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.


Purpose BAL101553, the prodrug of the microtubule-destabilizer BAL27862, previously showed signs of antitumor activity when administered as a 2-h infusion, but its use was limited by vascular toxicity. We investigated an alternative dosing strategy aimed at improving the safety profile of BAL101553. Methods This multicenter, open-label, Phase 1 dose-escalation study used a 3 + 3 design to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and antitumor activity of BAL101553 administered as a 48-h IV infusion on Days 1, 8, and 15 of a 28-day cycle. Patients received oral BAL101553 on Days 15-21 of cycle 2 to assess oral bioavailability. Results BAL101553 was well tolerated at doses up to ≤70 mg/m2. Three grade 3 DLTs occurred: hypotension (70 mg/m2), hyponatremia and neutropenia (both 90 mg/m2). The MTD for 48-h IV BAL101553 was 70 mg/m2. At this dose level, the AUC for BAL27862 was 8580 ng.h/mL and the Cmax was 144 ng/mL. No apparent dose-related effects on blood pressure were observed with 48-h BAL101553 IV infusion. BAL27862 oral bioavailability was >80%. Conclusions Continuous 48-h IV BAL101553 infusion achieved higher exposure of the BAL27862 active metabolite than a 2-h infusion at the RP2D and did not cause vascular toxicity. Clinicaltrials.gov registration: NCT02895360.

Keywords: BAL101553; Chemotherapy; Microtubule-targeting agent; Ovarian cancer.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Benzimidazoles / adverse effects
  • Benzimidazoles / blood
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / therapeutic use*
  • Female
  • Humans
  • Infusions, Intravenous
  • Male
  • Maximum Tolerated Dose
  • Microtubules
  • Middle Aged
  • Neoplasms / blood
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Oxadiazoles / adverse effects
  • Oxadiazoles / blood
  • Oxadiazoles / pharmacokinetics
  • Oxadiazoles / therapeutic use*
  • Prodrugs / adverse effects
  • Prodrugs / pharmacokinetics
  • Prodrugs / therapeutic use*
  • Treatment Outcome


  • Antineoplastic Agents
  • BAL27862
  • Benzimidazoles
  • Oxadiazoles
  • Prodrugs
  • lisavanbulin

Associated data

  • ClinicalTrials.gov/NCT02895360