Clinical trial NCT00291447: 111In-ch806 in Patients With Advanced Tumours Expressing the 806 Antigen
Official title: A Phase 1 Single Dose Escalation Trial of ch806 in Patients With Advanced Tumours Expressing the 806 Antigen
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Lead sponsor: Ludwig Institute for Cancer Research
Sponsor class: OTHER
First posted: 2006-02-14
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Open label, single dose escalation Phase I trial of ch806 in patients with advanced tumors expressing the 806 antigen.
Primary purpose: TREATMENT

Brief summary: The purpose of this clinical trial is to describe the toxicity, biodistribution, pharmacokinetics and tumour uptake of a single infusion of ch806 (tagged with a trace amount of radioactive 111-Indium: 111In-ch806) in patients with advanced tumours expressing the 806 antigen.

Detailed description: This clinical research study explores the activity of the new experimental antibody ch806 in humans for the first time.

Cancers arising from an organ can be cured in some cases with various combinations of surgery, chemotherapy and radiotherapy. However, once some cancers spread to other organs, treatment with commonly used methods is unlikely to cure the cancer and so treatment is then designed to control the growth of the cancer, and the problems it is causing. One newer treatment approach involves targeting a marker (antigen) called the epidermal growth factor receptor (EGFR), which is found on the tumour cell's surface, with a specially constructed monoclonal antibody (mAB) called "ch806".

Antibodies are proteins that are found in the blood. Antibodies normally protect us from foreign invaders, such as bacteria or viruses. They help destroy these foreign substances by binding to them and activating white blood cells or blood proteins, resulting in their destruction. Tumour cells also have antigens which can be targeted by antibodies. A receptor expressed in high amounts (over-expressed) on various cancer cells, called the epidermal growth factor (EGFR), has been identified, studied and targeted with a variety of antibodies.

One of these antibodies, monoclonal antibody 806 (mAb806), was originally made from mouse protein. Because mAb806 is a mouse antibody, if it were given to humans the body would see it as a foreign protein and would be likely to react to it with an unwanted immune response. To overcome this, the structure of the original mouse antibody called mAb 806 was changed to appear more "human-like" and the chimeric antibody (part mouse part human) called ch806 was produced.

The study is open to patients whose tumour is shown to express the 806 antigen by a special test. Further tests are required to determine eligibility for the study. These tests determine general health and include: physical examination; blood samples for routine tests; routine tests to determine the extent of tumour prior to starting treatment with 111In-ch806 (eg. X-ray, CT scan, etc.).

On study, 111In-ch806 is given by infusion into a vein over one hour. Blood samples to determine the amount of drug in the blood (pharmacokinetics), are taken a number of times on the day of the 111In-ch806 infusion; about every 2nd day for the first week; then 2 weeks, 3 weeks and 4 weeks after the infusion. Blood tests are also used to monitor general health and to see if the immune system recognizes the infused antibody by making another antibody against it. Such a response is called "anti-ch806 antibody" or "HACA". Gamma camera scans to see where 111In-ch806 goes in the body are done right after the first infusion, and 4 more times over the next seven days. The scan takes about one hour each time. Visits for weekly follow up examinations and blood tests until 30 days after the infusion are combined with further gamma camera scans. Tumour is reassessed 30 days after the infusion using the same type of scans as at study entry.

Further treatment with a course of 111In-ch806 is not available at this time, as this study is to test the safety of a single infusion only.

Eligibility criteria: Inclusion Criteria:

* Patients with advanced or metastatic tumours which are positive for 806 antigen expression based on chromogenic in situ hybridization (CISH) or immuno-histochemistry (IHC) of archived tumour samples.
* Histologically or cytologically proven malignancy.
* Measurable disease on CT scan with at least one lesion \>/= 2 cm diameter (to allow adequate imaging).
* Age greater than or equal to 18 years.
* Karnofsky performance scale \>/= 70.
* Within the last 2 weeks vital laboratory parameters should be within normal range, except for the following laboratory parameters, which should be within the ranges specified: Neutrophil count \>/= 1.5 x 10\^9/L; Platelet count \>/= 150 x 10\^9/L; Serum bilirubin \< 34 micromol/L; Creatinine clearance \> 50ml/min
* Able and willing to give valid written informed consent.

