Clinical Trials /

Nonmyeloablative Haploidentical Transplant Followed by MLN9708

NCT02169791

Description:

In an attempt to reduce relapse risk and improve outcomes following haploidentical transplantation for patients with high risk hematologic malignancies, the investigators will implement several strategies to augment the well documented effect of NK cell alloreactivity seen in HLA-mismatched transplantation. These strategies include (1) choosing potential haploidentical donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition post-transplant with MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect against graft-versus-host disease (GVHD), and (3) eliminating mycophenolate mofetil from the post-transplant immunosuppression regimen to improve NK cell reconstitution following haploidentical peripheral blood stem cell transplantation.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • Chronic Myeloid Leukemia
  • Lymphoma
  • Multiple Myeloma
  • Myelodysplastic Syndromes
  • Prolymphocytic Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nonmyeloablative Haploidentical Transplant Followed by MLN9708
  • Official Title: A Phase II Trial of Nonmyeloablative Haploidentical Peripheral Blood Stem Cell Transplantation Followed By Maintenance Therapy With the Novel Oral Proteasome Inhibitor, MLN9708, in Patients With High-risk Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: NSH 1074
  • SECONDARY ID: X16035
  • NCT ID: NCT02169791

Conditions

  • Acute Leukemia
  • Chronic Leukemia
  • Myelodysplastic Syndrome
  • Lymphomas
  • Multiple Myeloma

Interventions

DrugSynonymsArms
MLN9708Haploidentical Transplant

Purpose

In an attempt to reduce relapse risk and improve outcomes following haploidentical transplantation for patients with high risk hematologic malignancies, the investigators will implement several strategies to augment the well documented effect of NK cell alloreactivity seen in HLA-mismatched transplantation. These strategies include (1) choosing potential haploidentical donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition post-transplant with MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect against graft-versus-host disease (GVHD), and (3) eliminating mycophenolate mofetil from the post-transplant immunosuppression regimen to improve NK cell reconstitution following haploidentical peripheral blood stem cell transplantation.

Detailed Description

      Overview of Study Design:

      In an attempt to reduce relapse risk and improve outcomes following haploidentical
      transplantation for patients with high risk hematologic malignancies, the investigators will
      implement several strategies to augment the well documented effect of NK cell alloreactivity
      seen in HLA-mismatched transplantation. These strategies include (1) choosing potential
      haploidentical donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition
      post-transplant with MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect
      against graft-versus-host disease (GVHD), and (3) eliminating mycophenolate mofetil from the
      post-transplant immunosuppression regimen to improve NK cell reconstitution following
      haploidentical peripheral blood stem cell transplantation.

      Patients will receive a nonmyeloablative haploidentical transplant using a T-cell replete
      allograft and post-transplant cyclophosphamide as previously described at our center (Bashey
      et al. J Clin Oncol. 2013; 31(10):1310-6). MLN9708 will be administered once weekly for 3
      weeks on a 28 day cycle for one-year post-transplant. Post-transplant immunosuppression will
      consist of tacrolimus only (MLN9708 will substitute for mycophenolate mofetil as the second
      GVHD prophylactic medication).

      The primary endpoint of this trial will be the risk of relapse and/or progression at one-year
      post-transplant. Experience from the literature suggests that following a nonmyeloablative
      haploidentical transplant using post-transplant cyclophosphamide (haplo-pCy), the risk of
      relapse is approximately 50% at one year post-transplant. It is hoped that under this
      protocol, this rate will be at most 25%. Thus the investigators statistically formalize this
      study by testing the null hypothesis that p, the PFS rate is 0.25 or less versus the
      alternative hypothesis that p is greater than 0.5. A sample size of 25 patients gives 90%
      power with an alpha=0.05, using the formula for a one sample binomial (two-sided) test of a
      proportion.
    

Trial Arms

NameTypeDescriptionInterventions
Haploidentical TransplantExperimentalAll patients will receive a haploidentical donor transplant using a conditioning regimen of Fludarabine (Flu), cyclophosphamide (cy) and total body irradiation (TBI) followed by MLN9708.
  • MLN9708

Eligibility Criteria

        Inclusion Criteria:

          -  Availability of a 3/6 - 5/6 matched (HLA-A, B, DR) related donor

          -  Donor must have negative HLA cross-match in the host vs. graft direction.

