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

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

First in human, open-label, dose escalation (Phase I) and expansion study (Phase 2a) of oral lisavanbulin (BAL101553) in adult patients with advanced solid tumors and adult patients with recurrent or progressive glioblastoma (GBM) or high-grade glioma (HGG).

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: Lisavanbulin Phase 1 dose escalation portion; Drug: Lisavanbulin Phase 2a expansion portion

Detailed Description

This was the first study of the oral formulation (hard capsules) of lisavanbulin. Lisavanbulin was administered once daily during each day of a 28-day treatment cycle to adults with advanced or recurrent solid tumors or recurrent or progressive GBM / HGG who had failed standard therapy, or for whom no effective standard therapy was available.

In Phase 1, the highest dose of lisavanbulin was determined that could safely be given to adults with advanced or recurrent solid tumors, recurrent or progressive GBM / HGG.

In Phase 2a, the tolerability and potential anticancer activity of oral lisavanbulin was assessed in patients with recurrent GBM whose tumor tissue tests positive for end-binding protein 1 (EB1). The study also measured pharmacokinetics.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven
• Germany
  • Frankfurt, Germany, 60528
    • Klinikum der Goethe-Universität Frankfurt
  • Heidelberg, Germany, 69120
    • Universitatsklinikum Heidelberg
  • Regensburg, Germany, 93053
    • Universitätsklinikum Regensburg
  • Tübingen, Germany, 72076
    • Universitätsklinikum Tübingen
• Switzerland
  • Basel, Switzerland, 4031
    • Universitätsspital Basel
  • Bern, Switzerland, 3010
    • Inselspital Universitatsspital Bern
  • St. Gallen, Switzerland, 9007
    • Kantonsspital St. Gallen
  • Zürich, Switzerland, 8091
    • UniversitätsSpital Zürich
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Beatson West of Scotland Cancer Centre
  • London, United Kingdom, NW1 2BU
    • University College London NHS Foundation Trust
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Sir Bobby Robson Cancer Trials Research Centre; Northern Centre for Cancer Care
  • Sutton, United Kingdom, SM2 5PT
    • Royal Marsden Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Main Inclusion Criteria:

1. Age ≥ 18 years

2. Patients who had in the Phase 1 portion either of the following:

   1. a histologically- or cytologically confirmed advanced or recurrent solid tumor, who failed standard therapy, or for whom no effective standard therapy was available to them
   2. histologically-confirmed GBM or HGG, with progressive or recurrent disease after prior radiotherapy, with or without chemotherapy. This also included patients with histologically-confirmed low-grade glioma who presented with unequivocal evidence by imaging of transformation to GBM / HGG

   Phase 2a dose expansion portion:

   Recurrent, histologically confirmed, glioblastoma with tumor tissue positive for EB1; eligible patients with de novo glioblastoma after prior radical chemo-radiotherapy or secondary glioblastoma after prior chemotherapy or radiotherapy.

3. Phase 1: Patients had to have measurable disease; according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria v1.1 for patients with advanced or recurrent solid tumors, and per radiological assessment in neuro-oncology (RANO) criteria for patients with recurrent or progressive GBM /HGG. Phase 2a: Patients had to be evaluable per RANO criteria.
4. Life expectancy ≥ 12 weeks
5. Acceptable organ and marrow function at baseline (protocol defined laboratory parameters)
6. Patients with advanced solid tumors had to have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 and patients with recurrent or progressive glioblastoma had to have an ECOG performance status ≤ 2

Main Exclusion Criteria:

1. Patients with advanced or recurrent solid tumors who had received chemotherapy, radiotherapy, immunotherapy, or investigational agents within 4 weeks (2 weeks for single fraction of palliative radiotherapy, 6 weeks for nitrosoureas or mitomycin C) prior to starting study drug or who had not recovered from side effects of prior therapies

   Patients with recurrent or progressive GBM / HGG who had: received radiotherapy within 6 weeks (Phase 1) or 12 weeks (Phase 2a), unless there was a new area of enhancement consistent with recurrent tumor outside the radiation field; received administration of prior anti-tumor chemotherapy within 4 weeks, or within 6 weeks for nitrosoureas; undergone surgical resection within 4 weeks (Phase 2a: 2 weeks) or a stereotactic biopsy/core biopsy within 1 week prior to starting study drug;

2. Patients who have had prior exposure to lisavanbulin
3. Inability to swallow oral medication
4. Increase in steroid dose in GBM or HGG patients within 5 days prior to first study-drug administration or requirement for > 6 mg/day dexamethasone or equivalent for symptom control.
5. Patients with gastrointestinal disease or those who have had a procedure that was expected to interfere with the oral absorption or tolerance of lisavanbulin
6. Symptomatic brain metastases or leptomeningeal disease, which was indicative of active disease, in patients with advanced or recurrent solid tumors.
7. Peripheral neuropathy ≥ CTCAE grade 2.
8. Uncontrolled intercurrent illness that would have unduly increased the risk of toxicity or limit compliance with study requirements
9. Systolic blood pressure (SBP) ≥ 160 mmHg or diastolic blood pressure (DBP) ≥ 100 mmHg at the screening visit.
10. Blood pressure (BP) combination treatment with more than two antihypertensive medications.
11. Women who were pregnant or breast-feeding. Men or women of reproductive potential who were not willing to apply effective birth control

