Chemotherapy and Pembrolizumab, Followed by Pembrolizumab and Olaparib as Firstline Therapy in Her-2 Negative Gastric/GEJ Adenocarcinoma
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|ClinicalTrials.gov Identifier: NCT05268510|
Recruitment Status : Recruiting
First Posted : March 7, 2022
Last Update Posted : September 16, 2022
|Condition or disease||Intervention/treatment||Phase|
|Esophagogastric Adenocarcinoma||Drug: Pembrolizumab Drug: Olaparib Drug: mFOLFOX-6 Drug: CapOX||Phase 2|
Her-2 negative patients suffering from metastatic or unresectable gastric/GEJ adenocarcinoma will be included in the study. Eligible subjects will receive 2 six-week (q42d) cycles of mod. FOLFOX-6 plus pembrolizumab. Alternatively, subjects may receive 2 six-week (q42d) cycles of CAPOX plus pembrolizumab. The decision for either mod. FOLFOX-6 or CAPOX is made at the sole discretion of the investigator taking into account the best interest of the patient. Following the chemotherapy induction phase, the subjects are scheduled to receive pembrolizumab plus olaparib until tumor progression or occurrence of limiting toxicity for a maximum of 16 cycles (q42d, total 18 cycles, approx. 2 years).
The primary objective of this phase II study is to assess the overall survival at 1 year. Secondary objectives are the assessment of the objective response rate, the best overall response, progression-free survival, overall survival and treatment feasibility rate along with safety and toxicity of the treatment.
The exploratory objective is to assess whether clinical efficacy correlates with molecularly-defined subgroups (PD-L1 expression, HR alterations, MSI subtypes, and others).
The study will be accompanied by an explorative translational research analysis of blood and tumor samples.
The compositional changes of leukocyte states and their gene expression changes under combination immunotherapy will be analyzed using single cell RNA sequencing. Using factor analysis methods, we will analyze the environmental cues shaping leukocyte states and compare these features in responders and non-responders to therapy and correlate these with overall and progression-free survival. In addition, centralized PD-L1 expression and molecular sequencing of tumor tissue will be performed with a focus on alterations of HRD pathway.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||31 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||
Eligible subjects will receive 2 six-week (q42d) cycles of mod. FOLFOX-6 plus 400 mg pembrolizumab. Alternatively, subjects may receive 2 six-week (q42d) cycles of CAPOX plus 400 mg pembrolizumab. The decision for either mod. FOLFOX-6 or CAPOX is made at the sole discretion of the investigator taking into account the best interest of the patient.
Following the chemotherapy induction phase, the subjects are scheduled to receive up to 16 six-week (q42d) cycles of pembrolizumab (400 mg) plus olaparib (300 mg bid.).
|Masking:||None (Open Label)|
|Official Title:||Phase IIA Trial of Short-term Chemotherapy and Pembrolizumab, Followed by Pembrolizumab and Olaparib as Firstline Therapy in Her-2 Negative Gastric/Gastroesophageal-junction (GEJ) Adenocarcinoma|
|Actual Study Start Date :||September 15, 2022|
|Estimated Primary Completion Date :||September 2026|
|Estimated Study Completion Date :||March 2027|
Experimental: Chemotherapy plus Pembrolizumab followed by Pembrolizumab and Olaparib
Chemotherapy plus Pembrolizumab 2 cycles à 6 weeks:
Consolidation phase Pembrolizumab and Olaparib max 16 cycles à 6 weeks:
400 mg Pembrolizumab day 1 Q6W (max. 18 cycles)
Other Name: Keytruda
300 mg Olaparib bid. cont. day 1 to 42 (max. 16 cycles)
Other Name: Lynparza
Oxaliplatin 85 mg/m² 2h day 1, 15, 29 plus Leucovorin 400 mg/m² 2h day 1, 15, 29 plus 5-FU 400 mg/m² bolus, followed by 2.400 mg/m² 46h day 1, 15, 29; Q6W, 2 cycles
Oxaliplatin 130 mg/m² 2h day 1,22 plus Capecitabine 1.000 mg/m² bid. day 1-14, 22-35; Q6W, 2 cycles
- Overall survival (OS) rate at 1 year [ Time Frame: 1 year after enrolment ]Overall survival (OS) rate at 1 year defined as the percentage of patients who remain alive one year after enrollment into the study
- Progression-free survival (PFS) [ Time Frame: up to 55 months ]Progression-free survival (PFS), defined as time from enrollment to disease progression according to RECIST 1.1 and iRECIST or death due to any cause
- Objective response rate (ORR) [ Time Frame: up to 55 months ]ORR - percentage of patients with complete response (CR) or partial response (PR) according to RECIST 1.1 and iRECIST.
- Best Overall Response (BOR) [ Time Frame: up to 55 months ]BOR - best response recorded from enrollment to treatment discontinuation for any reason.
- Time to tumor progression (TTP) [ Time Frame: up to 55 months ]TTP - time from enrollment to disease progression according to RECIST 1.1 and iRECIST.
- Overall Survival (OS) [ Time Frame: up to 55 months ]OS - time from enrollment to the date of death of any cause.
- Feasibility rate [ Time Frame: 36 weeks ]Feasibility rate: severe toxicity/withdrawal rate before the fourth cycle of pembrolizumab/olaparib has been completed.
- Incidence and severity of adverse events [ Time Frame: up to 29 months (18 cycles a 6 weeks plus 110 days after last treatment) ](Serious) Adverse Events - Recorded and graded according to NCI-CTC V5.0. Occurrence of (Serious) Adverse Events at any time during the study. Description by nature (Primary System Organ Class and Preferred Term), severity and causal relationship to drug administration
- Immune cell states (exploratory translational outcome) [ Time Frame: up to 55 months ]Identification of immune cell states changing in abundance in responders vs non-responders under Pembrolizumab/chemotherapy. The compositional changes within cellular neighborhoods will be identified using a generalized linear model with an FDR of 0.025 and the following covariates: patient ID, timepoint (1st and 2nd sampling timepoint as per study protocol).
- Predictive value of PD-L1 CPS (exploratory translational outcome) [ Time Frame: up to 55 months ]Centralized analysis of the predictive value of PD-L1 combined prognostic score (CPS).
- Other exploratory translational outcomes: [ Time Frame: up to 55 months ]
- Descriptively define the dynamics of immune cell states and their factor loadings over the entire course of therapy, including consolidation therapy with Olaparib in combination with Pembrolizumab stratified by best response status (PD/SD vs PR) and by PFS and OS under Olaparib + Pembrolizumab.
- Correlation of efficacy of consolidation therapy with molecular alterations in the HRD pathway
- Compare mean factor loadings per patient in responders (according to RECIST 1.1) and non-responders within each major immune subset (CD4 T cells, CD8 T cells, Natural Killer cells, dendritic cells, monocytes, naïve B cells, memory B cells) using Mann-Whitney-U tests and the Benjamini-Hochberg method. For comparison within the first immune cell subset alpha will be set to 0.0125 and will be divided by 2 for every additional subset tested to not exceed an overall false discovery rate of 0.05 for all analyses.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05268510
|Contact: Georg Martin Haag, PD Dr.||0049 6221 56-8819||GeorgMartin.Haag@med.uni-heidelberg.de|
|Contact: Tanita Brulin||0049 69 email@example.com|
|Contact: Georg Martin Haag|
|Study Director:||Salah-Eddin Al-Batran, Prof. Dr.||Institut für Klinische Krebsforschung IKF GmbH|
|Principal Investigator:||Georg Martin Haag, PD Dr.||National Center for Tumor Diseases, University Hospital Heidelberg|