A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin

Our plain-English summary of A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin, by J.E. Gray, J.R. Infante, L.H. Brail, et al (Investigational New Drugs, 2015).

The study

• Authors: J.E. Gray, J.R. Infante, L.H. Brail, G.R. Simon, J.F. Cooksey, S.F. Jones, D.L. Farrington, A. Yeo, K.A. Jackson, K.H. Chow, M.J. Zamek-Gliszczynski, H.A. Burris
• Journal: Investigational New Drugs
• Published: 2015;33(6):1187-96
• Cited by: 67 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: LY2090314 (LY) is a glycogen synthase kinase 3 inhibitor with preclinical efficacy in xenograft models when combined with platinum regimens. A first-in-human phase 1 dose-escalation study evaluated the combination of LY with pemetrexed/carboplatin.

Patients And Methods: Forty-one patients with advanced solid tumors received single-dose LY monotherapy lead-in and 37 patients received LY (10-120 mg) plus pemetrexed/carboplatin (500 mg/m(2) and 5-6 AUC, respectively) across 8 dose levels every 21 days. Primary objective was maximum tolerated dose (MTD) determination; secondary endpoints included safety, antitumor activity, pharmacokinetics, and beta-catenin pharmacodynamics.

Results: MTD of LY with pemetrexed/carboplatin was 40 mg. Eleven dose-limiting toxicities (DLTs) occurred in ten patients. DLTs during LY monotherapy occurred at ≥ 40 mg: grade 2 visual disturbance (n = 1) and grade 3/4 peri-infusional thoracic pain during or shortly post infusion (n = 4; chest, upper abdominal, and back pain). Ranitidine was added after de-escalation to 80 mg LY to minimize peri-infusional thoracic pain. Following LY with pemetrexed/carboplatin therapy, DLTs included grade 3/4 thrombocytopenia (n = 4) and grade 4 neutropenia (n = 1). Best overall response by RECIST included 5 confirmed partial responses (non-small cell lung cancer [n = 3], mesothelioma, and breast cancer) and 19 patients having stable disease. Systemic LY exposure was approximately linear over dose range studied. Transient upregulation of beta-catenin measured in peripheral blood mononuclear cells (PBMCs) occurred at 40 mg LY.

Conclusions: The initial safety profile of LY2090314 was established. MTD LY dose with pemetrexed/carboplatin is 40 mg IV every 3 weeks plus ranitidine. Efficacy of LY plus pemetrexed/carboplatin requires confirmation in randomized trials.

In plain English

This was a first-in-human phase I trial, funded by Eli Lilly and Company. It tested an experimental drug, LY2090314, given by vein together with the chemotherapy drugs pemetrexed and carboplatin. Forty-one patients with advanced solid tumors were enrolled between November 2007 and February 2011. The most common tumor types were non-small cell lung cancer (24%) and mesothelioma (22%). The study did not examine asbestos exposure. Its main goal was to find the highest dose patients could tolerate. Ten patients had 11 dose-limiting side effects, including chest, back or upper abdominal pain around the time of infusion, visual disturbance, and low platelet counts. The maximum tolerated dose was 40 mg of LY2090314 with pemetrexed and carboplatin, plus ranitidine given beforehand. Of 35 patients who could be assessed, 5 had partial tumor shrinkage (three with non-small cell lung cancer, one with mesothelioma, one with breast cancer), 19 had stable disease and 11 had progressing disease. No deaths occurred during the study. The authors concluded that the drug's contribution to any benefit needs further evaluation, including randomized trials.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multicenter first-in-human phase I dose-escalation trial (standard 3+3 design) with a dose-confirmation cohort; analyses descriptive and exploratory
• Who was studied: 41 patients with advanced or metastatic solid tumors, enrolled November 2007 to February 2011. Median age was 59 years and 56% were male. The most common tumors were non-small cell lung cancer (10 patients, 24%) and mesothelioma (9 patients, 22%).
• Exposure: The experimental drug LY2090314 (a glycogen synthase kinase 3 inhibitor), given intravenously at 10 to 120 mg. It was combined with pemetrexed 500 mg/m2 and carboplatin AUC 5 or 6; later cohorts also received ranitidine premedication. Asbestos exposure was not studied.
• Main results:
  • The maximum tolerated dose was LY2090314 40 mg with pemetrexed 500 mg/m2 and carboplatin AUC 6, with ranitidine premedication.
  • Ten patients experienced 11 dose-limiting toxicities.
  • In the 120 mg cohort, 3 of 4 patients had dose-limiting toxicities during LY2090314 given alone: visual disturbance and peri-infusional thoracic pain.
  • With the three-drug combination, 36 of 37 patients (97.3%) had drug-related side effects. 22 patients (59.5%) had at least one grade 3/4 drug-related side effect, mainly blood-related.
  • 35 patients were evaluable for efficacy: 5 had partial responses, 19 had stable disease and 11 had progressive disease. Partial responses were in non-small cell lung cancer (3), mesothelioma and breast cancer.
  • Partial responses by tumor type, as reported in the article's summary.
  • 13 patients (31.7%) who received 6 or more cycles had extended clinical benefit (4 partial responses plus 9 stable disease).
  • No deaths occurred during the study period.
  • QTc (heart rhythm interval) changes occurred, but no measurements above 500 msec were reported. The changes were deemed clinically insignificant.
  • In four patients given 40 mg LY2090314 alone, beta-catenin in blood cells rose temporarily 4 to 8 hours after the dose and returned to baseline by 24 hours.
• The authors' conclusion: The authors concluded that the recommended dose is LY2090314 40 mg with ranitidine, given with pemetrexed/carboplatin. They stated that the drug's contribution to the clinical benefit observed requires further clinical evaluation, including a randomized trial.
• Limitations the authors state:
  • Few patients were treated with ranitidine premedication.
  • The small sample size prevents firm conclusions about whether LY2090314 increased blood-related side effects.
  • Beta-catenin data came only from the last few patients enrolled, which limited the sample size.
  • Pharmacokinetic data showed high variability.
  • Analyses were descriptive and exploratory only.

Topics

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Carboplatin, Neutropenia, Non-Small Cell Lung Cancer, Mesothelioma.

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