          -  Donor must be willing to donate mobilized peripheral blood stem cells

          -  Age ≥ 18 years

          -  Karnofsky status ≥ 70%

          -  One of the following high-risk malignancies:

          -  Chronic Myelogenous Leukemia (chronic phase, resistant and/or intolerant to tyrosine
             kinase inhibitors (OR) accelerated phase (OR) blast crisis in 2nd chronic phase
             following induction chemotherapy)

          -  Acute Myelogenous Leukemia (2nd or subsequent complete remission [CR] (OR) Primary
             induction chemotherapy failure, but subsequently entered into a CR(OR) 1st CR with
             poor risk cytogenetics or molecular markers; or arising from preceding hematological
             disease)

          -  Myelodysplastic Syndrome (treatment-related, monosomy 7 or complex cytogenetics, IPSS
             score of 1.5 or greater, Chronic myelomonocytic leukemia [CMML])

          -  Acute lymphocytic leukemia/lymphoblastic lymphoma (2nd or subsequent CR (OR) Primary
             induction chemotherapy failure, but subsequently entered into a CR (OR) 1st CR with
             poor risk cytogenetics)

          -  Chronic Lymphocytic Leukemia / Prolymphocytic Leukemia (Duration of remission <12
             months after receiving chemotherapy with a nucleoside analog (OR) High risk features
             (i.e. 17p deletion), (OR) Second or subsequent relapse)

          -  Hodgkin's or Non-Hodgkin's Lymphoma (including low-grade, mantle cell, and
             intermediate-grade/diffuse) (Previously treated disease that has either relapsed or
             failed to respond adequately to conventional-dose therapy or autologous
             transplantation (AND) Chemoresponsive to most recent salvage therapy

          -  Multiple Myeloma (Presence of a poor risk cytogenetic abnormality [i.e. 17p, t(4;14)],
             Relapse post autologous transplant)

        Exclusion Criteria:

          -  Poor cardiac function: left ventricular ejection fraction <40%

          -  Poor pulmonary function: FEV1, FVC, or DLCO <50% predicted

          -  Poor liver function: bilirubin >2.5 mg/dl (not due to hemolysis, Gilbert's or primary
             malignancy), AST/ALT > 3X ULN

          -  Poor renal function: Creatinine >2.0 mg/dl or creatinine clearance (calculated
             creatinine clearance is permitted) < 40 mL/min

          -  Ongoing or active systemic infection, active hepatitis B or C virus infection, or
             known human immunodeficiency virus (HIV) positive.

          -  Women of childbearing potential who currently are pregnant or who are not practicing
             adequate contraception

          -  Patients who have any debilitating medical or psychiatric illness which would preclude
             their giving informed consent or their receiving optimal treatment and follow-up.

          -  Systemic treatment, within 14 days before the first dose of MLN9708, with strong
             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.

          -  Patient has >/= Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical
             examination during the screening period.

          -  Participation in other clinical trials, including those with other investigational
             agents not included in this trial, within 21days of the start of this trial and
             throughout the duration of this trial.

          -  Infection requiring systemic antibiotic therapy or other serious infection within 14
             days before study enrollment.

          -  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.

          -  Known allergy to any of the study medications, their analogues, or excipients in the
             various formulations of any agent.

          -  Known GI disease or GI procedure that could interfere with the oral absorption or
             tolerance of MLN9708 including difficulty swallowing
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Relapse and progression
Time Frame:1 year
Safety Issue:
Description:To estimate the incidence of relapse/progression at one-year post-transplant.

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:3 years
Safety Issue:
Description:To obtain estimates of overall survival (OS)
Measure:Event Free
Time Frame:3 years
Safety Issue:
Description:To obtain estimates of event-free survival (EFS)
Measure:Non-relapsed mortality
Time Frame:3 years
Safety Issue:
Description:To obtain estimate of non-relapse mortality (NRM)
Measure:Graft-versus-host disease
Time Frame:3 years
Safety Issue:
Description:To obtain estimates of acute and chronic graft-versus-host disease (GVHD).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Northside Hospital, Inc.

Trial Keywords

  • hematologic malignancies

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