BEYOND: Second-line FOLFIRI + Panitumumab in Subjects With Wild Type RAS Metastatic Colorectal

Sponsor

Grupo Espanol Multidisciplinario del Cancer Digestivo (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03751176

Collaborator

Amgen (Industry), Pivotal S.L. (Industry)

Enrollment

Locations

Arms

48.7

Anticipated Duration (Months)

1.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To estimate progression-free-survival at 6 months in subjects treated in first-line with panitumumab and FOLFOX and with wild type RAS mCRC (metastatic colorectal cancer) confirmed in liquid biopsies before starting second line treatment will be screened for this trial and who have interrupted panitumumab for <3 months (panitumumab continuation). Control arm of subjects treated with FOLFIRI alone will be included.

The combinations of 5-fluorouracil (5-FU) with oxaliplatin (FOLFOX)are considered the backbone chemotherapy for mCRC. Clinical trials have shown the benefit of adding monoclonal antibodies to subjects without mutations in RAS, directed against the epidermal growth factor receptor (EGFR) (cetuximab and panitumumab) to conventional chemotherapy as first-line treatment of mCRC. This trial purposes to study the treatment beyond progression with panitumumab in subjects treated in first-line with an anti-EGFR monoclonal antibody, or rather,the re-introduction of the same targeted therapy after progression to first line.

The clinical hypothesis of this study is that the second-line regimen FOLFIRI + panitumumab, is sufficiently active (defined as a 6-months PFS higher than 30% [based on prior results with second-line FOLFIRI alone] and of at least 50%), justifying further study in this population.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Metastatic	Drug: Panitumumab Drug: Irinotecan Drug: Folinic acid Drug: 5-FU	Phase 2

Detailed Description

A phase II, multicentre, open-label, randomized two-arm study. Subjects treated in first-line with panitumumab and FOLFOX and with wild type RAS mCRC confirmed in liquid biopsies before starting second line treatment will be screened for this trial. Only subjects who have interrupted panitumumab for < 3 months (panitumumab continuation) will be included.

Eligible subjects will receive FOLFIRI + panitumumab until disease progression, onset of unacceptable drug toxicities, or subject/physician's request to discontinue. A control arm of subjects treated with FOLFIRI alone will be included. Subjects will be assigned in a 3:2 ratio to receive FOLFIRI + panitumumab (Group A) or FOLFIRI alone (Group B). Randomization will be stratified by primary tumour location (left vs right). A blood sample will be obtained at baseline and at disease progression in order to determine the mutational status of RAS/BRAF and other biomarkers.

Tumour response assessment will be performed by the investigator according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria (version 1.1). Subjects will be evaluated for tumour response every 8 weeks until documentation of disease progression. Responding disease will be confirmed no less than 28 days after the criteria for response are first met. Subjects with symptoms suggestive of progressive disease should be evaluated for tumour progression at the time the symptoms occur. After second-line treatment discontinuation, information on subsequent lines of treatments at the physician discretion and survival will be collected in follow-up visits carried out every 12 weeks (± 4 weeks) until the end of the study (approximately 20 months after the inclusion of the last subject in the study).

Study Design

Study Type:

Interventional

Actual Enrollment :

31 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Subjects will be assigned in a 3:2 ratio to receive FOLFIRI + panitumumab (Group A) or FOLFIRI alone (Group B). Randomization will be stratified by primary tumour location (left vs right).Subjects will be assigned in a 3:2 ratio to receive FOLFIRI + panitumumab (Group A) or FOLFIRI alone (Group B). Randomization will be stratified by primary tumour location (left vs right).

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase II Clinical Trial to Evaluate the Efficacy of Second-line FOLFIRI + Panitumumab in Subjects With Wild Type RAS Metastatic Colorectal Cancer Who Have Received FOLFOX + Panitumumab in First-line

Actual Study Start Date :

Nov 8, 2018

Actual Primary Completion Date :

Nov 30, 2020

Anticipated Study Completion Date :

