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Report for Clinical Trial NCT03829462

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Randomized Phase III Trial Assessing a Regorafenib-irinotecan Combination (REGIRI) Versus Regorafenib Alone in Metastatic Colorectal Cancer Patients After Failure of Standard Therapies, According to the A/A Genotype of Cyclin D1

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 Metastatic Colorectal Cancer (mCRC)
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

2 Interventions

Name: Regorafenib

Description: regorafenib tab 40 mg i.e 160 mg/day

Type: Drug

Irinotecan + regorafenib (REGIRI) regorafenib

Name: Irinotecan

Description: irinotecan 120 mg/m2 cycle 1, 150 mg/m2 cycle 2, 180 mg/m2 cycle 3 and more

Type: Drug

Irinotecan + regorafenib (REGIRI)


Primary Outcomes

Description: From randomization of first patient until the datebase cut-off

Measure: Overall survival

Time: Approximately 36 months

Secondary Outcomes

Description: From randomization of first patient until the datebase cut-off,

Measure: Progression-free survival (PFS)

Time: Approximately 36 months

Description: From randomization of first patient until the datebase cut-off,

Measure: Disease control rate (DCR)

Time: Tumor is assessed every 8 weeks

Description: From randomization of first patient until the datebase cut-off,

Measure: Objective response rate (OOR)

Time: Tumor is assessed at 8 weeks intervals

Description: From randomization of first patient until the end of treatment,

Measure: Assessment of adverse events by using the NCI-CTCAE version 5.0 scale

Time: Approximately 36 months

Description: From date of randomization until the date of end of treatment

Measure: Quality of life questionnaire

Time: questionnaire is assessed at 8 weeks intervals

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There is one SNP

SNPs


1 rs603965

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.



HPO Nodes


HPO:
Neoplasm of the large intestine
Genes 120
FLCN SDHC MLH1 PMS2 APC EPCAM SDHC PALLD SRC BUB1 APC GREM1 NTHL1 PMS1 PTEN SDHB MSH6 APC KIT SDHD KRAS BMPR1A FAN1 CTNNB1 MSH3 POLD1 KRAS RNF43 KEAP1 DICER1 DLC1 BMPR1A MSH2 MSH6 PIK3CA CDKN2A FGFR3 BMPR1A MUTYH PIK3CA BMPR1A EP300 FOXE1 ENG SMAD7 AXIN2 CHEK2 MLH1 RPS20 BRCA1 RPS19 PRKAR1A APC GPR35 MLH1 AKT1 POLE SMAD4 KIT TP53 TRIP13 COL14A1 MDM2 SMAD4 POLE BRCA2 AKT1 MSH6 HABP2 NRAS MUTYH BUB1B DOCK8 TGFBR2 STK11 AXIN2 EPCAM BUB3 DCC AXIN2 TCF4 KLLN MSH2 APC TP53 SEC23B PTEN TGFBR2 SEMA4A POLD1 PIK3CA PDGFRA MINPP1 APC SH3KBP1 BMPR1A TP53 BUB1 AAGAB SMAD4 BMPR1A MST1 MLH3 MSH2 PALB2 FLCN SDHA PMS2 SDHB BUB1B MSH2 MLH1 CEP57 MLH3 TP53 PTPRJ PMS1 APC CDKN2A APC