Neoplasms

All Conditions

Digestive System Diseases

Rare Diseases

Carcinoma

Adenocarcinoma

Stomach Neoplasms

Esophageal Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Stomach Diseases

Head and Neck Neoplasms

Esophageal Diseases

Stomach Cancer

Esophageal Cancer

All Drugs and Chemicals

Antineoplastic Agents

Pharmaceutical Solutions

Antibodies

Paclitaxel

Albumin-Bound Paclitaxel

Immunoglobulins

Ramucirumab

Tubulin Modulators

Antimitotic Agents

Angiogenesis Inhibitors

Growth Inhibitors

Participants with measurable disease and with evaluable disease as defined by RECIST v1.1 will be enrolled on this study.

AgenT-797 is an investigational product, composed of allogeneic human unmodified iNKT cells, isolated from mononuclear cell aphaeresis units from healthy donors

AgenT-797

Botensilimab is a novel, human, Fc-engineered IgG1 anti-CTLA-4 antibody

Botensilimab

Botensilimab is supplied as a sterile, single-use solution for IV administration

Balstilimab

Ramucirumab is a fully human anti-VEGFR2 monoclonal IgG1 antibody (IgG1) that binds with high affinity to the extracellular domain of VEGFR2. Ramucirumab is a part of standard of care treatment for advanced gastric cancer or GEJ adenocarcinoma, after prior treatment with fluoropyrimidine- or platinum-containing chemotherarapy.

Paclitaxel is widely used across multiple cancer types and is a part of standard of care treatment for advanced EG adenocarcinoma after prior treatment with fluoropyrimidine- or platinum-containing chemotherarapy.

Yelena Janjigian, MD

Geoffrey Ku, MD

Yelena Y Janjigian, MD

Participants will receive study treatment with agenT-797, botensilimab, balstilimab, ramucirumab, and paclitaxel. When participants start each agent will depend on how their disease is affecting them.

A Study of agenT-797 in Combination With Botensilimab, Balstilimab, Ramucirumab, and Paclitaxel for People With Esophageal, Gastric, or Gastro-esophageal Junction Cancer

A Phase II Study of agenT-797 (Invariant Natural Killer T Cells), Botensilimab, a Novel Fc-enhanced CTLA-4 Inhibitor, Plus Balstilimab (Anti-PD-1) With Ramucirumab and Paclitaxel for Patients With Previously Treated, Advanced Esophageal, Gastric, or Gastro-esophageal Junction Adenocarcinoma

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

Determine the efficacy of agenT-797, botensilimab and balstilimab in combination with ramucirumab and paclitaxel as second-line therapy in patients with advanced unresectable or metastatic esophagogastric cancer, as measured by ORR (defined as the percentage of patients who achieve either an objective complete response \[CR\] + partial response \[PR\])

Memorial Sloan Kettering Cancer Center

Symptoms and General Pathology

Recurrence

Disease Attributes

Antibodies, Monoclonal

Olaparib

Lexatumumab

Poly(ADP-ribose) Polymerase Inhibitors

Antineoplastic Agents, Immunological

Immunoglobulins, Intravenous

Immunologic Factors

Enzyme Inhibitors

Patients receive olaparib PO BID on days 1-14 of each cycle and ramucirumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Michael Cecchini

This phase I/II trial studies the side effects and best dose of olaparib when given together with ramucirumab and how well they work in treating patients with gastric or gastroesophageal junction cancer that has spread to other places in the body (metastatic), has come back (recurrent), or cannot be removed by surgery (unresectable). Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as ramucirumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving olaparib and ramucirumab may work better in treating patients with gastric or gastroesophageal junction cancer compared to ramucirumab and paclitaxel (a chemotherapy drug) or ramucirumab alone.

PRIMARY OBJECTIVES:

I. To determine the safe dose of olaparib with ramucirumab, but not to exceed olaparib dose of 300 mg twice daily (tablet formulation). (Phase I) II. To determine the efficacy of olaparib plus ramucirumab as measured by the objective response rates (ORR) stratified by BROCA-HR biomarker status. (Phase II).

SECONDARY OBJECTIVES:

I. To estimate median progression-free survival (PFS) stratified by BROCA-HR biomarker status.

II. To estimate median overall survival (OS) stratified by BROCA-HR biomarker status.

III. To measure the prevalence of the BROCA-HR biomarker in our study population.

IV. To determine toxicity of olaparib and ramucirumab combination.

EXPLORATORY OBJECTIVES:

I. To assess the correlation between the signature 3 status, and mutations in BROCA-HR panel.

II. To evaluate the association between findings from BROCA-HR panel with response to therapy.

III. To evaluate the association between findings from BROCA-HR panel and signature 3 results with response to therapy.

IV. To determine results of immunoassay for poly-ADP-ribosylated (PAR) substrates in tumor tissue.

V. To create a PDX model to study deoxyribonucleic acid (DNA) repair in gastric tumors treated with PARP inhibitors (PARPi) from both pre-treatment biopsy and repeat biopsy after 16 weeks of treatment.

VI. Development of a novel genomic assay for BRCAness. VII. Defining T cell receptor diversity of gastric cancer patients +/- BRCAness.

VIII. Biobank additional tumor tissue for future genomic analysis. IX. Biobank peripheral blood for future genomic analysis and assessment of circulating tumor DNA.

OUTLINE: This is a phase I, dose-escalation study of olaparib followed by a phase II study.

Patients receive olaparib orally (PO) twice daily (BID) on days 1-14 of each cycle and ramucirumab intravenously (IV) over 60 minutes on day 1 of each cycle. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks and then every 6 weeks thereafter.

Olaparib and Ramucirumab in Treating Patients With Metastatic or Locally Recurrent Gastric or Gastroesophageal Junction Cancer That Cannot Be Removed by Surgery

A Phase 1/2 Study of Olaparib in Combination With Ramucirumab in Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma (10017760)

The association of BROCA HR assay with Signature 3 will be assessed using a series of contingency table analyses. The association of the presence of an individual mutation from the BROCA HR panel with the signature 3 (yes/no) using Fisher's exact test. Using a Cochran Mantel Haenzel test the relationship across all three measures will be examined. Finally, the relationship of each of these measures with response will be examined. To do this multiple logistic regression models can be fit with the response (complete response/partial response vs stable disease/partial disease) considered as the outcome variable and the assay measures can be used predictors.

Will be assessed by National Cancer Institute (NCI) Common Terminology Criteria (CTCAE) for Adverse Events version 5.0.

Will be defined as complete or partial response assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Will be estimated using the 95% confidence interval (CI) based on Wilson's method. A 5% 2-sided alpha will be used. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables, respectively. The generalized non-linear model and logistic regression will be applied for multivariable data analysis. The adjusted p-value and 95% CI of the odds ratio will be reported.

Will be compared for duration of response survival with Kaplan-Meier estimates and log-rank tests. The Rothman CI will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the PFS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Will be compared for duration of response survival with Kaplan-Meier estimates and log-rank tests. The Rothman CI will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Will be assessed by NCI CTCAE version 5.0. Will be tabulated by type and grade and compared to established rates for ramucirumab monotherapy. Ninety-five percent confidence intervals will be calculated for each of these.

National Cancer Institute (NCI)

Trastuzumab

Trastuzumab deruxtecan

Camptothecin

Immunoconjugates

Topoisomerase I Inhibitors

Patients receive T-DXd IV over 30-90 minutes on day 1 of each cycle and azenosertib PO QD on days 1-5, 8-12, and 15-19 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA and collection of blood samples at screening and on study and undergo CT or MRI throughout the trial.

