Phase I Dose Finding and Pharmacokinetic Study of Intravenous APO010, a Recombinant Form of Human Fas Ligand, in Patients With Solid Tumors
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.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine of the maximum tolerated dose (MTD), based upon first cycle APO010-related DLT in patients with solid tumors.
Cristiana Sessa, Prof, MD
Oncology Institute of Southern Switzerland, Bellinzona Hospital, 6500 Bellinzona, Switzerland