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Leucovorin Calcium

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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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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

Spots Global Cancer Trial Database for stage iia gastric cancer ajcc v7