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An Exploratory Trial of Biomarkers for Panitumumab Response Among Previously Treated Patients With KRAS Wild Type Metastatic Colorectal Cancer.

18 Years
Open (Enrolling)
Metastatic Colorectal Cancer

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Trial Information

An Exploratory Trial of Biomarkers for Panitumumab Response Among Previously Treated Patients With KRAS Wild Type Metastatic Colorectal Cancer.

Colon cancer affects 20,000 Canadians a year. Despite efforts to improve screening, 8,500
patients will die of the disease (1). The agents used in both the adjuvant and metastatic
setting have dramatically changed over the past ten years. Even with the optimal treatment
and careful follow-up many patients will develop metastasis. For most this is an incurable
condition and the median survival for these patients is only 2 years (2).

Therapy with 5-Fluorouracil (FU)/Leucovorin, oxaliplatin and irinotecan with or without
bevacizumab are conventionally used as first and second line therapy for metastatic
colorectal cancer. Third line therapy options are limited to anti-epidermal growth factor
receptor (EGFR) therapy Cetuximab or Panitumumab either as monotherapy or in combination
with Irinotecan. Recent data (see Table 1) has demonstrated that KRAS mutation status is a
predictor of benefit to anti-EGFR therapy, with wild-type tumours demonstrating a response
rate of 10-17% to monotherapy while a 0% response rate is observed among KRAS mutant

The purpose of this exploratory study is to examine the correlation of biomarkers (PTEN,
BRAF, amphiregulin, c-MET, EGFR) with response rate among patients with KRAS wild type
tumours treated with panitumumab. If a high response subgroup can be identified, this may
support the use of Panitumumab with combination therapy in the first line setting. Secondary
objectives are to determine the prognostic and predictive value of CTCs for patients treated
with single agent panitumumab and to describe overall survival (OS) and progression free
survival (PFS) in registered patients.

Inclusion Criteria:

1. Histological proof of adenocarcinoma of colon or rectum. In addition, proof either
radiologically, or histologically that there is metastatic disease.

2. Archival, paraffin embedded tumour tissue block suitable for KRAS and biomarker, or,
willingness to undergo biopsy to obtain such.

3. Received a prior thymidylate synthase inhibitor (e.g. 5-fluorouracil (5- FU),
capecitabine, raltitrexed) for adjuvant and/or metastatic disease. Thymidylate
synthase inhibitor may have been given in combination with oxaliplatin or irinotecan.

4. Received or ineligible for irinotecan based therapy (i.e. single-agent or in
combination) for metastatic disease

5. Received or ineligible for oxaliplatin based therapy for metastatic and/or adjuvant

6. Measurable or evaluable disease by RECIST criteria.

7. Adequately recovered from recent surgery, chemotherapy and/or radiation therapy. At
least 4 weeks must have elapsed from major surgery, prior chemotherapy, and prior
treatment with an investigational agent or prior radiation therapy.

8. Must not have received any prior anti-EGFR therapies including tyrosine kinase
inhibitors or monoclonal antibodies.

9. An ECOG performance status of 0, 1 or 2.

10. Hematology done within 14 days and with initial values within the ranges specified

- Absolute granulocyte count (AGC) > 1.5 x 109/L

- Platelets > 100 x 109/L

- Hemoglobin > 100 g/L

11. Biochemistry done within 14 days and with initial values within the ranges specified

- Total bilirubin < 2.5 x institutional upper limit of normal

- ALT < 5.0 x institutional upper limit of normal

- AST < 5.0 x institutional upper limit of normal

- Serum creatinine < 1.5 x institutional upper limit of normal

12. Imaging investigations including chest x-ray and CT/MRI of abdomen/pelvis or other
scans as necessary to document all sites of disease done within 28 days prior to
randomization. Where chest x-ray is suspicious for or reveals metastatic disease, a
CT/MRI scan of the chest must also be performed. A CT/MRI scan of the chest within 28
days prior to randomization may be substituted for chest x-ray.

13. ECG done within 28 days prior to enrollment

14. Patient's age is >18 years.

15. Women of child bearing potential (WOCBP) and male partners of WOCBP must agree to use
adequate contraception prior to study entry, throughout the study and for a period of
6 months after cessation of protocol therapy.

16. Adequate contraception is defined as follows:

- Complete abstinence from intercourse from four weeks prior to administration of
the first dose until 6 months after the final dose of panitumumab

- Consistent and correct use of one of the following methods of birth control: i.
male partner who is sterile prior to the female subject's entry into the study
and is the sole sexual partner for that female subject; or ii. implants of
levonorgesterol; or iii. injectable progestagen; or iv. any intrauterine device
(IUD) with a documented failure rate of less than 1% per year; or v. oral
contraceptive pill (either combined or progesterone only); or vi. barrier
methods including diaphragm or condom with a spermicide.

17. The baseline assessment must be completed within 14 days prior to randomization.

18. Patients must be accessible for treatment and follow-up.

Exclusion Criteria:

1. Known hypersensitivity to panitumumab or any other component of the product;
life-threatening infusion reactions associated with previous administration of
monoclonal antibody therapy.

2. Women who are pregnant or breastfeeding, or intend to become pregnant within the
study period

3. Any active pathological condition which would render the protocol treatment dangerous
or impair the ability of the patient to receive protocol therapy.

4. Any condition (e.g. psychological, geographical, etc.) that does not permit
compliance with the protocol.

5. Significant history of uncontrolled angina, arrhythmias, cardiomyopathy, congestive
heart failure, or documented myocardial infarction within the 6 months preceding
registration (pre-treatment ECG evidence only of infarction will not exclude

6. Symptomatic metastases in the central nervous system.

7. A history of prior cetuximab or other therapy which targets the Epidermal Growth
Factor Receptor pathway (e.g. TarcevaTM (OSI-774), IressaTM (ZD1839), or others). A
history of prior murine monoclonal antibody therapy (e.g. EdrecolomabTM (MoAB17-1A),
or others).

8. Severe restrictive lung disease or radiological pulmonary findings of "interstitial
lung disease" on the baseline chest x-ray which, in the opinion of the investigator,
represents significant pathology.

9. Receipt of an experimental therapeutic agent within the past 30 days.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label

Outcome Measure:

Response rate

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Hagen Kennecke, MD

Investigator Role:

Study Chair

Investigator Affiliation:

British Columbia Cancer Agency


Canada: Ethics Review Committee

Study ID:




Start Date:

October 2009

Completion Date:

Related Keywords:

  • Metastatic Colorectal Cancer
  • KRAS wild type
  • metastatic colorectal cancer
  • KRAS wild type metastatic colorectal cancer with no prior exposure to EGFR inhibitors
  • Colorectal Neoplasms