FOLFIRI and Panitumumab in Treating Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer

• Sponsor: City of Hope Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02508077
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 1
• Locations: 4
• Arm: 1
• Actual Duration (Months): 18.9
• Patients Per Site: 0.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II trial studies how well fluorouracil, leucovorin calcium, and irinotecan hydrochloride (FOLFIRI) together with panitumumab work in treating patients with colorectal cancer that expresses the RAS and B-Raf proto-oncogene, serine/threonine kinase (BRAF) wild-type genes, has spread from the original site of growth to another part of the body (metastatic), resists the effects of treatment with prior cetuximab (or panitumumab) plus irinotecan hydrochloride-based therapy, and who have failed at least one subsequent non-anti-epidermal growth factor receptor (EGFR) containing treatment regimen. Drugs used in chemotherapy, such as fluorouracil, leucovorin calcium, and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as panitumumab, may block tumor growth in different ways by targeting certain cells. Giving FOLFIRI together with panitumumab may be an effective treatment for colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Colorectal Carcinoma; Stage IVA Colorectal Cancer; Stage IVB Colorectal Cancer	Drug: Fluorouracil; Drug: Irinotecan Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Leucovorin Calcium; Biological: Panitumumab	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Estimate the response rate (RR) and progression-free survival (PFS) with FOLFIRI + panitumumab in patients with acquired resistance to panitumumab (or cetuximab) + irinotecan (irinotecan hydrochloride)-based therapy after a documented clinical response or prolonged PFS and following progression on a subsequent non-anti-EGFR containing regimen in extended RAS wild-type and BRAF wild-type patients.

SECONDARY OBJECTIVES:

1. Estimate the overall survival (OS) in the re-challenge populations.

2. Describe the safety of re-challenge in this population.

3. Investigate the impact of PFS, RR on prior anti-EGFR + irinotecan-based exposure on the response and PFS on the current study.

TERTIARY OBJECTIVES:

1. Collect serial plasma samples to investigate the incidence of RAS and BRAF mutation in circulating free deoxyribonucleic acid (DNA) at baseline, every 2 months, and at the time to progression (and following progression when feasible).

2. Collect serial plasma samples for future biomarker exploration, including the potential investigation of micro-ribonucleic acid (RNA).

OUTLINE:

Patients receive panitumumab intravenously (IV) over 30-90 minutes, irinotecan hydrochloride IV over 90 minutes, leucovorin calcium orally (PO), and fluorouracil IV over 46 hours on day

1. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective Study of FOLFIRI Plus Panitumumab in Extended RAS Wild Type and BRAF Wild Type Metastatic Colorectal Cancer With Acquired Resistance to Prior Cetuximab (or Panitumumab) Plus Irinotecan-Based Therapy and Who Failed at Least One Subsequent Non-anti-EGFR Containing Regimen
• Actual Study Start Date: Feb 16, 2016
• Actual Primary Completion Date: Sep 13, 2017
• Actual Study Completion Date: Sep 13, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (panitumumab and FOLFIRI) Patients receive panitumumab IV over 30-90 minutes, irinotecan hydrochloride IV over 90 minutes, leucovorin calcium PO, and fluorouracil IV over 46 hours on day 1. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.

Drug: Fluorouracil; Given IV; Other Names: 5-Fluoro-2,4(1H, 3H)-pyrimidinedione 5-Fluorouracil 5-Fluracil 5-FU AccuSite Actino-Hermal Adrucil Arumel Cytosafe Efudex Efurix Fiverocil Fluoro Uracil Fluoroplex Fluouracil Flurablastin Fluracedyl Fluracil Fluril Fluroblastin Flurox Ribofluor Ro 2-9757 Ro-2-9757 Timazin ; Drug: Irinotecan Hydrochloride; Given IV; Other Names: Campto Camptosar Camptothecin 11 Camptothecin-11 CPT 11 CPT-11 U-101440E ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Leucovorin Calcium; Given PO; Other Names: Adinepar Calcifolin Calcium (6S)-Folinate Calcium Folinate Calcium Leucovorin Calfolex Calinat Cehafolin Citofolin Citrec Citrovorum Factor Cromatonbic Folinico Dalisol Disintox Divical Ecofol Emovis Factor, Citrovorum Flynoken A Folaren Folaxin FOLI-cell Foliben Folidan Folidar Folinac Folinate Calcium folinic acid Folinic Acid Calcium Salt Pentahydrate Folinoral Folinvit Foliplus Folix Imo Lederfolat Lederfolin Leucosar leucovorin Rescufolin Rescuvolin Tonofolin Wellcovorin ; Biological: Panitumumab; Given IV; Other Names: ABX-EGF ABX-EGF Monoclonal Antibody ABX-EGF, Clone E7.6.3 MoAb ABX-EGF Monoclonal Antibody ABX-EGF Vectibix