Patients receive T-DXd IV over 30-90 minutes on day 1 of each cycle and azenosertib PO QD on days 8-12 and 15-19 of cycle 1 and days 1-5, 8-12, and 15-19 in subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA and collection of blood samples at screening and on study and undergo CT or MRI throughout the trial. Patients also undergo biopsy at screening and on study.

Patients receive treatment as in the dose escalation arm. Patients also undergo ECHO or MUGA and collection of blood samples at screening and on study and undergo CT or MRI throughout the trial. Patients also undergo biopsy at screening and on study.

Azenosertib

Biopsy

Biospecimen Collection

Computed Tomography

Echocardiography

Magnetic Resonance Imaging

Multigated Acquisition Scan

Trastuzumab Deruxtecan

Funda Meric-Bernstam

This phase I trial tests the safety, side effects, and best dose of azenosertib in combination with trastuzumab deruxtecan in treating patients with HER2-positive and cyclin E amplified gastric or gastroesophageal junction cancer and other HER2-positive solid tumors that have spread to nearby tissue or lymph nodes (locally advanced), that have spread from where it first started (primary site) to other places in the body (metastatic), or that cannot be removed by surgery (unresectable). Azenosertib is in a class of medications called kinase inhibitors. It inhibits a protein called Wee1. Inhibition of the Wee1 protein can make tumor cells more vulnerable to chemotherapy drugs, leading to tumor cell death. Trastuzumab deruxtecan is in a class of medications called antibody-drug conjugates. It is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Giving azenosertib in combination with trastuzumab deruxtecan may be safe, tolerable, and/or more effective in treating patients with locally advanced, metastatic, or unresectable HER2-positive gastric, gastroesophageal junction, or other solid tumors, compared to just trastuzumab deruxtecan alone.

PRIMARY OBJECTIVE:

I. To evaluate the safety and tolerability of trastuzumab deruxtecan (T-DXd; DS-8201a) in combination with azenosertib (ZN-c3) in human epidermal growth factor receptor 2 (HER2)-expressing/amplified solid tumors.

SECONDARY OBJECTIVES:

I. To observe and record the antitumor activity of the T-DXd (DS-8201a) and azenosertib (ZN-c3) combination.

II. To assess the pharmacodynamic effects of T-DXd (DS-8201a) in combination with azenosertib (ZN-c3).

III. To assess predictors of response and acquired resistance to the T-DXd (DS-8201a) and azenosertib (ZN-c3) combination.

OUTLINE: This is a dose-escalation study of azenosertib followed by a dose-expansion study.

DOSE ESCALATION: Patients receive T-DXd intravenously (IV) over 30-90 minutes on day 1 of each cycle and azenosertib orally (PO) once daily (QD) on days 1-5, 8-12, and 15-19 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) and collection of blood samples at screening and on study and undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial.

DOSE EXPANSION: Patients are assigned to 1 of 2 cohorts.

COHORT 1: Patients receive T-DXd IV over 30-90 minutes on day 1 of each cycle and azenosertib PO QD on days 8-12 and 15-19 of cycle 1 and days 1-5, 8-12, and 15-19 in subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA and collection of blood samples at screening and on study and undergo CT or MRI throughout the trial. Patients also undergo biopsy at screening and on study.

COHORT 2: Patients receive treatment as in the dose escalation arm. Patients also undergo ECHO or MUGA and collection of blood samples at screening and on study and undergo CT or MRI throughout the trial. Patients also undergo biopsy at screening and on study.

After completion of study treatment, patients are followed up at 30 days and then every 3 months in years 1 and 2 and every 6 months in year 3.

Testing the Combination of the Anticancer Drugs Trastuzumab Deruxtecan (DS-8201a) and Azenosertib (ZN-c3) in Patients With Stomach or Other Solid Tumors

Phase 1 Study of Trastuzumab Deruxtecan (DS-8201a) in Combination With Azenosertib (ZN-c3) in HER2-Expressing/Amplified Cyclin E-Amplified Gastric/Gastroesophageal Junction Cancer and Other Solid Tumors With HER2 Expression

"NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page."

