A Phase I Dose Finding Study of APO010 in Patients With Solid Tumors — AP1001  

Cancer Clinical Trial

Official title: Phase I Dose Finding and Pharmacokinetic Study of Intravenous APO010, a Recombinant Form of Human Fas Ligand, in Patients With Solid Tumors

Status Completed

Clinical Trial Summary

Two-centre, open label, uncontrolled, dose-finding phase I study, to determine the safety and tolerability of APO010 administered by intravenous bolus injection once per week. It will be the first time this agent will be administered to humans. At lower dose levels, the first cycle duration is 7 weeks. In subsequent cycles, APO010 is administered as 4 weekly doses followed by a two-week drug rest, cycle duration is 6 weeks. Based on preclinical studies of APO010 may cause liver toxicity and a drop in platelets, that recover within 5 days. The main aim of the study is to identify the recommended dose of APO010 for future clinical studies of APO010.

Clinical Trial Description

Two-centre, open label, uncontrolled, dose-finding phase I study, to determine the safety and tolerability of APO010 administered by intravenous bolus injection once per week in patients with solid tumors, for whom therapy of proven efficacy does not exist or is no longer effective. The dose-escalations will follow a classical Fibonacci schedule, meaning at least three patient per dose-level, prior to further escalation. The dose-level assignment and patient registration is centralized by SENDO-Switzerland & Milan offices.

APO010, Apoxis' proprietary humanized recombinant mega-Fas-ligand, is a novel "First in class" investigational anticancer agent. APO010 is a protein that by specific binding to its cognate Fas receptor on the cell surface induces apoptosis (programmed cell death). This is called the extrinsic apoptotic pathway of cells. APO010 has shown to exert anticancer activity in vitro and in animal models carrying a human xenograft of a variety of cancers, including malignancies such as multiple myeloma, non-small cell lung cancer (NSCLC), ovarian cancer. Its activity is cell cycle independent, it does not cross react with known multi-drug resistance mechanism (MDR) and appears to be synergistic with a variety of commonly used anticancer drugs. Hence, APO010 may an attractive candidate for combination anticancer therapy and may be a effective drug in overcoming MDR.

In this study the starting dose is 2.5 microgram/m2. Normally 1/6 of the No-observed-adverse-effect level (NOAEL) dose-level in monkeys would be chosen as the first dose-level, however it has been decided to start at 25% of that dose-level. Across species (mice, rats and Cynomolgus monkeys) the rise in transaminases and drop in platelets occurred at 30 microgram/m2. The Nadir of these toxicities occurred within 6 hours and full recovery at day 5 after the bolus injection.

At the first occurrence of non-reversible (within 1 week) Common Toxicity Criteria (CTC) v3.0 Grade 2 liver function toxicity (Aspartate transaminase (AST)/Alanine transaminase (ALT) or alkaline phosphatase), i.e. Dose Limiting Toxicity (DLT), the patient accrual will be placed on hold until recovery and the subsequent timing of patient accrual to the existing and subsequent cohorts will be re-defined by the sponsor, the principal investigators and SENDO.

Pharmacokinetic assessments will be carried out in all patients during the first, and in consenting patients during the second cycles of treatment.

Assessment for immunogenicity (binding and/or neutralizing antibodies against APO010 will be carried out in all patients in all cycles of treatment before each dose and 2 weeks after the final dose. ;

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cancer

• NCT number: NCT00437736
• Study type: Interventional
• Source: Onxeo
• Status: Completed
• Phase: Phase 1
• Start date: February 2007
• Completion date: May 2009