Panitumumab and Irinotecan as Third-Line Therapy in Treating Patients With Metastatic Colorectal Cancer (PIMABI)

GERCOR - Multidisciplinary Oncology Cooperative Group

Status and phase

Completed

Phase 2

Conditions

Colorectal Cancer

Treatments

Genetic: Gene expression analysis

Genetic: Fluorescence in situ hybridization

Drug: Panitumumab

Genetic: Chromogenic in situ hybridization

Drug: Irinotecan hydrochloride

Other: Laboratory biomarker analysis

Study type

Interventional

Funder types

Other

Identifiers

NCT00655499

GERCOR-PIMABI-C07-1

EU-20836

CDR0000593012

AMGEN-GERCOR-PIMABI-C07-1

2007-004806-28 (EudraCT Number)

Details and patient eligibility

About

RATIONALE: Monoclonal antibodies, such as panitumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving panitumumab together with irinotecan may kill more tumor cells.

PURPOSE: This phase II clinical trial is studying giving panitumumab together with irinotecan to see how well it works as third-line therapy in treating patients with metastatic colorectal cancer.

Full description

OBJECTIVES:

Primary

To assess the objective response rate when panitumumab is administered in combination with irinotecan hydrochloride as third-line therapy in patients with advanced metastatic colorectal cancer without KRAS mutation (wild type) previously treated with FOLFOX or XELOX chemotherapy with or without bevacizumab and irinotecan hydrochloride alone or FOLFIRI or CAPIRI chemotherapy with or without bevacizumab.

Secondary

To assess the efficacy in terms of disease control rate, duration of response, time to response, progression-free survival, time to progression, time to treatment failure, and duration of stable disease.
To assess the efficacy and safety of this regimen, followed by panitumumab alone in patients who discontinue third-line irinotecan hydrochloride due to toxicity.

Tertiary

To correlate this regimen with EGFR expression, detection of the functional genetic polymorphisms of the EGFR gene, EGFR gene amplification (FISH), EGFR activation detection, EGFR downstream protein and gene expression parameters, proteomics, and epigenetics.

OUTLINE: This is a multicenter study.

Patients receive panitumumab IV over 30-90 minutes and irinotecan hydrochloride IV over 90 minutes on day 1. Patients who discontinue irinotecan hydrochloride may receive panitumumab monotherapy. Courses repeat every 14 days in the absence of disease progression and unacceptable toxicity.

Archived tumor tissue specimens are obtained at baseline for correlative laboratory studies. Tissue samples are analyzed for EGFR amplification status by chromogenic in situ hybridization and fluorescence in situ hybridization, KRAS and KRAF mutations, and STAT3 expression.

After completion of study therapy, patients are followed at approximately 56 days.

Enrollment

65 patients

Sex

All

Ages

18 to 80 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Histologically confirmed colorectal adenocarcinoma
- Metastatic disease
Wild-type KRAS (no mutation) by allelic discrimination on tumor DNA
Measurable disease (≥ 10 mm) per modified RECIST criteria
Previously treated for metastatic disease with oxaliplatin and fluoropyrimidines (i.e., fluorouracil/folinic acid or capecitabine) with or without bevacizumab, and irinotecan hydrochloride alone or in combination with fluoropyrimidines (i.e., fluorouracil/folinic acid or capecitabine) with or without bevacizumab
Must have paraffin-embedded tissue or unstained tumor slides from primary or metastatic tumor available for correlative studies
Must be registered with a national health care system (CMU included)
No CNS metastases unless previously treated or asymptomatic, provided patient has been off steroids for at least 30 days prior to study treatment

PATIENT CHARACTERISTICS:

WHO performance status of 0-2
ANC ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Hemoglobin ≥ 9 g/dL
Creatinine < 150 μmol/L or creatinine clearance > 30 mL/min
AST ≤ 3 times upper limit of normal (ULN) (5 times ULN if liver metastases present)
ALT ≤ 3 times ULN (5 times ULN if liver metastases present)
Bilirubin ≤ 1.5 times ULN
Magnesium normal
No significant cardiovascular disease, including unstable angina or myocardial infarction within the past 6 months
No history of treated or untreated ventricular arrhythmia
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective double barrier contraception during and for 6 months after completion of study treatment
No other malignant tumors within the past five years except basocellular carcinoma, in situ cancer of the cervix or uterus, or any UDAW cancers for which there has been complete resection for at least three years
No known hypersensitivity to an excipient (vehicle) of panitumumab or known hypersensitivity of irinotecan trihydrate chlorhydrate or known hypersensitivity excipient (vehicle) of irinotecan hydrochloride
No history of interstitial pneumonitis, pulmonary fibrosis or evidence of interstitial pneumonitis, or pulmonary fibrosis on baseline chest CT scan
No active inflammatory bowel disease, other bowel disease causing chronic diarrhea (defined as > 4 loose stools per day), or bowel occlusion
No history of Gilbert syndrome
No history of any medical condition that may increase the risks associated with study participation or may interfere with the interpretation of the study results
No known positive test for HIV infection, hepatitis C virus, chronic active hepatitis B infection
No comorbid disease that would increase risk of toxicity
No disorder that would compromise the patient's ability to give written informed consent and/or comply with study procedures
Must be willing and able to comply with study requirements
No grade IV toxicity associated with a past treatment with irinotecan hydrochloride

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
At least 14 days since prior treatment for systemic infection
No prior or concurrent anti-EGFR antibody therapy (e.g., cetuximab) or treatment with small molecule EGFR tyrosine kinase inhibitors (e.g., erlotinib hydrochloride)
- Patients who discontinued their first dose of anti-EGFR therapy (i.e., cetuximab) because of an infusion reaction are eligible
More than 30 days since prior and no other concurrent investigational agent (no delay for non-investigational treatment)
More than 14 days since prior CYP3A4 enzyme, including anticonvulsant medication (e.g., phenytoin, phenobarbital, or carbamazepine)
More than 14 days since prior rifampicin
More than 14 days since prior radiotherapy and recovered
More than 7 days since prior and no concurrent ketoconazole
More than 28 days since prior and no concurrent major surgical procedure
Concurrent topical, oral, or IV antibiotics used to treat skin- or nail-related toxicities are allowed at the investigator's discretion
No other concurrent experimental or approved anti-tumor therapies (e.g., bevacizumab), chemotherapy other than irinotecan hydrochloride, non-palliative radiotherapy, or systemic steroids (except when used for symptomatic skin or nail-related toxicities requiring withholding of the panitumumab dose, as chemotherapy premedication, or for an infusion reaction)
No concurrent St. John's wort (i.e., Hypericum perforatum)
No concurrent phenobarbital, clarithromycin, erythromycin, HIV protease inhibitors, cyclosporine or tacrolimus, or nefazodone
Concurrent minor surgery, procedures, or surgery arising as needed or necessary allowed
Concurrent elective surgery allowed in patients eligible for surgical resection of metastases as curative therapy