Nonmyeloablative Haploidentical Transplant Followed by MLN9708

Sponsor
Northside Hospital, Inc. (Other)
Overall Status
Completed
CT.gov ID
NCT02169791
Collaborator
Millennium Pharmaceuticals, Inc. (Industry)
29
Enrollment
1
Location
1
Arm
72.4
Actual Duration (Months)
0.4
Patients Per Site Per Month

Study Details

Study Description

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 Design

Study Type:
Interventional
Actual Enrollment :
29 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Prevention
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
Actual Study Start Date :
Jul 15, 2014
Actual Primary Completion Date :
Jul 28, 2020
Actual Study Completion Date :
Jul 28, 2020

Arms and Interventions

ArmIntervention/Treatment
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.

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.

Outcome Measures

Primary Outcome Measures

  1. Number of Participants Experiencing Relapse or Progression [1 year]

    To estimate the incidence of relapse/progression at one-year post-transplant.

Secondary Outcome Measures

  1. Neutrophil Engraftment [1 year]

    To obtain time to neutrophil engraftment post-transplant

  2. Time to Platelet Recovery Post Transplant [1 year]

    To measure the time to platelet recovery post-transplant

  3. Day 30 CD3 Donor Chimerism [30 days]

    To measure CD3 donor chimerism post-transplant

  4. Day 30 CD33 Donor Chimerism [30 days]

    To measure CD33 donor chimerism at Day 30

  5. Graft Versus Host Disease [100 days]

    To measure days to onset of acute graft versus host disease

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1Northside HospitalAtlantaGeorgiaUnited States30342

Sponsors and Collaborators

  • Northside Hospital, Inc.
  • Millennium Pharmaceuticals, Inc.

Investigators

None specified.

Study Documents (Full-Text)

More Information

Publications

Responsible Party:
Northside Hospital, Inc.
ClinicalTrials.gov Identifier:
NCT02169791
Other Study ID Numbers:
  • NSH 1074
  • X16035
First Posted:
Jun 23, 2014
Last Update Posted:
Sep 2, 2021
Last Verified:
Sep 1, 2021
Keywords provided by Northside Hospital, Inc.
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment DetailsThis study was opened at our site 7/15/2014 and closed to accrual on 8/28/18. Patients were recruited internally and were considered if they were undergoing a haploidentical transplant for a high risk malignancy.
Pre-assignment DetailThis was a single arm study with no assignment groups. If patients met criteria they were considered for the study. 29 patients were consented and 25 of those patients were deemed eligible to participate. 4 patients were considered screen failures.
Arm/Group TitleHaploidentical Transplant
Arm/Group DescriptionAll 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: MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at D+5 post-transplant.
Period Title: Overall Study
STARTED25
COMPLETED18
NOT COMPLETED7

Baseline Characteristics

Arm/Group TitleHaploidentical Transplant
Arm/Group DescriptionAll 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: MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at D+5 post-transplant.
Overall Participants25
Age (Count of Participants)
<=18 years
0
0%
Between 18 and 65 years
15
60%
>=65 years
10
40%
Sex: Female, Male (Count of Participants)
Female
7
28%
Male
18
72%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
1
4%
Not Hispanic or Latino
24
96%
Unknown or Not Reported
0
0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
Asian
0
0%
Native Hawaiian or Other Pacific Islander
0
0%
Black or African American
6
24%
White
19
76%
More than one race
0
0%
Unknown or Not Reported
0
0%
Region of Enrollment (participants) [Number]
United States
25
100%

Outcome Measures

1. Primary Outcome
TitleNumber of Participants Experiencing Relapse or Progression
DescriptionTo estimate the incidence of relapse/progression at one-year post-transplant.
Time Frame1 year

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleHaploidentical Transplant
Arm/Group DescriptionAll 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: MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at D+5 post-transplant.
Measure Participants25
Count of Participants [Participants]
10
40%
2. Secondary Outcome
TitleNeutrophil Engraftment
DescriptionTo obtain time to neutrophil engraftment post-transplant
Time Frame1 year

