A Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer.
18 Years
N/A
Both
Colorectal Neoplasms
Trial Information
A Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer.
This is a clinical trial of a laboratory produced humanised monoclonal antibody called
CS-1008. CS-1008 binds to a receptor found on cancer cells called death receptor 5 (DR5
receptor) which, when stimulated, can cause the cancer cell to be destroyed by a process
called apoptosis. CS-1008 could be an important potential therapeutic in patients with
colorectal cancer and other cancers.
The purpose of this study is to:
- Primarily
- Determine the influence of CS-1008 dose on initial biodistribution, pharmacokinetics
and tumour uptake of 111-In-CS-1008 (CS-1008 tagged with a small amount of radioactive
Indium - also called Indium-111) following single infusion of CS-1008, and determine
changes in these parameters following continuous sequential doses of CS-1008.
- Secondarily
- Determine changes in tumour metabolism following CS-1008 administration
- Describe anti-tumour response to CS-1008 in metastatic colorectal cancer.
- Determine changes in serum apoptosis biomarkers and serum tumour response markers
following treatment with CS‐1008.
Research design and methods:
This is a non-randomised, open label, single site (Austin Hospital), dose cohort study of
CS-1008 in patients with advanced colorectal carcinoma who have received at least one
previous regimen of chemotherapy treatment for metastatic disease. Consenting, eligible
patients will each receive a course of seven doses of CS-1008, given weekly as an
intravenous (IV) infusion over 30 minutes. The initial infusion of CS-1008 is trace labeled
with Indium-111 (111In-CS-1008). Ten to 25 patients will be treated in cohorts in which the
allocated initial and sequential weekly doses of CS-1008 are assessed. Each of the five dose
level cohorts will be made up of two patients and are expandable to five patients if
additional information about biodistribution and/or pharmacokinetics of the cohort dose is
required. The initial 111In-CS-1008 dose is followed by gamma camera imaging for
biodistribution and tumour uptake studies and with blood sampling over a 10 day period to
evaluate pharmacokinetics and serum biomarkers. Weekly infusions of CS-1008 will
subsequently occur. The day 36 infusion of CS-1008 will also be trace labeled with 111In,
with subsequent gamma camera imaging for biodistribution and tumour uptake and blood
sampling for pharmacokinetics and serum apoptosis biomarkers. Patients are reassessed for
disease status (by RECIST v1.1), serum tumour biomarkers (CEA - carcinoembryonic antigen)
and for development of human-anti-CS-1008-antibody development (HAHA) between day 44-50 (end
of cycle/study visit). Patients are assessed for changes in the tumour metabolism following
CS-1008 administration with 18F-FDG PET/CT scans at baseline, day 15 and end of cycle one.
Patients with stable disease or better at the day 44-50 reassessment may continue weekly
CS-1008 until disease progression in the absence of unacceptable toxicity or until the
patient or treating physician requests cessation of treatment.
Inclusion Criteria:
- Histologically proven metastatic colorectal cancer with one target lesion ≥2cm and
evaluable by gamma camera imaging. If this lesion has been previously irradiated,
there must be documented progression following radiotherapy.
- Received at least one prior course of chemotherapy for metastatic disease.
- Expected survival of at least 3 months.
- ECOG Performance Status ≤2
- Age ≥ 18 years old.
- Able and willing to give written informed consent.
- Within the last 1 week prior to first study drug administration, laboratory
parameters for vital functions should be in the normal range. Non clinically
significant laboratory abnormalities are generally permitted, except for the
following which must be within the ranges specified:
- Neutrophils - ≥ 1.5 x 10^9/L
- Platelets - ≥ 90 x 10^9/L
- INR - ≤ 1.5
- Serum bilirubin - ≤ 1.5 x ULN
- AST (SGOT), ALT (SGPT) - ≤ 2 x normal upper limit (≤ 5 x ULN if liver
metastases)
- Calculated creatinine clearance ≥ 55mL/min (Cockcroft-Gault formula)
Exclusion Criteria:
- Active central nervous system metastases. Definitively treated metastases are allowed
if stable for 6 weeks off therapy.
- Known immunodeficiency or HIV positivity.
- Serious illnesses e.g. serious infections requiring antibiotics, bleeding disorders,
or any condition that in the opinion of the Investigator would interfere with ability
of the patient to fulfill the study requirements.
- Other malignancy, except non-melanoma skin cancer, within 3 years prior to first
study drug administration, that in the opinion of the investigator has >10% risk of
relapse within 12 months.
- Chemotherapy, radiotherapy or investigational agent within 4 weeks prior to first
study drug administration.
- Regular corticosteroid, NSAID (other than paracetamol or low-dose aspirin) or other
immunosuppressive treatment within 3 weeks prior to first drug administration.
Intermittent dosing of corticosteroid or NSAID permitted if less than 4 doses within
a 3 day period.
- Mental impairment that may compromise ability to give informed consent and comply
with the requirements of the study.
- Lack of availability for clinical follow-up assessments.
- Pregnancy or breastfeeding.
- Women of childbearing potential: refusal or inability to use effective means of
contraception.
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Biodistribution and tumour uptake of CS1008 based on gamma camera imaging following initial single infusion 111In-CS-1008 and changes following continuous sequential doses of CS-1008.
Outcome Description:
Biodistribution and tumour localization following initial dose of 111In‐CS‐1008 assessed by gamma camera images post initial single 111In‐CS‐1008 infusion. Changes in biodistribution and tumour localisation following continuous sequential doses of CS-1008 are assessed by gamma camera images following Day 36 111In-CS-1008 infusion.
Outcome Time Frame:
43 days
Safety Issue:
No
Principal Investigator
Prof. Andrew M Scott MBBS, MD, FRACP, DDU
Investigator Role:
Principal Investigator
Investigator Affiliation:
Ludwig Institute for Cancer Research & Austin Health
Authority:
Australia: Department of Health and Ageing Therapeutic Goods Administration
Study ID:
LUD2010-002
NCT ID:
NCT01220999
Start Date:
October 2010
Completion Date:
September 2012
Related Keywords:
- Colorectal Neoplasms
- Clinical trial
- CS-1008 mAb
- monoclonal antibody CS-1008
- Positron-Emission Tomography
- Pharmacokinetics
- Pharmacodynamics
- apoptosis
- caspases
- Neoplasms
- Colorectal Neoplasms
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