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Nonmyeloablative Haploidentical Transplant Followed by MLN9708

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ClinicalTrials.gov Identifier: NCT02169791
Recruitment Status : Active, not recruiting
First Posted : June 23, 2014
Last Update Posted : May 10, 2019
Sponsor:
Collaborator:
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Northside Hospital, Inc.

Tracking Information
First Submitted Date  ICMJE June 19, 2014
First Posted Date  ICMJE June 23, 2014
Last Update Posted Date May 10, 2019
Actual Study Start Date  ICMJE July 15, 2014
Estimated Primary Completion Date August 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 20, 2014)
Incidence of Relapse and progression [ Time Frame: 1 year ]
To estimate the incidence of relapse/progression at one-year post-transplant.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02169791 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 20, 2014)
  • Overall Survival [ Time Frame: 3 years ]
    To obtain estimates of overall survival (OS)
  • Event Free [ Time Frame: 3 years ]
    To obtain estimates of event-free survival (EFS)
  • Non-relapsed mortality [ Time Frame: 3 years ]
    To obtain estimate of non-relapse mortality (NRM)
  • Graft-versus-host disease [ Time Frame: 3 years ]
    To obtain estimates of acute and chronic graft-versus-host disease (GVHD).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nonmyeloablative Haploidentical Transplant Followed by MLN9708
Official Title  ICMJE 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
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Acute Leukemia
  • Chronic Leukemia
  • Myelodysplastic Syndrome
  • Lymphomas
  • Multiple Myeloma
Intervention  ICMJE Drug: MLN9708
MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at D+5 post-transplant.
Study Arms  ICMJE Experimental: Haploidentical Transplant
All patients will receive a haploidentical donor transplant using a conditioning regimen of Fludarabine (Flu), cyclophosphamide (cy) and total body irradiation (TBI) followed by MLN9708.
Intervention: Drug: MLN9708
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: June 20, 2014)
25
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 30, 2020
Estimated Primary Completion Date August 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02169791
Other Study ID Numbers  ICMJE NSH 1074
X16035 ( Other Identifier: Millennium )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Northside Hospital, Inc.
Study Sponsor  ICMJE Northside Hospital, Inc.
Collaborators  ICMJE Millennium Pharmaceuticals, Inc.
Investigators  ICMJE Not Provided
PRS Account Northside Hospital, Inc.
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP