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

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)

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Other: Laboratory biomarker analysis; Drug: Panitumumab; Drug: Irinotecan hydrochloride; Genetic: Chromogenic in situ hybridization; Genetic: Fluorescence in situ hybridization; Genetic: Gene expression analysis

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Angers, France, 49036
    • Centre Paul Papin
  • Lyon, France, 69008
    • Hopital Prive Jean Mermoz
  • Metz, France, 57072
    • Hopital Clinique Claude Bernard
  • Montfermeil, France, 93370
    • Centre Hospitalier Intercommunal Le Raincy - Montfermeil
  • Paris, France, 75018
    • Hôpital Bichat - Claude Bernard
  • Paris, France, 75970
    • Hopital Tenon
  • Paris, France, 75571
    • Hopital Saint Antoine
  • Paris, France, 75013
    • Hôpital Pitié-Salpêtrière
  • Suresnes, France, 92151
    • Hopital Foch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: GERCOR - Multidisciplinary Oncology Cooperative Group
• Investigators: Principal Investigator: Thierry Andre, MD, GERCOR - Multidisciplinary Oncology Cooperative Group

Publications and helpful links

General Publications

• Andre T, Blons H, Mabro M, Chibaudel B, Bachet JB, Tournigand C, Bennamoun M, Artru P, Nguyen S, Ebenezer C, Aissat N, Cayre A, Penault-Llorca F, Laurent-Puig P, de Gramont A; GERCOR. Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study. Ann Oncol. 2013 Feb;24(2):412-419. doi: 10.1093/annonc/mds465. Epub 2012 Oct 5.

Helpful Links

• Annals of Oncology journal
• ASCO 2011 meeting

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): June 1, 2012
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: April 9, 2008
• First Submitted That Met QC Criteria: April 9, 2008
• First Posted (Estimate): April 10, 2008

Study Record Updates

• Last Update Posted (Actual): September 21, 2021
• Last Update Submitted That Met QC Criteria: August 26, 2021
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage IV rectal cancer; stage IV colon cancer; adenocarcinoma of the colon; recurrent colon cancer; recurrent rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Topoisomerase I Inhibitors; Irinotecan; Panitumumab
• Other Study ID Numbers: CDR0000593012; GERCOR-PIMABI-C07-1 (Other Identifier: GERCOR); 2007-004806-28 (EudraCT Number); EU-20836 (Other Identifier: EU Clinical Trials Register); AMGEN-GERCOR-PIMABI-C07-1 (Other Identifier: GERCOR, AMGEN)