INFINITY is a Phase II, multicentre, single-arm, multi-cohort trial aimed at evaluating the activity and safety of the combination of tremelimumab and durvalumab as neoadjuvant (Cohort 1) and definitive (Cohort 2) treatment for MSI-high gastric/gastroesophageal juction cancer patients eligible for radical surgery.
This study will pre-screen approximately 310 patients, in order to enrol a total number of 31 patients, 18 in Cohort 1 and 13 in Cohort 2, across 25 Italian Centres. After central confirmation of MSI-high, dMMR and EBV-negative status, patients with resectable gastric or gastroesophageal junction cancer (Siewert II/III), categorized as cT≥2, any cN, M0 or any cT, cN1-3, M0 according to TNM classification 8th edition, will be enrolled and they will receive a pre-operative treatment with tremelimumab 300 mg single administration (day 1) and durvalumab 1500 mg Q4W for 3 cycles (day 1, 29 and 57). All patients will undergo a complete disease restaging with chest-abdomen-pelvis CT scan, 18-FDG PET/CT, EUS with biopsies and liquid biopsy. In Cohort 1, patients will undergo standard gastrectomy with D2 lymphadenectomy between weeks 15 and 18 from enrolment (at least six weeks after the last treatment administration), followed by an active follow-up every 12 weeks for two years and then a standard follow-up every six months until the end of the fifth year from surgery. In Cohort 2, patients with no evidence of complete clinical response (defined as absence of disease persistence at radiological imaging, liquid biopsy and EUS) will be treated as in Cohort 1. Patients with complete clinical response will undergo a non-operative management (NOM) and will start an active follow-up phase every 12 weeks for two years with chest-abdomen-pelvis CT with contrast, 18-FDG PET/TC, if clinically indicated by the Investigator, EUS with multiple random biopsies of the tumor site and FNA of clinically suspicious regional nodes and liquid biopsy, followed by standard follow-up every six months until the end of the fifth year. At any time during follow-up, in case of clinical suspicion or confirmation of residual gastric cancer, either at imaging, pathologically at tissue biopsies/cytological specimens or at ctDNA in liquid biopsy, the patients will undergo standard surgery according to the clinical practice at their Centre (subtotal/total gastrectomy with D2 lymphadenectomy). Enrolment in Cohort 2 will start only after the completion of enrolment in Cohort 1 and after the extensive evaluation of the final results of Cohort 1 regarding to all endpoints (including exploratory endpoints) and after potential amendment(s) on study design, eligibility criteria and study procedures requested by the Sponsor's Steering Committee and an Independent Data Monitoring Committee made of foreign experts, and after the approval of the Ethics Committee and the Italian Medicines Agency.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
31
durvalumab 1500 mg Q4W for 3 cycles (day 1, 29 and 57).
tremelimumab 300 mg single administration (day 1)
Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
Milan, Italy
Primary outcome of Cohort 1: Pathological complete response (ypT0N0) and negative ctDNA status
Rate of patients (%) achieving both pathological complete response (ypT0N0) and negative ctDNA status after neoadjuvant immunotherapy in the intention-to-treat population of Cohort 1
Time frame: From the enrollment of the first patient in Cohort 1 up to 4 months from the enrollment of the last patient in Cohort 1
Primary outcome of Cohort 2: 2-year complete response rate
2-year complete response rate, defined as the absence of macroscopic or microscopic residual disease (locally, regionally and distantly) at radiological examinations, tissue and liquid biopsy, in absence of salvage gastrectomy.
Time frame: From the enrollment of the first patient in Cohort 2 up to 2 years from the end of pre-operative treatment of the last patient enrolled in Cohort 2
Patients' quality of life
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.
Time frame: For each Cohort, from the enrollment of the first patient up to 4 months from the last patient starting the pre-operative treatment phase
Patients' quality of life
Quality of life will be assessed through Patient reported outcomes (PRO) instrument. EORTC QLQ-STO22. For questions 31-52 of EORTC QLQ-STO22 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.
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Time frame: For each Cohort, from the enrollment of the first patient up to 4 months from the last patient starting the pre-operative treatment phase
Patients' quality of life
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.
Time frame: For each Cohort, from the enrollment of the first patient up to 4 months from the last patient starting the pre-operative treatment phase
3-year disease-free survival
time from the enrollment in the study to the occurrence of disease relapse (local and/or distant), second gastric or gastroesophageal junction cancer primary, or death from any cause.
Time frame: For each Cohort, from the enrollment of the first patient up to 3 years from the enrollment of the last patient
5-year overall survival
time from the enrollment in the study to the occurrence of death.
Time frame: For each Cohort, from the enrollment of the first patient up to 5 years from the enrollment of the last patient
Metastases-free survival
time from the enrollment in the study to the first evidence of metastases or death from any cause.
Time frame: For each Cohort, from the enrollment of the first patient up to 5 years from the enrollment of the last patient
Gastrectomy-free survival (Cohort 2 only)
time from the inclusion in the study to the occurrence of gastrectomy or death from any cause.
Time frame: From the enrollment of the first patient up to 5 years from the enrollment of the last patient
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
incidence of adverse events during the treatment and follow-up phases, assessed according to CTCAE v5.0.
Time frame: For each Cohort, from the enrollment of the first patient up to 5 years from the enrollment of the last patient
Post gastrectomy complications
Rate of post-gastrectomy complications following tremelimumab and durvalumab as pre-operative treatment strategy.
Time frame: For each Cohort, from the enrollment of the first patient up to 1 year from the enrollment of the last patient