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AzTrials

Colorectal CancerPhase 2NCT05845450

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

A Phase 2 study testing Trastuzumab deruxtecan, Durvalumab and Panitumumab in people with Colorectal Cancer and Resectable Colorectal Carcinoma, run by Gruppo Oncologico del Nord-Ovest at 1 site in Italy.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Trastuzumab deruxtecan, Durvalumab and Panitumumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
197 participants
Where
1 siteItaly
Study dates
11 May 2023to May 2028
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • General inclusion criteria
  • 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.
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  • 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).
  • Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
  • Subjects and their partners must be willing to avoid pregnancy during the trial and until a specific time interval after the last trial treatment: 7 months for female and 4 for male patients after last dose of trastuzumab-deruxtecan, 3 months for durvalumab, botensilimab and balstilimab and 2 months for panitumumab. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the Investigator (barrier contraceptive measure or oral contraception).
  • Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
  • Specific inclusion criteria for each Cohort
  • COHORT 1: pMMR/MSS status and HER2-positive status and LVEF ≥ 50% within 28 days before enrolment, international normalised ratio or Prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN
  • COHORT 2: Proofread domain mutations in POLE or POLD1 associated with ultra-mutated status, i.e. tumor mutational burden >100 Mut/Mb.
  • COHORT 3: pMMR/MSS status and wild-type status for RAS and BRAF, absence of molecular predictors of resistance (PRESSING panel negative), Left-sided and rectal primary tumor location, according to the specific inclusion criterion regarding rectal tumors.
  • COHORT 4: pMMR/MSS status and absence of HER2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status and absence of KRAS G12C mutation.
  • COHORT 5: pMMR/MSS status and absence of of HER2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status.
  • COHORT 6: dMMR/MSI-H status and absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status.
  • COHORT 7: dMMR/MSI-H status and absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status.
  • COHORT 8: pMMR/MSS status and KRAS G12C mutation, absence of HER2 overexpression/amplification and wild-type status for BRAF.
  • COHORT 9: pMMR/MSS status and absence of of HER2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status, absence of KRAS G12C mutation.
  • COHORT 10: pMMR/MSS status and absence of of HER2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status, absence of KRAS G12C mutation.
  • COHORT 11: pMMR/MSS status and wild-type status for RAS and BRAF, absence of molecular predictors of resistance (PRESSING panel negative except for MET alterations - MET amplifications and mutations are allowed), Left-sided and rectal primary tumor location, according to the specific inclusion criterion regarding rectal tumors.
  • COHORT 12: pMMR/MSS status and wild-type status for RAS and BRAF, absence of molecular predictors of resistance (PRESSING panel negative except for MET alterations - MET amplifications and mutations are allowed), Right-sided primary tumor location.
  • COHORT 1 of UNICORN part 2 (to enroll sequentially after completion of cohort 10): pMMR/MSS status and absence of molecular characteristics allowing enrollment in cohorts 1,2 and 8 (i.e HER2 overexpression/amplification, POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status, absence of KRAS G12C mutation. 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

Who cannot join

  • General exclusion criteria
  • 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.
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  • 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.
  • Specific exclusion criteria for each Cohort:
  • COHORT 1:
  • Previous treatment with a DXd-containing ADC or any anti-HER2 agent.
  • Has LVEF< 50% within 28 days before enrolment.
  • Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening. (eg, pulmonary emboli within 3 months of the enrolment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.).
  • Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the enrolment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.).
  • Any autoimmune, connective tissue, or inflammatory disorders where there is documented, or a suspicion of, pulmonary involvement at the time of Screening.
  • Prior pneumonectomy.
  • Has substance abuse or any other medical conditions that may interfere with the subject's participation in the clinical study or evaluation of the clinical study results.
  • Patients with a medical history of myocardial infarction within 6 months before randomization/enrolment, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out myocardial infarction.
  • Corrected QT interval (QTcF) prolongation to > 470 msec (females) or >450 msec (males) based on average of the screening triplicate12-lead ECG.
  • A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).
  • COHORT 2, 4, 5, 6, 7, 10 and Cohort 1 of UNICORN part 2:
  • History of autoimmune diseases or history of bone marrow or organ transplantation that requires immunosuppressive therapy.
  • History of active primary immunodeficiency.
  • Any condition requiring systemic treatment with corticosteroids at doses equal or superior to 10 mg daily of prednisone or equivalents, or other immunosuppressive drugs within 14 days from the inclusion in the study.
  • Administration of live vaccines within 4 weeks from the inclusion in the study. Note: patients, if enrolled, should not receive live vaccine while receiving study drug(s) and up to 30 days after the last dose of study drug(s).
  • Prior treatment with anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents.
  • COHORT 3 and 8
  • History of interstitial lung disease (e.g. pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan.
  • Magnesium below the LNL.
  • Prior treatment with an EGFR inhibitor.
  • COHORT 8:
  • Patients who are unable to take a drug by mouth or previous clinical conditions or surgical resection that may affect the absorption of the study drug.
  • Use of CYP3A4 or P-gp substrates with a narrow therapeutic window within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer.
  • Use of any herbal medications/supplements.
  • Tumors with KRAS, NRAS, HRAS, BRAF or PTPN11 (SHP2) mutations, except KRAS G12C.
  • Prior treatment with a KRAS G12C inhibitor.
  • COHORT 9 and 10:
  • Prior treatment with EP4 receptor antagonists.
  • Inability to swallow medications.
  • Presence of portal hypertension and/or oesophageal varices.
  • Known severe gastritis, duodenal or gastric ulcer, or any other condition that may lead to bleeding or perforation.
  • COHORTS 11 and 12:
  • Prior treatment with an anti-EGFR and/or MET inhibitor.
  • History of interstitial lung disease (e.g. pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan
  • Clinically active infectious liver disease
  • Any ophthalmologic condition that is clinically unstable

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Filippo Pietrantonio, MD contact

+39 0223903807

filippo.pietrantonio@istitutotumori.mi.it

Federica Palermo contact

+39 0223903835

unicornstudy@istitutotumori.mi.it

Italy1 site, 1 recruiting

  • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano

    Milan, Lombardia/MI, 20133

    Filippo Pietrantonio, MD, +39 0223903807, filippo.pietrantonio@istitutotumori.mi.it

    Federica Palermo, +39 0223903835, unicornstudy@istitutotumori.mi.it

    Recruiting

Other trials in Italy

About this study

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

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.

Read the 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.

Being tested
Trastuzumab deruxtecan, Durvalumab, Panitumumab, Botensilimab, Balstilimab
Keywords
targeted treatment, molecular alterations, platform trial
Medical subject headings
Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Trastuzumab deruxtecanDrug

    trastuzumab deruxtecan 5.4 mg/kg IV on day 1

  • DurvalumabDrug

    durvalumab 1500 mg IV on day 1

  • PanitumumabDrug

    panitumumab 6 mg/kg IV on days 1 and 15

  • BotensilimabDrug

    botensilimab 1 mg/kg on day 1

  • BalstilimabDrug

    balstilimab 3 mg/Kg on days 1 and 15

  • SotorasibDrug

    sotorasib 960 mg orally once daily from day 1 to 28

  • VorbipiprantDrug

    vorbipiprant 90 mg orally bid from day 1 to 28

  • NivolumabDrug

    240 mg IV on days 1 and 15

  • AmivantamabDrug

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

  • BotensilimabDrug

    Botensilimab at the dose of 75 mg, IV on day 1

  • BalstilimabDrug

    balstilimab at the dose of 240 mg, IV on days 1, 15, 29 and 43

Study groups in NCT05845450
Study groupRoleWhat they receive
Cohort 1: HER2 positiveExperimentalPatients 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.
Receives: Drug: Trastuzumab deruxtecan
Cohort 2: POLE/D1 mutated with ultra-mutated status (>100 Mut/Megabase)ExperimentalPatients 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.
Receives: Drug: Durvalumab
Cohort 3: EGFR-dependentExperimentalPatients 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.
Receives: Drug: Panitumumab
Cohort 4: pMMR/MSS statusExperimentalPatients 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.
Receives: Drug: Botensilimab
Cohort 5: pMMR/MSS statusExperimentalPatients 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.
Receives: Drug: Botensilimab; Drug: Balstilimab
Cohort 6: dMMR/MSI-H statusExperimentalPatients 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.
Receives: Drug: Botensilimab
Cohort 7: dMMR/MSI-H statusExperimentalPatients 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.
Receives: Drug: Botensilimab; Drug: Balstilimab
Cohort 8: KRAS G12C mutatedExperimentalPatients 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.
Receives: Drug: Panitumumab; Drug: Sotorasib
Cohort 9: pMMR/MSS statusExperimentalPatients 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.
Receives: Drug: Vorbipiprant
Cohort 10: pMMR/MSS statusExperimentalPatients 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.
Receives: Drug: Vorbipiprant; Drug: Nivolumab
Cohort 11: Left-sided hyperselected regardless of METExperimentalPatients 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
Receives: Drug: Amivantamab
Cohort 12: Right-sided hyperselected regardless of METExperimentalPatients 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.
Receives: Drug: Amivantamab
UNICORN part II (NEO-UNICORN) - Cohort 1ExperimentalPatients 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
Receives: Drug: Botensilimab; Drug: Balstilimab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 5 weeks

Secondary outcomes (13)

  1. Treatment safety

    incidence of AE (including SAEs) in each cohort during the short-course pre-operative treatment, assessed according to National Cancer Institute Common Toxicity Criteria version 5.0 (NCI-CTCAE v5.0).

    Measured: 5 weeks

  2. Overall Toxicity Rate

    percentage of patients, relative to the total of enrolled subjects of each cohort, experiencing any grade AE, according to NCI-CTCAE v5.0, during the short-course pre-operative treatment

    Measured: 5 weeks

  3. G3/4 Toxicity Rate

    percentage of patients, relative to the total of enrolled subjects in each cohort, experiencing any specific adverse event of grade 3/4, according to NCI-CTCAE v5.0, during the short-course pre-operative treatment.

    Measured: 5 weeks

  4. Surgical mortality

    the incidence of death occurring within 30 days after surgery in each cohort

    Measured: 10 weeks

  5. Surgical morbidity

    the incidence of a new onset temporary or permanent disability observed within 30 days after surgery in each cohort

    Measured: 10 weeks

  6. Surgical complications

    Surgical complications graded according to the Clavien-Dindo Classification of Surgical Complications and evaluated up to 90 days after surgery

    Measured: 18 weeks

  7. Quality of life - PRO EORTC-QLQ-C30

    Quality of life will be assessed through Patient reported outcomes (PRO) instrument. EORTC QLQ-C30 For questions 1-28 of EORTC QLQ-C30 a 4-point scale is used. It scores from 1 to 4: 1 ("Not at all"), 2 ("A little"), 3 ("Quite a bit")and 4 ("Very much"). Half points are not allowed. The range is 3. For the raw score, less points are considered to have a better outcome. For the questions 29 and 30 of EORTC QLQ-C30 a 7-points scale is used. It scores from 1 to 7: 1 ("very poor") to 7 ("excellent"). Half points are not allowed. The range is 6. First of all, raw score has to be calculated with mean values. Afterwards linear transformation is performed to be comparable. More points are considered to have a better outcome.

    Measured: 5 weeks

  8. Quality of life - PRO EORTC-QLQ-CR29

    Quality of life will be assessed through Patient reported outcomes (PRO) instrument. EORTC QLQ-CR29.

    For questions 31-59 of EORTC QLQ-CR29 a 4-point scale is used. It scores from 1 to 4: 1 ("Not at all"), 2 ("A little"),3 ("Quite a bit") and 4 ("Very much"). Half points are not allowed. The range is 3. For the raw score, less points are considered to have a better outcome.

    Measured: 5 weeks

  9. Quality of life - PRO EuroQol EQ-5D-5L

    Quality of life will be assessed through Patient reported outcomes (PRO) instrument. EuroQol EQ-5D-5L. The EQ-5D-5L uses for first 5 questions qualitative multiple choice answers with NO SCALE. For the last questions, a score from 0 to 100 indicates from the worst to the best outcome.

    Measured: 5 weeks

  10. changes in systemic immunity

    defined by the longitudinal analysis of the peripheral blood subpopulations including myeloid cells (including myeloid-derived suppressor cells), CD8+ and CD4+ T lymphocytes (including T regulatory and Th17 cells), their proliferation and activation/exhaustion state collected at different time points performed by multiparametric cytometry

    Measured: 5 weeks

  11. correlation of pCR/pMR with ctDNA mutational profiles

    The correlation of pCR/pMR with ctDNA mutational profiles and its clearance after the specific short-course preoperative targeted treatment will be assessed by using ultra-deep whole-exome sequencing with Unique Molecular Identifiers to evaluate with high accuracy the presence of ctDNA in longitudinally collected liquid biopsies.

    Measured: 5 weeks

  12. radiogenomic or radiomic signatures

    To investigate the prognostic and/or predictive impact of radiogenomic or radiomic signatures in specific molecular subgroups, the baseline imaging will be analyzed to predict specific molecular profiles in all pre-screened patients, while the matched pre- and post-treatment imaging will be analyzed to predict tumor heterogeneity and pathological response in each cohort.

    Measured: 5 weeks

  13. microbiota

    The prognostic and/or predictive value of microbiota in specific molecular subgroups will be defined by investigating the composition of the gut microbiome in stool samples collected at pre-screening and at the end of short-course pre-operative treatment, its impact on outcomes of populations of molecular interest and its influence on the local and systemic immune responses to specific short-course preoperative treatments in each cohort.

    Measured: 5 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 May 2023
  2. Study start11 May 2023
  3. Primary completionMay 2027 (estimated)
  4. Study completionMay 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Model description
Phase II, multicentre, single-arm, open-label, multi-cohort trial
Masking
None (open label)
Enrolment
197 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05845450
Sponsor's protocol ID
UNICORN
Status last verified
Sep 2026
First submitted
26 Apr 2023
Last updated
11 Sep 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: The trial results concerning the primary, secondary and exploratory outcomes will be published according to the standard guidelines. IPD could eventually be requested to the Sponsor and Principal Investigator, who will carefully evaluate the formal and motivated request

Publications

  • Ghelardi F, Ambrosini M, Raimondi A, Tyshevich A, Palermo F, Bergamo F, Nasca V, Manca P, Mulas I, Derosa L, Brown G, Chiodoni C, Di Maio M, Di Donato S, Chiaramonte A, Castagnoli L, Ni S, Nousome D, Spickard E, Tin A, Lentz R, Jurdi A, Sabella G, Spada D, Tamberi S, Passardi A, Morano F, Tamburini E, Rossi C, Azzolin L, Cambuli F, Martinetti A, Sottotetti E, Almonte AA, Iebba V, Ratti C, Cerantola R, Kutlu O, Cristarella E, Pupa SM, Villa C, Perissinotto E, Galassi M, Barina A, Vittadello F, Guaglio M, Baiocchi G, Sartore-Bianchi A, Rosati R, Cremolini C, Montroni I, Lonardi S, Sottoriva A, Pietrantonio F. Neoadjuvant botensilimab with or without balstilimab in pMMR and dMMR colon cancer: the phase 2 UNICORN trial. Nat Med. 2026 Nov 2. doi: 10.1038/s41591-026-04710-1. Online ahead of print.

    PubMed 42972108

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Trastuzumab deruxtecan, Durvalumab and Panitumumab in people with Colorectal Cancer and Resectable Colorectal Carcinoma, run by Gruppo Oncologico del Nord-Ovest at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 33 inclusion and 51 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 11 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Filippo Pietrantonio, MD (+39 0223903807, filippo.pietrantonio@istitutotumori.mi.it), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

major pathological response rate (time frame: 5 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05845450, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Sep 2026.

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