A Bayesian optimal interval design will be used to determine the maximum tolerated dose of the T-DXd (DS-8201a) and azenosertib (ZN-c3) combination.

DLTs will be defined as the below based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

The incidence of AEs of the T-DXd (DS-8201a) and azenosertib (ZN-c3) combination, including but not limited to treatment-emergent adverse events, serious adverse events, deaths, and clinical laboratory abnormalities, will be assessed by the NCI CTCAE version 5.0. AEs will be tabulated by grade and by relationship to the study drugs. The proportion of patients who discontinue study treatment due to AEs and the unacceptable toxicity rate will be estimated with a 95% confidence intervals (CIs).

ORR will be the percentage of patients with complete response (CR) or partial response (PR), as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR will be estimated with a 95% CIs.

Disease progression will be assessed by RECIST version 1.1. PFS will be estimated using the product-limit estimator of Kaplan-Meier.

Duration of response will be estimated using the product-limit estimator of Kaplan-Meier.

Two-sample t-test (or Wilcoxon rank sum test) or Chi-square test will be used to compare pharmacodynamic markers between the two expansion cohorts.

Predictors of response and acquired resistance may include baseline HER2 expression and copy number, cycle E amplification and expression and other genomic co-alterations, and transcriptional and proteomic profile. Logistic regression and Cox proportional hazards model will be used to assess the relationship between clinical responses and molecular and genomic biomarkers.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of agenT-797 in Combination With Botensilimab, Balstilimab, Ramucirumab, and Paclitaxel for People With Esophageal, Gastric, or Gastro-esophageal Junction Cancer	NCT06251973	Metastatic Esop... Advanced Unrese... Metastatic Gast... Metastatic Gast... Metastatic Esop... Metastatic Esop... Metastatic Gast... Metastatic Gast... Unresectable Es... Unresectable Es... Unresectable Ga... Unresectable Ga... Unresectable Ga...	AgenT-797 Botensilimab Balstilimab Ramucirumab Paclitaxel	18 Years -	Memorial Sloan Kettering Cancer Center
Olaparib and Ramucirumab in Treating Patients With Metastatic or Locally Recurrent Gastric or Gastroesophageal Junction Cancer That Cannot Be Removed by Surgery	NCT03008278	Metastatic Esop... Metastatic Gast... Metastatic Gast... Recurrent Esoph... Recurrent Gastr... Recurrent Gastr... Stage III Esoph... Stage III Gastr... Stage IV Esopha... Stage IV Gastri... Unresectable Es... Unresectable Ga... Unresectable Ga...	Olaparib Ramucirumab	18 Years -	National Cancer Institute (NCI)
Testing the Combination of the Anticancer Drugs Trastuzumab Deruxtecan (DS-8201a) and Azenosertib (ZN-c3) in Patients With Stomach or Other Solid Tumors	NCT06364410	Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Locally Advance... Locally Advance... Locally Advance... Metastatic Gast... Metastatic Gast... Metastatic Mali... Unresectable Ga... Unresectable Ga... Unresectable Ma...	Azenosertib Biopsy Biospecimen Col... Computed Tomogr... Echocardiograph... Magnetic Resona... Multigated Acqu... Trastuzumab Der...	18 Years -	National Cancer Institute (NCI)
Testing the Combination of the Anticancer Drugs Trastuzumab Deruxtecan (DS-8201a) and Azenosertib (ZN-c3) in Patients With Stomach or Other Solid Tumors	NCT06364410	Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Locally Advance... Locally Advance... Locally Advance... Metastatic Gast... Metastatic Gast... Metastatic Mali... Unresectable Ga... Unresectable Ga... Unresectable Ma...	Azenosertib Biopsy Biospecimen Col... Computed Tomogr... Echocardiograph... Magnetic Resona... Multigated Acqu... Trastuzumab Der...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for unresectable gastric carcinoma