Phase 1/2a Study of Oral BAL101553 in Adult Patients With Solid Tumors or Glioblastoma or High-grade Glioma

Study Overview
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Brief Summary
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First in human, open-label, sequential dose escalation and expansion study of oral BAL101553 in adult patients with advanced solid tumors and adult patients with recurrent or progressive glioblastoma or high-grade glioma.

Detailed Description
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This is the first study of the oral formulation of BAL101553. BAL101553 will be administered once daily during each day of a 28-day treatment cycle in capsule form to adults with advanced or recurrent solid tumors or recurrent or progressive glioblastoma or high-grade glioma who have failed standard therapy, or for whom no effective standard therapy is available. In Phase 1, the highest dose of BAL101553 was determined that can safely be given to adults with advanced or recurrent solid tumors, recurrent or progressive glioblastoma or high-grade glioma who have failed standard therapy, or for whom no effective standard therapy is available. In Phase 2a, the tolerability and potential anticancer activity of oral BAL101553 will be assessed in patients with recurrent glioblastoma whose tumor tissue tests positive for end-binding protein 1 (EB1). The study will also measure pharmacokinetics, pharmacodynamic effects and assess biomarkers.

Official Title
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An Open-label Phase 1/2a Study of Oral BAL101553 in Adult Patients With Advanced Solid Tumors and in Adult Patients With Recurrent or Progressive Glioblastoma or High-grade Glioma

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Oral daily administration of BAL101553


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Patients who have in the Phase 1 portion either of the following: a histologically- or cytologically confirmed advanced or recurrent solid tumor, who failed standard therapy, or for whom no effective standard therapy is available to them histologically-confirmed GBM or high-grade glioma, with progressive or recurrent disease after prior radiotherapy, with or without chemotherapy. This will also include patients with histologically-confirmed low-grade glioma who present with unequivocal evidence by imaging of transformation to high-grade glioma/GBM. Phase 2 portion: Recurrent, histologically confirmed, glioblastoma with tumor tissue positive for EB1; eligible are patients with de novo glioblastoma after prior radical chemo-radiotherapy or secondary glioblastoma after prior chemotherapy or radiotherapy. Patients must have measurable disease. Life expectancy ≥ 12 weeks Acceptable organ and marrow function at baseline (protocol defined laboratory parameters) Patients with advanced solid tumors must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 and patients with recurrent or progressive glioblastoma must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Other protocol-defined inclusion criteria may apply. Exclusion Criteria: Patients with advanced or recurrent 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 or progressive GBM or high-grade glioma 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. Patients who have had prior exposure to BAL1015533. Inability to swallow oral medication Increase in steroid dose in GBM or high-grade glioma patients within 5 days prior to first study-drug administration or requirement for > 6 mg/day dexamethasone or equivalent for symptom control. Patients with gastrointestinal disease or those who have had a procedure that is expected to interfere with the oral absorption or tolerance of BAL101553 Symptomatic brain metastases or leptomeningeal disease, indicative of active disease, in patients with advanced or recurrent solid tumors. 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) ≥ 160 mmHg or diastolic blood pressure (DBP) ≥ 100 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug: BAL101553<br>Oral daily administration of BAL101553 | Drug: Oral daily administration of BAL101553<br>* oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of daily oral BAL101553 based on the number of participants with adverse effects as measure of tolerability at various dose levels |  | 28 day cycles | 
| Phase 2a: Best objective response according to RANO criteria |  | 28 day cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of daily oral BAL101553 based on the number of participants with adverse events at various dose levels | Incidence of adverse events | 28 day cycles | 
| Safety and tolerability of daily oral BAL101553 based on the number of participants with safety laboratory changes versus baseline | Incidence of clinically relevant laboratory changes | 28 day cycles | 
| Safety and tolerability of daily oral BAL101553 based on the number of participants with ECG changes versus baseline | Incidence of clinically relevant ECG changes | 28 day cycles | 
| Cmax of BAL101553 and BAL27862 | Pharmacokinetic parameter Peak Plasma Concentration Cmax of BAL101553 and BAL27862 | 28 day cycles | 
| Tmax of BAL101553 and BAL27862 | Pharmacokinetic parameter Time to Peak Plasma Concentration Tmax of BAL101553 and BAL27862 | 28 day cycles | 
| AUC of BAL101553 and BAL27862 | Pharmacokinetic parameter Area under the plasma concentration versus time curve AUC of BAL101553 and BAL27862 | 28 day cycles | 
| Half-life of BAL101553 and BAL27862 | Pharmacokinetic parameter Half-life of BAL101553 and BAL27862 | 28 day cycles | 
| Anti-tumor activity of daily oral BAL101553 in cancer patients based on RECIST 1.1 -criteria (measurable disease of advanced or recurrent solid tumors). |  | 28 day cycles | 
| Anti-tumor activity of daily oral BAL101553 in cancer patients by contrast-enhanced MRI based on RANO criteria (recurrent or progressive GBM or high-grade glioma). |  | 28 day cycles |