Phase 2 Study of Talabostat and Rituximab in Patients with Advanced Chronic Lymphoctyic Leukemia (CLL) Previously Treated with a Rituximab/Fludarabine Regimen.

Background: Talabostat (T) is an orally available inhibitor of dipeptidyl peptidases (DPP) such as fibroblast activation protein (FAP). FAP is expressed in bone marrow, lymph nodes, and the stroma of solid tumors. T induces the production of cytokines and chemokines in lymph nodes and spleen, stimulating both adaptive and innate immune responses. T was shown to enhance the activity of rituximab (RTX) in a Phase 1 study in previously treated patients with B-cell malignancies, most likely by enhancing the antibody-dependent cytotoxicity of RTX. This study was conducted to evaluate the activity of T and RTX in patients with CLL who had previously failed a fludarabine/RTX (FR)-based regimen.

Methods: This is a single-arm, open-label study in up to 54 patients using the Simon 2-stage design. The 28-day treatment course consists of RTX 375mg/m² on Days 1, 8, 15, and 22, with T 300mcg BID tablets for 6 days following each RTX infusion; additional courses are permitted at the discretion of the investigator depending on response. Eligibility criteria include: CD20(+) B-CLL; Rai Stage III or IV, or Stages I and II with lymphadenopathy or hepatosplenomegaly; ECOG 0-2; primary resistance or PD following a FR-regimen; no CNS metastases. The primary endpoint is disease response (evaluated per NCI-WG criteria); secondary endpoints include response duration, progression-free survival, and survival.

Results: Of 20 patients treated to date, 19 patients (17 men, 2 women; median age 62, range 44 to 80) have completed at least 1 course of treatment and are considered evaluable for response:17 patients failed prior FR and 2 patients failed prior F (RTX naive). A partial response (PR) is reported in 4/19 patients (21%); 3 who had failed FR and one who had falied F. In 3 patients, the PR was reported at Day 29. One patient who failed FR was noted to be a PR after multiple courses. At Day 29, stable disease was reported in 12 patients and 4 had progressive disease. Most patients have received 1 course of treatment; 2 have received 2 courses and one PR has received 5 courses. The most frequent adverse events (AEs) include: edema (47%), pyrexia (35%), fatigue (24%), and dyspnea (24%). Grade 3 dyspnea has been reported in 2 patients. Grade 4 events include decreased platelets in one patient and hypoglycemia in one patient with a PR who was taking antidiabetic medications. Hypoglycemia is consistent with the inhibition of DPP-IV by T.

Conclusion: The addition of T to RTX shows promising activity in advanced CLL, with clinical responses reported in patients who failed an FR-based regimen. Edema was the most frequent AE, and other AEs are consistent with the safety profile of RTX. Updated results will be presented at the Annual Meeting.