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

NCT02250300 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: PRO00022660
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 1

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 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.

Conditions

Allogeneic Hematopoietic Stem Cell Transplantation

Keywords

Stem cell transplantation; Hematopoietic transplantation; Hematopoietic stem cell

Outcome Measures

Primary Outcomes (3)

• 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.

  4 weeks

• 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.

  1 year

• 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).

  4 weeks

Study Arms (5)

MLN9708 Phase II matched sibling

EXPERIMENTAL

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 (4.0 mg)

MLN9708 Phase II matched unrelated

EXPERIMENTAL

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 (4.0 mg)

MLN9708 Phase I (2.3 mg)

EXPERIMENTAL

Phase I Four doses of MLN9708 will be administered on days 1, 8, 15, \& 22 orally based on a dose escalation schema.

Drug: MLN9708 (2.3 mg)

MLN9708 Phase I (3.0 mg)

EXPERIMENTAL

Phase I Four doses of MLN9708 will be administered on days 1, 8, 15, \& 22 orally based on a dose escalation schema.

Drug: MLN9708 (3.0 mg)

MLN9708 Phase I (4.0 mg)

EXPERIMENTAL

Phase I Four doses of MLN9708 will be administered on days 1, 8, 15, \& 22 orally based on a dose escalation schema.

Drug: MLN9708 (4.0 mg)

Interventions

MLN9708 (2.3 mg) DRUG

2.3 mg

Also known as: Ixazomib

MLN9708 Phase I (2.3 mg)

MLN9708 (4.0 mg) DRUG

4.0 mg

Also known as: Ixazomib

MLN9708 Phase I (4.0 mg); MLN9708 Phase II matched sibling; MLN9708 Phase II matched unrelated

MLN9708 (3.0 mg) DRUG

3.0 mg

Also known as: Ixazomib

MLN9708 Phase I (3.0 mg)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Mehdi Hamadani: lead

Study Sites (1)

Froedtert Hospital and the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• 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.

  PMID: 32653622 RESULT

MeSH Terms

Interventions

ixazomib

Results Point of Contact

• Title: Mehdi Hamadani, MD
• Organization: Froedtert and the Medical college of Wisconsin

mhamadani@mcw.edu

414-805-4600

Study Officials

• Mehdi Hamadani, MD

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: August 7, 2014
• First Posted: September 26, 2014
• Study Start: November 19, 2014
• Primary Completion: October 6, 2020
• Study Completion: October 6, 2020
• Last Updated: March 8, 2023
• Results First Posted: March 8, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)