, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Emma Scott, OHSU Knight Cancer Institute

Brief Summary:
This phase Ib trial studies the side effects of combination chemotherapy and donor stem cell transplant followed by ixazomib citrate maintenance therapy in treating patients with multiple myeloma that has returned after a period of improvement and is likely to recur (come back), or spread. Giving chemotherapy before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving ixazomib citrate after the transplant may improve the overall treatment outcome without causing additional toxicities.

Condition or disease Intervention/treatment Phase
Plasma Cell Leukemia Recurrent Plasma Cell Myeloma Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Carmustine Drug: Cytarabine Drug: Etoposide Drug: Ixazomib Citrate Drug: Melphalan Drug: Methotrexate Procedure: Peripheral Blood Stem Cell Transplantation Other: Quality-of-Life Assessment Drug: Tacrolimus Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Feasibility Study of Myeloablative BEAM Allogeneic Transplantation Followed by Oral Ixazomib Maintenance Therapy in Patients With Relapsed High-Risk Multiple Myeloma
Actual Study Start Date : July 20, 2015
Estimated Primary Completion Date : July 1, 2020
Estimated Study Completion Date : July 1, 2021


Arm Intervention/treatment
Experimental: Treatment (BEAM allogeneic transplant, ixazomib)

BEAM CONDITIONING REGIMEN: Patients receive carmustine on day -6, cytarabine and etoposide on days -5 to -2, and melphalan on day -1.

PERIPHERAL BLOOD STEM CELL TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO on days -2 to at least 6 months with a taper as early as 3 months post-transplant and methotrexate IV on days 1, 3, 6, and 11.

MAINTENANCE THERAPY: Beginning between days 100 and 180 post-transplant, patients receive ixazomib PO on days 1 and 14 or days 1, 8, and 15 if the principal investigator deems it medically important. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic peripheral blood stem cell transplantation
Other Names:
  • Allogeneic Hematopoietic Cell Transplantation
  • allogeneic stem cell transplantation
  • HSC
  • HSCT

Drug: Carmustine
Given BEAM chemotherapy

Drug: Cytarabine
Given BEAM chemotherapy

Drug: Etoposide
Given BEAM chemotherapy

Drug: Ixazomib Citrate
Given PO

Drug: Melphalan
Given BEAM chemotherapy

Drug: Methotrexate
Given IV

Procedure: Peripheral Blood Stem Cell Transplantation
Undergo allogeneic peripheral blood stem cell transplantation

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Drug: Tacrolimus
Given IV or PO




Primary Outcome Measures :
  1. Incidence of grade III-IV acute (or overlap) graft versus host disease (GvHD) and ixazomib related grade III-IV toxicity [ Time Frame: Up to 2 years ]
    Time to event analysis will be conducted to estimate the incidence of acute (or overlap) GvHD and grade III-IV treatment related toxicity among those who receive ixazomib maintenance therapy, accounting for possible competing risks and events. All treatment related toxicity will be tabulated and summarized by severity and major organ categories defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

  2. Transplant related mortality (TRM) [ Time Frame: Day 100 ]
    Time to event analysis will be conducted to estimate day 100 TRM and its confidence interval among those who receive carmustine, cytarabine, etoposide, melphalan (BEAM) allogeneic transplantation.


Secondary Outcome Measures :
  1. Incidence of discontinuation of ixazomib maintenance therapy [ Time Frame: At 1 year post initiation ]
    Reasons for discontinuation will be described.

  2. Incidence of discontinuation of ixazomib maintenance therapy [ Time Frame: At 2 years post initiation ]
    Reasons for discontinuation will be described.

  3. Overall survival [ Time Frame: At 2 years ]
    Overall survival will be determined.

  4. Progression-free survival [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years ]
    Progression-free survival will be determined.

  5. Proportion of patients who are eligible to start ixazomib maintenance therapy [ Time Frame: Up to day 180 post-transplant ]
    Exact 95% confidence interval will be reported.

  6. Response rates (complete response [CR], very good partial response [VGPR] and partial response [PR]) [ Time Frame: At day 100 ]
    Response will be assessed using International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.

  7. Response rates (complete response [CR], very good partial response [VGPR] and partial response [PR]) [ Time Frame: At 12 months after transplant ]
    Response will be assessed using International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.

  8. Response rates (complete response [CR], very good partial response [VGPR] and partial response [PR]) [ Time Frame: At 24 months after transplant ]
    Response will be assessed using International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.

