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

Primary Purpose

Neoplasms

Status

Completed

Phase

Phase 1

Locations

Switzerland

Study Type

Interventional

Intervention

BAL101553

BAL101553 at MTD

About this trial

This is an interventional treatment trial for Neoplasms

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Oncology Institute of Southern Switzerland; Ospedale Regionale San Giovanni Bellinzona e Valli
Inselspital Bern
Cantonal Hospital of Grisons, Department of Oncology/ Haematology
Centre Hospitalier Universitaire Vaudois
Cantonal Hospital of St. Gallen, Dep. Medical Oncology & Hematology
UniversitaetsSpital Zürich

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Phase 1

Phase 2a

Arm Description

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

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).

Cmax of BAL101553 and BAL27862

Pharmacokinetic parameter "Peak Plasma Concentration" Cmax of BAL101553 and BAL27862. Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862).

Tmax of BAL101553 and BAL27862

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

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)

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

Full Information

NCT ID

NCT02895360

First Posted

September 5, 2016

Last Updated

May 9, 2023

Sponsor

Basilea Pharmaceutica

1. Study Identification

Unique Protocol Identification Number

NCT02895360

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Completed

Study Start Date

August 24, 2016 (Actual)

Primary Completion Date

August 7, 2020 (Actual)

Study Completion Date

August 7, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Basilea Pharmaceutica

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Neoplasms

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

43 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Phase 1

Arm Type

Experimental

Arm Description

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

Arm Title

Phase 2a

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

BAL101553

Intervention Description

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)

Intervention Type

Drug

Intervention Name(s)

BAL101553 at MTD

Intervention Description

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

Primary Outcome Measure Information:

Title

Maximum Tolerated Dose (MTD) of BAL101553

Description

Time Frame

28 day cycle

Secondary Outcome Measure Information:

Title

Description

Time Frame

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

Title

AUC of BAL101553 and BAL27862

Description

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

Title

Cmax of BAL101553 and BAL27862

Description

Pharmacokinetic parameter "Peak Plasma Concentration" Cmax of BAL101553 and BAL27862. Lisavanbulin (BAL101553) is the prodrug of avanbulin (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.

Title

Tmax of BAL101553 and BAL27862

Description

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

Time Frame

Title

Bioavailability of Daily Oral BAL101553 Measured by BAL27862 in Phase 1

Description

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

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.

Title

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

Description

Time Frame

28 day cycles

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Thomas Kaindl, MD

Organizational Affiliation

Basilea Pharmaceutica

Official's Role

Study Director

Facility Information:

Facility Name

Oncology Institute of Southern Switzerland; Ospedale Regionale San Giovanni Bellinzona e Valli

City

Bellinzona

ZIP/Postal Code

6500

Country

Switzerland

Facility Name

Inselspital Bern

City

Bern

ZIP/Postal Code

3010

Country

Switzerland

Facility Name

Cantonal Hospital of Grisons, Department of Oncology/ Haematology

City

Chur

ZIP/Postal Code

7000

Country

Switzerland

Facility Name

Centre Hospitalier Universitaire Vaudois

City

Lausanne

ZIP/Postal Code

1011

Country

Switzerland

Facility Name

Cantonal Hospital of St. Gallen, Dep. Medical Oncology & Hematology

City

St. Gallen

ZIP/Postal Code

9007

Country

Switzerland

Facility Name

UniversitaetsSpital Zürich

City

Zürich

ZIP/Postal Code

8091

Country

Switzerland

12. IPD Sharing Statement

Citations:

PubMed Identifier

31471863

Citation

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.

Results Reference

derived

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

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