Intermittent or Continuous Panitumumab Plus FOLFIRI for Left Sided RAS/B-RAF Wild-type Metastatic Colorectal Cancer
NCT Number: NCT06509126
Acronym: IMPROVE-2
Status: RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE3
Conditions: Colorectal Cancer Stage IV
Interventions: DRUG: Panitumumab|DRUG: Irinotecan|DRUG: 5-fluorouracil|DRUG: L-folinic acid
Sponsor: National Cancer Institute, Naples
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 500
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-06-12
Completion Date: 2028-06
Locations: Istituto Nazionale Tumori di Napoli - IRCCS - Fondazione G. Pascale, Napoli, 80131, Italy

Summary:
The investigators hypothesize that intermittent first-line Panitumumab plus FOLFIRI is effective in first line as the same regimen given continuously, resulting in a Time to Treatment Failure (TTF) not inferior to that obtained with standard continuous regimen of Panitumumab plus FOLFIRI, in the treatment of metastatic left sided RAS/B-RAF wild-type colorectal cancer patients.

Correlative mechanistic studies on tissue and blood samples, liquid biopsies, could identify potential biomarkers of efficacy and help understanding the evolutionary dynamics of tumors in response to therapy thus optimizing the treatment approach with a personalized anti-EGFR treatment strategy.

Primary Outcome Measures: Time to Treatment Failure, Time to treatment failure (TTF) is defined as the time from randomization to the objective disease progression by RECIST 1.1 criteria occurred during the treatment (objective disease progression during treatment free intervals are excluded) or death due to any cause, whichever occurs first, or a treatment delay \> 28 days for toxicity, up to 1 year last patients randomized
Secondary Outcome Measures: Overall survival, (OS) is calculated as the time from randomization until the date of death from any cause., up to 1 year last patients randomized
Other Outcome Measures: Objective Tumor Response Rate, Objective Tumor Response Rate (ORR) is defined as as the proportion of patients achieving complete or partial response relative to total enrolled patients, up to 1 year last patients randomized|Disease Control Rate, Disease Control Rate (DCR) is defined as the proportion of patients with complete/partial response and stable disease as their best response during randomized phase, up to 1 year last patients randomized|Depth of Response, Depth of response (DpR) assessed, during randomized phase, as the percentage of tumor shrinkage observed at the lowest point (nadir) compared with baseline. For the evaluation of DpR, the diameter of the RECIST vs 1.1 target lesions will be measured, longest tumor diameter, and summed for each assessment, up to 1 year last patients randomized|Progression free survival on treatment, Progression-free survival on treatment (PFSot) is measured as the time from randomization to the disease progression occurred during treatment or death due to any cause, whichever occurs first., up to 1 year last patients randomized|Toxicities, Overall Toxicity rate is defined as the proportion of patients experiencing any grade AE accordingly to the NCI Common Terminology Criteria of Adverse Events (NCI CTC-AE) Version 5, relative to the total of patients receiving at least one cycle of treatment, up to 30 days after last cycle of every patients randomized|Assessment of patients health related quality of life, Quality of life (QoL) investigated through the EORTC QOL-C30 questionnaire at baseline (prior to treatment start, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death., up the date of first documented progression, assessed up to 100 months.|Longitudal toxicity over time, Tolerability evaluated as longitudinal toxicity over time will be expressed by bar charts, that depicts the frequency and proportion of each grade level for a given AE across patients by cycle. It will be evaluated at the end of every cycle (each cycle is 14 days), up to 30 days after last cycle of every patients randomized|Genetic alterations on tumor samples, A comprehensive NGS assay (50 cancer related genes) will be employed to carry out molecular profile of actionable genes on fully automatized NGS platform (Genexus System, Thermofisher in accordance with manufacturer procedures). The biomarkers will be correlated to the clinical outcome to define the predictive and/or prognostic role of the alterations detected. A final algorithm including the biomarkers with predictive value will be built in order to generate more robust tool for patient response and outcome and toxicity evaluation. Genetic alteration will be evaluated on tumor tissue before the start of therapy, baseline|Circulating tumor DNA (liquid biopsy), To explore the prognostic and predictive value as well as the potential to monitor treatment activity, leading to develop to personalized treatment strategy, will be performed by next generation sequencing (NGS), from blood samples ("liquid biopsy") collected at baseline, at week 16 and thereafter every 8 weeks, concomitantly with tumor assessment, and at progression of disease., up the date of first documented progression, assessed up to 100 months|Metabolomic profiling, Peripheral blood will be collected, at all the time points previously described (Costantini S, et al. Front Oncol, 2022), in serum tubes through 21G needles aliquoted and stored at -80°C.

Metabolomic profiling will be evaluated by nuclear magnetic resonance (NMR) Spectrometer (600 MHz). 1H and 2D spectra on sera samples will be acquired by 600-MHz Bruker Avance DRX NMR spectrometer with a TSI probe as previously reported by Sorice et al. \[41\]. The metabolite assignments will be based on the comparison of chemical shifts and spin-spin couplings with reference spectra and tables present in the SBASE-1-1-1 database by AMIX package (Bruker, Biospin, Germany), the human metabolome database (HMDB) and the biological magnetic resonance database (BMRB). Metabolic profiling will be evaluated on blood samples collected at baseline, at week 16 and thereafter every 8 weeks until progression disease., up the date until first progression date, assessed up to 100 months|Health related quality of life, Quality of life (QoL) investigated through the EORTC QOL-CR29 questionnaire at baseline (prior to treatment start, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death., up the date of first documented progression, assessed up to 100 months.