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

• ClinicalTrials.gov Identifier: NCT02895360
• Recruitment Status: Completed
• First Posted: September 9, 2016
• Results First Posted: October 11, 2021
• Last Update Posted: December 1, 2022
• Sponsor: Basilea Pharmaceutica
• Information provided by (Responsible Party): Basilea Pharmaceutica

Tracking Information

• First Submitted Date: September 5, 2016
• First Posted Date: September 9, 2016
• Results First Submitted Date: August 5, 2021
• Results First Posted Date: October 11, 2021
• Last Update Posted Date: December 1, 2022
• Actual Study Start Date: August 24, 2016
• Actual Primary Completion Date: August 7, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 14, 2021)

Maximum Tolerated Dose (MTD) of BAL101553 [ Time Frame: 28 day cycle ]

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

Original Primary Outcome Measures (submitted: September 5, 2016)

To determine the maximum tolerated dose and characterize dose limiting toxicities of BAL101553 based on the number of participants with adverse effects as measure of tolerability at various dose levels [ Time Frame: 28 day cycles ]

First 28-day treatment cycle dose limiting toxicities (DLT) graded according to CTCAE

Current Secondary Outcome Measures (submitted: September 14, 2021)

• 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 [ Time Frame: TEAEs with onset on or after Day 1 of the study and until 28 days after the last dose ]
  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
• AUC of BAL101553 and BAL27862 [ Time Frame: 0 to 168 hours post-dose at Day 1 of Cycle 1 and Cycle 2 in each cohort in Phase 1, 28-day cycles ]
  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).
• Cmax of BAL101553 and BAL27862 [ Time Frame: 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. ]
  Pharmacokinetic parameter "Peak Plasma Concentration" Cmax of BAL101553 and BAL27862. Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862).
• Tmax of BAL101553 and BAL27862 [ Time Frame: 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. ]
  Pharmacokinetic parameter "Time to Peak Plasma Concentration" Tmax of BAL101553 and BAL27862
• Bioavailability of Daily Oral BAL101553 Measured by BAL27862 in Phase 1 [ Time Frame: 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. ]
  Ratio of AUCs of avanbulin after oral and IV administration (relative bioavailability) of BAL101553 (lisavanbulin) which is the prodrug of avanbulin (BAL27862)
• Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria [ Time Frame: 28 day cycles ]
  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

Original Secondary Outcome Measures (submitted: September 5, 2016)

• To evaluate safety and tolerability of BAL101553 treatment based on the number of participants with adverse events at various dose levels [ Time Frame: 28 day cycles ]
  Incidence of adverse events
• To evaluate safety and tolerability of BAL101553 treatment based on the number of participants with safety laboratory changes versus baseline [ Time Frame: 28 day cycles ]
  Incidence of clinically relevant laboratory changes
• To evaluate safety and tolerability of BAL101553 treatment based on the number of participants with ECG changes versus baseline [ Time Frame: 28 day cycles ]
  Incidence of clinically relevant ECG changes
• BAL101553 and BAL27862 pharmacokinetics (PK) [ Time Frame: 28 day cycles ]
  Pharmacokinetic parameter "Peak Plasma Concentration" Cmax of BAL101553 and BAL28762
• BAL101553 and BAL27862 pharmacokinetics (PK) [ Time Frame: 28 day cycles ]
  Pharmacokinetic parameter "Time to Peak Plasma Concentration" Tmax of BAL101553 and BAL28762
• BAL101553 and BAL27862 pharmacokinetics (PK) [ Time Frame: 28 day cycles ]
  Pharmacokinetic parameter "Area under the plasma concentration versus time curve" AUC of BAL101553 and BAL28762
• BAL101553 and BAL27862 pharmacokinetics (PK) [ Time Frame: 28 day cycles ]
  Pharmacokinetic parameter systemic clearance
• BAL101553 and BAL27862 pharmacokinetics (PK) [ Time Frame: 28 day cycles ]
  Pharmacokinetic parameter volume of distribution
• To assess the anti-tumor activity of BAL101553 [ Time Frame: 28 day cycles ]
  Response rate per RECIST guidelines
• To assess the bioavailability of daily oral BAL101553 [ Time Frame: One week during Cycle 2 ]
• Exploratory assessment of baseline levels and change from baseline of circulating tumor cells and other biomarkers to characterize pharmacodynamic effects of daily oral BAL101553 [ Time Frame: 28 day cycles ]
• Exploratory assessment of baseline levels and change from baseline of circulating tumor cells and other biomarkers in blood and/or tumor tissue for potential utility as predictive biomarkers. [ Time Frame: 28 day cycles ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase 1/2a Study of BAL101553 as 48-hour Infusions in Patients With Advanced Solid Tumors or Recurrent Glioblastoma
• Official Title: 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
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Neoplasms

Intervention

• Drug: BAL101553
  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)
• Drug: BAL101553 at MTD
  BAL101553 48-hour infusion on day 1, 8, and 15 of each 28-day cycle; treatment with maximum tolerated dose (MTD)

Study Arms

• Experimental: Phase 1
  Fixed 3+3 dose escalation of BAL101553 in patients with advanced solid tumors
  Intervention: Drug: BAL101553
• Experimental: Phase 2a
  BAL101553 at MTD in patients with platinum-resistant/refractory ovarian cancer or recurrent glioblastoma
  Intervention: Drug: BAL101553 at MTD

• Publications *: Joerger M, Stathis A, Metaxas Y, Hess D, Mantiero M, Mark M, Volden M, Kaindl T, Engelhardt M, Larger P, Lane H, Hafner P, Levy N, Stuedeli S, Sessa C, von Moos R. A Phase 1 study of BAL101553, a novel tumor checkpoint controller targeting microtubules, administered as 48-h infusion in adult patients with advanced solid tumors. Invest New Drugs. 2020 Aug;38(4):1067-1076. doi: 10.1007/s10637-019-00850-z. Epub 2019 Aug 30.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 16, 2019): 43
• Original Estimated Enrollment (submitted: September 5, 2016): 82
• Actual Study Completion Date: August 7, 2020
• Actual Primary Completion Date: August 7, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age ≥ 18 years

2. 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.

3. 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.

4. Life expectancy ≥ 12 weeks
5. Acceptable organ and marrow function at baseline (protocol defined laboratory parameters)
6. 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.
7. Other protocol-defined inclusion criteria may apply.

Exclusion Criteria:

1. 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.

2. Patients who have had prior exposure to BAL101553.
3. Peripheral neuropathy ≥ CTCAE grade 2.
4. Uncontrolled intercurrent illness that would unduly increase the risk of toxicity or limit compliance with study requirements
5. Systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg at the screening visit.
6. Blood pressure (BP) combination treatment with more than two antihypertensive medications.
7. Women who are pregnant or breast-feeding. Men or women of reproductive potential who are not willing to apply effective birth control.
8. Other protocol-defined exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Switzerland

Administrative Information

• NCT Number: NCT02895360
• Other Study ID Numbers: CDI-CS-003
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Basilea Pharmaceutica
• Original Responsible Party: Same as current
• Current Study Sponsor: Basilea Pharmaceutica
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Thomas Kaindl, MD; Basilea Pharmaceutica

• PRS Account: Basilea Pharmaceutica
• Verification Date: November 2022