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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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An Open-label Phase II Trial of Panitumumab Plus Irinotecan for Patients With Advanced Metastatic Colorectal Cancer Without KRAS Mutation (Wild-type) in Third-line Chemotherapy (FOLFOX/XELOX ± Bevacizumab and Irinotecan Alone or FOLFIRI/CAPIRI ± Bevacizumab)

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Panitumumab
* Drug: Irinotecan hydrochloride
* Genetic: Chromogenic in situ hybridization
* Genetic: Fluorescence in situ hybridization
* Genetic: Gene expression analysis
* Other: Laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panitumumab + CPT11 (irinotecan hydrochloride)<br>1 cycle every 14 days (J1= J15) | Drug: Panitumumab<br>* 6 mg/kg<br>* Other names: Vectibix;Drug: Irinotecan hydrochloride<br>* 180 mg/kg<br>* Other names: Camptosar;Genetic: Chromogenic in situ hybridization<br> <br> Genetic: Fluorescence in situ hybridization<br> <br> Genetic: Gene expression analysis<br> <br> Other: Laboratory biomarker analysis<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) During the Combination Therapy Phase | Per the modified Response Evaluation Criteria in Solid Tumors (m-RECIST) for target lesions and radiogically assessed (CT Scans; optionally MRI): Complete Response (CR; Disappearance of all target lesions) or Partial Response (PR; At least a 30% decrease in the sum of the LD of target lesions) during the combination therapy phase.Overall Response (OR) = CR + PR. | Up to 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) | Per the modified Response Evaluation Criteria in Solid Tumors (m-RECIST) for target lesions and radiogically assessed (CT Scans; optionally MRI): confirmed complete (CR; Disappearance of all target lesions) or partial response (PR; At least a 30% decrease in the sum of the longest diameter of target lesions), or stable disease (SD; Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the nadir longest diameter since the treatment started) while on the combination therapy treatment phase or over the entire treatment strategy. DCR = CR / PR / SD | Up to 20 months | 
| Progression-free Survival (PFS) | PFS was defined as time from enrollment date to date of first radiologically observed progression or death (whichever comes first) during the combination therapy phase or over the entire treatment strategy. Per the Response Evaluation Criteria in Solid Tumors (RECIST) analyzed using Kaplan-Meier methods and the quartiles and event rates at various weeks presented with 95% CIs. | Up to 20 months | 
| Overall Survival (OS) | OS was defined as time from inclusion to death (from any cause or to the last date the patient was known to be alive) during the combination therapy phase or over the entire treatment strategy. Per the Response Evaluation Criteria in Solid Tumors (RECIST) analyzed using Kaplan-Meier methods and the quartiles and event rates at various weeks presented with 95% CIs. | Up to 20 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the colon, adenocarcinoma of the rectum, stage IV colon cancer, recurrent rectal cancer, stage IV rectal cancer, recurrent colon cancer