Nov 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FOLFIRI + panitumumab Patients received panitumumab plus FOLFIRI in 14-day cycles until disease progression, unacceptable toxicity, investigator's decision or patient withdrawal of consent, at the following doses: Panitumumab: 6 mg/kg administered by intravenous (IV) infusion over 60 min on days 1 and 14 of every cycle just before administration of chemotherapy FOLFIRI: Irinotecan: 180 mg/m2 as IV infusion over 90 min on day 1 Folinic acid: (leucovorin) 200-400 mg/m2 IV over 2 hours on day 1 5-FU: 400 mg/m2 bolus followed by 2400 mg/m2 IV continuous infusion over 46-48 hours on days 1 and 2	Drug: Panitumumab Panitumumab 6 mg/kg will be administered by intravenous (IV) infusion over 60 min on days 1 and 14 of every cycle just before administration of chemotherapy Other Names: Vectibix Drug: Irinotecan Irinotecan 180 mg/m2 will be administered as IV infusion over 90 min on day 1 Other Names: Any marketed Drug: Folinic acid Folinic acid 200-400 mg/m2 will be administered as IV infusion over 2 hours on day 1 Other Names: Any marketed Leucovorin Drug: 5-FU 5-FU will be administered IV 400 mg/m2 bolus followed by 2400 mg/m2 IV continuous infusion over 46-48 hours on days 1 and 2 Other Names: Any marketed 5-fluorouracil
Active Comparator: FOLFIRI Patients received FOLFIRI in 14-day cycles until disease progression, unacceptable toxicity, investigator's decision or patient withdrawal of consent, at the following doses: Irinotecan: 180 mg/m2 as IV infusion over 90 min on day 1 Folinic acid: (leucovorin) 200-400 mg/m2 IV over 2 hours on day 1 5-FU: 400 mg/m2 bolus followed by 2400 mg/m2 IV continuous infusion over 46-48 hours on days 1 and 2	Drug: Irinotecan Irinotecan 180 mg/m2 will be administered as IV infusion over 90 min on day 1 Other Names: Any marketed Drug: Folinic acid Folinic acid 200-400 mg/m2 will be administered as IV infusion over 2 hours on day 1 Other Names: Any marketed Leucovorin Drug: 5-FU 5-FU will be administered IV 400 mg/m2 bolus followed by 2400 mg/m2 IV continuous infusion over 46-48 hours on days 1 and 2 Other Names: Any marketed 5-fluorouracil

Arm

Intervention/Treatment

Experimental: FOLFIRI + panitumumab

Patients received panitumumab plus FOLFIRI in 14-day cycles until disease progression, unacceptable toxicity, investigator's decision or patient withdrawal of consent, at the following doses: Panitumumab: 6 mg/kg administered by intravenous (IV) infusion over 60 min on days 1 and 14 of every cycle just before administration of chemotherapy FOLFIRI: Irinotecan: 180 mg/m2 as IV infusion over 90 min on day 1 Folinic acid: (leucovorin) 200-400 mg/m2 IV over 2 hours on day 1 5-FU: 400 mg/m2 bolus followed by 2400 mg/m2 IV continuous infusion over 46-48 hours on days 1 and 2

Drug: Panitumumab

Panitumumab 6 mg/kg will be administered by intravenous (IV) infusion over 60 min on days 1 and 14 of every cycle just before administration of chemotherapy

Other Names:

Vectibix

Drug: Irinotecan

Irinotecan 180 mg/m2 will be administered as IV infusion over 90 min on day 1

Other Names:

Any marketed

Drug: Folinic acid

Folinic acid 200-400 mg/m2 will be administered as IV infusion over 2 hours on day 1

Other Names:

Any marketed

Leucovorin

Drug: 5-FU

5-FU will be administered IV 400 mg/m2 bolus followed by 2400 mg/m2 IV continuous infusion over 46-48 hours on days 1 and 2

Other Names:

Any marketed

5-fluorouracil

Active Comparator: FOLFIRI

Patients received FOLFIRI in 14-day cycles until disease progression, unacceptable toxicity, investigator's decision or patient withdrawal of consent, at the following doses: Irinotecan: 180 mg/m2 as IV infusion over 90 min on day 1 Folinic acid: (leucovorin) 200-400 mg/m2 IV over 2 hours on day 1 5-FU: 400 mg/m2 bolus followed by 2400 mg/m2 IV continuous infusion over 46-48 hours on days 1 and 2

Drug: Irinotecan

Irinotecan 180 mg/m2 will be administered as IV infusion over 90 min on day 1

Other Names:

Any marketed

Drug: Folinic acid

Folinic acid 200-400 mg/m2 will be administered as IV infusion over 2 hours on day 1

Other Names:

Any marketed

Leucovorin

Drug: 5-FU

5-FU will be administered IV 400 mg/m2 bolus followed by 2400 mg/m2 IV continuous infusion over 46-48 hours on days 1 and 2

Other Names:

Any marketed

5-fluorouracil

Outcome Measures

Primary Outcome Measures

Progression-free survival at 6 months [6 months after inclusion]
The proportion of subjects progression free at 6 months

