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UNICORN

Introduction

UNICORN is a Phase II, multicentre, window-of-opportunity umbrella platform trial aimed at evaluating the activity and safety of short-course pre-operative targeted treatments in patients with molecularly selected and resectable primary colorectal cancer.
Patients with histologically confirmed non metastatic radiologically staged as cT3-4 colorectal cancer eligible for radical surgery will be molecularly prescreened by means of next-generation sequencing OncomineTM Comprehensive Assay (OCA) Plus panel (a panel including 510 genes and able to detect single nucleotide variants, copy number variations and gene fusions), HER2 IHC +/- HER2 silver-in situ hybridization and MMR proteins IHC (MLH1, PMS2, MSH2 and MSH6 expression by IHC). All the molecular analyses will be centrally performed at the Coordinating Center (Fondazione IRCCS Istituto Nazionale dei Tumori of Milan) 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 shortcourse 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 selected for the presence of 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 selected for the presence of a proof-read domain pathogenic mutation of POLE or POLD1 associated with ultra-mutated status (>100 Mut/Megabase) will receive a short-course preoperative immunotherapy treatment with the anti-PDL-1 monoclonal antibody durvalumab 1500 mg IV on day 1.
Cohort 3: patients selected for the presence of pMMR/MSS status, RAS and BRAF wild type status, PRESSING negative status (HER2 amplification/activating mutations, MET amplification, NTRK/ROS1/ALK/RET fusions and PIK3CA/PTEN/AKT1 mutations) and left-sided primary cancer will receive treatment with the anti-EGFR agent panitumumab 6 mg/kg IV on days 1 and 15.
Cohort 4: patients selected for the presence of pMMR/MSS status and absence of the molecular alterations allowing enrollment in the other protocol-specified cohorts will receive a short-course preoperative treatment with the antiCTLA4 antibody botensilimab 1 mg/kg on day 1.
Cohort 5 (will be opened sequentially, after completion of Cohort 4): patients selected for the presence of pMMR/MSS status and absence of the molecular alterations allowing enrollment in the other protocol-specified cohorts will receive a short-course preoperative treatment with the antiCTLA4 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 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.
Cohort 7(will be opened sequentially, after completion of Cohort 6): 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 antiPD-1 balstilimab 3 mg/Kg on days 1 and 15.
Cohort 8: patients selected for the presence of KRAS G12C mutatation will receive a short-course preoperative treatment with the KRAS G12C inhibitor sotorasib at the dose of 960 mg daily oral from day 1 to day 28 plus the anti-EGFR agent panitumumab 6 mg/kg IV on day 1 and day 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. Translational analyses will be performed on archival tumor tissue, on tissue collected on an optional pre-treatment colonoscopy and at surgery. Longitudinal plasma samples will be collected at baseline ad at day 15, prior to surgery and during follow-up visits until disease relapse, patients’ withdrawal or study closure, while PBMC only at baseline, during pre-operative treatment, at re-staging and at surgery. Stools samples will be collected pre and post the short-course pre-operative treatment for microbiome analysis.

Selection criteria

This study will enroll a total number of 14 patients in each cohort.

General inclusion criteria:
  1. Provide a signed and dated informed consent document.
  2. Age ≥ 18 years at time of informed consent.
  3. ECOG PS of 0 and 1.
  4. 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.
  5. Radiological stage cT3-4, N0-2, M0 using computed tomography (CT) as in the pivotal FOxTROT study.
  6. 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.
  7. Able to provide enough archival FFPE tumor specimen that is already available from initial diagnostic procedures for the purpose of molecular pre-screening.
  8. Presence of one of the selected molecular profile/alteration after central pre-screening and necessary for the assignment to a matching treatment cohort.
  9. No prior systemic treatment for colorectal cancer or neoadjuvant radiation therapy for rectal cancer.
  10. Adequate bone marrow function, renal function, hepatic function.
  11. Adequate contraception measures as defined by protocol.
General exclusion criteria
  1. Distant metastases at any site, as defined by negativity of chest/abdomen/pelvis contrast-enhanced computed tomography (CT).
  2. Risk criteria for obstructing disease at radiology or endoscopy as defined in the pivotal FOxTROT study.
  3. Need to receive neoadjuvant radiation or chemoradiation in patients with rectal cancer.
  4. 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.
  5. Previous or concurrent malignancy within 2 years of study entry.
  6. Impaired cardiovascular function or clinically significant cardiovascular diseases.
  7. Known history of HIV infection, active infection including tuberculosis, hepatitis B, hepatitis C or other severe acute or chronic diseases that may increase the risk associated with study participation.
  8. Any psychiatric condition that would limit compliance.
  9. Women with child-bearing potential or sexually active men not willing to use adequate contraception during whole study period.
  10. Women in pregnancy or lactation condition.
  11. Use of any disallowed drugs.

Objectives

Primary objective

To assess the activity of each specific short-course preoperative targeted treatment as measured in terms of pathological complete response (pCR) plus major response (pMR) rate in each cohort.

Secondary Objectives
  1. To assess the safety and the tolerability of each specific short-course preoperative targeted treatment and to describe the morbidity of surgical procedures.
  2. To assess the impact of each specific short-course preoperative targeted treatment on the patient quality of life.
  3. To perform tumor tissue spatial profiling of matched pre- and post-treatment samples to uncover transcriptional tumor/microenvironmental/immune changes induced by each specific short-course preoperative targeted treatment.
  4. To evaluate the changes in systemic immune profiles induced by each specific short-course preoperative targeted treatment.
  5. To perform ultra-deep sequencing of circulating tumor DNA (ctDNA) in liquid biopsies to track treatment resistance mechanisms by mathematical/computational modeling.
  6. To perform radiogenomic and radiomic analyses for predicting the presence of specific molecular targets (in all pre-screened patients), tumor heterogeneity and pathological response to each specific short-course preoperative targeted treatment.
  7. To analyze microbiota to evaluate the existence of a prognostic/predictive gut immune signature in specific molecular subgroups.
Primary endpoint:

The study primary endpoint will be the major pathological response rate defined as the percentage of patients, relative to the total of enrolled subjects in the intention-to-treat population for each cohort, who will achieve a pathologic complete response (pCR = 0% of residual vital cells in primary tumor and lymphnodes) or a pathological major response (pMR, less than 10% of residual vital cells in primary tumor and lymphnodes) as per central pathological review.
The surgical samples will be analyzed at the Coordinating Center for a Central review to define and confirm the tumor regression grade and the % of residual cells will be measured.

Secondary endpoints
  1. The safety/tolerability of the specific short-course pre-operative targeted treatment in nonmetastatic colorectal cancer, in terms of treatment safety, overall toxicity rate, G3/4 toxicity rate, surgical mortality, surgical morbidity, surgical complications.
  2. The impact on health-related quality of life, defined by Patient Reported Outcomes, of the shortcourse pre-operative targeted treatment.
  3. The characterization of the transcriptional tumor/microenvironment changes induced by the specific short-course pre-operative targeted treatment thanks to the evaluation of gene expression profiles in different tumor compartments.
  4. The evaluation of the changes in systemic immunity with longitudinal analysis of peripheral blood subpopulations.
  5. The correlation of pCR/pMR with ctDNA mutational profiles and its clearance after the shortcourse pre-operative targeted treatment.
  6. The evaluation of the prognostic and/or predictive impact of radiogenomic or radiomic signatures in specific molecular subgroups thanks to the analysis of the baseline and post-treatment tumor imaging.
  7. The evaluation of the prognostic and/or predictive value of microbiota in specific molecular subgroups thanks to the analysis of the composition of gut microbiome in stool samples collected before the start and after the end of the short-course pre-operative targeted treatment.
Explorative objectives and endpoints
  1. To assess the disease-free survival (DFS) achieved by the specific short-course preoperative targeted treatment followed by standard treatment in each cohort.
  2. To assess the overall survival (OS) achieved by the specific short-course preoperative targeted treatment followed by standard treatment in each cohort

Participating centers