NCT05845450

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

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
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 197 (estimated)
• Sponsor: Gruppo Oncologico del Nord-Ovest · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

Detailed 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 - COMPLETED - 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 - COMPLETED - 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 (opened sequentially, after completion of Cohort 4) -COMPLETED - 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 - COMPLETED - 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 (opened sequentially, after completion of Cohort 6) - COMPLETED - 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. Cohort 9 - patients selected for the presence of pMMR/MSS status and absence of HER-2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status, absence of KRAS G12C mutated status, will receive a short-course preoperative treatment with the anti-EP4 oral agent vorbipiprant 90 mg bid from day 1 to day 28. Cohort 10 - Patients selected for the presence of pMMR/MSS status and absence of HER-2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status, absence of KRAS G12C mutated status, will receive a short-course preoperative treatment with the anti-EP4 oral agent vorbipiprant 90 mg bid from day 1 to day 28 plus the anti PD-1 antibody nivolumab 240 mg on days 1 and 15. Cohort 11: Left-sided hyperselected regardless of MET Patients selected for the presence of pMMR/MSS status, RAS and BRAF wild type status, PRESSING negativity but regardless of MET status, and left-sided primary cancer will receive treatment with the anti-EGFR/MET bispecific antibody amivantamab 1600 mg (2240 mg if body weight ≥ 80 Kg) subcutaneously on days 1,8,15 and 22. Cohort 12: Right-sided hyperselected regardless of MET Patients selected for the presence of pMMR/MSS status, RAS and BRAF wild type status, PRESSING negativity but regardless of MET status, and right-sided primary cancer will receive treatment with the anti-EGFR/MET bispecific antibody amivantamab 1600 mg (2240 mg if body weight ≥ 80 Kg) subcutaneously on days 1,8,15 and 22. 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. In UNICORN part II (NEO-UNICORN) Cohort 1 - 29 patients selected for the presence of pMMR/MSS status and absence of HER-2 overexpression/amplification, absence of POLE/D1 proof-reading domain pathogenic mutation associated with ultra-mutated status, absence of KRAS G12C mutated status, will receive a 2-month neoadjuvant treatment with the anti-CTLA-4 agent botensilimab, intravenously, at the dose of 75 mg on day 1 and the anti-PD-1 agent balstilimab, intravenously, at the dose of 240 mg on days 1, 15, 29 and 43. Patients with tumor characteristics of EGFR dependency (regardless of MET) will be eligible for cohort 1 of UNICORN part 2 only after completion of cohort 11 or 12 (depending on primary tumor sidedness) and upon discussion with the Sponsor After receiving study treatment, patients will undergo radical surgery on day 56 +/- 5 days and standard post-operative management as per national and international guidelines and according to a central multidisciplinary evaluation. 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 (week 6-7 for UNICORN part 2). 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 patientreported outcomes questionnaires (EORTC QLQ-C30, EORTC QLQ-CR29, Euro QoL EQ-5D-5L) at baseline, during pre-operative treatment and at restaging. Furthermore, for patients enrolled in NEO-UNICORN, health-related quality of life questionnaire will also be administered at 6 and 12 months after surgery.

Conditions

• Colorectal Cancer
• Resectable Colorectal Carcinoma

Interventions

Type	Name	Description
DRUG	Trastuzumab deruxtecan	trastuzumab deruxtecan 5.4 mg/kg IV on day 1
DRUG	Durvalumab	durvalumab 1500 mg IV on day 1
DRUG	Panitumumab	panitumumab 6 mg/kg IV on days 1 and 15
DRUG	Botensilimab	botensilimab 1 mg/kg on day 1
DRUG	Balstilimab	balstilimab 3 mg/Kg on days 1 and 15
DRUG	Sotorasib	sotorasib 960 mg orally once daily from day 1 to 28
DRUG	Vorbipiprant	vorbipiprant 90 mg orally bid from day 1 to 28
DRUG	Nivolumab	240 mg IV on days 1 and 15
DRUG	Amivantamab	amivantamab at the dose of 1600 mg (2240 mg if body weight ≥ 80 Kg), subcutaneously, on days 1, 8, 15 and 22
DRUG	Botensilimab	Botensilimab at the dose of 75 mg, IV on day 1
DRUG	Balstilimab	balstilimab at the dose of 240 mg, IV on days 1, 15, 29 and 43

Timeline

• Start date: 2023-05-11
• Primary completion: 2026-05-01
• Completion: 2028-05-01
• First posted: 2023-05-06
• Last updated: 2026-03-12

Locations

1 site across 1 country: Italy