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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione GONO G.I.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 May 2023 → ongoing

Decision date (initial)

2023-04-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca S.p.A. · AGENUS INC. · Amgen S.r.l.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

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. For patients enrolled in cohorts 11 and 12, a co-primary endpoint consists in timely surgery, which is defined as the performance of planned surgery with a delay of no more than 14 days beyond the pre-specified 35 days after treatment start owing to treatment-related adverse events.

Secondary objectives 7

1. To assess the safety and the tolerability of each specific short-course preoperative targeted or neoadjuvant treatment and to describe the morbidity of surgical procedures.
2. To assess the impact of each specific short-course preoperative targeted or neoadjuvant 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 or neoadjuvant treatment.
4. To evaluate the changes in systemic immune profiles induced by each specific short-course preoperative targeted or neoadjuvant treatment.
5. To perform 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 or neoadjuvant treatment.
7. To analyze microbiota to evaluate the existence of a prognostic/predictive gut immune signature in specific molecular subgroups.

Conditions and MedDRA coding

Molecularly selected and resectable primary colorectal cancer

Study design 1 period

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. General inclusion criteria for the study population. • Provide a signed and dated informed consent document prior to any study procedure. • Age ≥ 18 years at time of informed consent. • ECOG PS of 0 or 1. • Histologically confirmed colorectal 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 (see Section 5.1.1). • 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). • Absence of distant metastases at baseline as defined by negativity of chest/abdomen/pelvis contrast-enhanced computed tomography (CT). • 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 characterized by the following at screening. • 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 characterized by the following at screening. • Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. • Subjects and their partners must be willing to avoid pregnancy during the trial and until a specific time interval after the last trial treatment: 4 months after last dose of trastuzumab-deruxtecan, 3 months for durvalumab, botensilimab and balstilimab and 2 months for panitumumab alone or in combination with sotorasib. 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.

Exclusion criteria 1

1. General exclusion criteria for the study population Patients meeting any of the following criteria will be excluded from the study: • Distant metastases at any site. • Risk criteria for obstructing disease at radiology or endoscopy as defined in the pivotal FOxTROT study (see Section 5.1.1). • 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 (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), 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 polymerase chain reaction 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 drug, as explained in Section 9.2, that cannot be suspended ≤ 1 week before study treatment start.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 pCR or pMR response as per central pathological review.

Secondary endpoints 7

1. Safety and tolerability will be assessed in terms of AEs (including SAEs), laboratory data, vital signs, ECGs, and exposure, that will be collected for all patients enrolled in the trial and receiving at least 1 dose of any study drugs.
2. Quality of life will be defined by a series of Patient Reported Outcomes (PROs) assessed in each cohort by the completion of quality-of-life questionnaires, European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-CR-29 and EuroQol EQ-5DL, during the pre-operative treatment phase.
3. The transcriptional tumor/microenvironmental changes induced by the specific pre-operative targeted treatment will be resolved spatially by the evaluation of the gene expression profiles in different tumor compartments (cancer cells, lymphocytes, and macrophages) in matching pre- and post-treatment samples by comprehensive transcriptomic analyses on the GeoMx DSP platform and by multiplex IHC (CODEX).
4. The changes in systemic immunity induced by the specific pre-operative targeted treatment will be 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. 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.
6. 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.
7. 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione GONO G.I.

Sponsor organisation

Fondazione GONO G.I.

Address

Via Goffredo Mameli 3/1

City

Genoa

Postcode

16122

Country

Italy

Scientific contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Public contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Third parties 1

Locations

1 EU/EEA country · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 53 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications