Neoplasms

Digestive System Diseases

All Conditions

Rare Diseases

Stomach Neoplasms

Adenocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Stomach Diseases

Stomach Cancer

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Hematinics

Bone Density Conservation Agents

Vitamins

Paclitaxel

Carboplatin

Pembrolizumab

Leucovorin

Fluorouracil

Levoleucovorin

Albumin-Bound Paclitaxel

Oxaliplatin

Calcium

Folic Acid

Calcium, Dietary

Vitamin B Complex

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Hormones

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Antidotes

Protective Agents

Trace Elements

Folinic Acid

Folate

Vitamin B9

Computed Tomography

Laboratory Biomarker Analysis

Leucovorin Calcium

Positron Emission Tomography

Radiation Therapy

Therapeutic Conventional Surgery

Harry H. Yoon, M.D.

This phase Ib/II trial studies the side effects and best way to give pembrolizumab with combination chemotherapy and radiation therapy before surgery and to see how well it works in treating adult patients with gastroesophageal junction or gastric cardia cancer that has spread from where it started to nearby tissue and can be removed by surgery. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Drugs used in chemotherapy 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. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving pembrolizumab, combination chemotherapy, and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of pembrolizumab when combined with radiotherapy plus carboplatin and paclitaxel in locally advanced gastroesophageal junction (GEJ)/cardia adenocarcinoma. (Phase Ib) II. To evaluate the pathological complete response (pathCR) rate of pembrolizumab when combined with radiotherapy plus carboplatin and paclitaxel in locally advanced GEJ/cardia adenocarcinoma. (Phase II)

SECONDARY OBJECTIVES:

I. To determine progression-free survival (PFS), determine time to relapse (TTR), disease-free survival (DFS), R0 rate, and overall survival (OS) of pembrolizumab when combined with radiotherapy plus carboplatin and paclitaxel.

TRANSLATIONAL RESEARCH OBJECTIVES:

I. To identify tissue and/or circulating biomarkers that are associated with pathCR, DFS, and other clinical outcomes in patients with locally advanced GEJ/cardia adenocarcinoma treated with neoadjuvant pembrolizumab-based therapy.

II. To determine differences in pre-treatment vs post-treatment tissue expression of immune markers, including PDL1 and tumor infiltrating lymphocytes (CD8+, FOXP3+ Tregs, CD45RO, granzyme B), in patients treated with neoadjuvant pembrolizumab-based therapy.

III. To identify immune markers in pretreatment tissues that correlate with pathCR and long-term outcome in patients treated with neoadjuvant pembrolizumab-based therapy.

IV. To explore whether an EBV-associated tumor molecular profile89 is associated with pathCR and long-term outcome in patients treated with neoadjuvant pembrolizumab-based therapy.

V. To explore whether a microsatellite-unstable (MSI) tumor molecular profile89 is associated with pathCR and long-term outcome in patients treated with neoadjuvant pembrolizumab-based therapy.

OUTLINE:

NEOADJUVANT TREATMENT: Patients receive pembrolizumab intravenously (IV) over 30 minutes on days -7, 15, and 36 and carboplatin IV and paclitaxel IV over 1-96 hours on days 1, 8, 15, 22 and 29. Patients also undergo radiation therapy once daily (QD) 5 days per week for 4 weeks and 3 days (23 fractions).

Patients with progressive disease receive pembrolizumab IV over 30 minutes, paclitaxel IV over 1-96 hours, and carboplatin IV on day 1. Treatment repeats every 21 days for 2-4 courses in the absence of disease progression or unacceptable toxicity.

NEOADJUVANT TREATMENT (RE-INITIATED): Patients receive pembrolizumab IV over 30 minutes on days 1 and 22 and oxaliplatin IV over 2-6 hours, leucovorin calcium IV over 15 minutes to 2 hours, and fluorouracil IV over 46-48 hours on days 1, 15, and 29. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Patients with progressive disease receive pembrolizumab IV over 30 minutes on days 1 and 22, oxaliplatin IV over 2-6 hours, leucovorin calcium over 15 minutes to 2 hours, and fluorouracil IV over 46-48 hours on days 1, 15, and 29. Treatment repeats every 41 days (6 weeks) for 1-3 courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Within 5-8 weeks after completion of radiation therapy or 3-6 weeks after completion of chemotherapy for patients receiving chemotherapy alone, patients undergo curative-intent surgery.

ADJUVANT TREATMENT: Patients receive pembrolizumab IV over 30 minutes every 21 days. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, every 4 months for 1 year, and then every 6 months for 1 year.

