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

Colorectal Cancer Clinical Trial

— PIMABI  

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00655499
• Other study ID #: CDR0000593012
• Secondary ID: GERCOR-PIMABI-C0
• Status: Completed
• Phase: Phase 2
• Start date: June 2008
• Est. completion date: June 2012

Study information

• Verified date: August 2016
• Source: GERCOR - Multidisciplinary Oncology Cooperative Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 65
• Est. completion date: June 2012
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Drug:
• Panitumumab
6 mg/kg
• Irinotecan hydrochloride
180 mg/kg

Genetic:
• Chromogenic in situ hybridization

• Fluorescence in situ hybridization

• Gene expression analysis

Other:
• Laboratory biomarker analysis

Locations

Country	Name	City	State
France	Centre Paul Papin	Angers
France	Hopital Prive Jean Mermoz	Lyon
France	Hopital Clinique Claude Bernard	Metz
France	Centre Hospitalier Intercommunal Le Raincy - Montfermeil	Montfermeil
France	Hopital Bichat - Claude Bernard	Paris
France	Hopital Pitie-Salpetriere	Paris
France	Hopital Saint Antoine	Paris
France	Hopital Tenon	Paris
France	Hopital Foch	Suresnes

Sponsors (1)

Lead Sponsor	Collaborator
GERCOR - Multidisciplinary Oncology Cooperative Group

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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

External Links

•   Annals of Oncology journal
•   ASCO 2011 meeting