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An Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer

This study has been completed.
Sponsor:
Collaborator:
Daiichi Sankyo Inc.
Information provided by:
Ludwig Institute for Cancer Research
ClinicalTrials.gov Identifier:
NCT01220999
First received: October 12, 2010
Last updated: February 27, 2013
Last verified: February 2013
  Purpose

This is a clinical trial of CS-1008 which is a humanized monoclonal antibody.

This trial explores where CS-1008 distributes in the body, and the activity of CS-1008 in patients with metastatic colorectal cancer. The purpose of this study is to give patients with metastatic colorectal cancer a series of different CS-1008 antibody doses in order to:

  • Study how the dose of CS-1008 effects where the CS-1008 distributes in the body (biodistribution), how long it circulates in blood (pharmacokinetics) and how much attaches to tumour (tumour uptake). These issues are studied after the initial infusion of 111In-CS-1008 (CS-1008 tagged with a small amount of radioactive Indium - also called Indium-111 or 111In), and also during and after a cycle of weekly infusions of CS-1008 antibody.
  • Study changes in the function (metabolism) of tumour cells following CS-1008 administration.
  • Assess whether repeat doses of CS-1008 cause shrinkage of the tumour.
  • Study whether experimental treatment with CS-1008 changes chemicals in the blood that may indicate tumour cell death (serum apoptosis biomarkers) and/or tumour response to treatment (serum tumour biomarkers (CEA - carcinoembryonic antigen)).

Condition Intervention Phase
Colorectal Neoplasms
Drug: 111In-CS-1008, CS-1008
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer.

Resource links provided by NLM:


Further study details as provided by Ludwig Institute for Cancer Research:

Primary Outcome Measures:
  • 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. [ Time Frame: 43 days ] [ Designated as safety issue: No ]
    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.

  • Pharmacokinetics of 111In-CS-1008 and CS-1008 protein by gamma counting and ELISA of serum samples following initial single infusion 111In-CS-1008 and changes following continuous sequential doses of CS-1008. [ Time Frame: 43 days ] [ Designated as safety issue: No ]
    Pharmacokinetics (PK) by gamma counting and ELISA to assess serum radioactivity (111In‐CS‐1008) and CS‐1008 protein concentration, respectively in sera following initial dose single 111In-CS-1008 infusion. Changes in pharmacokinetics (PK) following Day 36 111In-CS-1008 infusion are assessed by gamma counting and ELISA to assess serum radioactivity (111In‐CS‐1008) and CS‐1008 protein concentration, respectively in sera following continuous sequential doses of CS-1008.


Secondary Outcome Measures:
  • Tumour metabolism response to CS‐1008 will be assessed by 18F‐FDG PET [ Time Frame: 50 days ] [ Designated as safety issue: No ]
    Tumour metabolic response to CS‐1008 will be assessed by 18F‐FDG PET/CT scan performed pre‐study and then during and following a treatment cycle of CS‐1008.

  • Tumour response to CS-1008 measured by RECIST (v1.1). [ Time Frame: 50 days ] [ Designated as safety issue: No ]
    Tumour response assesses according to the Response Evaluation Criteria in Solid Tumours (revised RECIST v1.1).

  • Changes in serum apoptotic biomarkers following treatment with CS-1008. [ Time Frame: 50 days. ] [ Designated as safety issue: No ]
    Changes in serum apoptosis biomarkers (e.g. caspase 3/7, 8 and M30) following treatment with CS‐1008.

  • Changes in serum tumour response markers following treatment with CS-1008. [ Time Frame: 50 days ] [ Designated as safety issue: No ]
    Changes in serum tumour response markers (e.g. CEA - carcinoembryonic antigen) following treatment with CS‐1008.


Enrollment: 19
Study Start Date: October 2010
Study Completion Date: September 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 111In-CS-1008, CS-1008 Drug: 111In-CS-1008, CS-1008

CS-1008 will be given in 5 dose cohorts.

Weekly doses of CS-1008 are administered for 7 consecutive weeks in Cycle 1. On each dosing day, CS-1008 will be infused intravenously over approximately 30 minutes.

  • Cohort No.: Pts - Dose Day 1 - Day 8 - Day15,22,29 - Day 36 - Day 43
  • Cohort #1: 2-5 pts - 0.2 mg/kg - 6 mg/kg - 2 mg/kg - 2 mg/kg - 2 mg/kg
  • Cohort #2: 2-5 pts - 1 mg/kg - 6 mg/kg - 2 mg/kg - 2 mg/kg - 2 mg/kg
  • Cohort #3: 2-5 pts - 2 mg/kg - 6 mg/kg - 2 mg/kg - 2 mg/kg - 2 mg/kg
  • Cohort #4: 2-5 pts - 4 mg/kg - 4 mg/kg - 2 mg/kg - 2 mg/kg - 2 mg/kg
  • Cohort #5: 2-5 pts - 6 mg/kg - 2 mg/kg - 2 mg/kg - 2 mg/kg - 2 mg/kg

Day 1 and Day 36 doses will be trace labelled with Indium-111 (111In-CS-1008)

Additional treatment cycles in suitable patients with stable disease or better at the day 44-50 reassessment may continue be given as weekly infusions of CS-1008 at 2 mg/kg per week. Disease reassessment is planned after every second 4-week cycle.


Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01220999

Locations
Australia, Victoria
Ludwig Institute Tumor Targeting Program, Austin Health
Heidelberg (Melbourne), Victoria, Australia, 3084
Sponsors and Collaborators
Ludwig Institute for Cancer Research
Daiichi Sankyo Inc.
Investigators
Principal Investigator: Prof. Andrew M Scott MBBS, MD, FRACP, DDU Ludwig Institute for Cancer Research & Austin Health
  More Information

No publications provided

Responsible Party: Linda Pan, Pharm.D. Assistant Director, Clinical Trials Management, Ludwig Institute for Cancer Research
ClinicalTrials.gov Identifier: NCT01220999     History of Changes
Other Study ID Numbers: LUD2010-002
Study First Received: October 12, 2010
Last Updated: February 27, 2013
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration

Keywords provided by Ludwig Institute for Cancer Research:
Clinical trial
CS-1008 mAb
monoclonal antibody CS-1008
Positron-Emission Tomography
Pharmacokinetics
Pharmacodynamics
apoptosis
caspases

Additional relevant MeSH terms:
Colorectal Neoplasms
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases

ClinicalTrials.gov processed this record on November 20, 2014