A phase 1 study of OSI-930 in combination with erlotinib in patients with advanced solid tumours

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Abstract

Aim

To determine the maximum tolerated dose (MTD) of OSI-930 that can be combined with erlotinib, and establish recommended phase 2 doses when both agents are administered daily in patients with advanced solid tumours.

Patients and methods

Eligible patients with advanced solid tumours were enrolled into this standard “three + three” dose escalation study. Study treatment commenced on day 1 with OSI-930, and erlotinib was introduced on day 8. PK profiles of OSI-930, erlotinib and its active metabolite, OSI-420, were determined. Changes in sVEGFR2 as a pharmacodynamic biomarker of OSI-930 activity were assessed.

Results

Twenty one patients were enrolled to 1 of 3 cohorts: 200 mg OSI-930 BID + 100 mg erlotinib QD; 200 mg OSI-930 BID + 150 mg erlotinib QD; 300 mg OSI-930 BID + 150 mg erlotinib QD. The most common adverse events were anorexia (85%), diarrhoea (75%), rash (70%) and lethargy (65%). The MTD was not reached but the onset of cumulative toxicity necessitating dose modification after the 28-d DLT assessment period was common at the highest dose level. A PK interaction was identified with co-administration of both agents resulting in a two-fold increase in OSI-930 exposure. Pharmacodynamic activity was observed with a decline in sVEGFR levels detected in all patients. Ten patients had disease stabilization (median duration 119 d).

Conclusions

200 mg OSI-930 BID + 150 mg erlotinib QD were the recommended doses for further evaluation of this combination.

Introduction

Extensive cross-talk between the vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) receptor signalling pathways provides a rationale for combined inhibition of these receptor tyrosine kinases.1, 2, 3, 4, 5, 6, 7, 8 However, the results of recent phase III trials evaluating dual targeting of VEGF and EGFR signalling in colorectal cancer and non-small cell lung cancer (NSCLC) have been disappointing9, 10, 11, 12, 13, 14, 15 and the optimal agent, disease setting, and patient selection for this approach remain uncertain.

OSI-930 is a novel small molecule tyrosine kinase inhibitor with potent activity against vascular endothelial growth factor receptor 2 (VEGFR2)/kinase insert domain receptor (KDR), c-Kit and platelet-derived growth factor receptor (PDGFR).16, 17 Dose limiting toxicities for OSI-930 monotherapy included grade 3 rash, myalgia, fatigue, raised lipase and grade 4 raised gamma glutamyl transferase whilst common grade 1/2 toxicities included rash, fatigue, diarrhoea, nausea and anorexia.17 In preclinical studies the combination of OSI-930 and erlotinib, a selective EGFR kinase inhibitor, demonstrated enhanced efficacy compared to either agent alone.18 The primary objective of this study was therefore to determine the maximum tolerated dose (MTD) of OSI-930 that could be combined with erlotinib and to establish recommended doses of both agents when administered in combination.

Section snippets

Patients and eligibility criteria

This was a phase I, multi-centre dose-escalation study of OSI-930 and erlotinib, co-administered orally in patients with advanced solid tumours. The study was conducted in accordance with the principles of International conference on harmonisation good clinical practice (ICH GCP) and approved by the Research Ethics Committee at each institution.

Eligible patients had a pathologically confirmed advanced solid malignancy, refractory to conventional therapy; age ⩾18; life expectancy ⩾12 weeks;

Patient characteristics

Twenty-one patients were enrolled in three treatment cohorts (Table 1). One patient in cohort 2 experienced rapid disease progression and did not receive either study drug. The median duration of treatment was 77 (range 7–176) days with one patient continuing study treatment at the time of study data closure. Patient characteristics are summarised in Table 2.

Dose limiting toxicity

All 20 patients who received at least one dose of OSI-930 were evaluable for safety, whilst 18 patients were evaluable for dose-limiting

Discussion

Defining the MTD has been the standard approach for determining the recommended starting dose of a cytotoxic agent which is then usually administered intermittently and for a defined treatment course. However, cumulative toxicity is an important consideration in determining the recommended doses of agents that are administered in protracted oral daily schedules, often until disease progression. In this phase 1 trial DLTs included grade 4 neutropenia and grade 3 lethargy/asthenia, but no

Funding

This study was supported by OSI Pharmaceuticals LLC. The Glasgow Experimental Cancer Medicine Centre is supported by Cancer Research UK and by the Chief Scientist Office (Scotland).

Role of Funding Source

This study was sponsored and funded by OSI Pharmaceuticals LLC. The sponsor was involved in the design of the study and in the analysis and interpretation of data. Financial support to cover the cost of running the study was provided by OSI Pharmaceuticals LLC. The sponsor reviewed and contributed to the manuscript which was primarily written by I.M.

Conflict of interest statement

S. Poondru, R. Gedrich, K. Brock, and A. Stephens are current or previous employees of OSI Pharmaceuticals. R. Gedrich held stock in OSI Pharmaceuticals when the research was performed. T.R.J. Evans has received research funding from OSI Pharmaceuticals. All remaining authors have declared no conflicts of interest.

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