Outcome Measure Data

Analysis Population Description
All 25 patients were analyzed for time to engraftment
Arm/Group TitleHaploidentical Transplant
Arm/Group DescriptionAll 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: MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at D+5 post-transplant.
Measure Participants25
Median (Full Range) [days]
16
3. Secondary Outcome
TitleTime to Platelet Recovery Post Transplant
DescriptionTo measure the time to platelet recovery post-transplant
Time Frame1 year

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleHaploidentical Transplant
Arm/Group DescriptionAll 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: MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at D+5 post-transplant.
Measure Participants25
Median (Full Range) [days]
29
4. Secondary Outcome
TitleDay 30 CD3 Donor Chimerism
DescriptionTo measure CD3 donor chimerism post-transplant
Time Frame30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleHaploidentical Transplant
Arm/Group DescriptionAll 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: MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at D+5 post-transplant.
Measure Participants25
Median (Full Range) [percentage of chimerism]
100
5. Secondary Outcome
TitleDay 30 CD33 Donor Chimerism
DescriptionTo measure CD33 donor chimerism at Day 30
Time Frame30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleHaploidentical Transplant
Arm/Group DescriptionAll 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: MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at D+5 post-transplant.
Measure Participants25
Median (Full Range) [percentage of chimerism]
100
6. Secondary Outcome
TitleGraft Versus Host Disease
DescriptionTo measure days to onset of acute graft versus host disease
Time Frame100 days

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleHaploidentical Transplant
Arm/Group DescriptionAll 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: MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at D+5 post-transplant.
Measure Participants25
Median (Full Range) [days]
28.5

Adverse Events

Time FrameAdverse Events were collected from the first dose of study drug through 30 days after administration of the last dose of MLN9708.
Adverse Event Reporting Description We used the standard definition of adverse events. Only grade 3-4 adverse events were tracked and reported. Grade 3 & 4 AEs are listed in the 'other non-serious' adverse events as they were documented. They did not meet the definition of serious therefore are listed in the separate category.
Arm/Group TitleHaploidentical Transplant
Arm/Group DescriptionAll 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: MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at D+5 post-transplant.
All Cause Mortality
Haploidentical Transplant
Affected / at Risk (%)# Events
Total8/25 (32%)
Serious Adverse Events
Haploidentical Transplant
Affected / at Risk (%)# Events
Total10/25 (40%)
Blood and lymphatic system disorders
Edema1/25 (4%) 1
Thrombotic microangiopathy1/25 (4%) 1
Gastrointestinal disorders
Nausea & vomiting2/25 (8%) 2
DIarrhea1/25 (4%) 1
General disorders
Hernia1/25 (4%) 1
Graft Versus Host Disease2/25 (8%) 2
Infections and infestations
Fever10/25 (40%) 15
Pneumonia3/25 (12%) 3
Bacteremia1/25 (4%) 1
HHV6 infection1/25 (4%) 1
Nervous system disorders
Spinal cord compression1/25 (4%) 1
Renal and urinary disorders
Dysuria1/25 (4%) 1
Acute Renal Failure2/25 (8%) 2
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure1/25 (4%) 1
Hypoxia1/25 (4%) 1
Vascular disorders
Vasculitis1/25 (4%) 1
Other (Not Including Serious) Adverse Events
Haploidentical Transplant
Affected / at Risk (%)# Events
Total22/25 (88%)
Blood and lymphatic system disorders
Neutropenia5/25 (20%) 5
Cardiac disorders
Hypertension8/25 (32%) 8
Syncope2/25 (8%) 2
Gastrointestinal disorders
Diarrhea7/25 (28%) 7
General disorders
Graft versus host disease7/25 (28%) 7
Infections and infestations
Pneumonia3/25 (12%) 3
Investigations
Elevated AST4/25 (16%) 4
Hyperglycemia4/25 (16%) 4
Metabolism and nutrition disorders
Hypokalemia2/25 (8%) 2
Skin and subcutaneous tissue disorders
Skin rash with or without pruritis8/25 (32%) 8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/TitleScott R. Solomon, MD
OrganizationNorthside Hospital
Phone404-255-1930
Emailssolomon@bmtga.com
Responsible Party:
Northside Hospital, Inc.
ClinicalTrials.gov Identifier:
NCT02169791
Other Study ID Numbers:
  • NSH 1074
  • X16035
First Posted:
Jun 23, 2014
Last Update Posted:
Sep 2, 2021
Last Verified:
Sep 1, 2021