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

Sponsor
Gruppo Oncologico del Nord-Ovest
Study ID
NCT05845450
Phase
PHASE2
Status
Recruiting
Apply to this trial

Conditions

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

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

Study Details

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.

Key Dates

Start date
May 11, 2023
Status verified
Mar 2026
Primary completion
May 31, 2026
Completion
May 31, 2028

Study Design

Enrollment
197 participants (estimated)
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Experimental: Cohort 1: HER2 positive
    Patients selected for the presence of pMMR/MSS status and HER2 overexpression/amplification defined as HER2 IHC 3+ or IHC 2+/ISH+ will receive the HER2 directed ADC trastuzumab deruxtecan 5.4 mg/kg IV on day 1. After receiving the short-course preoperative treatment, patients will undergo standard radical surgery. After surgery, patients will receive 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.
  • Experimental: Cohort 2: POLE/D1 mutated with ultra-mutated status (>100 Mut/Megabase)
    Patients selected for the presence of a proof-read domain pathogenic mutation of POLE/D1 associated with ultra-mutated status will receive a short-course preoperative immunotherapy treatment with the anti-PDL-1 monoclonal antibody durvalumab 1500 mg IV on day 1. After receiving the short-course preoperative treatment, patients will undergo standard radical surgery. After surgery, patients will receive 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.
  • Experimental: Cohort 3: EGFR-dependent
    Patients selected for the presence of pMMR/MSS status, RAS and BRAF wild type status, PRESSING negative status and left-sided primary cancer will receive treatment with the anti-EGFR agent panitumumab 6 mg/kg IV on days 1 and 15. After receiving the short-course preoperative treatment, patients will undergo standard radical surgery. After surgery, patients will receive 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.
  • Experimental: Cohort 4: pMMR/MSS status
    Patients selected for the presence of 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 a short-course preoperative treatment with the anti-CTLA4 antibody botensilimab 1 mg/kg on day 1. After receiving the short-course preoperative treatment, patients will undergo standard radical surgery. After surgery, patients will receive 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.
  • Experimental: Cohort 5: pMMR/MSS status
    Patients selected for the presence of 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 a short-course preoperative treatment with 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 After receiving the short-course preoperative treatment, patients will undergo standard radical surgery. After surgery, patients will receive 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.
  • Experimental: Cohort 6: dMMR/MSI-H status
    Patients selected for the presence of dMMR/MSI-H status and absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status will receive a short-course preoperative treatment with the anti-CTLA4 antibody botensilimab 1 mg/kg on day 1. After receiving the short-course preoperative treatment, patients will undergo standard radical surgery. After surgery, patients will receive 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.
  • Experimental: Cohort 7: dMMR/MSI-H status
    Patients selected for the presence of dMMR/MSI-H status and absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status will receive a short-course preoperative treatment with 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. After receiving the short-course preoperative treatment, patients will undergo standard radical surgery. After surgery, patients will receive 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.
  • Experimental: Cohort 8: KRAS G12C mutated
    Patients selected for the presence of pMMR/MSS status and KRAS G12C mutation will receive a short-course preoperative targeted treatment with the KRAS G12C inhibitor sotorasib 960 mg orally once daily from day 1 to 28 plus the EGFR inhibitor panitumumab 6 mg/kg IV on days 1 and 15.
  • Experimental: Cohort 9: pMMR/MSS status
    Patients selected for the presence of pMMR/MSS status, absence of HER2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status and absence of KRAS G12C status will receive a short-course preoperative targeted treatment with the anti-EP4 agent vorbipiprant.
  • Experimental: Cohort 10: pMMR/MSS status
    Patients selected for the presence of pMMR/MSS status, absence of HER2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status and absence of KRAS G12C status will receive a short-course preoperative targeted treatment with the anti-EP4 agent vorbipiprant plus the anti PD-1 antibody nivolumab.
  • Experimental: 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
  • Experimental: 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.
  • Experimental: UNICORN part II (NEO-UNICORN) - Cohort 1
    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

Primary Outcome Measure

major pathological response rate [ Time Frame: 5 weeks ]

Central Contacts

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