Colorectal Cancer
Conditions
Keywords
adenocarcinoma of the colon, adenocarcinoma of the rectum, stage IV colon cancer, recurrent rectal cancer, stage IV rectal cancer, recurrent colon cancer
Brief 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.
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.
Interventions
DRUGPanitumumab
6 mg/kg
DRUGIrinotecan hydrochloride
180 mg/kg
GENETICFluorescence in situ hybridization
GENETICGene expression analysis
OTHERLaboratory biomarker analysis
Sponsors
GERCOR - Multidisciplinary Oncology Cooperative Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) During the Combination Therapy Phase | Up to 20 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | Up to 20 months | 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 |
| Progression-free Survival (PFS) | Up to 20 months | 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. |
| Overall Survival (OS) | Up to 20 months | 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. |
Countries
France
Participant flow
Recruitment details
From July 2008 to Oct. 2010, 69 patients were enrolled in the study, 4 were not eligible.The study was conducted in 11 French centers
Pre-assignment details
Patient wih pathologically confirmed mCRC, KRAS codon 12 and 13 wild type, previously treated with irinotecan, oxaliplatin, fluoropyrimidines and bevacizumab. Eligibility criteria also included : age ≥ 18 years, normal hematopoietic , hepatic and renal functions, measurable disease.No prior treatment with anti-EGFR antibodies.
Participants by arm
| Arm | Count |
|---|---|
| Panitumumab Combined With Irinotecan 1cycle every 14 days (J1=J15). Panitumumab : 6mg/kg in IV infusion over 60 minutes on day 1. Irinotecan : 180mg/m² in IV infusion over 90 minutes on day 1 just after panitumumab administration | 65 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | not eligible | 4 |
Baseline characteristics
| Characteristic | Panitumumab Combined With Irinotecan |
|---|---|
| Adjuvant chemotherapy No | 48 participants |
| Adjuvant chemotherapy Yes | 17 participants |
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 31 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants |
| Age, Continuous | 62 years |
| ECOG Performance status ECOG performance status - PS = 0 | 25 participants |
| ECOG Performance status ECOG - PS=1 | 33 participants |
| ECOG Performance status ECOG - PS=2 | 7 participants |
| First line chemotherapy Irinotecan-based therapy | 22 participants |
| First line chemotherapy Oxaliplatin- and irinotecan-based therapy | 1 participants |
| First line chemotherapy Oxaliplatin-based therapy | 42 participants |
| Number of metastatic sites >1 metastatic site | 28 participants |
| Number of metastatic sites 1 metastatic site | 37 participants |
| Primary tumor type Both | 3 participants |
| Primary tumor type Colon | 45 participants |
| Primary tumor type Rectum | 17 participants |
| Prior treatment with bevacizumab No | 12 participants |
| Prior treatment with bevacizumab Yes | 53 participants |
| Region of Enrollment France | 65 participants |
| Second line chemotherapy Irinotecan-based therapy | 43 participants |
| Second line chemotherapy No second line | 8 participants |
| Second line chemotherapy Oxaliplatin-based therapy | 14 participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 39 Participants |
| Time between diagnosis and inclusion ≥12-24 months | 21 participants |
| Time between diagnosis and inclusion < 12 months | 13 participants |
| Time between diagnosis and inclusion > 24 months | 31 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 29 / 65 |
| serious Total, serious adverse events | 10 / 65 |
Outcome results
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.
Time frame: Up to 20 months
Population: Panitumumab combined with irinotecan
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Panitumumab Combined With Irinotecan | Objective Response Rate (ORR) During the Combination Therapy Phase | Patients with KRAS, NRAS or BRAF mutations | 0 percentage of patients |
| Panitumumab Combined With Irinotecan | Objective Response Rate (ORR) During the Combination Therapy Phase | Whole study population | 29.2 percentage of patients |
| Panitumumab Combined With Irinotecan | Objective Response Rate (ORR) During the Combination Therapy Phase | Confirmed wild-type KRAS population | 35.2 percentage of patients |
| Panitumumab Combined With Irinotecan | Objective Response Rate (ORR) During the Combination Therapy Phase | All wild-type population | 46.3 percentage of patients |
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
Time frame: Up to 20 months
Population: Panitumumab combined with irinotecan
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Panitumumab Combined With Irinotecan | Disease Control Rate (DCR) | Overall period | 63.1 percentage of participants |
| Panitumumab Combined With Irinotecan | Disease Control Rate (DCR) | Confirmed wild-type KRAS population | 66.7 percentage of participants |
| Panitumumab Combined With Irinotecan | Disease Control Rate (DCR) | All Wild-type population | 80.5 percentage of participants |
| Panitumumab Combined With Irinotecan | Disease Control Rate (DCR) | Patients with KRAS, NRAS or BRAF mutation | 21.1 percentage of participants |
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.
Time frame: Up to 20 months
Population: Panitumumab combined with irinotecan
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Panitumumab Combined With Irinotecan | Overall Survival (OS) | Study population | 9.7 percentage of participant |
| Panitumumab Combined With Irinotecan | Overall Survival (OS) | Confirmed wild-type KRAS population | 11.9 percentage of participant |
| Panitumumab Combined With Irinotecan | Overall Survival (OS) | All wild-type population | 15.8 percentage of participant |
| Panitumumab Combined With Irinotecan | Overall Survival (OS) | Patients with KRAS, NRAS or BRAF mutation | 4.6 percentage of participant |
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.
Time frame: Up to 20 months
Population: Panitumumab combined with irinotecan
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Panitumumab Combined With Irinotecan | Progression-free Survival (PFS) | Overall Period | 5.5 percentage of participants |
| Panitumumab Combined With Irinotecan | Progression-free Survival (PFS) | Confirmed wild-type KRAS population | 6.3 percentage of participants |
| Panitumumab Combined With Irinotecan | Progression-free Survival (PFS) | All wild-type population | 8.7 percentage of participants |
| Panitumumab Combined With Irinotecan | Progression-free Survival (PFS) | Patient with KRAS, NRAS or BRAF mutations | 1.9 percentage of participants |