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Allogeneic Hematopoietic Stem Cell TransplantationPhase 1/2NCT02250300

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

A Phase 1/2 study testing MLN9708 (2.3 mg), MLN9708 (4.0 mg) and MLN9708 (3.0 mg) in people with Allogeneic Hematopoietic Stem Cell Transplantation, run by Mehdi Hamadani at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
MLN9708 (2.3 mg), MLN9708 (4.0 mg) and MLN9708 (3.0 mg)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
68 participants
Where
1 siteUnited States
Study dates
19 Nov 2014to 6 Oct 2020
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients with a history of a hematological malignancy or bone marrow failure syndrome undergoing (or status post) a peripheral blood allogeneic HCT.
  • Patients aged ≥18 are eligible.
  • All patients must have received or plan to receive an allograft from a suitable human leukocyte antigens (HLA) -matched sibling or unrelated donor according to transplant center's guidelines (for selection of appropriate donor).
  • 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of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
  • Bilirubin ≤ 2 x the upper limit of normal (ULN). For patients with Gilbert's syndrome or suspected mild veno-occlusive disease, bilirubin ≤ 3 x ULN is permitted.
  • Creatinine clearance of ≥ 30 mL/min calculated by Cockcroft-Gault equation.
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  • Karnofsky performance status > 60.
  • 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.
  • 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.)
  • No evidence of uncontrolled bacterial, viral or fungal infections at the time of enrollment.
  • No known active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.

Who cannot join

  • Patients with active ≥ grade 3 peripheral neuropathy or grade 2 with pain on clinical examination during the screening period will be excluded.
  • Patients with history of allergy and/or intolerance to MLN9708 are not eligible.
  • Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty swallowing is not permitted.
  • Patients receiving (or status post) a cord blood or a haplo-identical allograft will not be eligible.
  • Patients undergoing (or status post) a T-cell depleted allogeneic transplantation will not be eligible.
  • Patients receiving (or status post) conditioning regimens containing antithymocyte globulin, and/or campath, one receiving post-HCT planned cyclophosphamide will not be eligible.
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  • 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 Granulocyte- colony stimulating factor (CSF) alone; however donors receiving allografts mobilized with experimental agents (e.g. plerixafor) will remain eligible for the study.
  • 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.
  • Donor lymphocyte infusions between day zero of HCT and first dose of MLN9708 are not permitted.
  • 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.
  • 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.
  • 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.
  • Patients with active chronic GVHD (although unlikely before day +100) will be excluded.
  • No major surgery within 14 days before enrollment.
  • 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.
  • 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.
  • No systemic treatment, within 14 days before the first dose of MLN9708, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450, family 3, subfamily A (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.
  • No serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Froedtert Hospital and the Medical College of Wisconsin

    Milwaukee, Wisconsin, 53226

Other trials in United States

About this study

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 will be enrolled on the same arm to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD).

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.

Read the 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, cluster of differentiation 34 (CD34) + cell selection, or post-HCT cyclophosphamide) will be permitted.
  • During the phase I portion for chronic GVHD prophylaxis, four doses of MLN9708 will be 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.

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 would be 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 will be permitted.

  • MTD is defined at maximum dose level with fewer than two of six patients experiencing DLT.
  • 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.
Being tested
MLN9708 (2.3 mg), MLN9708 (4.0 mg), MLN9708 (3.0 mg)
Keywords
Stem cell transplantation, Hematopoietic transplantation, Hematopoietic stem cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MLN9708 (2.3 mg)Drug

    Also called Ixazomib

    2.3 mg

  • MLN9708 (4.0 mg)Drug

    Also called Ixazomib

    4.0 mg

  • MLN9708 (3.0 mg)Drug

    Also called Ixazomib

    3.0 mg

Study groups in NCT02250300
Study groupRoleWhat they receive
MLN9708 Phase II matched siblingExperimentalPhase 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.
Receives: Drug: MLN9708 (4.0 mg)
MLN9708 Phase II matched unrelatedExperimentalPhase 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.
Receives: Drug: MLN9708 (4.0 mg)
MLN9708 Phase I (2.3 mg)ExperimentalPhase I Four doses of MLN9708 will be administered on days 1, 8, 15, \& 22 orally based on a dose escalation schema.
Receives: Drug: MLN9708 (2.3 mg)
MLN9708 Phase I (3.0 mg)ExperimentalPhase I Four doses of MLN9708 will be administered on days 1, 8, 15, \& 22 orally based on a dose escalation schema.
Receives: Drug: MLN9708 (3.0 mg)
MLN9708 Phase I (4.0 mg)ExperimentalPhase I Four doses of MLN9708 will be administered on days 1, 8, 15, \& 22 orally based on a dose escalation schema.
Receives: Drug: MLN9708 (4.0 mg)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum-tolerated Dose of MLN9708.

    Maximum-tolerated dose of ixazomib (MLN9708) will be determined from the incidence of dose limiting toxicities at each dosage. Results for both escalation phase cohorts (3.0 mg and 4.0 mg) were used to determine the maximum tolerated dose.

    Measured: 4 weeks

  2. Cumulative Incidence of Chronic Graft-versus-host Disease.

    The number of participants who have graft-versus-host disease. The two expansion phase cohorts (3.0 mg and 4.0 mg) were not included in this analysis.

    Measured: 1 year

  3. Number of Participants Experiencing Dose-limiting Toxicity of MLN9708

    A 3+3 design will be employed. At each dose, three patients will be initially evaluated. If no dose limiting toxicities are observed, the MLN9708 dose will be increased; if one dose limiting toxicity is observed, three additional patients will be treated at that dose. A dose at which two DLTs are observed in three or six patients are judged to be too toxic, the lower dose will be defined as the maximally tolerated dose (MTD).

    Measured: 4 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Sep 2014 (estimated)
  2. Study start19 Nov 2014
  3. Primary completion6 Oct 2020
  4. Study completion6 Oct 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
68 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02250300
Sponsor's protocol ID
PRO00022660
Status last verified
Jan 2023
First submitted
7 Aug 2014
Last updated
8 Mar 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Chhabra S, Visotcky A, Pasquini MC, Zhu F, Tang X, Zhang MJ, Thompson R, Abedin S, D'Souza A, Dhakal B, Drobyski WR, Fenske TS, Jerkins JH, Douglas Rizzo J, Runaas L, Saber W, Shah NN, Shaw BE, Horowitz MM, Hari PN, Hamadani M. Ixazomib for Chronic Graft-versus-Host Disease Prophylaxis following Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2020 Oct;26(10):1876-1885. doi: 10.1016/j.bbmt.2020.07.005. Epub 2020 Jul 9.

    PubMed 32653622

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing MLN9708 (2.3 mg), MLN9708 (4.0 mg) and MLN9708 (3.0 mg) in people with Allogeneic Hematopoietic Stem Cell Transplantation, run by Mehdi Hamadani at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 Mar 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum-tolerated Dose of MLN9708. (time frame: 4 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02250300, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Mar 2023.

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