Clinical trial NCT06522919: 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
Official title: Sequential Immunochemotherapy Treatment with Pembrolizumab Plus Dendritic Cell (DC) Vaccine Followed by Trifluridine/Tipiracil (FTD/TPI) Plus Bevacizumab in Refractory Mismatch-repair-proficient (pMMR) or Microsatellite-stable (MSS) Metastatic Colorectal Cancer (CombiCoR-Vax)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Colorectal Cancer Metastatic
Microsatellite Stable Colorectal Carcinoma
Refractory Mismatch-repair-proficient (pMMR) Metastatic Colorectal Cancer
Lead sponsor: Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRST S.r.l. IRCCS
Sponsor class: OTHER
First posted: 2024-07-26
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single-arm, open-label, multicenter phase 2 clinical trial
Primary purpose: TREATMENT

Brief 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.

Detailed description: Metastatic colorectal cancer (mCRC) remains an incurable disease characterized by a poor prognosis. Recently, in the global phase 3 SUNLIGHT (NCT04737187) study, adding Bevacizumab to Trifluridine/Tipiracil (FTD/TPI) in the treatment of refractory mCRC significantly improved overall survival. Therefore, this combination regimen is going to become the new standard of care for refractory mCRC. Immune checkpoint inhibitors (ICIs), including Pembrolizumab, have shown excellent results in MSI-H or dMMR mCRC, and recent trials evaluating both concomitant and sequential chemoimmunotherapy in MSS/pMMR mCRC (in particular ATEZOTRIBE and MAYA trials), have shown promising results. Since 2001, we have treated more than 80 advanced melanoma patients with a tumor lysate loaded autologous DC vaccine, observing a clinical benefit of 54.1% and, more importantly, an ORR of 63.6% to subsequent chemotherapy, suggesting that immunotherapy might improve the activity of sequential chemotherapy. Moreover, our team has recently concluded the first step of 2 ongoing clinical studies with DC vaccine administration, in radically resected mCRC and metastatic mesothelioma patients - showing that the vaccine was safe and promoted immunological responses that allowed it to continue with patients enrollment.

Eligibility criteria: Inclusion Criteria:

* Be willing and able to provide written informed consent.
* Histologically confirmed pMMR or MSS mCRC
* Male or female, aged ≥ 18 years
* Life expectancy greater than 12 weeks
* ECOG performance status \<2
* Patient suitable for the collection of biological material from leukapheresis: negative serological tests (HIV, HBV, HCV, Treponema pallidum); normal cardiological parameters (12-lead ECG and echocardiogram); evaluation by transfusionist to exclude possible contraindications to leukapheresis; recovered (grade 1 or less by CTCAE 5.0) from all the adverse events related to previous treatments.Exclusion Criteria:
* Patients must have measurable disease by RECIST v 1.1 criteria on CT (or MRI) scan of the chest, abdomen and pelvis. See section 9.2 and Appendix D for the evaluation of measurable disease.
* Prior treatment with 1-2 chemotherapy regimens in an advanced setting, including (if not contraindicated) fluoropyrimidines, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody and/or anti-EGFR monoclonal antibody for RAS wild-type tumors.
* Patients must have normal organ and marrow function as defined below:

leukocytes \>3,000/μL, absolute neutrophil count \>1,500/μL, platelets \>100,000/μL, total bilirubin \< 1.5 X institutional upper limit of normal (ULN), AST(SGOT)/ALT(SGPT) \<2.5 X ULN, creatinine \< 1.5 X ULN OR creatinine clearance \>30 mL/min/1.73 m2

* The autologous surgical specimen needed for vaccine manufacturing must have been collected and sent to the Somatic Cell Therapy Lab of IRCCS IRST and must fulfill all the acceptance criteria prescribed by the GMP procedures
* Recovery (grade 1 or less by CTCAE 5.0) from all the adverse events related to previous surgery.
* A female participant is eligible to participate if she is not pregnant and not breastfeeding. Female patients of childbearing potential and all male patients must accept and be compliant with a highly effective contraceptive method
* Participant is willing and able to give informed consent for participation in the study.

Exclusion Criteria:

The participant may not enter the study if ANY of the following apply:

* Prior treatment with FTD/TPI for mCRC
* Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
* Participation in another clinical trial with any investigational agents within 30 days prior to study screening.
* Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to Pembrolizumab, FTD/TPI, Bevacizumab or components of the DC vaccine.
* History of congenital or acquired immunodeficiency, including history of organ transplantation.
* Any active inflammatory or autoimmune disease requiring systemic steroids or other immunomodulatory agents
* Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Other known malignant neoplastic diseases in the patient's medical history with a disease-free interval of less than 5 years (except for previously treated basal cell carcinoma and in situ carcinoma of the uterine cervix).

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 2 years
Secondary outcomes:
measure: Progression free survival (PFS)
timeFrame: 2 years
measure: Safety evaluation
timeFrame: 2 years
measure: Overall Survival (OS)
timeFrame: 2 years
measure: In vivo immunomonitoring through DTH test:
timeFrame: 2 years
measure: Characterization of patient's HLA class I immune response
timeFrame: 2 years
measure: Characterization of patient's HLA class II immune response
timeFrame: 2 years
measure: Characterization of patient's HLA-restricted immune response
timeFrame: 2 years
measure: Definition of the prognostic and predictive role of peripheral immune cell subsets and soluble factors
timeFrame: 2 years
measure: In situ characterization of pMMR mCRC through Next Generation Sequencing analysis
timeFrame: 2 years
measure: In situ characterization of MSS mCRC through Next Generation Sequencing analysis
timeFrame: 2 years
measure: In situ protein validation at the single cell level
timeFrame: 2 years
measure: Identification of tumor infiltrating immune cell subsets
timeFrame: 2 years
Other outcomes:
Locations:
city: Meldola
country: Italy
facility: IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"-IRST S.r.l.
state: Forlì Cesena
city: Tricase
country: Italy
facility: Pia Fondazione di Culto e Religione Azienda Ospedaliera "Card.G.Panico"
state: Lecce
Study officials:
affiliation: IRCCS IRST
name: Alessandro Passardi
role: PRINCIPAL_INVESTIGATOR
References: