Phase 1/2a Study of BAL101553 as 48-hour Infusions in Patients With Advanced Solid Tumors or Recurrent Glioblastoma

Study Overview
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Brief Summary
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Single-agent, open-label, multi-center sequential dose escalation and expansion study of BAL101553, administered as an intravenous (IV) infusion over 48 hours to adults with advanced or recurrent solid tumors or recurrent glioblastoma.

Detailed Description
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This is the first study of prolonged intravenous infusion of BAL101553 (lisavanbulin). BAL101553 will be administered as an intravenous infusion over 48 hours, to adults with advanced or recurrent solid tumors or recurrent glioblastoma who have failed standard therapy, or for whom no effective standard therapy is available. The primary goal of the study is to find the highest dose of BAL101553 that can safely be given to humans and to assess what side effects occur. The study will start by treating patients with a low dose. Once it has been shown that this low dose is well tolerated, new patients will be treated at higher dose levels (dose escalation). Once the highest, well tolerated dose is identified, up to 20 new patients with platinum-resistant/refractory ovarian cancer and up to 20 new patients with recurrent glioblastoma will be treated at that dose (this part is called dose expansion) to further assess as secondary goal the tolerability and potential anticancer activity of BAL101553. A further secondary goal of this study is to assess the pharmacokinetics of BAL101553.

Official Title
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An Open-label Phase 1/2a Study of BAL101553 Administered as Intravenous 48-hour Infusions in Adult Patients With Advanced Solid Tumors or Recurrent Glioblastoma

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: BAL101553
* Drug: BAL101553 at MTD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Phase 1: Patients with either histologically or cytologically confirmed advanced or recurrent solid tumor, who failed standard therapy or for whom no effective standard therapy is available. Phase 2a: Patients with platinum-resistant/refractory ovarian, fallopian tube or primary peritoneal cancer (high-grade serous, endometrioid, or carcinosarcoma histotypes) or glioblastoma in first relapse. Patients with solid tumors must have measurable disease according to Response Evaluation Criteria in Solid Tumors [RECIST] v1.1. Patients with recurrent glioblastoma must have measurable disease defined by contrast-enhancing magnetic resonance imaging. Life expectancy ≥ 12 weeks Acceptable organ and marrow function at baseline (protocol defined laboratory parameters) Patients with solid tumors must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 and patients with recurrent glioblastoma must have an ECOG performance status ≤ 2. Other protocol-defined inclusion criteria may apply. Exclusion Criteria: Patients with solid tumors who have received chemotherapy, radiotherapy, immunotherapy, or investigational agents within 4 weeks prior to starting study drug or who have not recovered from side effects of prior therapies. Patients with recurrent glioblastoma who have: received radiotherapy within 12 weeks, unless there is a new area of enhancement consistent with recurrent tumor outside the radiation field, or there is histological confirmation of unequivocal tumor progression; received administration of prior antitumor chemotherapy within 4 weeks, or within 6 weeks for nitrosoureas; undergone surgical resection within 4 weeks or a stereotactic biopsy/core biopsy within 1 week prior to starting study drug, or have been treated previously with bevacizumab. Patients who have had prior exposure to BAL101553. Peripheral neuropathy ≥ CTCAE grade 2. Uncontrolled intercurrent illness that would unduly increase the risk of toxicity or limit compliance with study requirements Systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg at the screening visit. Blood pressure (BP) combination treatment with more than two antihypertensive medications. Women who are pregnant or breast-feeding. Men or women of reproductive potential who are not willing to apply effective birth control. Other protocol-defined exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1<br>Fixed 3+3 dose escalation of BAL101553 in patients with advanced solid tumors | Drug: BAL101553<br>* BAL101553 48-hour infusion on day 1, 8, and 15 of each 28-day cycle; oral capsule daily for one week during Cycle 2 (study days 15-21)<br>|
| Experimental: Phase 2a<br>BAL101553 at MTD in patients with platinum-resistant/refractory ovarian cancer or recurrent glioblastoma | Drug: BAL101553 at MTD<br>* BAL101553 48-hour infusion on day 1, 8, and 15 of each 28-day cycle; treatment with maximum tolerated dose (MTD)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of BAL101553 | First 28-day treatment cycle dose limiting toxicities (DLT) graded according to CTCAE in the MTD-determining population in Phase 1 based on the number of participants with adverse effects as measure of tolerability at various dose levels | 28 day cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of BAL101553 Treatment Based on Number of Patients With Related Treatment-emergent Adverse Events (TEAEs) in the Phase 1 and Phase 2a Safety Population at Various Dose Levels and Indication | TEAEs are defined as all events occurring after BAL101553 treatment begins, up to 28 days after last study drug administration according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 | TEAEs with onset on or after Day 1 of the study and until 28 days after the last dose | 
| AUC of BAL101553 and BAL27862 | Pharmacokinetic parameter Area under the plasma concentration versus time curve AUC0-last (of BAL101553 and BAL27862 has been assessed after a 48-hour IV infusion. Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862). | 0 to 168 hours post-dose at Day 1 of Cycle 1 and Cycle 2 in each cohort in Phase 1, 28-day cycles | 
| Cmax of BAL101553 and BAL27862 | Pharmacokinetic parameter Peak Plasma Concentration Cmax of BAL101553 and BAL27862. Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862). | Pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48, 52, 54, 72 h, and 168 h after the start of study-drug infusion on Day 1 of Cycle 1 and pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48, 72 h, and 168 h after the start of study-drug infusion on Day 1 of Cycle 2. | 
| Tmax of BAL101553 and BAL27862 | Pharmacokinetic parameter Time to Peak Plasma Concentration Tmax of BAL101553 and BAL27862 | Pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48, 52, 54, 72 h, and 168 h after the start of study-drug infusion on Day 1 of Cycle 1 and pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48, 72 h, and 168 h after the start of study-drug infusion on Day 1 of Cycle 2. | 
| Bioavailability of Daily Oral BAL101553 Measured by BAL27862 in Phase 1 | Ratio of AUCs of avanbulin after oral and IV administration (relative bioavailability) of BAL101553 (lisavanbulin) which is the prodrug of avanbulin (BAL27862) | Relative oral bioavailability, calculated as dose-normalized AUC0-τ following oral administration on Cycle 2 Day 21 divided by dose normalized AUC0-∞ following IV administration on Cycle 1 Day 1 for each cohort. | 
| Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria | The objective response rate (ORR) was calculated using the efficacy evaluable populations (EEPs in Phase 2a) and the full analysis population (FAP in Phase 1 and Phase 2a) based on RECIST v1.1 guidelines (defines criteria for the radiological assessment in tumor response) for patients with solid tumors (excluding GBM (glioblastoma)) and RANO criteria (assessment Incorporating MRI and clinical factors) for patients with GBM. ORR = Rate of complete and partial responses | 28 day cycles |