Secondary Outcome Measures

Progression-free survival (PFS) [38 months]
Time from randomization to progression or death (Kaplan-Meier estimate)
Overall response rate (ORR) [38 months]
Proportion of subjects with an objective response (complete or partial response) per RECIST 1.1 criteria
Overall survival (OS) [38 months]
Time from randomization to the date of death, with participants alive or lost to follow-up at the analysis data cut-off date censored at their last contact date (Kaplan-Meier estimate)
Safety and tolerability. ( assessment will consist of monitoring adverse events (AEs), including serious adverse events (SAEs) and laboratory safety parameters) [38 months]
Safety assessment will consist of monitoring adverse events (AEs), including serious adverse events (SAEs) and laboratory safety parameters. AEs will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
Biomarkers analysis by liquid biopsies. [38 months]
Conversion rate of RAS/BRAF status according to liquid biopsy determinations at second-line treatment initiation and at the time of disease progression after second-line treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Man or woman at least 18 years old
Capable of understand, sign and date an informed consent approved by an IEC (investigational Ethics Committee)
Histologically confirmed adenocarcinoma of the colon or rectum in subjects with metastatic disease
Having received a 1st line chemotherapy regimen for mCRC consisting of FOLFOX + panitumumab and having at least achieved stable disease ( i.e., CR (Complete Response) PR (Partial Response) or SD (stable disease) )
Wild-type RAS tumour status confirmed in liquid biopsies before starting second-line treatment
At least one unidimensionally measurable lesion of at least 10 mm per RECIST criteria (version 1.1)
Subjects not candidates for metastasectomy
Tumour disease staging according to RECIST (version 1.1) by investigator up to 4 weeks prior to start of study treatment
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
Adequate bone marrow function: neutrophils ≥1.5 x109/ L; platelets ≥100 x109/L; haemoglobin ≥9 g/dL
Hepatic, renal and metabolic function as follows:

Total bilirubin count ≤1.5 x upper limit of normal (ULN), ALT (alanine aminotransferase) and AST (aspartate aminotransferase) <2.5 x ULN; or in case of liver metastasis ALT and AST <5 x ULN
Renal function, calculated as creatinine clearance or 24-hour creatinine clearance ≥ 50 mL/min
Magnesium > lower limit of normal (LLN) -

Exclusion Criteria:

Diagnosis of progressive disease more than 3 months after the last panitumumab administration
First-line PFS of less than 3 months
Subjects given less than 3 months (consecutive) of first-line panitumumab
History of prior or concurrent central nervous system (CNS) metastases
History of another primary cancer, except: curatively treated in situ cervical cancer, or curatively resected non-melanoma skin cancer, or other primary solid tumour curatively treated with no known active disease present and no treatment administered for ≥ 5 years before inclusion
Prior irinotecan therapy
Unresolved toxicities of a previous systemic treatment that, in the opinion of the investigator, cause the subject unfit for inclusion
Prior hormonal therapy, immunotherapy or approved or experimental antibody/proteins ≤ 30 days before inclusion (excluding panitumumab)
Any investigational agent within 30 days prior to inclusion
Evidence of previous acute hypersensitivity reaction, of any grade, to any component of the treatment
History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest computerised tomography
Acute or subacute intestinal occlusion and/or active inflammatory bowel disease or other bowel disease that causes chronic diarrhoea (defined as grade ≥ 2 diarrhoea according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03)
Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiating study treatment or a history of ventricular arrhythmia
History of Gilbert disease or known dihydropyrimidine deficiency syndrome
Known positive test for human immunodeficiency virus infection, hepatitis C virus, chronic active hepatitis B infection
Treatment for systemic infection within 14 days before the start of study treatment
History of any disease that may increase the risks associated with study participation or may interfere with the interpretation of study results
Surgery (excluding diagnostic biopsy or placement of a central venous catheter) and/or radiotherapy within 28 days prior to inclusion in the study.
Pregnant or breastfeeding woman
Male or female of childbearing age who do not agree with taking adequate contraceptive precautions, i.e. use contraception double barrier (e.g., diaphragm plus condoms) or abstinence during the course of the study and for 6 months after the last administration of study drug for women and 1 month for men
The subject is unwilling or unable to meet the requirements of the study
Psychological, geographical, familial or sociological conditions that potentially prevent compliance with the study protocol and follow-up schedule. These conditions should be discussed with the subject before inclusion in the trial. -

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ICO Girona Dr. Josep Trueta	Gerona	Barcelona	Spain	17007
2	Hospital de Granollers	Granollers	Barcelona	Spain	08402
3	Hospital Mutua de Terrassa	Terrassa	Barcelona	Spain	08221
4	Hospital General Universitario de Elche	Alicante	Elche	Spain	03203
5	Hospital Universitario Fundación Alcorcón	Alcorcón	Madrid	Spain	28922
6	H. Universitari Sant Joan de Reus	Reus	Tarragona	Spain	43204
7	Hospital de La Ribera de Alzira	Alzira	Valencia	Spain	46600
8	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
9	Hospital Clínic de Barcelona	Barcelona		Spain	08036
10	Hospital de la Santa Creu I Sant Pau	Barcelona		Spain	08041
11	Hospital 12 de Octubre	Madrid		Spain	28041
12	Hospital Universtiario la Paz	Madrid		Spain	28046
13	CIOCC Sanchinarro	Madrid		Spain	28050
14	Complejo Hospitalario de Navarra	Navarro		Spain	31008
15	Corporació Sanitaria Parc Taulí	Sabadell		Spain	08208
16	Fundación Instituto Valenciano de Oncología	Valencia		Spain	46009
17	Hospital Universitario Dr. Peset	Valencia		Spain	46017
18	Hospital Universitario y Politécnico La Fe	Valencia		Spain	46026