Pre-operative Targeted Treatments in Molecularly Selected Resectable Colorectal Cancer (UNICORN)

Colorectal Cancer Clinical Trial

Official title: Window-of-opportunity Umbrella Platform Trial of Short-course Pre-operative Targeted Treatments in Patients With Molecularly Selected and Resectable Primary Colorectal Cancer: the UNICORN Study

Status Recruiting

Clinical Trial Summary

This is a window-of-opportunity umbrella platform trial enrolling non-metastatic resectable colorectal patients selected for the presence of a specific targetable molecular alteration. The study aims to test the activity of specific targeted agents/combinations given as a short-course pre-operative strategy, matched with the specific alteration detected, followed by standard of care surgery.

Clinical Trial Description

Patients with histologically confirmed non metastatic, radiologically staged as cT3-4 colorectal cancer eligible for radical surgery will be centrally molecularly prescreened by means of next-generation sequencing, HER2 IHC +/- HER2 silver-in situ hybridization and MMR proteins IHC with the aim to identify the presence of selected targetable molecular profiles/alterations. Whenever a pre-specified molecular profile/alteration is identified, the patient will be eligible for the matching Cohort and, after enrollment, will receive a specific short-course preoperative targeted treatment.

A total of 14 patients will be enrolled in each pre-specified molecularly-identified Cohort, according to the review of a Molecular Tumor Board established by the Sponsor, that will specifically evaluate the occurring and co-occurring molecular alterations.

Cohort 1 - patients with pMMR/MSS status and HER2 overexpression/amplification will receive the HER2 directed ADC trastuzumab deruxtecan 5.4 mg/kg IV on day 1.

Cohort 2 - patients with POLE/D1 mutation with ultra-mutated status (>100Mut/Megabase) will receive the anti-PDL-1 monoclonal antibody durvalumab 1500 mg IV on day 1.

Cohort 3 - patients with EGFR-dependent tumor (pMMR/MSS status, RAS and BRAF wild type status, PRESSING negative status and left-sided primary cancer) will receive the anti-EGFR agent panitumumab 6 mg/kg IV on days 1 and 15.

Cohort 4 - patients with pMMR/MSS status and absence of HER2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status will receive the anti-CTLA4 antibody botensilimab 1 mg/kg on day 1.

Cohort 5 (will be opened sequentially, after completion of Cohort 4) - patients with pMMR/MSS status and absence of HER2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status will receive the anti-CTLA4 antibody botensilimab 1 mg/kg on day 1 plus the anti-PD-1 balstilimab 3 mg/Kg on days 1 and 15.

Cohort 6 - patients with dMMR/MSI-H status and absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status will receive the anti-CTLA4 antibody botensilimab 1 mg/kg on day 1.

Cohort 7 (will be opened sequentially, after completion of Cohort 6) - patients with dMMR/MSI-H status and absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status will receive the anti-CTLA4 antibody botensilimab 1 mg/kg on day 1 plus the anti-PD-1 balstilimab 3 mg/Kg on days 1 and 15.

Cohort 8 - patients with pMMR/MSS status and KRAS G12C mutation will receive the KRAS G12C inhibitor sotorasib 960 mg orally once daily from day 1 to 28 plus the anti-EGFR inhibitor panitumumab 6 mg/kg IV on days 1 and 15.

After receiving the pre-specified study treatment, patients will be submitted to radical surgery at day 35 +/- 5 days. After surgery, patients will receive standard adjuvant chemotherapy as per national and international guidelines and according to the suggestion of a central multidisciplinary team. Then, standard follow up will be started as per local guidelines. Baseline assessments include radiological imaging (chest-abdomen-pelvis CT scan with contrast or abdomen MRI with contrast plus thorax CT without contrast if indicated, pelvis MRI mandatory for rectal cancer, and 18-FDG-PET scan if clinically indicated). Tumor re-assessments will be performed immediately prior to surgery at week 4-5. Safety assessments include monitoring of adverse events, clinical laboratory tests (chemistry, hematology, coagulation and urinalysis), vital signs, physical examinations and ECG as applicable.

Health-care related quality of life analysis will be done thanks to the administration of patient-reported outcomes questionnaires (EORTC QLQ-C30, EORTC QLQ-CR29, Euro QoL EQ-5D-5L) at baseline, during pre-operative treatment and at restaging. ;

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Resectable Colorectal Carcinoma

• NCT number: NCT05845450
• Study type: Interventional
• Source: Gruppo Oncologico del Nord-Ovest
• Contact: Filippo Pietrantonio, MD
• Phone: +39 0223903807
• Email: filippo.pietrantonio@istitutotumori.mi.it
• Status: Recruiting
• Phase: Phase 2
• Start date: May 11, 2023
• Completion date: May 2028