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

• Sponsor: GERCOR - Multidisciplinary Oncology Cooperative Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00655499
• Collaborator: (none)
• Enrollment: 65
• Locations: 9
• Arm: 1
• Duration (Months): 48
• Patients Per Site: 7.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: Panitumumab; Drug: Irinotecan hydrochloride; Genetic: Chromogenic in situ hybridization; Genetic: Fluorescence in situ hybridization; Genetic: Gene expression analysis; Other: Laboratory biomarker analysis	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Study Start Date: Jun 1, 2008
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Panitumumab + CPT11 (irinotecan hydrochloride) 1 cycle every 14 days (J1= J15)	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; Other: Laboratory biomarker analysis

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centre Paul Papin	Angers		France	49036
2	Hopital Prive Jean Mermoz	Lyon		France	69008
3	Hopital Clinique Claude Bernard	Metz		France	57072
4	Centre Hospitalier Intercommunal Le Raincy - Montfermeil	Montfermeil		France	93370
5	Hopital Pitie-Salpetriere	Paris		France	75013
6	Hopital Bichat - Claude Bernard	Paris		France	75018
7	Hopital Saint Antoine	Paris		France	75571
8	Hopital Tenon	Paris		France	75970
9	Hopital Foch	Suresnes		France	92151

Sponsors and Collaborators

• GERCOR - Multidisciplinary Oncology Cooperative Group

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Annals of Oncology journal
• ASCO 2011 meeting

Publications

None provided.

• Responsible Party: GERCOR - Multidisciplinary Oncology Cooperative Group
• ClinicalTrials.gov Identifier: NCT00655499
• Other Study ID Numbers: CDR0000593012; GERCOR-PIMABI-C07-1; 2007-004806-28; EU-20836; AMGEN-GERCOR-PIMABI-C07-1
• First Posted: Apr 10, 2008
• Last Update Posted: Sep 21, 2021
• Last Verified: Aug 1, 2016

• Keywords provided by GERCOR - Multidisciplinary Oncology Cooperative Group: adenocarcinoma of the colon; adenocarcinoma of the rectum; stage IV colon cancer; recurrent rectal cancer; stage IV rectal cancer; recurrent colon cancer
• Additional relevant MeSH terms: Colorectal Neoplasms; Irinotecan; Panitumumab

Study Results

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 Detail	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.

Arm/Group Title	Panitumumab Combined With Irinotecan
Arm/Group Description	65 patients were eligible (69 patients were enrolled and 4 patients were not eligible).
Period Title: Overall Study
STARTED	69
COMPLETED	65
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Panitumumab Combined With Irinotecan
Arm/Group Description	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
Overall Participants	65
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	34 52.3%
>=65 years	31 47.7%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	26 40%
Male	39 60%
Region of Enrollment (participants) [Number]
France	65 100%
ECOG Performance status (participants) [Number]
ECOG performance status - PS = 0	25 38.5%
ECOG - PS=1	33 50.8%
ECOG - PS=2	7 10.8%
Primary tumor type (participants) [Number]
Colon	45 69.2%
Rectum	17 26.2%
Both	3 4.6%
Number of metastatic sites (participants) [Number]
1 metastatic site	37 56.9%
>1 metastatic site	28 43.1%
Adjuvant chemotherapy (participants) [Number]
Yes	17 26.2%
No	48 73.8%
Time between diagnosis and inclusion (participants) [Number]
< 12 months	13 20%
≥12-24 months	21 32.3%
> 24 months	31 47.7%
First line chemotherapy (participants) [Number]
Oxaliplatin-based therapy	42 64.6%
Irinotecan-based therapy	22 33.8%
Oxaliplatin- and irinotecan-based therapy	1 1.5%
Second line chemotherapy (participants) [Number]
Oxaliplatin-based therapy	14 21.5%
Irinotecan-based therapy	43 66.2%
No second line	8 12.3%
Prior treatment with bevacizumab (participants) [Number]
No	12 18.5%
Yes	53 81.5%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR) During the Combination Therapy Phase
Description	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

Outcome Measure Data

Analysis Population Description

Panitumumab combined with irinotecan

Arm/Group Title	Panitumumab Combined With Irinotecan
Arm/Group Description	69 patients were enrolled in the study. 4 patients were not eligible. 65 eligible patients were analysed
Measure Participants	65
Whole study population	29.2
Confirmed wild-type KRAS population	35.2
All wild-type population	46.3
Patients with KRAS, NRAS or BRAF mutations	0

2. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	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

Outcome Measure Data

Analysis Population Description

Panitumumab combined with irinotecan

Arm/Group Title	Panitumumab Combined With Irinotecan
Arm/Group Description	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
Measure Participants	65
Overall period	63.1 97.1%
Confirmed wild-type KRAS population	66.7 102.6%
All Wild-type population	80.5 123.8%
Patients with KRAS, NRAS or BRAF mutation	21.1 32.5%

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	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

Outcome Measure Data

Analysis Population Description

Panitumumab combined with irinotecan

Arm/Group Title	Panitumumab Combined With Irinotecan
Arm/Group Description	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
Measure Participants	65
Overall Period	5.5 8.5%
Confirmed wild-type KRAS population	6.3 9.7%
All wild-type population	8.7 13.4%
Patient with KRAS, NRAS or BRAF mutations	1.9 2.9%

4. Secondary Outcome

Title	Overall Survival (OS)
Description	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

Outcome Measure Data

Analysis Population Description

Panitumumab combined with irinotecan

Arm/Group Title	Panitumumab Combined With Irinotecan
Arm/Group Description	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
Measure Participants	65
Study population	9.7
Confirmed wild-type KRAS population	11.9
All wild-type population	15.8
Patients with KRAS, NRAS or BRAF mutation	4.6

Adverse Events

Time Frame	From the date of inclusion to 56 ± 3 days after the last dosing of study treatment
Adverse Event Reporting Description	Adverse events (AE) were collected during the treatment period and safety follow-up phases and were graded using NCI-CTCAE version 3.0.
Arm/Group Title	Panitumumab + CPT11
Arm/Group Description	1 cycle every 14 days (J1= J15) panitumumab: Panitumumab : 6mg/kg irinotecan hydrochloride: 180mg/kg chromogenic in situ hybridization fluorescence in situ hybridization gene expression analysis laboratory biomarker analysis
All Cause Mortality
	Panitumumab + CPT11
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Panitumumab + CPT11
	Affected / at Risk (%)	# Events
Total	10/65 (15.4%)
Cardiac disorders
Tachycardia	1/65 (1.5%)	1
Gastrointestinal disorders
occlusion	4/65 (6.2%)	4
Diarrhoea	3/65 (4.6%)	3
General disorders
General physical health deterioration	3/65 (4.6%)	3
Nervous system disorders
Epilepsy	1/65 (1.5%)	1
Respiratory, thoracic and mediastinal disorders
dyspnea	1/65 (1.5%)	1
Vascular disorders
Occular hemorraghe	1/65 (1.5%)	1
Other (Not Including Serious) Adverse Events
	Panitumumab + CPT11
	Affected / at Risk (%)	# Events
Total	29/65 (44.6%)
Blood and lymphatic system disorders
Neutropenia	8/65 (12.3%)
Gastrointestinal disorders
Diarrhoea	10/65 (15.4%)
Mucositis	1/65 (1.5%)
Skin and subcutaneous tissue disorders
skin toxicity	21/65 (32.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.