Clinical trial NCT02250300 (phase 1/phase 2, status: completed)
Conditions: allogeneic hematopoietic stem cell transplantation
ICD codes: M31.11
Drugs: mln9708
SMILES: [H][C@@](CC(C)C)(N=C(O)CN=C(O)C1=C(Cl)C=CC(Cl)=C1)B(O)O
Eligibility 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 human
             leukocyte antigens (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             that consent may be withdrawn by the patient at any time without prejudice to future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 upper limit of normal (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 Granulocyte- colony stimulating factor (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
             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.

         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.