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 dose escalation portion; Phase 1 dose escalation portion - an accelerated 3+3 titration design in patients with: advanced or recurrent solid tumors; recurrent or progressive GBM / HGG	Drug: Lisavanbulin Phase 1 dose escalation portion; Lisavanbulin hard capsules, containing 1 mg or 5 mg study drug, were given orally to fasted patients once daily in the dose range of 2 to 35 mg/day; Other Names: BAL101553
Experimental: Phase 2a dose expansion portion; Phase 2a expansion portion (Simon's two-stage design) - Patients with recurrent and EB1-positive GBM	Drug: Lisavanbulin Phase 2a expansion portion; Recommended Phase 2 dose (RP2D) of 25 mg/day lisavanbulin hard capsules containing 5 mg study drug was administered once daily.; Other Names: BAL101553

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Maximum Tolerated Dose (MTD) of Daily Oral Lisavanbulin	First 28-day treatment cycle dose limiting toxicities (DLT) graded according to Common Terminology Criteria for Adverse Events (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	During first 28 day cycle
Phase 2a: Best Objective Response	The best objective response was calculated as the proportion of patients responding (i.e., with a best observed objective response of complete or partial response) based on "radiological assessment in neuro-oncology (RANO)" criteria	Until the study discontinuation, on average 161 days (maximum of 381 days)
Phase 2a: Objective Response Rate (ORR)	The ORR was calculated as the percentage of patients (rate) with complete and partial responses and its 95% Confidence Interval (CI) based on RANO criteria	Until the study discontinuation, on average 161 days (maximum of 381 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With CTCAE Grade 3-4 TEAEs	Number of patients experiencing treatment-emergent adverse events (TEAE) of CTCAE Grade 3 or 4	TEAEs were defined as all events occurring after lisavanbulin treatment began and up to 28 days after last study drug administration which corresponded to a maximum of 1653 days (4,5 years)
Cmax of Avanbulin (BAL27862)	Pharmacokinetic parameter "Peak Plasma Concentration" Cmax of avanbulin Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862)	Plasma PK profiles were obtained on Cycle 1, Day 1 and on Cycle 2, Day 1 (pre-dose and from 0 up to 24 h post-dose) for all patients in the Phase 1 study who received lisavanbulin. For Phase 2 a study, PK parameters were obtained only on Cycle 1, Day 1
Tmax of Avanbulin (BAL27862)	Pharmacokinetic parameter "Time to Peak Plasma Concentration" Tmax of avanbulin (BAL27862) Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862).	Plasma PK profiles were obtained on Cycle 1, Day 1 and on Cycle 2, Day 1 (pre-dose and from 0 up to 24 h post-dose) for all patients in the Phase 1 study who received lisavanbulin. For Phase 2 a study, PK parameters were obtained only on Cycle 1, Day 1
AUC of Avanbulin (BAL27862)	Pharmacokinetic parameter "Area under the plasma concentration versus time curve" AUC of avanbulin (BAL27862) Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862).	Plasma PK profiles were obtained on Cycle 1, Day 1 and on Cycle 2, Day 1 (pre-dose and from 0 up to 24 h post-dose) for all patients in the Phase 1 study who received lisavanbulin. For Phase 2 a study, PK parameters were obtained only on Cycle 1, Day 1
Phase 1: Best Objective Response	The best objective response was calculated as the proportion of patients responding (i.e., with a best observed objective response of complete response (CR) or partial response (PR), according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria v1.1 for patients with advanced or recurrent solid tumors); and based on RANO criteria for patients with recurrent or progressive GBM / HGG	Until the end of treatment, on average 151 days (maximum of 1653 days), every other 28 day cycle
Phase 1: Objective Response Rate (ORR)	The ORR was calculated as the percentage of patients (rate) with complete and partial responses and its 95% CI based on RECIST criteria v1.1 for patients with advanced or recurrent solid tumors; and based on RANO criteria for patients with recurrent or progressive GBM / HGG	Until the study discontinuation, on average 151 days (maximum 1653 days), every other 28 day cycle
Phase 2a: PFS	PFS was defined as the interval between the date of drug administration and the earliest date of objective disease progression based on RANO criteria for patients with recurrent or progressive GBM / HGG. Patients who have not progressed or died at the end of the study were censored at the time of their latest objective tumor assessment.	1 year
Phase 2a: PFS at 6 Months	Percentage of patients without disease progression based on RANO criteria 6 months after the start of treatment. The values were determined using the Kaplan-Meier and Brookmeyer-Crowley methods.	6 months
Phase 2a: Overall Survival (OS) at 12 Months	Percentage of patients alive 12 months after the start of treatment. The values were determined using the Kaplan-Meier and Brookmeyer-Crowley methods.	1 year

Collaborators and Investigators

• Sponsor: Basilea Pharmaceutica
• Investigators: Study Director: Thomas Kaindl, MD, Basilea Pharmaceutica International Ltd, Allschwil

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2015
• Primary Completion (Actual): September 30, 2022
• Study Completion (Actual): November 24, 2022

Study Registration Dates

• First Submitted: June 25, 2015
• First Submitted That Met QC Criteria: July 2, 2015
• First Posted (Estimated): July 7, 2015

Study Record Updates

• Last Update Posted (Actual): June 26, 2024
• Last Update Submitted That Met QC Criteria: June 25, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Recurrent glioblastoma; Advanced solid tumors; High-grade glioma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Glioma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Lisavanbulin
• Other Study ID Numbers: CDI-CS-002