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A first-in-human (FIH) dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenous BAL101553, a novel microtubule inhibitor, in adult patients with advanced solid tumors.
Journal article

A first-in-human (FIH) dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenous BAL101553, a novel microtubule inhibitor, in adult patients with advanced solid tumors.

  • Calvert, Alan Hilary University College London, London, United Kingdom
  • Gonzalez, Michael The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
  • Ganguli, Sushila University College London Hospitals NHS Foundation Trust, london, United Kingdom
  • Ng, Matthew The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
  • Benafif, Sarah University College London Hospitals NHS Foundation Trust, London, United Kingdom
  • Capelan, Marta The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
  • Goldstein, Robert University College London Hospitals NHS Foundation Trust, London, United Kingdom
  • Shah, Krunal The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
  • Jarvis, Claire University College London Hospitals NHS Foundation Trust, London, United Kingdom
  • Flynn, Michael University College London, London, United Kingdom
  • Forster, Martin University College London, London, United Kingdom
  • Anderson, Stephanie Basilea Pharmaceutica International Ltd, Basel, Switzerland
  • Schmitt-Hoffman, Anne Basilea Pharmaceutica International Ltd, Basel, Switzerland
  • Lane, Heidi Basilea Pharmaceutica International Ltd., Basel, Switzerland
  • Engelhardt, Marc Basilea Pharmaceutica International Ltd, Basel, Switzerland
  • Hannah, Alison L. Consultant, Sebastopol, CA
  • Tzankov, Alexandar Institute of Pathology, University Hospital Basel, Basel, Switzerland
  • Bachmann, Felix Basilea Pharmaceutica International Ltd., Basel, Switzerland
  • Molife, L Rhoda The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
  • Kristeleit, Rebecca University College London, London, United Kingdom
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Published in:
  • Journal of Clinical Oncology. - American Society of Clinical Oncology (ASCO). - 2013, vol. 31, no. 15_suppl, p. 2566-2566
Cancer Research
Oncology
English 2566 Background: BAL101553, a pro-drug of the small molecule BAL27862, is a novel microtubule targeting agent (MTA) with cytotoxic and vascular disrupting properties. Pre-clinical data showed anti-proliferative activity in several in vitro and xenograft tumour models, including tumours refractory to conventional MTAs through diverse resistance mechanisms. Primary objectives of this FIH study were determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included the evaluation of PK, PD and anti-tumour activity. Methods: An accelerated titration dose-escalation design was used. Eligible patients (pts) with advanced solid tumours, who had failed standard therapy, received BAL101553 as a 2-h intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Adverse events (AEs) were assessed according to CTCAEv4. Disease response was assessed by RECIST 1.1 every 2 cycles. Results: 16 pts (7 male; median age 52 years; range 29-80) with solid tumours were treated at 4 dose levels (15, 30, 45 and 60 mg/m2). DLTs were observed at 60 mg/m2 and included rapidly reversible grade (G) 3 hypertension (HTN) and G3 reduced mobility/ dizziness. DLT criteria for HTN were subsequently modified. Frequent drug-related AEs were injection site reactions, nausea, vomiting (all G1-2), and G2-3 HTN (transient during the infusion; responding to nifedipine). One pt experienced G2 peripheral neuropathy at 60 mg/m2. PK analyses indicated conversion of BAL101553 to the active BAL27862, dose proportional exposure for both compounds and a half-life of BAL27862 in a range of 11 to 27 h. Preliminary tumour PD data comparing pre/post biopsies showed loss of CD34+ capillaries and focally decreased proliferation. A confirmed partial response was demonstrated in 1 pt with ampullary (pancreaticobiliary) cancer maintained on treatment for >16 cycles with intra-pt dose escalation. 2 pts (laryngeal and rectal cancer) demonstrated stable disease >16 weeks. Conclusions: BAL101553 is well tolerated up to 60 mg/m2 with evidence of anti-tumour activity. Dose escalation continues to determine the MTD. Clinical trial information: NCT01397929.
Language
  • English
Open access status
closed
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Persistent URL
https://sonar.ch/global/documents/81746
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