Nonmyeloablative Haploidentical Transplant Followed by MLN9708
Condition: Acute Leukemia; Chronic Leukemia; Myelodysplastic Syndrome; Lymphomas; Multiple Myeloma
MeSH terms: Leukemia; Multiple Myeloma; Myelodysplastic Syndromes
Intervention: MLN9708
Intervention description: MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at D+5 post-transplant.
Intervention MeSH terms: Ixazomib
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 29.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: hematologic malignancies

Summary:

      In an attempt to reduce relapse risk and improve outcomes following haploidentical
      transplantation for patients with high risk hematologic malignancies, the investigators will
      implement several strategies to augment the well documented effect of NK cell alloreactivity
      seen in HLA-mismatched transplantation. These strategies include (1) choosing potential
      haploidentical donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition
      post-transplant with MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect
      against graft-versus-host disease (GVHD), and (3) eliminating mycophenolate mofetil from the
      post-transplant immunosuppression regimen to improve NK cell reconstitution following
      haploidentical peripheral blood stem cell transplantation.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Availability of a 3/6 - 5/6 matched (HLA-A, B, DR) related donor

          -  Donor must have negative HLA cross-match in the host vs. graft direction.

          -  Donor must be willing to donate mobilized peripheral blood stem cells

          -  Age ≥ 18 years

          -  Karnofsky status ≥ 70%

          -  One of the following high-risk malignancies:

          -  Chronic Myelogenous Leukemia (chronic phase, resistant and/or intolerant to tyrosine
             kinase inhibitors (OR) accelerated phase (OR) blast crisis in 2nd chronic phase
             following induction chemotherapy)

          -  Acute Myelogenous Leukemia (2nd or subsequent complete remission [CR] (OR) Primary
             induction chemotherapy failure, but subsequently entered into a CR(OR) 1st CR with
             poor risk cytogenetics or molecular markers; or arising from preceding hematological
             disease)

          -  Myelodysplastic Syndrome (treatment-related, monosomy 7 or complex cytogenetics, IPSS
             score of 1.5 or greater, Chronic myelomonocytic leukemia [CMML])

          -  Acute lymphocytic leukemia/lymphoblastic lymphoma (2nd or subsequent CR (OR) Primary
             induction chemotherapy failure, but subsequently entered into a CR (OR) 1st CR with
             poor risk cytogenetics)

          -  Chronic Lymphocytic Leukemia / Prolymphocytic Leukemia (Duration of remission <12
             months after receiving chemotherapy with a nucleoside analog (OR) High risk features
             (i.e. 17p deletion), (OR) Second or subsequent relapse)

          -  Hodgkin's or Non-Hodgkin's Lymphoma (including low-grade, mantle cell, and
             intermediate-grade/diffuse) (Previously treated disease that has either relapsed or
             failed to respond adequately to conventional-dose therapy or autologous
             transplantation (AND) Chemoresponsive to most recent salvage therapy

          -  Multiple Myeloma (Presence of a poor risk cytogenetic abnormality [i.e. 17p, t(4;14)],
             Relapse post autologous transplant)

        Exclusion Criteria:

          -  Poor cardiac function: left ventricular ejection fraction <40%

          -  Poor pulmonary function: FEV1, FVC, or DLCO <50% predicted

          -  Poor liver function: bilirubin >2.5 mg/dl (not due to hemolysis, Gilbert's or primary
             malignancy), AST/ALT > 3X ULN

          -  Poor renal function: Creatinine >2.0 mg/dl or creatinine clearance (calculated
             creatinine clearance is permitted) < 40 mL/min

          -  Ongoing or active systemic infection, active hepatitis B or C virus infection, or
             known human immunodeficiency virus (HIV) positive.

          -  Women of childbearing potential who currently are pregnant or who are not practicing
             adequate contraception

          -  Patients who have any debilitating medical or psychiatric illness which would preclude
             their giving informed consent or their receiving optimal treatment and follow-up.

          -  Systemic treatment, within 14 days before the first dose of MLN9708, with strong
             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.

          -  Patient has >/= Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical
             examination during the screening period.

          -  Participation in other clinical trials, including those with other investigational
             agents not included in this trial, within 21days of the start of this trial and
             throughout the duration of this trial.

          -  Infection requiring systemic antibiotic therapy or other serious infection within 14
             days before study enrollment.

          -  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.

          -  Known allergy to any of the study medications, their analogues, or excipients in the
             various formulations of any agent.

          -  Known GI disease or GI procedure that could interfere with the oral absorption or
             tolerance of MLN9708 including difficulty swallowing