Pembrolizumab, Combination Chemotherapy, and Radiation Therapy Before Surgery in Treating Adult Patients With Locally Advanced Gastroesophageal Junction or Gastric Cardia Cancer That Can Be Removed by Surgery

Phase 1b/2 Clinical Trial of Neoadjuvant Pembrolizumab Plus Concurrent Chemoradiotherapy With Weekly Carboplatin and Paclitaxel in Adult Patients With Resectable, Locally Advanced Adenocarcinoma of the Gastroesophageal Junction or Gastric Cardia

Defined as number of patients with pathologic complete responses (pCR) divided by total evaluable patients. pCR is defined as no recognized cancer and margins free of tumor as found by the pathologist following resection of the esophageal specimen and accompanying lymph nodes.

Defined as the number of patients who achieve R0 resection divided by total number of evaluable patients.

The median DFS and confidence interval will be estimated using the method of Kaplan-Meier.

The median TTR and confidence interval will be estimated using the method of Kaplan-Meier.

The distribution of OS will be estimated using the method of Kaplan-Meier. Two-year OS rate and confidence interval will be estimated based on Kaplan-Meier curve.

The distribution of PFS will be estimated using the method of Kaplan-Meier. Two-year PFS rate and confidence interval will be estimated based on Kaplan-Meier curve.

The maximum grade for each type of adverse events that are possibly, probably or definitely related to study treatments will be recorded for each patient. The frequency tables will be reviewed to determine the patterns.

National Cancer Institute (NCI)

Mayo Clinic

Therapeutic Conventional Surgery: Undergo curative-intent surgery

Treatment (Pembrolizumab, Chemotherapy, Radiation, Surgery)

See Detailed Description\>

\> Carboplatin: Given IV\>

\> Computed Tomography: Undergo CT scan\>

\> Fluorouracil: Given IV\>

\> Laboratory Biomarker Analysis: Correlative studies\>

\> Leucovorin Calcium: Given IV\>

\> Oxaliplatin: Given IV\>

\> Paclitaxel: Given IV\>

\> Pembrolizumab: Given IV\>

\> Positron Emission Tomography: Undergo PET scan\>

\> Radiation Therapy: Undergo radiation therapy\>

\> Therapeutic Conventional Surgery: Undergo curative-intent surgery

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Gastroesophageal junction

Gastric cardia

Tumor Location

G2 (moderately differentiated)

G3 (poorly differentiated)

GX (grade cannot be assessed)

Histologic Grade (differentiation)

Size and extent of the primary tumor; higher number tumor stage indicates a larger and more invasive tumor.

T0 No evidence of primary tumor T1 Tumor invades the lamina propria, muscularis mucosae, or submucosa T2 Tumor invades the muscularis propria T3 Tumor invades adventitia T4 Tumor invades adjacent structures

Clinical Tumor Stage

Regional lymph node involvement of the tumor; a higher number indicates more involvement of regional lymph nodes.

N0 No regional lymph node metastasis N1 Metastasis in 1-2 regional lymph nodes N2 Metastasis in 3-6 regional lymph nodes N3 Metastasis in 7 or more regional lymph nodes

Clinical Nodal Stage

Having a signet ring cell histology is associated worse disease outcomes.

Signet Ring Cell Histology

≥10

Unknown

Higher PD-L1 CPS corresponds to a greater likelihood of responding effectively to anti-PD-1 therapy

PD-L1 Combined Positive Score (CPS)

Harry H Yoon MD MHS

See Detailed Description \>

\> Carboplatin: Given IV

\>

\> Computed Tomography: Undergo CT scan

\>

\> Fluorouracil: Given IV

\>

\> Laboratory Biomarker Analysis: Correlative studies

\>

\> Leucovorin Calcium: Given IV

\>

\> Oxaliplatin: Given IV

\>

\> Paclitaxel: Given IV

\>

\> Pembrolizumab: Given IV

\>

\> Positron Emission Tomography: Undergo PET scan

\>

\> Radiation Therapy: Undergo radiation therapy

\>

\> Therapeutic Conventional Surgery: Undergo curative-intent surgery

Pathological Complete Response (PathCR) Rate

Complete Resection With no Tumor Within 1 mm of the Resection Margins (R0) Rate

Disease-free Survival (DFS)

Time to Relapse (TTR)

Overall Survival (OS)

Progression-free Survival (PFS)

Incidence of Dose-limiting Toxicities (DLTs) Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0

Overall Study

Esophageal Neoplasms

Carcinoma, Squamous Cell

Esophageal Squamous Cell Carcinoma

Neoplasms, Second Primary

Neoplasms, Squamous Cell

Head and Neck Neoplasms

Esophageal Diseases

Esophageal Cancer

Adavosertib

Enzyme Inhibitors

Patients undergo radiation therapy QD 5 days per week for 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive adavosertib PO QD for 2-5 days (depending on dose level) during weeks 1 and 3 of radiation therapy in the absence of disease progression or unacceptable toxicity.

