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



Status:Active, not recruiting
Conditions:Hematology
Therapuetic Areas:Hematology
Healthy:No
Age Range:18 - Any
Updated:3/14/2019
Start Date:November 2014
End Date:September 2022

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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.

- 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.

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.
We found this trial at
1
site
Milwaukee, Wisconsin
Principal Investigator: Mehdi Hamadani, MD
Phone: 866-680-0505
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mi
from
Milwaukee, WI
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