A phase I trial of BNC105P and ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) was projected to cause 4320 deaths in 2021 in the US [1]. Chemo-immunotherapy regimens are commonly associated with unfavorable adverse events (AEs) [2, 3]. Targeted therapies such as the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib are better tolerated and have become standard of care for CLL. Ibrutinib causes egress of CLL cells from their stromal niche leading to peripheral lymphocytosis [4]. While initially successful in treatment of naïve, relapsed/refractory, and high risk CLL (deletion 17p), most high risk patients experienced disease progression, indicating a need to improve BTK-targeted therapy regimens [5-8]. Microtubule inhibitors kill CLL cells ex vivo with dependence on c-Jun N-terminal kinase (JNK) activation and induction of NOXA [9]. Vincristine activated JNK but not NOXA in circulating CLL cells in vivo [10]. BNC105, a colchicine-site microtubule inhibitor, was more potent at activating the JNK-NOXA apoptotic cascade [11]. BNC105P, the prodrug of BNC105, had a monotherapy maximum tolerated dose (MTD) of 16 mg/m 2 in solid tumor patients with on-target polymerized tubulin reduction activity starting at 12.6 mg/m 2 [12]. The study rationale was to target CLL cell egress from the stromal niche with ibrutinib and eliminate CLL cells in circulation with BNC105P to potentially obtain deep, long-lasting responses [13]. We therefore conducted an open-label, Phase Ib, dose escalation study of BNC105P and ibrutinib in patients with relapsed/refractory CLL (NCT03454165). Patients were enrolled at the Dartmouth Cancer Center using a Dartmouth College and Dartmouth-Hitchcock Health Institutional Review Board approved protocol and written informed consent. Study patients provided written informed consent prior to the performance of any study procedures and given a copy of the signed written informed consent.BNC105P (Bionomics Limited, Thebarton, Australia) was administered via IV infusion on days 1 and 8 (cycle 1) and days 8 and 15 (cycles 2-6) of 21-day cycles. Ibrutinib 420 mg was self-administered orally on days 1-21 (cycles 2-6). In drug combination cycles, ibrutinib was taken ≥30 min prior to BNC105P infusion. A standard 3 + 3 Phase I dose escalation design was used with planned BNC105P dose cohorts of 8 mg/m 2 (cohort 1), 12 mg/m 2 (cohort 2), and 16 mg/m 2 (cohort 3).The primary study objective was to determine the MTD of BNC105P in combination with ibrutinib in CLL patients.All patient inclusion and exclusion criteria for study NCT03454165 are detailed at https://clinicaltrials.gov/ct2/show/NCT03454165.

S-72, a Novel Orally Available Tubulin Inhibitor, Overcomes Paclitaxel Resistance via Inactivation of the STING Pathway in Breast Cancer

“…However, to date, none of these CBSIs have gained FDA approval, mainly due to their toxicity and lack of clinical benefits, problems that are related to their specific chemical structures. Compounds such as CA-4P, VERU-111, OXi4503, ABT-751, BNC105P and ZD6126 are currently undergoing or have completed clinical trials [ 17 , 18 , 19 , 20 ], but none are currently approved for clinical applications in cancer treatment due to their causation of undesirable adverse events [ 21 ], lack of bioavailability and low aqueous solubility [ 22 , 23 ]. Some other compounds are in preclinical studies.…”