Obatoclax in Combination with Fludarabine and Rituximab (FR) Is Well-Tolerated and Shows Promising Clinical Activity in Relapsed CLL/SLL

Abstract 2865

Obatoclax is a small molecule mimetic of the BH3 domain of Bcl-2 family proteins. Obatoclax is broadly specific, with activity against Bcl-2, Bcl-X, Bcl-w and Mcl-1. CLL cells overexpress Bcl-2, Bcl-X_L and Mcl-1 in particular, and obatoclax can induce apoptosis of CLL cells in vitro. A phase 1 study of single-agent obatoclax in heavily pretreated largely refractory CLL patients demonstrated that the dose-limiting toxicity was neurologic, including euphoria and ataxia, leading to a maximum tolerated dose of 28 mg/m² given over 3 hours every 3 weeks. One PR was observed along with biologic activity demonstrated by reductions in lymphocyte counts and improvements in cytopenias. We therefore undertook this phase 1 study of the combination of obatoclax with FR in CLL patients relapsed after at least one prior therapy and in need of therapy again. Obatoclax was given as a three hour infusion on days 1 and 3 at three dose levels, 10, 14, and 20 mg/m² per dose. Fludarabine was given at 25 mg/m² days 1–5, and rituximab 375 mg/m² day 1 following an option to split the dose in cycle 1. Thirteen patients were enrolled, seven men and six women, with median age 58. 5 (38%) had stage 3–4 disease. FISH showed one patient with del17p, one with complex karyotype, and five with del11q. Six of nine patients evaluable had high risk unmutated IGHV, and nine of ten patients evaluable were positive for ZAP-70. The median number of prior therapies was two, with 9 patients having had prior fludarabine-based combination chemotherapy, 10 patients having had prior rituximab, and 8 patients having had prior alkylator-based combination chemotherapy. The study therapy was well-tolerated, with a median of five cycles administered. One dose-limiting toxicity (DLT) was observed at the 20 mg/m² obatoclax dose; this DLT was a greater than two week treatment delay for persistent grade 2–3 neutropenia in a patient who had had a similar event previously with FR alone. This DLT led to expansion of the third and highest cohort, which enrolled seven patients with no further DLTs observed. Other grade 3–4 toxicities have been limited and include neutropenia (n=5), thrombocytopenia (n=2), fever without neutropenia (n=2), increased ALT/AST (n=1), and dizziness (n=1). Neurologic side effects were easily managed and resembled alcohol intoxication, including grade 1–2 euphoria (n=6), ataxia (n=5), dizziness (n=6), anxiety (n=4), speech impairment (n=4) and confusion (n=3). The ORR by NCI-WG criteria was 85% (11/13; 90% CI 59–97%) with 15% CR (2/13; 90% CI 3–41%) and 38% nPRs (5/13; 90% CI 17–65%). With the addition of CT scan measurement of lymphadenopathy the ORR declined to 54% (7/13; 90% CI 29–78%) with no CRs. With a median follow-up of 26 months from the start of the study, three patients are in ongoing remission, six have relapsed with three receiving further therapy to date, two patients have gone on to stem cell transplantation, and two patients have died of disease. The median time to progression is 20 months (95% CI 9, 35 mos). We were able to demonstrate increased apoptosis compared to baseline in peripheral blood CLL lymphocytes during cycle 1 therapy in 9 of 13 patients, using Annexin V propidium iodide staining. We conclude that the FR-obatoclax regimen is well-tolerated and highly active in a relapsed CLL population. An extension of this study to increase the frequency of obatoclax dosing to days 1–3, and to change the chemotherapy backbone to FCR, is planned pending the availability of obatoclax.