A phase I pilot study of the insulin-like growth factor 1 receptor pathway modulator AXL1717 in combination with gemcitabine HCl and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer

Med Oncol. 2015 Apr;32(4):129. doi: 10.1007/s12032-015-0578-y. Epub 2015 Mar 21.

Abstract

AXL1717 is an orally bioavailable IGF-1R pathway modulator that has been shown to have anti-tumoral effects. The objectives of the present study were to define maximum tolerated dose and the recommended phase II dose (RPTD) of AXL1717 in combination with gemcitabine HCl and carboplatin in non-small cell lung cancer (NSCLC). Patients with previously untreated, locally advanced, or metastatic NSCLC (squamous cell cancer or adenocarcinoma) in good performance status and with preserved major organ functions were enrolled in the study. The study was an open-label phase I study with planned cohorts of three patients per dose level of AXL1717 (215, 290, and 390 mg BID). In total, 12 patients were enrolled in the study, and of these, two were prematurely excluded. AXL1717 was administered at one dose level, 215 mg BID. A total number of 81 unique adverse events were reported. Bone marrow toxicity was reported in 10 out of 12 patients, and this organ class showed the largest number of related events. AXL1717 in combination with gemcitabine HCl and carboplatin is a possible treatment approach in previously untreated, locally advanced, or metastatic non-small cell lung cancer. However, due to the bone marrow toxicity profile shown in the present study, further dose increases of AXL1717 above 215 mg BID will probably not be feasible. Therefore, 215 mg BID constitutes maximum tolerated dose and RPTD.

Publication types

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

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / secondary
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carboplatin / administration & dosage
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / secondary
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / secondary
  • Cohort Studies
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Female
  • Follow-Up Studies
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Lymphatic Metastasis
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasm Staging
  • Pilot Projects
  • Podophyllotoxin / analogs & derivatives*
  • Podophyllotoxin / pharmacokinetics
  • Podophyllotoxin / therapeutic use
  • Prognosis
  • Receptor, IGF Type 1 / metabolism*
  • Tissue Distribution

Substances

  • picropodophyllin
  • Deoxycytidine
  • gemcitabine
  • Carboplatin
  • Receptor, IGF Type 1
  • Podophyllotoxin