Phase I Dose Finding and Pharmacokinetic Study of Intravenous APO010, a Recombinant Form of Human Fas Ligand, in Patients With Solid Tumors
18 Years
N/A
Both
Cancer
Trial Information
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.
Inclusion Criteria:
- Histological/cytological diagnosis of non-resectable solid tumors for which therapy
of proven efficacy does not exist or is no longer effective.
- ECOG performance status ≤1.
- Ongoing toxicity associated with prior anticancer therapy ≤Grade 1 (NCI-CTCAE v.3.0).
- No more than 3 prior chemotherapy lines for advanced disease (not including
neo/adjuvant chemotherapy; reintroduced chemotherapy is considered only 1 line, e.g.
platinum reintroduction in ovarian cancer). Exceptions must to be discussed with, and
agreed by the Co-ordinating Investigator.
- Adequate hematological, liver and renal function, e.g.:
- Hemoglobin ≥9 mg/dl; ANC ≥1.5x109/l; platelets ≥100x109/l; normal coagulation factors
(INR, PTT, PT).
- Serum bilirubin ≤upper normal limit (UNL); ALT, AST ≤UNL but ≤ 2.5xUNL in case of
liver metastases; alkaline phosphatase (liver isoenzyme fraction) ≤UNL or ≤1.5xUNL of
in case liver metastases; albumin within normal limits.
- Creatinine ≤1.5 mg/dl (≤133µmole/l) or calculated creatinine clearance ≥60 ml/min.
- Life expectancy of at least 3 months.
- Capability of understanding the nature of the trial and giving written informed
consent.
Exclusion Criteria:
- Less than 4 weeks since last chemotherapy, radiotherapy or prior investigational
therapy. Less than 2 weeks since last hormone or immunotherapy or signal transduction
therapy.
- More than 30% liver parenchyma involvement assessed by CTscan.
- History of hypersensitivity to preparations containing human albumin, and to
intravenously administered proteins/peptides/antibodies.
- Active infection.
- Presence of cirrhosis with abnormal liver function test or chronic viral hepatitis.
- Presence of serious cardiac (congestive heart failure, angina pectoris, myocardial
infarction within one year prior to study entry, uncontrolled hypertension or
arrhythmia), neurological or psychiatric disorder.
- Presence of uncontrolled intercurrent illness or any condition which in the judgement
of the investigator would place the subject at undue risk or interfere with the
results of the study.
- Symptomatic brain metastases, primary brain tumors or leptomeningeal disease.
- Pregnancy or lactation, or unwillingness to use adequate method of birth control
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
To determine of the maximum tolerated dose (MTD), based upon first cycle APO010-related DLT in patients with solid tumors.
Outcome Time Frame:
3 months
Safety Issue:
Yes
Principal Investigator
Cristiana Sessa, Prof, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Oncology Institute of Southern Switzerland, Bellinzona Hospital, 6500 Bellinzona, Switzerland
Authority:
Switzerland: Swissmedic
Study ID:
AP1001
NCT ID:
NCT00437736
Start Date:
February 2007
Completion Date:
May 2009
Related Keywords:
- Cancer
- solid tumor
- phase I study
- dose-escalation
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