Clinical Trials

Date: 2018-01-03

Type of information: update on patient enrollment

phase: 2a

Announcement: update on patient enrollment

Company: Basilea Pharmaceutica (Switzerland)

Product: BAL101553

Action mechanism:

• microbutubule inhibitor. BAL101553 is an intravenous and oral microtubule-targeting agent. This highly water-soluble prodrug of the synthetic small molecule BAL27862 allows intravenous and oral administration without solubilizing excipients associated with adverse effects. BAL27862 arrests tumor cell proliferation and induces tumor cell death through a characteristic destabilizing effect on microtubules that is distinct from other anti-cancer agents also directed against the microtubule network. Anti-tumor activity has been demonstrated across a broad panel of solid tumor models, including those resistant against conventional microtubule-targeting drugs such as taxanes or Vinca alkaloids.
• In addition to the activity in glioblastoma tumor lines, BAL101553 was shown to have potent anticancer activity against glioblastoma stem-like cells in a pre-clinical model as reported in a recent publication co-authored by Basilea and the research group of Prof. Diane Braguer of Aix-Marseille University, France. Tumor stem-like cells contribute to glioblastoma regrowth as well as brain invasion, a phenomenon which also occurs in the pre-clinical model used. The publication further reported the observation that BAL101553 promoted the loss of stem-cell properties. These published data further support the potential of BAL101553 to target glioblastoma, a tumor often associated with poor prognosis for patients. 

Disease: advanced solid tumors including glioblastoma

Therapeutic area: Cancer - Oncology

Country: Switzerland, UK

Trial details:

• Two phase 1/2a studies are evaluating BAL101553 in adult patients with solid tumors. (NCT02490800 and NCT02895360)

Latest news:

• • On January 3, 2018, Basilea  announced an update on two open-label phase 1/2a clinical studies to explore different dosing regimens of BAL101553 in patients with advanced solid tumors, one study with weekly 48-hour continuous infusion and the other with once-daily oral dosing. The oral study was amended in late 2016 to also enroll patients with recurrent or progressive glioblastoma. Phase 1 recruitment of patients in the solid tumor part of the oral study and the 48-hour continuous infusion study has been completed and the Maximum Tolerated Doses (MTDs) have been established. Dose-limiting adverse events observed in both studies included reversible hallucinations and reversible hyponatremia (low sodium levels). Basilea plans to present the phase 1 results at upcoming scientific conferences. The company expects to complete phase 1 patient recruitment into the separate glioblastoma arm of the oral study in the first half of 2018 and is finalizing its strategy for exploring specific patient populations in an expansion of the 48-hour continuous infusion phase 1/2a study.
• • On December 2, 2016, Basilea Pharmaceutica announced the expansion of its ongoing oncology drug candidate BAL101553 clinical phase 1/2a oral formulation study. The first patient has been dosed in an additional arm containing adult patients with recurrent or progressive glioblastoma (brain cancer) after prior radiotherapy with or without chemotherapy.
• The ongoing phase 1/2a study includes patients with advanced or recurrent solid tumors who have failed standard therapy or for whom no effective standard therapy was available. Phase 1 dose escalation to determine the maximum tolerated dose (MTD) of daily oral dosing is currently ongoing. A subsequent phase 2a extension of the study is planned to further evaluate the safety, tolerability and the pharmacokinetic profile of oral BAL101553 at the MTD, and to assess its anti-tumor activity. Furthermore, biomarkers are assessed in both the phase 1 and phase 2a parts of the study to determine their utility in identifying patients who are most likely to respond to treatment, including biomarkers with potential relevance to glioblastoma.• On September 6, 2016, Basilea Pharmaceutica announced that the first patient has been dosed in a new phase 1/2a continuous infusion study with its tumor checkpoint controller BAL101553 in patients with advanced solid cancers. The open-label, multicenter study is being conducted in Switzerland. It includes adult patients with advanced solid tumors who failed standard therapy or for whom no effective standard therapy is available. Study participants receive i.v. BAL101553 administered as 48-hour continuous infusions.
• • On June 9, 2016, Basilea Pharmaceutica announced that the final clinical data from the first-in-human phase 1/2a study with the intravenous  form of its tumor checkpoint controller BAL101553 were presented at the American Society of Clinical Oncology (ASCO) annual meeting. 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 was presented.
• 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.
• • On June 26, 2014, Basilea Pharmaceutica reported that it initiated a phase 2a study with BAL101553. The study is designed to further characterize safety and tolerability, and to obtain efficacy data in adult patients with advanced or recurrent solid tumors who have failed standard therapy or for whom no effective standard therapy is available. Tumor types were selected based on clinical observations in the phase 1 study and a detailed analysis of potential patient stratification biomarkers across tumor indications. The study will also continue the extensive biomarker testing initiated in Phase 1, to further evaluate dose and patient populations most likely to respond.
• • On June 2, 2014, Basilea Pharmaceutica reported that phase 1 study results of BAL101553  were presented at the American Society of Clinical Oncology (ASCO) annual meeting (Abstract 2562). The maximum tolerated dose (MTD) was determined and the results indicated first evidence of clinical antitumor activity. The currently reported phase 1 open-label, dose-escalation study included adult patients with advanced solid tumors who had failed standard therapy. The study investigated safety and tolerability of intravenous BAL101553 and evaluated pharmacokinetics, pharmacodynamics and antitumor activity. In total, 24 patients received BAL101553 as a two-hour intravenous infusion of up to 80 mg/m2 on day 1, 8 and 15 of a 28-day treatment cycle. BAL101553 was well tolerated up to 60 mg/m2. Drug-related events included injection site reactions, nausea, vomiting, diarrhea, peripheral neuropathy (all mild or moderate), and well-manageable, transient hypertension. Gait disturbance together with peripheral sensory neuropathy were dose-limiting events. One patient demonstrated a confirmed partial response lasting more than two years, and five patients showed stable disease, lasting more than four months in two patients. Comparison of post to pre-treatment tumor biopsies demonstrated a pronounced reduction of tumor cell proliferation and tumor vascularization. Basilea has announced that the company will now proceed into phase 2a development for the further investigation of selected solid tumor types. The company will also continue to assess stratification biomarkers to identify patients most likely to respond to treatment with BAL101553. • On June 4, 2013, Basilea Pharmaceutica has reported the presentation of interim data of BAL101553 from its ongoing phase 1 study in patients with advanced solid tumors at the Annual Meeting of the American Society of Clinical Oncology (ASCO), held in Chicago, Illinois (USA) from May 31 to June 4. The presented data demonstrated that intravenously administered BAL101553 was well tolerated at the doses studied thus far and provided first evidence of anti-tumor activity. Among the 18 patients treated, one patient experienced a partial response (decrease in tumor lesion size) and an additional five patients reported stable disease of which two patients showed stable disease for more than 16 weeks. The main side effects observed were nausea/vomiting and transient blood pressure elevations which were well manageable. Dose escalation continues to determine the maximum tolerated dose. Pharmacokinetic profiles from the study indicated dose-proportionality; initial pharmacodynamic analyses showed vascular disrupting and anti-proliferative effects in post-treatment tumor biopsies.
• Poster on BAL101553: A first-in-human (FIH) dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenous BAL101553, a novel microtubule inhibitor, in adult patients with advanced solid tumors
• •  On November 6, 2012,  Basilea Pharmaceutica has presented data on BAL101553 at the 24th Symposium on "Molecular Targets and Cancer Therapeutics" taking place in Dublin, Ireland, from November 6 to 9, 2012, hosted by the European Organisation for Research and Treatment of Cancer (EORTC), the U.S. National Cancer Institute (NCI) and the American Association for Cancer Research (AACR).
• The posters on BAL101553/BAL27862 to be presented in poster session "Tubulin-Interacting Agents" on November 8, 2012 are:
• • Dual mechanism of action of the novel microtubule-targeting drug BAL27862 (active moiety of the prodrug BAL101553): targeting tumor and vascular cells - F. Bachmann, H.A. Lane; poster #421
• • Antitumor activity of BAL27862 (active moiety of the prodrug BAL101553) is associated with the generation of short non-centrosomal microtubules - A. Rovini, S. Honoré, N. McKay, F. Bachmann, H.A. Lane, D. Braguer; poster #422Basilea Pharmaceutica has reported that new research data on its anti-cancer drug BAL101553 are being presented at the 24th Symposium on "Molecular Targets and Cancer Therapeutics" taking place in Dublin, Ireland, from November 6 to 9, 2012, hosted by the European Organisation for Research and Treatment of Cancer (EORTC), the U.S. National Cancer Institute (NCI) and the American Association for Cancer Research (AACR).
• BAL27862 has potential for both intravenous and oral administration. The injectable form is currently being tested in a phase I study in patients with advanced solid tumors. BAL101553 has a dual mechanism of action (poster/abstract #421) with direct activity against drug-resistant cancer cells and a pronounced effect on eliminating tumor blood supply. In animal models, short-term treatment of tumors led to a dramatic reduction in tumor cell growth and viability, associated with almost complete eradication of functional tumor blood vessels. Importantly, blood vessel function in normal tissue was not affected. Vascular disruption activity was also shown in an in vitro model that mimics capillary formation. Further data supporting the unique anti-cancer profile and mode of action of this novel agent were generated in collaboration with the group of Diane Braguer of the Aix-Marseille University, France. Details of distinct effects on microtubule biology are presented (poster/abstract #422). These show that BAL27862 blocks tumor cell division by altering microtubule dynamics in a unique way as compared to conventional microtubule-targeting agents.
• • On April 4, 2012, Basilea Pharmaceutica announced that research data on a potential biomarker predicting response to its novel microtubule-targeting phase I oncology drug candidate BAL101553 were presented at the American Association of Cancer Research (AACR) Annual Meeting in Chicago, Illinois, USA.
• Results of collaborative studies between the Basilea research group and the team of Dr. Michael Boutros, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany, were presented at AACR. These preclinical studies demonstrate that BubR1 protein kinase function is required for the antiproliferative action of BAL27862 (the active moiety of BAL101553) in tumor cells. BubR1 plays a key regulatory role in the assembly of the microtubule mitotic spindle required for cell division. Using small interfering RNA (siRNA) approaches and diverse cancer models, it was found that susceptibility to BAL27862 correlated with BubR1 expression levels. This work provides a robust dataset across tumor types, supportive of the further evaluation of BubR1 as a potential marker of tumor response to BAL101553. Anti-cancer activity of BAL101553 has been demonstrated across a broad panel of preclinical models of human cancer, including those resistant against conventional microtubule-targeting drugs such as taxanes or vinca alkaloids. The injectable form of BAL101553 is currently being tested in a phase I clinical program with patients suffering from advanced solid tumors. Phase I data are expected in the second half of 2012.
• • On June 29, 2011, Basilea Pharmaceutica Ltd. has announced the start of the first clinical study with its anti-cancer drug BAL101553. The phase I open-label, dose-escalation study investigates safety, tolerability and pharmacokinetics of intravenous BAL101553 to establish dose and administration schedule for phase II studies. The study includes adult patients with advanced solid tumors who have failed standard therapy or for whom no effective standard therapy is available.

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