A Phase I Dose Finding Study of APO010 in Patients With Solid Tumors (AP1001)
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.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Dose Finding and Pharmacokinetic Study of Intravenous APO010, a Recombinant Form of Human Fas Ligand, in Patients With Solid Tumors|
- To determine of the maximum tolerated dose (MTD), based upon first cycle APO010-related DLT in patients with solid tumors. [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
- A description of the frequency and severity of adverse events based on the NCI-CTCAE v.3.0. [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
- A description of the local toxicity at site of administration by route of administration based on the NCI-Common Terminology Criteria for Adverse Events (NCI-CTCAE v.3.0); the intervention required and by photographic record. [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
- A definition of the proportion of patients with neutralizing antibodies against APO010. [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
- A description of any objective tumor response based on modified RECIST criteria [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
|Study Start Date:||February 2007|
|Study Completion Date:||May 2009|
|Primary Completion Date:||November 2008 (Final data collection date for primary outcome measure)|
|Experimental: Single arm dose escalation||
APO010 starting at 2.5 µg/m² IV on D1, D15, D22 and D29 followed by a two-week drug rest. The current dosage level is 60 µg/m² IV.
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-CH & 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 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) CTC v3.0 Grade 2 liver function toxicity (AST/ALT or alkaline phosphatase), i.e. 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.
|Oncology Institute of Southern Switzerland, Hospital of Bellinzona|
|Bellinzona, Switzerland, 6500|
|Multidisciplinary Oncology Center, Cantonal University Hospital of Vaud|
|Lausanne, Switzerland, 1011|
|Principal Investigator:||Cristiana Sessa, Prof, MD||Oncology Institute of Southern Switzerland, Bellinzona Hospital, 6500 Bellinzona, Switzerland|