Neoplasms

Digestive System Diseases

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Rare Diseases

Esophageal Neoplasms

Adenocarcinoma

Stomach Neoplasms

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Stomach Diseases

Head and Neck Neoplasms

Esophageal Diseases

Esophageal Cancer

Stomach Cancer

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Paclitaxel

Albumin-Bound Paclitaxel

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Ramucirumab

Lexatumumab

Antineoplastic Agents, Immunological

Immunoglobulins, Intravenous

Tubulin Modulators

Antimitotic Agents

Immunologic Factors

Immune Checkpoint Inhibitors

Angiogenesis Inhibitors

Growth Inhibitors

Patients receive nivolumab IV over 30 minutes on day 1 of each cycle, ramucirumab IV over 30-60 minutes on days 1 and 15 of each cycle, and paclitaxel IV over 30 minutes on days 1, 8 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan and MRI throughout the study. Patients may also optionally undergo blood sample collection on study.

Patients receive ramucirumab IV over 30-60 minutes on days 1 and 15 of each cycle and paclitaxel IV over 30 minutes on days 1, 8 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan and MRI throughout the study. Patients may also optionally undergo blood sample collection on study.

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Questionnaire Administration

Site Public Contact

Bryan A. Faller

Deborah W. Wilbur

Anwaar Saeed

This phase II/III trial compares the addition of nivolumab to the usual treatment of paclitaxel and ramucirumab to paclitaxel and ramucirumab alone in treating patients with gastric or esophageal adenocarcinoma that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ramucirumab is a monoclonal antibody that may prevent the growth of new blood vessels that tumors need to grow. Paclitaxel is in a class of medications called antimicrotubule agents. It stops cancer cells from growing and dividing and may kill them. Adding nivolumab to ramucirumab and paclitaxel may work better to treat patients with advanced stomach or esophageal cancer.

PRIMARY OBJECTIVES:

I. To assess whether progression-free survival (PFS) is sufficiently improved in participants randomized to nivolumab + paclitaxel + ramucirumab compared to those randomized to paclitaxel + ramucirumab to warrant a phase III study with overall survival (OS) as the primary endpoint. (Phase II) II. To compare OS in participants randomized to nivolumab + paclitaxel + ramucirumab versus those randomized to paclitaxel + ramucirumab. (Phase III)

SECONDARY OBJECTIVES:

I. To compare PFS between those randomized to nivolumab + paclitaxel + ramucirumab versus those randomized to paclitaxel + ramucirumab. (Phase III) II. To compare OS between participants randomized to nivolumab + paclitaxel + ramucirumab compared to those randomized to paclitaxel + ramucirumab in the event that the trial is completed before the phase III portion.

III. To compare the overall response rate (ORR, including confirmed and unconfirmed, complete, and partial response, according to Response Evaluation Criteria in Solid Tumors \[RECIST 1.1\] criteria) between those randomized to nivolumab + paclitaxel + ramucirumab compared to those randomized to paclitaxel + ramucirumab among participants with measurable disease.

IV. To compare the overall disease control rate (DCR = ORR + stable disease) between those randomized to nivolumab + paclitaxel + ramucirumab compared to those randomized to paclitaxel + ramucirumab among participants with measurable disease.

V. To evaluate the safety and tolerability of each treatment regimen. VI. To compare health-related quality of life (QOL) by treatment arm at 8 weeks after randomization, measured using the Functional Assessment of Cancer Therapy - Gastric (FACT-Ga) Trial Outcome Index (TOI).

VII. To compare health-related QOL between treatment arms at 8 weeks after randomization using the FACT-Ga total score.

VIII. To compare longitudinal changes in health-related QOL between treatment arms using FACT-Ga TOI up to 24 weeks after randomization.

IX. To compare patient-reported symptoms using selected Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) items including gastrointestinal as well as constitutional symptoms of fatigue, anorexia, and weight loss between treatment arms.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 of each cycle, ramucirumab IV over 30-60 minutes on days 1 and 15 of each cycle, and paclitaxel IV over 30 minutes on days 1, 8 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan and magnetic resonance imaging (MRI) throughout the study. Patients may also optionally undergo blood sample collection on study.

ARM 2: Patients receive ramucirumab IV over 30-60 minutes on days 1 and 15 of each cycle and paclitaxel IV over 30 minutes on days 1, 8 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan and MRI throughout the study. Patients may also optionally undergo blood sample collection on study.

After completion of study treatment, patients are followed up at 30, 60, 90 days and then every 6 months for up to 3 years.

Adding Nivolumab to Usual Treatment for People With Advanced Stomach or Esophageal Cancer, PARAMUNE Trial

Randomized Phase II/III Trial of 2nd Line Nivolumab + Paclitaxel + Ramucirumab Versus Paclitaxel + Ramucirumab in Patients With PD-L1 CPS &gt;/= 1 Advanced Gastric and Esophageal Adenocarcinoma (PARAMMUNE)

"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."

The hazard ratio of DFS and the corresponding 95% confidence intervals will be estimated for subgroups defined by sex, race, and ethnicity, respectively.

The distribution of PFS will be estimated using the method of Kaplan-Meier and compared using a 1-sided stratified log-rank test.

The distribution of OS will be estimated using the method of Kaplan-Meier and compared using a 1-sided stratified log-rank test.

Will be compared across arms in participants with measurable disease via Fisher's exact test.

DCR = ORR + stable disease per Response Evaluation Criteria in Solid Tumors 1.1. Will be compared across arms in participants with measurable disease via Fisher's exact test.

National Cancer Institute (NCI)

Pharmaceutical Solutions

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

Irinotecan

Topoisomerase I Inhibitors

Enzyme Inhibitors

Patients receive irinotecan IV over 90 minutes and berzosertib IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo endoscopic or CT assisted biopsy and MRI on study.

Berzosertib

Computed Tomography Assisted Biopsy

Endoscopic Biopsy

Jordan D Berlin

This phase II trial studies the how well berzosertib and irinotecan work in treating patients with gastric or gastroesophageal junction cancer that is growing, spreading or getting worse (progressive), has spread to other places in the body (metastatic), or cannot be removed by surgery (unresectable). Berzosertib may stop the growth of tumor cells by blocking some of the enzymes needed for growth. Chemotherapy drugs, such as irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving berzosertib and irinotecan may work better than irinotecan alone in treating patients with gastric and gastroesophageal junction cancer.

PRIMARY OBJECTIVE:

I. Determine objective response rate (ORR) superiority (target 25%) in TP53 mutant patients with progressive metastatic or unresectable gastric/gastroesophageal junction (GEJ) cancer who receive berzosertib (M6620) and irinotecan compared to ORR (5%) in historical control patients treated with single agent irinotecan alone.

SECONDARY OBJECTIVES:

I. Determine duration of response (DOR), time to progression (TTP), progression-free survival (PFS), and overall survival (OS) superiority in TP53 mutant gastric/GEJ cancer patients who receive M6620 and irinotecan compared to these measures in historical control patients treated with irinotecan alone.

II. Perform the following correlative studies in 9 patients: gamma-H2AX, KAP1 phosphorylated (p)-Ser 824 and p-ATR analysis from biopsies collected at 24 hours (+/- 1 hour) post-irinotecan infusion on cycle 1 day 2 (C1D2) and at 24 hours (+/- 1 hour) post-M6620 on cycle 2 day 2 (C2D2).

EXPLORATORY OBJECTIVES:

I. Determine ORR, DOR, TTP, PFS, and OS in patients with other concomitant damage response defects (DDRD), such as mutations in BRCA1, BRCA2, MRE11, RAD50, RAD51, RAD52, RAD54L, NBN, ATM, H2AX, PALB2, RPA, BRIP1, BARD1, ATR, ATRX, CHK1, CHK2, MDM2, MDM4, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, treated with the experimental combination.

II. Determine whether patients with first line platinum sensitivity (PFS \> 3 months) demonstrate improved ORR, DOR, TTP, PFS, and OS compared to patients who were platinum insensitive (PFS \< 3 months).

OUTLINE:

Patients receive irinotecan intravenously (IV) over 90 minutes and berzosertib IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo endoscopic or computed tomography (CT) assisted biopsy and magnetic resonance imaging (MRI) on study.

After completion of study treatment, patients are followed up for 30 days and then every 2 months for up to 1 year.

Berzosertib and Irinotecan in Treating Patients With Progressive, Metastatic, or Unresectable TP53 Mutant Gastric or Gastroesophageal Junction Cancer

A Phase 2 Single-Arm Study of M6620 in Combination With Irinotecan in Patients With Progressive TP53 Mutant Gastric and Gastro-Esophageal Junction Cancer

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

Will be summarized as frequency counts and percent of study group.

Will be estimated using the method of Kaplan and Meier. 95% confidence intervals for all point estimates of effect sizes (odd ratios, hazard ratios, differential pre-post biomarker expression) among subgroups will be estimated.

Pembrolizumab

Lenvatinib

Protein Kinase Inhibitors

Patients receive pembrolizumab IV over 30 minutes on day 1 and lenvatinib PO QD, Treatment repeats every 42 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

Mariela Blum, MD

Mariela Blum

This early phase I trial studies the effect of pembrolizumab and lenvatinib in treating patients with gastroesophageal adenocarcinoma that has spread to other places in the body (advanced/metastatic) or cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Lenvatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and lenvatinib may kill more tumor cells.

PRIMARY OBJECTIVE:

I. To estimate the overall response rate (ORR) of pembrolizumab plus lenvatinib by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in adult subjects with previously treated advanced (unresectable and/or metastatic) gastroesophageal adenocarcinoma.

SECONDARY OBJECTIVES:

I. To evaluate the duration of response (DOR), disease control rate (DCR), time-to-progression (TTP), progression-free survival (PFS), using RECIST 1.1 and immune-related (i)RECIST criteria and overall survival (OS).

II. To determine the safety and tolerability of pembrolizumab plus lenvatinib in adult subjects with previously treated advanced (unresectable and/or metastatic) gastroesophageal adenocarcinoma.

EXPPLORATORY OBJECTIVES:

I. To perform exploratory biomarker analyses to study the correlation between immunological and molecular changes in tumor tissues and peripheral blood with clinical outcomes (DOR, DCR, TTP, PFS, and OS) using RESIST 1.1 and iRECIST.

II. To explore the association between PD-L1 expression by immunohistochemistry (IHC), shed PD-L1 levels, somatic gene expression profiling (18-gene T-cell inflamed GEP) and antitumor efficacy of pembrolizumab based on RECIST 1.1 imaging criteria as well as OS.

III. To explore the relationship between genomic variation and response to the treatment administered.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and lenvatinib orally (PO) once daily (QD). Treatment repeats every 42 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Adding Nivolumab to Usual Treatment for People With Advanced Stomach or Esophageal Cancer, PARAMUNE Trial	NCT06203600	Advanced Esopha... Advanced Gastri... Advanced Gastro... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Metastatic Esop... Metastatic Gast... Metastatic Gast... Unresectable Es... Unresectable Ga... Unresectable Ga...	Biospecimen Col... Computed Tomogr... Magnetic Resona... Nivolumab Paclitaxel Questionnaire A... Ramucirumab	18 Years -	National Cancer Institute (NCI)
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
Berzosertib and Irinotecan in Treating Patients With Progressive, Metastatic, or Unresectable TP53 Mutant Gastric or Gastroesophageal Junction Cancer	NCT03641313	Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Metastatic Gast... Metastatic Gast... Unresectable Ga... Unresectable Ga...	Berzosertib Computed Tomogr... Endoscopic Biop... Irinotecan Magnetic Resona...	18 Years -	National Cancer Institute (NCI)
Pembrolizumab and Lenvatinib for the Treatment of Advanced, Unresectable, or Metastatic Gastroesophageal Adenocarcinoma	NCT05041153	Advanced Gastri... Advanced Gastro... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Metastatic Gast... Metastatic Gast... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Unresectable Ga... Unresectable Ga...	Lenvatinib Pembrolizumab	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for unresectable gastric adenocarcinoma