Colorectal Cancer Clinical Trial
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
NCT number | NCT05845450 |
Other study ID # | UNICORN |
Secondary ID | |
Status | Recruiting |
Phase | Phase 2 |
First received | |
Last updated | |
Start date | May 11, 2023 |
Est. completion date | May 2028 |
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.
Status | Recruiting |
Enrollment | 112 |
Est. completion date | May 2028 |
Est. primary completion date | May 2025 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | Inclusion Criteria: 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. - 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. Exclusion Criteria: 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. - 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: - 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. |
Country | Name | City | State |
---|---|---|---|
Italy | Fondazione IRCCS Istituto Nazionale dei Tumori di Milano | Milan | Lombardia/MI |
Lead Sponsor | Collaborator |
---|---|
Gruppo Oncologico del Nord-Ovest |
Italy,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Disease-free survival | time from enrollment to the first documentation of disease recurrence or death due to any cause, whichever occurs first. DFS will be censored on the date of the last follow-up visit documenting absence of disease for patients who are alive, on study and disease free at the time of the analysis. | 36 months | |
Other | Overall survival | Overall survival will be defined as the time from enrollment to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive. | 36 months | |
Primary | 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 | 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). | 5 weeks | |
Secondary | 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 | 5 weeks | |
Secondary | 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. | 5 weeks | |
Secondary | Surgical mortality | the incidence of death occurring within 30 days after surgery in each cohort | 10 weeks | |
Secondary | Surgical morbidity | the incidence of a new onset temporary or permanent disability observed within 30 days after surgery in each cohort | 10 weeks | |
Secondary | Surgical complications | Surgical complications graded according to the Clavien-Dindo Classification of Surgical Complications and evaluated up to 90 days after surgery | 18 weeks | |
Secondary | 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. | 5 weeks | |
Secondary | 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. |
5 weeks | |
Secondary | 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. | 5 weeks | |
Secondary | 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 | 5 weeks | |
Secondary | 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. | 5 weeks | |
Secondary | 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. | 5 weeks | |
Secondary | 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. | 5 weeks |
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