Eric D Miller

This phase I trial investigates the side effects and best dose of adavosertib and how well it works when given in combination with radiation therapy in treating patients with esophageal or gastroesophageal junction cancer for which no treatment is currently available (incurable). Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving adavosertib together with radiation therapy kill more tumor cells than radiation therapy alone in treating patients with esophageal and gastroesophageal junction cancer.

PRIMARY OBJECTIVE:

I. To identify the maximally tolerated dose of adavosertib (AZD1775) to be used in combination with radiation therapy for patients with esophageal/gastroesophageal junction (GEJ) cancer that is metastatic or inoperable and not eligible for definitive chemoradiation.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To evaluate the efficacy of AZD1775 when administered in combination with radiation therapy by assessing changes in Ogilvie dysphagia score following treatment, time to second intervention for dysphagia, and overall survival.

III. To identify biomarkers that are predictive for response to experimental therapy.

OUTLINE: This is a dose escalation study of adavosertib.

Patients undergo radiation therapy once daily (QD) 5 days per week for 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive adavosertib orally (PO) QD for 2-5 days (depending on dose level) during weeks 1 and 3 of radiation therapy in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3 weeks, every 3 months for 2 years, then every 6 months for 3 years.

Testing the Addition of an Anti-cancer Drug, Adavosertib, to Radiation Therapy for Patients With Incurable Esophageal and Gastroesophageal Junction Cancers

A Phase 1 Trial Combining WEE1 Inhibitor Adavosertib (AZD1775) With Radiation Therapy for Metastatic or Inoperable and Ineligible for Definitive Chemoradiation Esophageal and Gastroesophageal 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 employ a BOIN design where the target toxicity rate for the MTD is 25% with 75% dose-elimination cut-off.

Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized with descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.

Will be calculated with 95% binomial confidence intervals.

Patient dysphagia will be evaluated using the Ogilvie dysphagia score, comparing pre-treatment to post-treatment scores

Survival will initially be analyzed using Kaplan-Meier methods, resulting in median survival times with 95% confidence interval (CI).

The scores will be summarized and compared using paired t-test or Wilcoxon signed-rank test. Patient dysphagia will be evaluated using the Ogilvie dysphagia score, comparing pre-treatment to post-treatment scores.

Will be described graphically or summary measures (e.g. mean and standard errors, or median and range) and compared between responders and non-responders using a two sample t-test or Wilcoxon test if the data is not normally distributed.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pembrolizumab, Combination Chemotherapy, and Radiation Therapy Before Surgery in Treating Adult Patients With Locally Advanced Gastroesophageal Junction or Gastric Cardia Cancer That Can Be Removed by Surgery	NCT02730546	Gastric Cardia ... Gastroesophagea... Stage IB Gastri... Stage II Gastri... Stage IIA Gastr... Stage IIB Gastr... Stage IIIA Gast... Stage IIIB Gast...	Carboplatin Computed Tomogr... Fluorouracil Laboratory Biom... Leucovorin Calc... Oxaliplatin Paclitaxel Pembrolizumab Positron Emissi... Radiation Thera... Therapeutic Con...	18 Years - 80 Years	Mayo Clinic
Pembrolizumab, Combination Chemotherapy, and Radiation Therapy Before Surgery in Treating Adult Patients With Locally Advanced Gastroesophageal Junction or Gastric Cardia Cancer That Can Be Removed by Surgery	NCT02730546	Gastric Cardia ... Gastroesophagea... Stage IB Gastri... Stage II Gastri... Stage IIA Gastr... Stage IIB Gastr... Stage IIIA Gast... Stage IIIB Gast...	Carboplatin Computed Tomogr... Fluorouracil Laboratory Biom... Leucovorin Calc... Oxaliplatin Paclitaxel Pembrolizumab Positron Emissi... Radiation Thera... Therapeutic Con...	18 Years - 80 Years	Mayo Clinic
Testing the Addition of an Anti-cancer Drug, Adavosertib, to Radiation Therapy for Patients With Incurable Esophageal and Gastroesophageal Junction Cancers	NCT04460937	Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Clinical Stage ... Distal Esophagu... Gastric Cardia ... Metastatic Esop... Metastatic Esop... Metastatic Gast... Metastatic Mali... Metastatic Mali... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... 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... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Postneoadjuvant... Unresectable Es... Unresectable Es... Unresectable Es... Unresectable Ga...	Adavosertib Radiation Thera...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for gastric cardia adenocarcinoma