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

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

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.

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).

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. -