Sequential Immunochemotherapy Treatment With Pembrolizumab Plus Dendritic Cell (DC) Vaccine Followed by Trifluridine/Tipiracil Plus Bevacizumab in Refractory Mismatch-repair-proficient (pMMR) or Microsatellite-stable (MSS) Metastatic Colorectal Cancer
NCT Number: NCT06522919
Acronym: CombiCoR-Vax
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE2
Conditions: Colorectal Cancer Metastatic|Microsatellite Stable Colorectal Carcinoma|Refractory Mismatch-repair-proficient (pMMR) Metastatic Colorectal Cancer
Interventions: BIOLOGICAL: Autologous Dendritic Cell (DC) Vaccine
Sponsor: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 36
Study Design: Allocation: NA|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-09-01
Completion Date: 2026-09-01
Locations: IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"-IRST S.r.l., Meldola, Forlì Cesena, 47014, Italy|Pia Fondazione di Culto e Religione Azienda Ospedaliera "Card.G.Panico", Tricase, Lecce, 73039, Italy

Summary:
Single-arm, open-label, multicenter phase 2 clinical trial evaluating the clinical and the immunological activity of an innovative strategy with an induction combo immunotherapy (Pembrolizumab plus DC Vaccine) followed by a maintenance chemotherapy (FTD/TPI plus Bevacizumab) in patients with refractory MSS/pMMR metastatic colorectal cancer.

Primary Outcome Measures: Overall Response Rate (ORR), The primary endpoint is Overall Response Rate (ORR) of chemotherapy, defined as the percentage of patients experiencing partial response (PR) or complete response (CR), according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, after starting the treatment with FTD/TPI plus Bevacizumab., 2 years
Secondary Outcome Measures: Progression free survival (PFS), Measured as the time from the start of the treatment with FTD/TPI plus Bevacizumab to the date of first progression, or the date of death from any cause, or the date of the last restaging in non-progressed patients, 2 years|Safety evaluation, All adverse events will be recorded during the observation period (i.e. from the day of the first DC vaccine dose administered in the induction phase up to 30 days after the last dose of chemotherapy), will be reported and graded according to NCI CTCAE 5.0., 2 years|Overall Survival (OS), Measured from the start of the induction treatment until the date of death from any cause or the last date on which it was known that the patient was alive., 2 years|In vivo immunomonitoring through DTH test:, In vivo immunomonitoring through DTH test: DTH testing will be performed in all patients on day 0 (pre-treatment DTH), after the induction phase (post-combo immuno treatment DTH), after the maintenance phase, at the end of treatment and at disease progression. The diameter of induration/erythema observed after 24 hours is recorded according to the following scale: 0-5 mm grade 1, 6-10 mm grade 2, 11-20 mm grade 3, and \> 21 mm grade 4. As DTH reactivity to lower concentrations of the antigen(s) is strictly related to more intense antigen specific immune responses, score results will be normalized against the concentration itself and transformed into a 0-80 scale for analysis purposes. Best results obtained for each patient at any of the posttreatment DTHs, either for tumor homogenate or keyhole limpet hemocyanin (KLH), will be taken into account for data analysis (best normalized score)., 2 years|Characterization of patient's HLA class I immune response, The typing of the locus A-B-C-DR and DQA/DQB will be performed by the Genetic Laboratory by means of the sequence-specific oligonucleotide probe reverse hybridization (PCR-SSO) method. This information will be used to design patient's HLA restricted peptides for personalized functional in vitro immune assays (such as IFN-γ ELISPOT assay and INF-γ secretion assay), as well as for tetramer-guided peripheral monitoring of the antigen specific response. Moreover, statistical analysis will be conducted to correlate the strength of the recorded immunological response to the full HLA haplotype and the clinical outcome., 2 years|Characterization of patient's HLA class II immune response, The typing of the locus A-B-C-DR and DQA/DQB will be performed by the Genetic Laboratory by means of the sequence-specific oligonucleotide probe reverse hybridization (PCR-SSO) method. This information will be used to design patient's HLA restricted peptides for personalized functional in vitro immune assays (such as IFN-γ ELISPOT assay and INF-γ secretion assay), as well as for tetramer-guided peripheral monitoring of the antigen specific response. Moreover, statistical analysis will be conducted to correlate the strength of the recorded immunological response to the full HLA haplotype and the clinical outcome., 2 years|Characterization of patient's HLA-restricted immune response, The typing of the locus A-B-C-DR and DQA/DQB will be performed by the Genetic Laboratory by means of the sequence-specific oligonucleotide probe reverse hybridization (PCR-SSO) method. This information will be used to design patient's HLA restricted peptides for personalized functional in vitro immune assays (such as IFN-γ ELISPOT assay and INF-γ secretion assay), as well as for tetramer-guided peripheral monitoring of the antigen specific response. Moreover, statistical analysis will be conducted to correlate the strength of the recorded immunological response to the full HLA haplotype and the clinical outcome., 2 years|Definition of the prognostic and predictive role of peripheral immune cell subsets and soluble factors, Definition of the prognostic and predictive role of peripheral immune cell subsets and soluble factors: PBMC samples taken before treatment, during and after treatment will be evaluated by multiparametric flow cytometry to assess abundance of regulatory cell subsets (regulatory T cells and immunosuppressive myeloid cells). Moreover, an automated platform of multianalyte will be applied in longitudinal plasma samples. Results will be analyzed by means of bioinformatics and statistical tools and correlated with all the relevant clinical parameters., 2 years|In situ characterization of pMMR mCRC through Next Generation Sequencing analysis, NGS approaches (WES and RNAseq analysis) together with in house available bioinformatics pipeline will be used to score the antigen/neoantigen expression in pre-treatment and, whenever available, post-treatment tissue. Deconvolution methods will be used to enumerate immune cells abundance from transcriptional data. Moreover, expression of other TME-related transcripts will be addressed and correlated to the clinical outcome., 2 years|In situ characterization of MSS mCRC through Next Generation Sequencing analysis, NGS approaches (WES and RNAseq analysis) together with in house available bioinformatics pipeline will be used to score the antigen/neoantigen expression in pre-treatment and, whenever available, post-treatment tissue. Deconvolution methods will be used to enumerate immune cells abundance from transcriptional data. Moreover, expression of other TME-related transcripts will be addressed and correlated to the clinical outcome., 2 years|In situ protein validation at the single cell level, In situ protein validation at the single cell level: using an in-house-developed multiplex immunohistochemistry (IHC), well-known mCRC antigens (i.e. survivin, EGFR, p53, MUC-1, mesothelin) will be monitored at the tissue level., 2 years|Identification of tumor infiltrating immune cell subsets, Tumor infiltrating immune cell subsets will be identified and quantified (i.e. positive cell score and close proximity score). Moreover, the predictive effect of the frequency and the distribution of infiltrating immune cell subsets will be correlated with the patient's clinical outcome, 2 years