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

Colorectal Cancer Metastatic Clinical Trial

— BEYOND  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03751176
• Other study ID #: GEMCAD-17-01
• Secondary ID: 2017-004519-38
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: November 8, 2018
• Est. completion date: November 30, 2022

Study information

• Verified date: June 2021
• Source: Grupo Espanol Multidisciplinario del Cancer Digestivo
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 31
• Est. completion date: November 30, 2022
• Est. primary completion date: November 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

1. Man or woman at least 18 years old

2. Capable of understand, sign and date an informed consent approved by an IEC (investigational Ethics Committee)

3. Histologically confirmed adenocarcinoma of the colon or rectum in subjects with metastatic disease

4. 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) )

5. Wild-type RAS tumour status confirmed in liquid biopsies before starting second-line treatment

6. At least one unidimensionally measurable lesion of at least 10 mm per RECIST criteria (version 1.1)

7. Subjects not candidates for metastasectomy

8. Tumour disease staging according to RECIST (version 1.1) by investigator up to 4 weeks prior to start of study treatment

9. Eastern Cooperative Oncology Group (ECOG) performance status = 2

10. Adequate bone marrow function: neutrophils =1.5 x109/ L; platelets =100 x109/L; haemoglobin =9 g/dL

11. 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:

1. Diagnosis of progressive disease more than 3 months after the last panitumumab administration

2. First-line PFS of less than 3 months

3. Subjects given less than 3 months (consecutive) of first-line panitumumab

4. History of prior or concurrent central nervous system (CNS) metastases

5. 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

6. Prior irinotecan therapy

7. Unresolved toxicities of a previous systemic treatment that, in the opinion of the investigator, cause the subject unfit for inclusion

8. Prior hormonal therapy, immunotherapy or approved or experimental antibody/proteins = 30 days before inclusion (excluding panitumumab)

9. Any investigational agent within 30 days prior to inclusion

10. Evidence of previous acute hypersensitivity reaction, of any grade, to any component of the treatment

11. History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest computerised tomography

12. 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)

13. Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiating study treatment or a history of ventricular arrhythmia

14. History of Gilbert disease or known dihydropyrimidine deficiency syndrome

15. Known positive test for human immunodeficiency virus infection, hepatitis C virus, chronic active hepatitis B infection

16. Treatment for systemic infection within 14 days before the start of study treatment

17. History of any disease that may increase the risks associated with study participation or may interfere with the interpretation of study results

18. Surgery (excluding diagnostic biopsy or placement of a central venous catheter) and/or radiotherapy within 28 days prior to inclusion in the study.

19. Pregnant or breastfeeding woman

20. 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

21. The subject is unwilling or unable to meet the requirements of the study

22. 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. -

Related Conditions & MeSH terms

• Colorectal Cancer Metastatic
• Colorectal Neoplasms

Intervention

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
• Irinotecan
Irinotecan 180 mg/m2 will be administered as IV infusion over 90 min on day 1
• Folinic acid
Folinic acid 200-400 mg/m2 will be administered as IV infusion over 2 hours on day 1
• 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

Locations

Country	Name	City	State
Spain	Hospital Universitario Fundación Alcorcón	Alcorcón	Madrid
Spain	Hospital General Universitario de Elche	Alicante	Elche
Spain	Hospital de La Ribera de Alzira	Alzira	Valencia
Spain	Hospital Clínic de Barcelona	Barcelona
Spain	Hospital de la Santa Creu I Sant Pau	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	ICO Girona Dr. Josep Trueta	Gerona	Barcelona
Spain	Hospital de Granollers	Granollers	Barcelona
Spain	CIOCC Sanchinarro	Madrid
Spain	Hospital 12 de Octubre	Madrid
Spain	Hospital Universtiario la Paz	Madrid
Spain	Complejo Hospitalario de Navarra	Navarro
Spain	H. Universitari Sant Joan de Reus	Reus	Tarragona
Spain	Corporació Sanitaria Parc Taulí	Sabadell
Spain	Hospital Mutua de Terrassa	Terrassa	Barcelona
Spain	Fundación Instituto Valenciano de Oncología	Valencia
Spain	Hospital Universitario Dr. Peset	Valencia
Spain	Hospital Universitario y Politécnico La Fe	Valencia

Sponsors (3)

Lead Sponsor	Collaborator
Grupo Espanol Multidisciplinario del Cancer Digestivo	Amgen, Pivotal S.L.

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival at 6 months	The proportion of subjects progression free at 6 months	6 months after inclusion
Secondary	Progression-free survival (PFS)	Time from randomization to progression or death (Kaplan-Meier estimate)	38 months
Secondary	Overall response rate (ORR)	Proportion of subjects with an objective response (complete or partial response) per RECIST 1.1 criteria	38 months
Secondary	Overall survival (OS)	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)	38 months
Secondary	Safety and tolerability. ( assessment will consist of monitoring adverse events (AEs), including serious adverse events (SAEs) and laboratory safety parameters)	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	38 months
Secondary	Biomarkers analysis by liquid biopsies.	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	38 months

External Links

•   GEMCAD (Grupo Español Multidisciplinar en Cancer Digestivo) web page