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

NCT05845450 | Recruiting Phase 2 DMC

• 1 other identifier: UNICORN
• Study Type: interventional
• Target: 197
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Colorectal Cancer; Resectable Colorectal Carcinoma

Keywords

targeted treatment; molecular alterations; platform trial

Outcome Measures

Primary Outcomes (1)

• major pathological response rate

  percentage of patients, relative to the total of enrolled subjects in the intention-to-treat population for each cohort, who will achieve a pathological complete response (pCR), defined as 0 or less residual viable tumor in both the primary tumor bed and lymphnodes, or major response (pMR), defined as 10% or less residual viable tumor, as per central pathological review in each Cohort.

  5 weeks

Secondary Outcomes (13)

• Treatment safety

  5 weeks

• Overall Toxicity Rate

  5 weeks

• G3/4 Toxicity Rate

  5 weeks

• Surgical mortality

  10 weeks

• Surgical morbidity

  10 weeks

Other Outcomes (2)

• Disease-free survival

  36 months

• Overall survival

  36 months

Study Arms (13)

Cohort 1: HER2 positive

EXPERIMENTAL

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.

Drug: Trastuzumab deruxtecan

Cohort 2: POLE/D1 mutated with ultra-mutated status (>100 Mut/Megabase)

EXPERIMENTAL

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.

Drug: Durvalumab

Cohort 3: EGFR-dependent

EXPERIMENTAL

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.

Drug: Panitumumab

Cohort 4: pMMR/MSS status

EXPERIMENTAL

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.

Drug: Botensilimab

Cohort 5: pMMR/MSS status

EXPERIMENTAL

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.

Drug: Botensilimab; Drug: Balstilimab

Cohort 6: dMMR/MSI-H status

EXPERIMENTAL

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.

Drug: Botensilimab

Cohort 7: dMMR/MSI-H status

EXPERIMENTAL

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.

Drug: Botensilimab; Drug: Balstilimab

Cohort 8: KRAS G12C mutated

EXPERIMENTAL

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.

Drug: Panitumumab; Drug: Sotorasib

Cohort 9: pMMR/MSS status

EXPERIMENTAL

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.

Drug: Vorbipiprant

Cohort 10: pMMR/MSS status

EXPERIMENTAL

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.

Drug: Vorbipiprant; Drug: Nivolumab

Cohort 11: Left-sided hyperselected regardless of MET

EXPERIMENTAL

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

Drug: Amivantamab

Cohort 12: Right-sided hyperselected regardless of MET

EXPERIMENTAL

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.

Drug: Amivantamab

UNICORN part II (NEO-UNICORN) - Cohort 1

EXPERIMENTAL

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

Drug: Botensilimab; Drug: Balstilimab

Interventions

Trastuzumab deruxtecan DRUG

trastuzumab deruxtecan 5.4 mg/kg IV on day 1

Cohort 1: HER2 positive

Durvalumab DRUG

durvalumab 1500 mg IV on day 1

Cohort 2: POLE/D1 mutated with ultra-mutated status (>100 Mut/Megabase)

Panitumumab DRUG

panitumumab 6 mg/kg IV on days 1 and 15

Cohort 3: EGFR-dependent; Cohort 8: KRAS G12C mutated

Botensilimab DRUG

botensilimab 1 mg/kg on day 1

Cohort 4: pMMR/MSS status; Cohort 5: pMMR/MSS status; Cohort 6: dMMR/MSI-H status; Cohort 7: dMMR/MSI-H status

Balstilimab DRUG

balstilimab 3 mg/Kg on days 1 and 15

Cohort 5: pMMR/MSS status; Cohort 7: dMMR/MSI-H status

Sotorasib DRUG

sotorasib 960 mg orally once daily from day 1 to 28

Cohort 8: KRAS G12C mutated

Vorbipiprant DRUG

vorbipiprant 90 mg orally bid from day 1 to 28

Cohort 10: pMMR/MSS status; Cohort 9: pMMR/MSS status

Nivolumab DRUG

240 mg IV on days 1 and 15

Cohort 10: pMMR/MSS status

Amivantamab DRUG

amivantamab at the dose of 1600 mg (2240 mg if body weight ≥ 80 Kg), subcutaneously, on days 1, 8, 15 and 22

Cohort 11: Left-sided hyperselected regardless of MET; Cohort 12: Right-sided hyperselected regardless of MET

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provide a signed and dated informed consent document.
• Age ≥ 18 years at time of informed consent.
• ECOG PS of 0 and 1.
• Histologically confirmed colorectal cancer adenocarcinoma that is judged as initially resectable with elective surgery aimed at radical intent with R0 margins as per multidisciplinary team assessment.
• Radiological stage cT3-4, N0-2, M0 using computed tomography (CT) as in the pivotal FOxTROT study.
• Patients with rectal cancer candidate for R0 resection, not requiring pre-operative radiotherapy based on multidisciplinary team assessment, with the following characteristics on high-resolution thin slice (3 mm) contrast-enhanced magnetic resonance imaging (MRI):
• ≤ T3a defined at the MRI (perivisceral fat infiltration \<2 mm) and clinical N0
• Upper-medium, defined as tumors with distal margin ≥ 5 cm from the anal verge.
• Absence of mesorectal fascia invasion, as defined as a distance ≥ 1 mm between tumor and the mesorectal fascia.
• Able to provide enough archival FFPE tumor specimen that is already available from initial diagnostic procedures for the purpose of molecular pre-screening.
• Presence of one of the selected molecular profile/alteration after central pre-screening and necessary for the assignment to a matching treatment cohort.
• No prior systemic treatment for colorectal cancer or neoadjuvant radiation therapy for rectal cancer.
• Adequate bone marrow function (absolute neutrophil count ≥ 1.5 × 109/L; platelet count ≥ 100 × 109/L; hemoglobin ≥ 9.0 g/dL)
• Adequate renal function characterized by serum creatinine ≤ 1.5 × upper limit of normal (ULN) or calculated by Cockroft-Gault formula or directly measured creatinine clearance ≥ 50 mL/min at screening.
• Adequate hepatic function (serum total bilirubin ≤ 1.5 × ULN and \< 2 mg/dL. Note: Patients who have a total bilirubin level 1.5 × ULN will be allowed if their indirect bilirubin level is ≤ 1.5 × ULN; Alanine aminotransferase and/or aspartate aminotransferase ≤ 2.5 × ULN).

You may not qualify if:

• Distant metastases at any site, as defined by negativity of chest/abdomen/pelvis contrast-enhanced computed tomography (CT).
• Risk criteria for obstructing disease at radiology or endoscopy as defined in the pivotal FOxTROT study.
• Need to receive neoadjuvant radiation or chemoradiation in patients with rectal cancer.
• Patients with known hypersensitivity to the study drug of the assigned cohort or to its excipients or to drugs belonging to the same drug class.
• Previous or concurrent malignancy within 2 years of study entry.
• Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: history of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤ 6 months prior to start of study treatment; symptomatic congestive heart failure (i.e., Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality ≤ 6 months prior to start of study treatment, except atrial fibrillation and paroxysmal supraventricular tachycardia.
• Known history of HIV infection.
• Active infection including tuberculosis, hepatitis B, hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible only in case of negativity of HBV DNA. Patients positive for hepatitis C (HCV) antibody are eligible only if PCR is negative for HCV RNA.
• Other severe acute or chronic diseases that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient an inappropriate candidate for the study.
• Any psychiatric condition that would prohibit the understanding or rendering of informed consent and that would limit compliance with trial requirements.
• Women in pregnancy or lactation condition. Women with child-bearing potential or sexually-active men not willing to use adequate contraception during whole study period.
• Use of any disallowed drugs.
• COHORT 1:
• Previous treatment with a DXd-containing ADC or any anti-HER2 agent.
• Has LVEF\< 50% within 28 days before enrolment.

Sponsors & Collaborators

• Gruppo Oncologico del Nord-Ovest: lead

Study Sites (1)

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano

Milan, Lombardia/MI, 20133, Italy

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

trastuzumab deruxtecan; durvalumab; Panitumumab; balstilimab; sotorasib; Nivolumab; amivantamab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Filippo Pietrantonio, MD

  Fondazione IRCCS - Istituto Nazionale dei Tumori di Milano

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Filippo Pietrantonio, MD

CONTACT

+39 0223903807; filippo.pietrantonio@istitutotumori.mi.it

Federica Palermo

CONTACT

+39 0223903835; unicornstudy@istitutotumori.mi.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase II, multicentre, single-arm, open-label, multi-cohort trial

Study Record Dates

• First Submitted: April 26, 2023
• First Posted: May 6, 2023
• Study Start: May 11, 2023
• Primary Completion: May 1, 2026
• Study Completion (Estimated): May 1, 2028
• Last Updated: March 12, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)