OREANDA-NEWS. Basilea Pharmaceutica Ltd. (SIX: BSLN) announced today that the final clinical data from the first-in-human phase 1/2a study with the intravenous (i.v.) form of its tumor checkpoint controller BAL101553 were presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago, USA, on June 3-7, 2016. The study showed signals of clinical activity at doses associated with a promising safety profile. In addition, the design of a phase 1/2a study with the oral formulation of BAL101553 given once daily as well as the design of the first-in-human phase 1 study with the oral panRAF/SRC kinase inhibitor BAL3833 were presented. Dose-escalation in these studies is currently ongoing.

In the open-label phase 1/2a study, i.v. BAL101553 was administered over two hours on days 1, 8 and 15 of 28-day treatment cycles to patients with advanced solid tumors who failed standard therapy or for whom no effective standard therapy was available. Based on preclinical data and the evaluation of a range of biomarkers, patients with colorectal cancer, non-small cell lung cancer, pancreatic, ovarian, gastric and triple negative breast cancer were included in the phase 2a part of the study.

Across the entire study, out of the 59 patients who were evaluable for efficacy, 39 patients received 30 mg/m2 as starting dose or after adjustment. Of these 39 patients, one long-lasting partial response of more than two years and one prolonged stable disease of six months were observed in two patients with ampullary (pancreaticobiliary) cancers. Nine additional patients presented stable disease lasting between two and eight months. Overall, the drug was well-tolerated in the 15-30 mg/m2 dose groups; these patients were on treatment longer and showed more signals of clinical activity than patients treated at higher doses of 45-80 mg/m2. This may be related to different tumor vascular effects at low versus high BAL101553 doses.

The recommended Phase 2 dose for BAL101553 when given as a 2-hour infusion once per week was therefore determined to be 30 mg/m2. Dose-limiting adverse effects at higher dosages included transient and reversible grade 2 to grade 3 gait disturbance, which occurred together with transient grade 1 to grade 2 peripheral sensory neuropathy, and asymptomatic and reversible myocardial ischemia. These adverse effects appeared to be primarily related to the peak drug plasma concentration (Cmax), while preclinical data1 indicate that the anti-proliferative effects are driven by total drug exposure (area under the curve, AUC). This suggests that there may be a possibility to further widen the therapeutic window of BAL101553 through alternative dosing regimens, such as using daily oral dosing. After completion of four dose cohorts, no dose-limiting toxicities have been observed in the ongoing oral study.

In addition, the design of the ongoing first-in-human open-label multi-center phase 1 study with the oral panRAF/SRC kinase inhibitor BAL3833, also known as CCT3833, in patients with advanced solid tumors including metastatic melanoma, was presented at ASCO.

In the study, after receiving initial single oral doses for clinical safety and pharmacokinetic analysis, patients are administered oral BAL3833 once-daily on a continuous basis over 28-day treatment cycles. In the dose-escalation part, the safety and tolerability profile of BAL3833 will be evaluated and the maximum tolerated dose (MTD) as well as the recommended phase 2 dose (RP2D) will be established. The study further includes pharmacokinetic analyses and assessments of patient blood and tumor samples for drug response biomarkers as well as exploratory patient selection biomarkers. The protocol provides that, once the MTD and RP2D are defined, there will be an expansion phase in patients with locally advanced or metastatic malignant melanoma, such as untreated BRAF-mutant melanoma, variants with progression under conventional BRAF-inhibitor therapy as well as RAS-mutant melanoma.

The study is expected to include 69 patients and is conducted in the United Kingdom at the Royal Marsden and Christie NHS Foundation Trusts in collaboration with The Institute of Cancer Research, London, and The CRUK Manchester Institute, The University of Manchester. To date, four cohorts have completed enrollment without experiencing dose-limiting toxicity.