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MLN9708 for the Prophylaxis of Chronic Graft-versus-host Disease in Patient Undergoing Allogeneic Transplantation

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ClinicalTrials.gov Identifier: NCT02250300
Recruitment Status : Active, not recruiting
First Posted : September 26, 2014
Last Update Posted : May 3, 2018
Sponsor:
Information provided by (Responsible Party):
Mehdi Hamadani, Medical College of Wisconsin

Brief Summary:

This is a phase I/II study of MLN9708 for the prophylaxis of chronic graft-versus-host-disease (GVHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT).

During the phase I portion patients undergoing both sibling and unrelated donor transplantation were enrolled on the same arm to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD).

It was determined that the maximum tolerated dose is 4 mg. Phase I is closed.

During the phase II portion of the trial, patients will be enrolled into two separate and independent cohorts: a) Matched sibling transplants and b) Unrelated donors transplants. Both cohorts will be enrolled and analyzed separately.


Condition or disease Intervention/treatment Phase
Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation Drug: MLN9708 Phase 1 Phase 2

Detailed Description:
  • For potential candidates for this trial, the recommended acute GVHD prophylaxis is a tacrolimus, methotrexate and atorvastatin combination. However, any acute GVHD prophylaxis regimen at the discretion of treating physician (not involving in-vivo or ex-vivo T-cell depletion, CD34+ cell selection, or post-HCT cyclophosphamide) will be permitted.
  • During the phase I portion, which is now closed, for chronic GVHD prophylaxis, four doses of MLN9708 were administered orally (to patients undergoing either matched sibling or unrelated donor transplantation) on days 1, 8, 15 and 22, starting on day +60 to +74 post allogeneic HCT.
  • Dose escalation started at dose level 1 and was carried out according to standard 3+3 design. The plan was as follows: If zero of three patients experiences DLT, dose escalation would proceed to the next higher dose level, at which three patients will be enrolled. The cohort would be expanded to six patients. Dose escalation would continue if no greater than one of six patients experience DLT, up to a maximum dose of 4 mg.

If zero of three patients experienced DLT at dose level 2, then it would be considered a MTD. If two or more patients experienced a DLT, dose escalation would halt and the dose level below was expanded to six patients to determine the MTD. If the dose level below already has six patients, enrolled, then it will be considered the MTD. If two or more patients experience DLT on first dose level (i.e., dose level 1), then, patients will be enrolled on dose level -1. No intrapatient dose escalation was permitted.

•MTD is defined at maximum dose level with fewer than two of six patients experiencing DLT.

NOTE: It was determined that the maximum tolerated dose is 4 mg. Phase I is closed.

  • The phase II portion will utilize the MTD for MLN9708, determined from phase I portion of the study. In phase II, patients will be enrolled in two independent cohorts of matched sibling and matched unrelated donor transplants.
  • During the phase II portion, for chronic GVHD prophylaxis, four doses of MLN9708 will be administered orally on days 1, 8, 15 and 22, starting on day +60 to +90 post allogeneic HCT.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 57 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: MLN9708 for the Prophylaxis of Chronic Graft-versus-host Disease in Patient Undergoing Allogeneic Transplantation
Study Start Date : November 2014
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : September 2022


Arm Intervention/treatment
Experimental: MLN9708 Phase II matched sibling
Phase II Patients will be enrolled in two independent cohorts of matched sibling and matched unrelated donor transplants. Four doses of MLN9708 will be administered on days 1, 8, 15, & 22 starting on day +60 to +90 post allogeneic HCT.
Drug: MLN9708
Experimental: MLN9708 Phase II matched unrelated
Phase II Patients will be enrolled in two independent cohorts of matched sibling and matched unrelated donor transplants. Four doses of MLN9708 will be administered on days 1, 8, 15, & 22 starting on day +60 to +90 post allogeneic HCT.
Drug: MLN9708
Experimental: MLN9708 Phase I
Phase I Four doses of MLN9708 will be administered on days 1, 8, 15, & 22 orally based on a dose escalation schema NOTE: It was determined that the maximum tolerated dose is 4 mg. Phase I is closed.
Drug: MLN9708



Primary Outcome Measures :
  1. Maximum tolerated dose of MLN9708 [ Time Frame: 4 weeks ]

    Phase I-To determine the maximum tolerated dose (MTD) for the prophylaxis of chronic GVHD in patients undergoing allogeneic hematopoietic cell transplantation (HCT) Safety, toxicity

    NOTE: It was determined that the maximum tolerated dose is 4 mg. Phase I is closed.


  2. Cumulative incidence of chronic GVHD [ Time Frame: 1 year ]
    Phase II: Determine the 1 year (from the date of HCT) cumulative incidence of chronic GVHD following MLN9708 administration as prophylaxis in patients undergoing matched sibling allogeneic HCT or unrelated donor allogeneic HCT.

  3. Dose limiting toxicity of MLN9708 [ Time Frame: 4 weeks ]
    Phase I: To determine the dose limiting toxicity (DLT) of MLN9708 for the prophylaxis of chronic GVHD in patients undergoing allogeneic hematopoietic cell transplantation (HCT)


Secondary Outcome Measures :
  1. Cumulative incidence of corticosteroid requiring GVHD [ Time Frame: 1 year ]
    To assess the 1 year (from the date of HCT) cumulative incidence of corticosteroid requiring chronic GVHD in the matched sibling cohorts and unrelated donors

  2. Recommend phase II dose (RDP) [ Time Frame: 4 weeks ]
    To determine the recommended phase II dose (RDP) of MLN9708 for the prophylaxis of chronic GVHD in patients undergoing allogeneic hematopoietic cell transplantation (HCT)

  3. Cumulative incidence grade II-IV GVHD [ Time Frame: +100 days ]
    To assess cumulative incidence of grade II-IV acute GVHD at days +100 in matched sibling cohort and unrelated donor



Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Patients with a history of a hematological malignancy or bone marrow failure syndrome undergoing (or status post) a peripheral blood allogeneic HCT.
  2. Patients aged ≥18 are eligible.
  3. All patients must have received or plan to receive an allograft from a suitable HLA-matched sibling or unrelated donor according to transplant center's guidelines (for selection of appropriate donor).
  4. Voluntary written consent must be given before patient registration and 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.
  5. Bilirubin ≤ 2 x the ULN. For patients with Gilbert's syndrome or suspected mild veno-occlusive disease, bilirubin ≤ 3 x ULN is permitted.
  6. Creatinine clearance of ≥ 30 mL/min calculated by Cockcroft-Gault equation.
  7. Karnofsky performance status > 60.
  8. A negative pregnancy test will be required for all women of child bearing potential. Females of child bearing potential should 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 [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.). Breast feeding is not permitted.
  9. Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following: practice effective barrier contraception during the entire study treatment period and through 90 days 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 (eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
  10. No evidence of uncontrolled bacterial, viral or fungal infections at the time of enrollment.
  11. No known active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.

Exclusion Criteria:

  1. Patients with active ≥ grade 3 peripheral neuropathy or grade 2 with pain on clinical examination during the screening period will be excluded.
  2. Patients with history of allergy and/or intolerance to MLN9708 are not eligible.
  3. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty swallowing is not permitted.
  4. Patients receiving (or status post) a cord blood or a haplo-identical allograft will not be eligible.
  5. Patients undergoing (or status post) a T-cell depleted allogeneic transplantation will not be eligible.
  6. Patients receiving (or status post) conditioning regimens containing antithymocyte globulin, and/or campath, one receiving post-HCT planned cyclophosphamide will not be eligible.
  7. Method of stem-cell collection from the donor will be at the discretion of the treating physician. Although it is anticipated that majority of patients will receive allograft mobilized with G-CSF alone; however donors receiving allografts mobilized with experimental agents (e.g. plerixafor) will remain eligible for the study.
  8. Patients experiencing disease relapse (for those in complete remission at the time of HCT) or progression (for those in partial remission, stable or refractory disease at the time of HCT) will be excluded.
  9. Donor lymphocyte infusions between day zero of HCT and first dose of MLN9708 are not permitted.
  10. Rituximab (or other B-cell depleting monoclonal antibodies) or bortezomib administration between day zero of HCT and before the first day of MLN9708 is not permitted.
  11. Patients with steroid refractory (defined as no improvement of symptoms after 7 days of systemic corticosteroids at a dose of ≥1mg/kg/day) grade II-IV acute GVHD, that is active at the time of enrollment will be excluded.
  12. Patients with grade III-IV acute GVHD (even if it is not meeting criteria for steroid refractory acute GVHD), that is active at the time of enrollment will be excluded. Patients with controlled grade I-II acute GVHD can be enrolled after discussing with study PI. Topical or systemic corticosteroids therapy, as per standard of care for such grade I-II acute GVHD patients is permitted.
  13. Patients with active chronic GVHD (although unlikely before day +100) will be excluded.
  14. No major surgery within 14 days before enrollment.
  15. No radiotherapy within 14 days before enrollment. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708.
  16. No 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. Cardiac enzyme elevations for reasons other than document myocardial infarction is not an exclusion.
  17. No systemic treatment, within 14 days before the first dose of MLN9708, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), 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.
  18. No serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  19. No participation in other clinical trials, including those with other investigational agents within 21days of the start of this trial and throughout the duration of this trial. However co-enrollment on trials evaluating conditioning regimens, institutional protocols evaluating atorvastatin for acute GVHD prophylaxis, and stem cell collection protocols in transplant donors will be permitted. In addition patients randomized to standard-of-care (non experimental) arms of available phase II/III trials will be eligible for this study.

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): NCT02250300


Locations
United States, Wisconsin
Froedtert Hospital and the Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Mehdi Hamadani
Investigators
Principal Investigator: Mehdi Hamadani, MD Medical College of Wisconsin

Responsible Party: Mehdi Hamadani, Associate Professor, Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT02250300     History of Changes
Other Study ID Numbers: PRO00022660
First Posted: September 26, 2014    Key Record Dates
Last Update Posted: May 3, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Ixazomib
Glycine
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Glycine Agents
Neurotransmitter Agents
Physiological Effects of Drugs