Exclusion Criteria:

* Untreated active metastatic disease to the central nervous system (new or enlarging lesions on CT or MRI), or within 3 months of treatment (i.e. surgery or radiotherapy) for brain metastases. Primary central nervous system tumour (e.g. Glioblastoma Multiforme) is not an exclusion criterion.
* Other serious illnesses, e.g., serious infections requiring antibiotics, bleeding disorders.
* Chemotherapy, radiation therapy, or immunotherapy within 4 weeks before study entry (6 weeks for nitrosoureas).
* Clinically significant cardiac disease (New York Heart Association Class III/IV).
* Other malignancy within 3 years prior to entry into the study, except for treated non-melanoma skin cancer and cervical carcinoma in situ.
* Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study.
* Lack of availability for immunological and clinical follow-up assessments.
* Participation in any other clinical trial involving another investigational agent within 4 weeks prior to enrollment.
* Pregnancy or breastfeeding.
* Women of childbearing potential: Refusal or inability to use effective means of contraception.
* Concomitant treatment with systemic corticosteroids except for patients with Glioblastoma. (Topical or inhalational corticosteroids are permitted.)
* Prior administration of monoclonal antibody or antibody fragment, and positive human anti-chimeric antibody (HACA) titre.

Primary outcomes:
measure: Number of Patients With Adverse Events
timeFrame: 30 days
Secondary outcomes:
measure: Biodistribution of 111In-ch806 Using Whole Body Clearance Methodology or Biological Halftime (T1/2-biol) Following the First Infusion.
timeFrame: Day 0 (1-4 hours after 111In-ch806 infusion), and on Day 1, Day 2 or 3, Day 4 or 5, and Day 6 or 7 post 111In-ch806 infusion.
measure: Mean Normal Organ Dosimetry of 111In-ch806 Using Normal Organ Absorbed Dose (mGy/MBq) Following the First Infusion.
timeFrame: Day 0 (1-4 hours after 111In-ch806 infusion), and on Day 1, Day 2 or 3, Day 4 or 5, and Day 6 or 7 following 111In-ch806 infusion.
measure: Number of Patients With Tumour Uptake of 111In-ch806 Based on Qualitative Assessment of Biodistribution Images and Dosimetry Following the First Infusion.
timeFrame: Day 0 (1-4 hours after 111In-ch806 infusion), Day 1, Day 2 or 3, Day 4 or 5, and Day 6 or 7 following 111In-ch806 infusion.
measure: Mean Half-life as Measured by Half-life of Initial Phase of Disposition (T½α) and Terminal Phase of Distribution (T½β) of 111In-ch806 Following the First Infusion .
timeFrame: Day 0 - pre 111In-ch806 infusion; then at 5 minutes, 60 minutes, 2 hours and 4 hours post 111In-ch806 infusion, Day 1, Day 2 or 3, Day 4 or 5, Day 6 or 7, Day 14 (± 2 days) and Day 21 (± 2 days) and Day 30 (± 2 days) post infusion.
measure: Mean Volume of the Central Compartment (V1) of 111In-ch806 Following the First Infusion.
timeFrame: Day 0 - pre 111In-ch806 infusion; then at 5 minutes, 60 minutes, 2 hours and 4 hours post 111In-ch806 infusion, Day 1, Day 2 or 3, Day 4 or 5, Day 6 or 7, Day 14 (± 2 days) and Day 21 (± 2 days) and Day 30 (± 2 days) post infusion.
measure: Mean Total Serum Clearance (CL) of 111In-ch806 Following the First Infusion.
timeFrame: Day 0 - pre 111In-ch806 infusion; then at 5 minutes, 60 minutes, 2 hours and 4 hours post 111In-ch806 infusion, Day 1, Day 2 or 3, Day 4 or 5, Day 6 or 7, Day 14 (± 2 days) and Day 21 (± 2 days) and Day 30 (± 2 days) post infusion.
measure: Mean Area Under the Serum Concentration Curve (AUC) of 111In-ch806 Following the First Infusion.
timeFrame: Day 0 - pre 111In-ch806 infusion; then at 5 minutes, 60 minutes, 2 hours and 4 hours post 111In-ch806 infusion, Day 1, Day 2 or 3, Day 4 or 5, Day 6 or 7, Day 14 (± 2 days) and Day 21 (± 2 days) and Day 30 (± 2 days) post infusion.
measure: Number of Subjects With Best Overall Tumor Response by Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: 30 days
measure: Number of Patients With Human Anti-chimeric ch806 Antibodies (HACA)
timeFrame: 30 days
Other outcomes:
Locations:
city: Heidelberg
country: Australia
facility: Ludwig Institute Tumor Targeting Program, Austin Health
state: Victoria
Study officials:
affiliation: Ludwig Institute for Cancer Research
name: A/Prof Andrew M Scott, MBBS MD DDU
role: PRINCIPAL_INVESTIGATOR
References:
citation: Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000 Feb 2;92(3):205-16. doi: 10.1093/jnci/92.3.205.