  9. Time to engraftment (defined by absolute neutrophil count [ANC] > 500 and platelets > 20,000) [ Time Frame: Up to 1 year ]
    Time to engraftment is defined by ANC > 500 and platelets > 20,000.


Other Outcome Measures:
  1. Cumulative incidence of chronic graft versus host disease (GvHD) [ Time Frame: Up to 1 year ]
    Graded according to the BMT CTN MOP. Estimated using the cumulative incidence function.

  2. Cumulative incidence of disease progression rates [ Time Frame: Up to 1 year ]
    The cumulative incidence of disease progression rates will be estimated.

  3. Cumulative incidence of grade III-IV acute graft versus host disease (GvHD) [ Time Frame: Up to 1 year ]
    Graded according to the Blood and Marrow Transplant (BMT) Clinical Trials Network (CTN) Manual of Procedures (MOP). Estimated using the cumulative incidence function.

  4. Donor and recipient chimerism [ Time Frame: Up to 14 days after the last dose of study drug (end of treatment) ]
    Donor and recipient chimerism will be described.

  5. Health related quality of life [ Time Frame: Up to 14 days after the last dose of study drug (end of treatment) ]
    Will be analyzed by the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and Multiple Myeloma Module (EORTC My-20). The total score of each questionnaire will be summarized using descriptive statistics and table by each time point in order to evaluate trends of questionnaire scores over time. For FACT-BMT, questionnaire scores will summarized by subcategories such as physical well-being, social family well-being, emotional well-being, functional well-being

  6. Immune reconstitution [ Time Frame: Up to 14 days after the last dose of study drug (end of treatment) ]
    Immune reconstitution will be described.

  7. Incidence of treatment emergent peripheral neuropathy (all grades) [ Time Frame: Up to 1 year ]
    The incidence of treatment emergent peripheral neuropathy (all grades) will be determined.

  8. Rates of >= grade 3 toxicities using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 [ Time Frame: Up to 14 days after the last dose of study drug (end of treatment) ]
    Provided with 95% confidence interval.

  9. Rates of minimal residual disease by deep sequencing (by ClonoSEQ, Adaptive Biotechnologies) [ Time Frame: Up to 1 year ]
    Provided with 95% confidence interval.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Relapsed multiple myeloma in patients that have been treated previously with autologous hematopoietic stem cell transplantation (auto-HCT), bortezomib and an imunomodulatory agent, AND with at least one of the following high-risk criteria

    • High-risk multiple myeloma defined by cytogenetic or fluorescence in situ hybridization (FISH) detection of any one or more of the following:

      • Deletion 17p
      • Translocation t(4;14)
      • Translocation t(14;16)
      • Translocation t(14;20)
      • Chromosome 1q gain
      • Chromosome 1p deletion
      • Deletion 13q by conventional karyotyping (FISH only not acceptable)
      • Hypodiploidy
    • High-risk gene expression profiling (GEP) at the time of relapse (by Signal Genetics Myeloma Prognostic Risk Signature [MyPRS] score)
    • Beta-2 (B2) microglobulin > 5.5mg
    • Plasmablastic morphology (> 2%)
    • OR relapsed plasma cell leukemia
  • Chemo-sensitive disease; patients with relapsed plasma cell leukemia may have received systemic therapy including an autologous transplant but it is not required; patients with relapsed multiple myeloma (MM) must have received prior systemic therapy including an autologous transplant; patient must be in at least a PR at the time of transplant; early relapse (VGPR) from complete response will be allowed
  • Measurable disease at the time of relapse, defined as a monoclonal immunoglobulin spike on serum electrophoresis of >= 1 gm/dL (immunoglobulin [IG]G) or >= 0.5 gm/dL (IGA) and/or urine monoclonal immunoglobulin spike of > 200 mg/24 hours and/ or involved free light chain (FLC) level >= 10 mg/dl and the serum FLC ratio is abnormal
  • Non-secretors must have measurable disease such as plasmacytomas, or positron emission tomography (PET) avid lytic lesions or bone marrow plasmacytosis >= 30% at the time of relapse to be eligible
  • The patient must have an available sibling or matched unrelated donor with at least a 7/8 human leukocyte antigen (HLA) match
  • Creatinine =< 2.0 mg/dL
  • Ejection Fraction >= 45%
  • Diffusing capacity of the lungs for carbon monoxide (DLCO) >= 50%
  • Forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) >= 50% predicted
  • Both men and women and members of all races and ethnic groups will be included
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)
  • Willing to use adequate contraception for the duration of time on the study and for 6 months after the last therapy
  • Female patients must meet one of the following:

    • Postmenopausal for at least 1 year before the screening visit, OR
    • Surgically sterile, OR
    • If they are of childbearing potential:

      • Agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, AND
      • Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
      • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
  • Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:

    • Agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, OR
    • Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
    • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
  • 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
  • DONOR: HLA genotypically identical sibling matched relative
  • DONOR: HLA matched unrelated donor according to Standard Practice HLA matching criteria:

    • Matched HLA-A, -B, -C, and -DRB1 alleles by high resolution typing
    • Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing

Exclusion Criteria:

  • Previous allogeneic stem cell transplant
  • POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [protein] and skin changes)
  • Impaired kidney function requiring dialysis or glomerular filtration rate (GFR) < 40mL/min (estimated or calculated)
  • Bilirubin > 1.5 x the upper limit of normal
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5 x the upper limit of normal
  • Patients with >= grade III or grade II with pain peripheral neuropathy (National Cancer Institute [NCI] CTCAE version [v.] 4.03 criteria)
  • Receiving steroids > the equivalent of 10 mg prednisone daily for other medical conditions, e.g., asthma, systemic lupus erythematosis, rheumatoid arthritis
  • Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment
  • Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive
  • Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months
  • Second malignancy requiring concurrent treatment or those with non-hematological malignancies (except non-melanoma skin cancers); cancer treated with curative intent < 5 years previously will not be allowed unless approved by the Protocol Chair; cancer treated with curative intent > 5 years previously is allowed
  • Other serious medical or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol
  • Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
  • Radiotherapy within 14 days before enrollment; if the involved field is limited to a single site, 7 days will be considered a sufficient interval between treatment and administration of the ixazomib
  • Systemic treatment, within 14 days before the first dose of ixazomib, with strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John?s wort
  • Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing
  • Female patients who are lactating or have a positive serum pregnancy test during the screening period
  • Failure to have fully recovered (i.e., =< grade 1 toxicity) from the reversible effects of prior chemotherapy
  • Major surgery within 14 days before enrollment
  • Central nervous system involvement
  • Participation in other clinical treatment trials, including those with other investigational agents not included in this trial, within 21 days of the start of this trial and throughout the duration of this trial
  • DONOR: Identical twin
  • DONOR: Donors unwilling to donate PBSC
  • DONOR: Pregnancy
  • DONOR: Infection with HIV
  • DONOR: Inability to achieve adequate venous access
  • DONOR: Known allergy to filgrastim (G-CSF)
  • DONOR: Current serious systemic illness
  • DONOR: Failure to meet institutional criteria for stem cell donation
  • DONOR: Patient and donor pairs must not be homozygous at mismatched allele

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): NCT02504359


Locations
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Cristina Gasparetto    919-668-1017    cristina.gasparetto@duke.edu   
Principal Investigator: Cristina Gasparetto         
United States, Oregon
OHSU Knight Cancer Institute Recruiting
Portland, Oregon, United States, 97239
Contact: Emma C. Scott    503-494-2398    scottem@ohsu.edu   
Principal Investigator: Emma C. Scott         
Sponsors and Collaborators
OHSU Knight Cancer Institute
National Cancer Institute (NCI)
Investigators
Principal Investigator: Emma Scott OHSU Knight Cancer Institute

Responsible Party: Emma Scott, Principal Investigator, OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT02504359     History of Changes
Other Study ID Numbers: IRB00011097
NCI-2015-01065 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
HEM-14099-LM
IRB00011097 ( Other Identifier: OHSU Knight Cancer Institute )
P30CA069533 ( U.S. NIH Grant/Contract )
First Posted: July 21, 2015    Key Record Dates
Last Update Posted: May 16, 2018
Last Verified: May 2018

Keywords provided by Emma Scott, OHSU Knight Cancer Institute:
BEAM
allogeneic
myeloma
ixazomib
transplant
plasma cell leukemia

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Leukemia, 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
Leukemia
Methotrexate
Cytarabine
Tacrolimus
Etoposide
Ixazomib
Melphalan
Etoposide phosphate
Carmustine
Citric Acid
Glycine
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs