Description Module
The Description Module contains narrative descriptions of the clinical trial, including a brief summary and detailed description. These descriptions provide important information about the study's purpose, methodology, and key details in language accessible to both researchers and the general public.
Description Module path is as follows:
Study -> Protocol Section -> Description Module
Description Module
Ignite Creation Date:
2025-12-24 @ 5:18 PM
Ignite Modification Date:
2025-12-24 @ 5:18 PM
NCT ID:
NCT05845450
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.
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.
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.
Study:
NCT05845450
Study Brief:
Protocol Section:
NCT05845450