Open-label, Phase II Study of MLN9708 in Patients With Relapsed/Refractory Cutaneous and Peripheral T-cell Lymphomas
Open-label, Phase II Study of MLN9708 in Patients With Relapsed/Refractory Cutaneous and Peripheral T-cell Lymphomas
Historically cutaneous and peripheral T-cell lymphomas have response rates of approximately
 30% to standard chemotherapy regimens. We alternatively hypothesize that MLN9708 will be
 active in this disease and will improve best objective response.

 We will also determine the extent to which MLN9708 inhibits GATA-3 (Trans-acting
 T-cell-specific transcription factor) expression, which is associated with poor prognosis,
 and whether GATA-3 expression represents a novel predictive biomarker for MLN9708
 sensitivity.
Up to 25 patients meeting the inclusion and exclusion criteria will be enrolled into this
 trial in two stages. All enrolled patients will be treated with MLN9708 4 mg PO weekly (days
 1, 8, 15 every 28 days) until disease progression or unacceptable toxicity. In the initial
 stage of the study a total of 11 patients will be enrolled and treated with MLN9708. Should
 at least 4 patients exhibit a response (CR/CRu, PR), the second stage of 14 patients will
 open for enrollment. Efficacy will be assessed radiographically, by peripheral blood and bone
 marrow examination (when indicated), and physical exam every 8 weeks. Safety will be assessed
 by periodic physical exams, laboratory studies, and adverse events. All patients will have a
 follow-up visit 35 days (+/-7 days) following the last study drug treatment. Patients with
 accessible tumor tissue will be asked to undergo a biopsy for a fresh tissue sample for
 assessment of GATA-3 expression. Archived tissue samples from the initial diagnostic biopsy
 and the most recent lymphoma biopsy will be obtained in the event a fresh tumor biopsy cannot
 be obtained. Patients with GATA-3+ TCL and accessible tumor tissue will undergo a tumor
 biopsy at day 21 (+/- 7 days) of cycle 1. All baseline fresh or archived tissue will undergo
 central pathology review to confirm the diagnosis of TCL. The rationale for proteasome
 inhibition in T-cell lymphomas, based on the pre-clinical (and previous phase II) data, is
 compelling. Therefore, this phase II study will not be restricted to patients with GATA-3
 expressing lymphomas.
Inclusion Criteria:

 -  Male or female patients 18 years or older at the time of enrollment.

 -  Voluntary written consent must be given.

 -  Female patients who are postmenopausal for at least 1 year before the screening visit,
 OR surgically sterile, OR agree to practice 2 effective methods of contraception, at
 the same time, through 90 days after the last dose of study drug, AND adhere to the
 guidelines of any treatment-specific pregnancy prevention program, OR agree to
 practice true abstinence.

 -  Male patients must agree to practice effective barrier contraception through 90 days
 after the last dose of study drug, OR adhere to the guidelines of any
 treatment-specific pregnancy prevention program, OR agree to practice true abstinence.

 -  Patients must have histologically proven T-cell lymphoma, including Peripheral T-cell
 lymphoma, Angioimmunoblastic T-cell lymphoma, Anaplastic large cell lymphoma (ALK
 positive), Anaplastic large cell lymphoma (ALK negative), Mycosis fungoides, Sezary
 syndrome.

 -  CTCL patients must have stage IIb-IV disease.

 -  Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.

 -  Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3.

 -  Platelet transfusions are not allowed within 3 days before study enrollment.

 -  Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN).

 -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ to 3 x ULN.

 -  Creatinine clearance ≥30 mL/min.

 -  Documented disease progression after receiving at least one prior therapeutic regimen.

 Exclusion Criteria:

 -  Female patients who are lactating or have a positive serum pregnancy test.

 -  Failure to have recovered (ie, less than or equal to Grade 1 toxicity) from the
 reversible effects of prior chemotherapy.

 -  Major surgery within 14 days of enrollment.

 -  Radiotherapy within 14 days of enrollment. If the field is small, 7 days will be
 considered a sufficient interval between treatment and administration of the MLN9708.

 -  Known central nervous system involvement.

 -  Infection requiring systemic intravenous antibiotic therapy or other serious infection
 within 7 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.

 -  Systemic treatment, within 14 days before the first dose of MLN9708, with strong
 inhibitors of CYP1A2, strong inhibitors of CYP3A or strong CYP3A inducers or use of
 Ginkgo biloba or St. John's wort.

 -  Ongoing or active systemic infection, active hepatitis B or C virus infection, or HIV
 positive.

 -  Any serious medical or psychiatric illness that could potentially interfere with the
 completion of treatment according to this protocol.

 -  Known allergy to any of the study medications, their analogues, or excipients.

 -  Known GI disease or GI procedure that could interfere with the oral absorption or
 tolerance of MLN9708 including difficulty swallowing.

 -  Diagnosed or treated for another malignancy within 2 years before study enrollment or
 previously diagnosed with another malignancy and have any evidence of residual
 disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are
 not excluded if they have undergone complete resection.

 -  Patient has greater than or equal to Grade 3 peripheral neuropathy, or Grade 2 with
 pain on clinical examination during the screening period.

 -  Participation in other clinical trials with other investigational agents not included
 in this trial, within 21days of the start of this trial and throughout the duration of
 this trial.

 -  Prior allogeneic hematopoietic stem cell transplant.

 -  Prior autologous hematopoietic stem cell transplant within 90 days of study entry.

 -  Prior treatment with bortezomib.