Parallel phase Ib studies of two schedules of buparlisib (BKM120) plus carboplatin and paclitaxel (q21 days or q28 days) for patients with advanced solid tumors

Cancer Chemother Pharmacol. 2015 Apr;75(4):747-55. doi: 10.1007/s00280-015-2693-z. Epub 2015 Feb 12.

Abstract

Purpose: Phosphatidylinositol-3-kinase I (PI3K) inhibition sensitizes a wide range of cancer cell lines to platinum/taxane-based chemotherapy. This phase I study combines buparlisib, a pan-class 1A PI3K inhibitor, with two schedules of carboplatin and paclitaxel for patients with advanced solid tumors (ClinicalTrials.gov, NCT01297452).

Methods: There were two regimens: Group 1 received carboplatin AUC 5 and paclitaxel 175 mg/m(2), on day 1 of a 21-day cycle with pegfilgrastim support; Group 2 received carboplatin AUC 5 (day 1) and paclitaxel 80 mg/m(2) (days 1, 8, and 15) on a 28-day cycle without growth factor support. In both groups, three dose levels of buparlisib were explored: 50, 80, and 100 mg/day. Primary endpoint was to identify recommended phase II doses of buparlisib in both groups.

Results: Thirty subjects enrolled, 16 in Group 1 and 14 in Group 2. The DLTs were elevated alkaline phosphatase (n = 1) and uncomplicated neutropenia (n = 2). The median numbers of cycles were 5 (Group 1) and 6 (Group 2). The MTDs for buparlisib were 100 mg/day in Group 1 and 80 mg/day in Group 2. Among 25 patients with measurable disease, the confirmed objective response rate was 20% (one complete response, four partial responses). Among three patients with known loss of PTEN expression, all derived clinical benefit from treatment.

Conclusion: The addition of buparlisib to carboplatin + paclitaxel was well tolerated, and preliminary activity was notable against tumors with loss of PTEN expression.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aminopyridines / administration & dosage
  • Aminopyridines / adverse effects
  • Aminopyridines / pharmacokinetics
  • Aminopyridines / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carboplatin / administration & dosage
  • Carboplatin / adverse effects
  • Carboplatin / pharmacokinetics
  • Carboplatin / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Filgrastim
  • Granulocyte Colony-Stimulating Factor / administration & dosage
  • Granulocyte Colony-Stimulating Factor / adverse effects
  • Granulocyte Colony-Stimulating Factor / pharmacokinetics
  • Granulocyte Colony-Stimulating Factor / therapeutic use
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Morpholines / administration & dosage
  • Morpholines / adverse effects
  • Morpholines / pharmacokinetics
  • Morpholines / therapeutic use
  • Neoplasms / drug therapy*
  • Neoplasms / etiology
  • Neoplasms / pathology
  • Paclitaxel / administration & dosage
  • Paclitaxel / adverse effects
  • Paclitaxel / pharmacokinetics
  • Paclitaxel / therapeutic use
  • Phosphoinositide-3 Kinase Inhibitors
  • Polyethylene Glycols
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / pharmacokinetics
  • Recombinant Proteins / therapeutic use
  • Treatment Outcome
  • Young Adult

Substances

  • Aminopyridines
  • Morpholines
  • NVP-BKM120
  • Phosphoinositide-3 Kinase Inhibitors
  • Recombinant Proteins
  • Granulocyte Colony-Stimulating Factor
  • pegfilgrastim
  • Polyethylene Glycols
  • Carboplatin
  • Paclitaxel
  • Filgrastim

Associated data

  • ClinicalTrials.gov/NCT01297452