ALBERT

Description: Background: Talabostat (PT-100), an orally available inhibitor of dipeptidyl peptidases, is in Phase 2 studies for B-cell malignancies and solid tumors. Talabostat increases production of cytokines and chemokines in lymph nodes and spleen, stimulating both adaptive and innate immune responses (Adams S, Cancer Research, 2004;64:5471). Talabostat may thus enhance the antibody-dependent cytotoxicity of MAbs such as rituximab. Methods: This is a Phase 1 study to evaluate the safety and activity of talabostat and rituximab in patients with indolent NHL who did not respond or progressed following rituximab. Rituximab 375mg/m2 was administered weekly x 4. Total daily doses of talabostat 400μg (n=6), 600μg (n=3), or 800μg (n=6) were administered BID for 6 days following each dose of rituximab. Cytokines and chemokines were assessed pre-, 2, and 6 hours post-talabostat on Days 1, 6, 13, 20, and 27. Flow cytometry was performed at baseline and Day 28. Clinical and laboratory evaluations were performed at specified times. Adverse events (AEs) were graded per NCI-CTC and recorded throughout the study. Disease assessments were performed on Days 28 and 84. Results: 11 men and 4 women aged 48–82 with NHL (n=10) or SLL/CLL (n=5) have been treated. 9 patients completed the 28-day study: 4 at 400μg, 1 at 600μg, and 4 at 800μg. Enrollment continues at 400μg/day. The most frequent AEs have been edema (67%), nausea (47%), dizziness (40%), hypotension (33%), fatigue (33%), vomiting (33%), constipation (33%), thrombocytopenia (27%), and weight gain (27%). Grade 3 toxicities include: dizziness, myopathy (400μg/day), and 2 events of thrombocytopenia (600μg/day). Grade 3 peripheral edema, myalgia, dehydration, electrolyte imbalance, hypereosinophilia, elevated CPK (primarily CK-MM), and rhabdomyolysis were seen in 2/6 patients at 800μg/day; these events were DLTs. One partial response (PR) lasting 7 months was seen in one patient (800μg/day). A PR was seen in a second patient at 800μg/day but did not meet the strict NCI-WG criteria for response. Elevations in cytokines 〉ULN were reported across all doses following talabostat: G-CSF (13/15), IL-1β (10/15), IL-2 (7/15), IL-6 (8/15), IL-8 (8/15), IL-10 (11/15), TNF-α (11/15), and IFN-γ (3/15). At Day 28 or early termination, CD20 was decreased in most (12/15) patients. Increases were seen in the percentage of CD3 (12/15), CD3/4 (11/15) and CD3/8 (9/15). In all 5 patients with SLL/CLL, CD5+/CD20+ was