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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
13
University of Michigan Hospital
Ann Arbor, Michigan, United States
Objective Response Rate
The percentage of patients with an objective response rate will be determined. The overall response will be based on response in each compartment (skin, blood, lymph nodes and viscera) using a global composite scoring system. Objective response is considered (CR) Complete Response (Complete disappearance of all clinical evidence of disease), CRu (Complete Response Unconfirmed), or (PR) Partial Response (Regression of measurable disease).
Time frame: Up to 24 months after initiation of study treatment
Number Patients That Experience Adverse Events, Grades 3-5
To assess the safety and tolerability of MLN9708, the number of patients experiencing Adverse Events (AEs) greater than or equal to grade 3 will be recorded.
Time frame: 30 days after the last dose of study drug
Median Progression Free Survival Time
Progression Free Survival (PFS) is defined as the time from study start until disease progression or death.
Time frame: 24 months after initiation of study treatment
Median Overall Survival Time
Overall Survival (OS) is defined as the time from study start until death.
Time frame: 24 months after initiation of study treatment
Duration of Response
Time from documentation of tumor response to disease progression.
Time frame: 24 months after initiation of study treatment
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