Patients with metastatic colorectal cancer (mCRC) who have received all approved standard treatments (except Regorafenib and TAS 102) no longer have treatment options available while maintaining a good performance status which would allow them to receive a new treatment

NCT03829462

Conditions

1. Metastatic Colorectal Cancer (mCRC)

Interventions

1. Drug: Regorafenib
2. Drug: Irinotecan

MeSH:Colorectal Neoplasms

HPO:Neoplasm of the large intestine

Inclusion Criteria: - Signed informed consent obtained before any study specific procedures - Male or female ≥ 18 years of age - Histological or cytological documentation of adenocarcinoma of the colon or rectum - Patients with metastatic colorectal cancer - Progression during or within 3 months following the last administration of approved standard therapies, which must include a fluoropyrimidine (or raltitrexed), oxaliplatin, irinotecan, anti VEGF therapy and an anti EGFR therapy (for RAS wild-type tumors) - ECOG performance status ≤1 - Life expectancy of at least 3 months - Patients with A/A CCND1 genotype of rs603965 CCND1 - Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment: Amylase and lipase ≤1.5 x ULN,Total bilirubin ≤ 1.5 x ULN,Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN (≤ 5 x ULN for patients with liver involvement of their cancer), Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with liver involvement for their cancer and/or have bone metastases), Platelet count ≥ 100,000/mm3; Hemoglobin (Hb) ≥ 9 g/dL; Absolute neutrophil count (ANC) ≥ 1,500/ mm3.

Exclusion Criteria: - Patients with A/G or G/G CCND1 genotype of rs603965 CCND1 - Prior treatment with regorafenib or sorafenib - Prior treatment with TAS 102 - Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study drug - Pregnant or breast-feeding subjects.

(Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management) - Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE V5.0 Grade 2 dyspnea) - Ongoing infection > Grade 2 NCI-CTCAE V5.0 - Known history of human immunodeficiency virus (HIV) infection - Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy - Patients with seizure disorder requiring medication - History of organ allograft - Patients with evidence or history of any bleeding diathesis, irrespective of severity - Any hemorrhage or bleeding event ≥ NCI-CTC V5.0 Grade 3 within 4 weeks prior to the start of study medication - Non-healing wound, ulcer, or bone fracture - Dehydration NCI-CTCAE V5.0 Grade ≥ 1 - Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results - Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation - Any illness or medical conditions that are unstable or could - jeopardize the safety of the subject and his/her compliance in the study - Persistent proteinuria of NCI-CTCAE V5.0 Grade 3 (> 3.5g/24 hours) - Patients unable to swallow oral medications - Any malabsorption condition - Chronic inflammatory bowel disease and / or bowel obstruction - Unresolved toxicity higher than NCI-CTCAE V.5.0 Grade 1 attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced neurotoxicity ≤ Grade 2 - Concomitant participation or participation within the last 30 days in another clinical trial - Systemic anticancer therapy during this trial or within 4 weeks before randomization - Concomitant intake of st John's wort - Live attenuated vaccines are prohibited 10 days before the treatment, during the treatment and 6 months after the termination of treatment - History of gastrointestinal fistula or perforation Inclusion Criteria: - Signed informed consent obtained before any study specific procedures - Male or female ≥ 18 years of age - Histological or cytological documentation of adenocarcinoma of the colon or rectum - Patients with metastatic colorectal cancer - Progression during or within 3 months following the last administration of approved standard therapies, which must include a fluoropyrimidine (or raltitrexed), oxaliplatin, irinotecan, anti VEGF therapy and an anti EGFR therapy (for RAS wild-type tumors) - ECOG performance status ≤1 - Life expectancy of at least 3 months - Patients with A/A CCND1 genotype of rs603965 CCND1 - Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment: Amylase and lipase ≤1.5 x ULN,Total bilirubin ≤ 1.5 x ULN,Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN (≤ 5 x ULN for patients with liver involvement of their cancer), Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with liver involvement for their cancer and/or have bone metastases), Platelet count ≥ 100,000/mm3; Hemoglobin (Hb) ≥ 9 g/dL; Absolute neutrophil count (ANC) ≥ 1,500/ mm3.

The A870A rs603965 polymorphism of cyclin D1, a molecule involved in the initiation of cell division, was favorable to the NEXIRI combination on overall survival with a median of 19.6 months versus 6.2 months for two other genotypes A/G and G/G.