Outcome Measures

Primary Outcome Measures

1. 4-month Progression-free Survival (PFS) Rate [At 4 months]

   PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Will be estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (including baseline sum), or a measurable increase in a non-target lesion, or the appearance of new lesions.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participant must have the ability to understand and the willingness to sign a written informed consent document

• Participant must be willing to comply with study and/or follow-up procedures

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Life expectancy of 3 >= months

• Histologically confirmed colon or rectal cancer with metastatic disease

• Extended RAS and BRAF wild type status documented on archival tumor tissue or on fresh biopsy if no archival tissue present

• Measurable disease defined by at least 1 lesion >= 1 cm

• Documented objective response or stable disease lasting for 6 months or more to last prior anti-EGFR (cetuximab or panitumumab) in combination with irinotecan or FOLFIRI

• Progression within 6 weeks following their last dose of anti-EGFR therapy

• Treatment with a non-EGFR targeting regimen following progression on anti-EGFR plus irinotecan-based therapy

• At least 4 months from prior anti-EGFR therapy prior to start of study treatment

• At least three weeks from any non-anti-EGFR therapy prior to start of study treatment; any number of prior therapies is permitted

• Adequate recovery in the investigators opinion from any clinically significant toxicity from prior therapy

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

• Hemoglobin (Hgb) >= 9 g/dL without transfusions

• Platelets (PLT) >= 100 x 10^9/L without transfusions

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and/or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x upper limit of normal (ULN); patient with liver metastases =< 5 x ULN

• Total bilirubin =< ULN

• Creatinine =< 1.5 mg/dL

• Magnesium >= 1.2mg/dL or 0.5 mmol/L

• Negative serum beta-human chorionic gonadotropin (HCG) test (female patient of childbearing potential only), to be performed locally within the screening period

• Agreement by females of childbearing potential and sexually active males to use an effective method of contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for three months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately

Exclusion Criteria:

• History of severe anti-EGFR toxicity requiring drug discontinuation or dose-modification within the first 4 months of prior anti-EGFR therapy

• History of intolerance to irinotecan at dose-intensity of 125 mg/m^2/2 weeks or lower

• History of intolerance to 5-FU at dose-intensity of 1800 mg/m^2/2 weeks or lower

• Current use (or planned use during the treatment period) of other investigational agents, or biological, chemotherapy, radiation or other anti-tumor therapy

• Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids, such as systemic cyclosporine and tacrolimus

• No St John's wort supplement or other herbal supplementation is allowed while on trial; patients are not to take grapefruit juice during study treatment

• Use of drugs known to inhibit UDP glycosyltransferase 1 family, polypeptide A1 gene (UGT1A1), such as Atazanavir, Gemfibrozil, Indinavir, or Ketoconazole while on study treatment; (patients using these drugs must not take these drugs on the day study treatment begins and for the duration of study treatment)

• Planned use of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors or CYP3A4 inducers while on study treatment unless deemed clinically necessary with no reasonable alternatives and with expressed permission from the principal investigator

• If on anticoagulation, participant must be on stable therapeutic dose prior to enrollment

• Impairment of gastrointestinal function or gastrointestinal disease (e.g., active ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, extensive small bowel resection)

• Major surgery =< 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure

• Unstable pulmonary embolism, deep vein thrombosis, or other significant arterial/venous thromboembolic event =< 30 days before enrollment

• Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) =< 6 months prior to enrollment

• History of interstitial lung disease (ILD) eg, interstitial pneumonitis, pulmonary fibrosis or evidence of ILD on baseline chest computed tomography (CT) or magnetic resonance imaging (MRI)

• Other active malignancies except cervical carcinomas in situ or clinically insignificant non-melanoma skin cancers

• Clinically significant uncontrolled illness or active infections

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan, 5-FU, leucovorin or any of the products to be administered during dosing

• Pregnant women and women who are lactating; breastfeeding should be discontinued if the mother is enrolled on this study

• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/psychological issues, etc

• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Medical Center	Duarte	California	United States	91010
2	City of Hope Antelope Valley	Lancaster	California	United States	93534
3	City of Hope Rancho Cucamonga	Rancho Cucamonga	California	United States	91730
4	South Pasadena Cancer Center	South Pasadena	California	United States	91030

Sponsors and Collaborators

• City of Hope Medical Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Marwan Fakih, City of Hope Comprehensive Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 7, 2016

More Information

Publications

None provided.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT02508077
• Other Study ID Numbers: 15117; NCI-2015-01241; 118713; 15117
• First Posted: Jul 24, 2015
• Last Update Posted: Aug 16, 2018
• Last Verified: Jul 1, 2018

• Additional relevant MeSH terms: Colorectal Neoplasms; Calcium, Dietary; Leucovorin; Folic Acid; Antineoplastic Agents, Immunological; Panitumumab; Fluorouracil; Irinotecan; Camptothecin; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Calcium; Levoleucovorin

Study Results

Participant Flow

Arm/Group Title	Treatment (Panitumumab and FOLFIRI)
Arm/Group Description	Patients receive 6mg/kg panitumumab IV over 30-90 minutes, 180mg/m2 irinotecan hydrochloride IV over 90 minutes, 400mg/m2 leucovorin calcium PO, and 2400mg/m2 fluorouracil IV over 46 hours on day 1. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Leucovorin Calcium: Given PO Panitumumab: Given IV
Period Title: Overall Study
STARTED	1
COMPLETED	1
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Panitumumab and FOLFIRI)
Arm/Group Description	Patients receive 6mg/kg panitumumab IV over 30-90 minutes, 180mg/m2 irinotecan hydrochloride IV over 90 minutes, 400mg/m2 leucovorin calcium PO, and 2400mg/m2 fluorouracil IV over 46 hours on day 1. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Leucovorin Calcium: Given PO Panitumumab: Given IV
Overall Participants	1
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	1 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	1 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	1 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	1 100%

Outcome Measures

1. Primary Outcome

Title	4-month Progression-free Survival (PFS) Rate
Description	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Will be estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (including baseline sum), or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	At 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Panitumumab and FOLFIRI)
Arm/Group Description	Patients receive 6mg/kg panitumumab IV over 30-90 minutes, 180mg/m2 irinotecan hydrochloride IV over 90 minutes, 400mg/m2 leucovorin calcium PO, and 2400mg/m2 fluorouracil IV over 46 hours on day 1. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Leucovorin Calcium: Given PO Panitumumab: Given IV
Measure Participants	1
Number [percentage of participants]	0 0%

Adverse Events

Time Frame	Adverse events occurred over a period of 12 weeks.
Adverse Event Reporting Description	"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Arm/Group Title	Treatment (Panitumumab and FOLFIRI)
Arm/Group Description	Patients receive 6mg/kg panitumumab IV over 30-90 minutes, 180mg/m2 irinotecan hydrochloride IV over 90 minutes, 400mg/m2 leucovorin calcium PO, and 2400mg/m2 fluorouracil IV over 46 hours on day 1. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Fluorouracil: Given IV Irinotecan Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Leucovorin Calcium: Given PO Panitumumab: Given IV
All Cause Mortality
	Treatment (Panitumumab and FOLFIRI)
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Serious Adverse Events
	Treatment (Panitumumab and FOLFIRI)
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Panitumumab and FOLFIRI)
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Blood and lymphatic system disorders
Leukocytosis	1/1 (100%)	1
blood anion gap decreased.	1/1 (100%)	1
Gastrointestinal disorders
Nausea	1/1 (100%)	1
Metabolism and nutrition disorders
Hypermagnesemia	1/1 (100%)	1
Hyponatremia	1/1 (100%)	1
Obesity	1/1 (100%)	1
Renal and urinary disorders
Hematuria	1/1 (100%)	1
Skin and subcutaneous tissue disorders
Dry skin	1/1 (100%)	2
Rash acneiform	1/1 (100%)	1
Rash maculo-papular	1/1 (100%)	1
Vascular disorders
Thromboembolic event	1/1 (100%)	1

Limitations/Caveats

Study was terminated early due to poor accrual.

More Information

Certain Agreements

All Principal Investigators ARE 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.