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Lisavanbulin

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Fixed 3+3 dose escalation of BAL101553 in patients with advanced solid tumors

BAL101553 at MTD in patients with platinum-resistant/refractory ovarian cancer or recurrent glioblastoma

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)

BAL101553

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

BAL101553 at MTD

Thomas Kaindl, MD

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.

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.

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

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

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

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

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).

Pharmacokinetic parameter "Peak Plasma Concentration" Cmax of BAL101553 and BAL27862.

Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862).

Pharmacokinetic parameter "Time to Peak Plasma Concentration" Tmax of BAL101553 and BAL27862

Ratio of AUCs of avanbulin after oral and IV administration (relative bioavailability) of BAL101553 (lisavanbulin) which is the prodrug of avanbulin (BAL27862)

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

Basilea Pharmaceutica

TEAEs with onset on or after Day 1 of the study and until 28 days after the last dose.

BAL101553 30 mg/m² intravenously over 48 hours on Days 1, 8 and 15 of each (at least one) 28-day treatment cycle. During cycle 2, oral BAL101553 was administered on study days 15-21. The oral dose was selected to match the weekly IV dose of 30 mg/m².

Phase 1 - 30 mg/m² Cohort

BAL101553 45 mg/m² intravenously over 48 hours on Days 1, 8 and 15 of each (at least one) 28-day treatment cycle. During cycle 2, oral BAL101553 was administered on study days 15-21. The oral dose was selected to match the weekly IV dose of 45 mg/m².

Phase 1 - 45 mg/m² Cohort

BAL101553 70 mg/m² intravenously over 48 hours on Days 1, 8 and 15 of each (at least one) 28-day treatment cycle. During cycle 2, oral BAL101553 was administered on study days 15-21. The oral dose was selected to match the weekly IV dose of 70 mg/m².

Phase 1 - 70 mg/m² Cohort

BAL101553 90 mg/m² intravenously over 48 hours on Days 1, 8 and 15 of each (at least one) 28-day treatment cycle. During cycle 2, oral BAL101553 was administered on study days 15-21. The oral dose was selected to match the weekly IV dose of 90 mg/m².

Phase 1 - 90 mg/m² Cohort

BAL101553 at 70 mg/m² (MTD) BAL101553 48-hour infusion on day 1, 8, and 15 of each 28-day cycle

Phase 2a - Ovarian Cancer Cohort

Phase 2a - Recurrent Glioblastoma Cohort

30 mg/m² Cohort

45 mg/m² Cohort

70 mg/m² Cohort

90 mg/m² Cohort

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Switzerland

Region of Enrollment

Thomas Kaindl, MD, Global Medical Director, Oncology

All patients meeting the criteria of the MTD-determining population in Phase 1 during the first 28-day treatment cycle with intravenous BAL101553 at doses of 30, 45, 70 and 90 mg/m²

MTD-determining Population in Phase 1

MTD-determining population in Phase 1: All patients who meet the following minimum criteria during the first 28-day treatment cycle (Cycle 1)

* received at least one partial or complete dose of BAL101553 and has experienced a DLT;
* received all three doses of BAL101553 without experiencing a DLT (including the ability to initiate treatment Cycle 2), have been observed for ≥ 28 days following the first dose, and have been evaluated for safety.

Maximum Tolerated Dose (MTD) of BAL101553

Patients with ≥1 related AE

Patients with CTCAE Grade 3/4 or severe related AE

Patients with ≥1 related serious AE

BAL101553 at 70 mg/m² (MTD)

BAL101553 48-hour infusion on day 1, 8, and 15 of each 28-day cycle

All patients who receive at least one full or partial dose of BAL101553 and had at least one post-baseline safety assessment is included in the safety analysis population.

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

BAL27862

30 mg/m² Cycle 1 Day 1

30 mg/m² Cycle 2 Day 1

45 mg/m² Cycle 1 Day 1

45 mg/m² Cycle 2 Day 1

70 mg/m² Cycle 1 Day 1

70 mg/m² Cycle 2 Day 1

90 mg/m² Cycle 1 Day 1

90 mg/m² Cycle 2 Day 1

The PK analysis set includes all patients who received at least one partial or complete dose of study drug and had at least one post-baseline PK assessment.

AUC of BAL101553 and BAL27862

Cmax of BAL101553 and BAL27862

Tmax of BAL101553 and BAL27862

Patients with both Cycle 1 Day 1 AUC0-∞ and Cycle 2 Day 1 AUC0-τ evaluations

30 mg/m²

45 mg/m²

70 mg/m²

90 mg/m²

Bioavailability of Daily Oral BAL101553 Measured by BAL27862 in Phase 1

All dose cohorts (30 mg/m², 45 mg/m², 70 mg/m² and 90 mg/m²) of BAL101553 in patients with advanced solid tumors

BAL101553 48-hour infusion on day 1, 8, and 15 of each 28-day cycle; oral capsule daily for one week during Cycle 2

Phase 1- in the FAP

Phase 2a - Patients With Ovarian Cancer in the FAP

Phase 2a - Patients With Ovarian Cancer in the EEP

Phase 2a - Patients With Recurrent Glioblastoma in the FAP

Phase 2a - Patients With Recurrent Glioblastoma in the EEP

FAP:

Patients who receive at least one partial or complete dose of BAL101553.

EEP:

Patients with progressive disease who completed at least Cycle 1 dosing and at least one on-study tumor assessment (clinical or radiological by RECIST v1.1 or RANO criteria) Patients with stable disease, partial or complete response, based on a radiological assessment by RECIST v1.1 or RANO criteria at the end of Cycle 2, with at least 4 doses of study drug in the first two cycles.

Anti-tumor Activity of BAL101553 by Best Response Rate Per RECIST / RANO Criteria

BAL101553 at 70 mg/m² (MTD)

BAL101553 as 48-hour infusion on day 1, 8, and 15 of each 28-day cycle

Spots Global Cancer Trial Database for bal101553 at mtd