Clinical Trials /

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

NCT02504359

Description:

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.

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

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Combination Chemotherapy and Donor Stem Cell Transplant Followed by Ixazomib Citrate Maintenance Therapy in Treating Patients With Relapsed High-Risk Multiple Myeloma
  • Official Title: A Feasibility Study of Myeloablative BEAM Allogeneic Transplantation Followed by Oral Ixazomib Maintenance Therapy in Patients With Relapsed High-Risk Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: IRB00011097
  • SECONDARY ID: NCI-2015-01065
  • SECONDARY ID: HEM-14099-LM
  • SECONDARY ID: IRB00011097
  • SECONDARY ID: P30CA069533
  • NCT ID: NCT02504359

Conditions

  • Plasma Cell Leukemia
  • Recurrent Plasma Cell Myeloma

Interventions

DrugSynonymsArms
CarmustineTreatment (BEAM allogeneic transplant, ixazomib)
CytarabineTreatment (BEAM allogeneic transplant, ixazomib)
EtoposideTreatment (BEAM allogeneic transplant, ixazomib)
Ixazomib CitrateTreatment (BEAM allogeneic transplant, ixazomib)
MelphalanTreatment (BEAM allogeneic transplant, ixazomib)
MethotrexateTreatment (BEAM allogeneic transplant, ixazomib)
TacrolimusTreatment (BEAM allogeneic transplant, ixazomib)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Safety of BEAM (carmustine, cytarabine, etoposide, melphalan) allogeneic transplant within
      100 days, defined as the day 100 transplant related mortality (TRM).

      II. Safety of oral ixazomib maintenance therapy from day 100 post allogeneic transplant up to
      2 years, defined by the incidence of grade III-IV acute (or overlap) graft-versus-host
      disease (GvHD) and grade III-IV ixazomib related toxicity.

      SECONDARY OBJECTIVES:

      I. To assess the proportion of patients who are eligible to start ixazomib maintenance
      therapy.

      II. To determine the incidence of discontinuation of ixazomib maintenance therapy at one and
      two years post initiation.

      III. To determine response rates (complete response [CR], very good partial response [VGPR]
      and partial response [PR]) by day 100 and at 12 and 24 months after transplant.

      IV. To determine two year progression-free survival and overall survival rate. V. To evaluate
      time to engraftment (defined by absolute neutrophil count [ANC] > 500 and platelets >
      20,000).

      TERTIARY OBJECTIVES:

      I. To determine rates of minimal residual disease by deep sequencing (by ClonoSEQ, Adaptive
      Biotechnologies).

      II. To estimate the cumulative incidence of disease progression rates. III. To determine
      rates of >= grade 3 toxicities using the Common Terminology Criteria for Adverse Events
      (CTCAE) version 4.03.

      IV. To determine the incidence of treatment emergent peripheral neuropathy (all grades).

      V. To determine the cumulative incidence and severity of chronic GvHD. VI. To determine the
      cumulative incidence of grades III-IV acute GvHD. VII. To evaluate health related quality of
      life. VIII. To determine donor and recipient chimerism. IX. To evaluate immune
      reconstitution.

      OUTLINE:

      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 intravenously (IV) or orally (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.

      After completion of study treatment, patients are followed up every 4 months for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (BEAM allogeneic transplant, ixazomib)ExperimentalBEAM 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.
  • Carmustine
  • Cytarabine
  • Etoposide
  • Ixazomib Citrate
  • Melphalan
  • Methotrexate
  • Tacrolimus

Eligibility 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
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Incidence of discontinuation of ixazomib maintenance therapy
Time Frame:At 1 year post initiation
Safety Issue:
Description:Reasons for discontinuation will be described.
Measure:Incidence of discontinuation of ixazomib maintenance therapy
Time Frame:At 2 years post initiation
Safety Issue:
Description:Reasons for discontinuation will be described.
Measure:Overall survival
Time Frame:At 2 years
Safety Issue:
Description:Overall survival will be determined.
Measure:Progression-free survival
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Progression-free survival will be determined.
Measure:Proportion of patients who are eligible to start ixazomib maintenance therapy
Time Frame:Up to day 180 post-transplant
Safety Issue:
Description:Exact 95% confidence interval will be reported.
Measure:Response rates (complete response [CR], very good partial response [VGPR] and partial response [PR])
Time Frame:At day 100
Safety Issue:
Description:Response will be assessed using International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.
Measure:Response rates (complete response [CR], very good partial response [VGPR] and partial response [PR])
Time Frame:At 12 months after transplant
Safety Issue:
Description:Response will be assessed using International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.
Measure:Response rates (complete response [CR], very good partial response [VGPR] and partial response [PR])
Time Frame:At 24 months after transplant
Safety Issue:
Description:Response will be assessed using International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.
Measure:Time to engraftment (defined by absolute neutrophil count [ANC] > 500 and platelets > 20,000)
Time Frame:Up to 1 year
Safety Issue:
Description:Time to engraftment is defined by ANC > 500 and platelets > 20,000.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

Trial Keywords

  • BEAM
  • allogeneic
  • myeloma
  • ixazomib
  • transplant
  • plasma cell leukemia

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