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
Overview
- Phase
- Phase 1
- Intervention
- Carboplatin
- Conditions
- Gastric Cardia Adenocarcinoma
- Sponsor
- Mayo Clinic
- Enrollment
- 31
- Locations
- 2
- Primary Endpoint
- Pathological Complete Response (PathCR) Rate
- Status
- Completed
- Last Updated
- 10 months ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically or cytologically confirmed adenocarcinoma involving the gastroesophageal junction or gastric cardia
- •Central pathology review to determine evaluability of archived esophagogastroduodenoscopy (EGD)/biopsy sample
- •NOTE: If archived sample was collected \> 8 weeks prior to pre-registration (reg), is not available in a timely manner, or was collected outside of Mayo Clinic and considered unevaluable, then baseline EGD with primary tumor biopsy at Mayo Clinic must be performed unless clinically contraindicated; patient is allowed to enroll regardless of whether this Mayo Clinic tissue sample is evaluable; (Only 1 EGD with primary tumor biopsy performed at Mayo Clinic =\< 8 weeks prior to pre-reg is required)
- •NOTE: For both archival or newly obtained tissue, only biopsies are adequate (fine needle aspiration \[FNA\] is not adequate)
- •Willing to provide mandatory tissue samples for research purposes
- •Baseline imaging with an fludeoxyglucose (FDG)-positron emission tomography (PET) scan negative for distant metastatic disease must be obtained =\< 28 days prior to registration
- •Surgically resectable (T2N0, T3N0, Tany with node positivity, M0), as determined by endoscopic ultrasound (EUS) and the following minimum diagnostic work-up:
- •Whole-body PET/computed tomography (CT) (PET/CT of skull base to mid-thigh is acceptable)
- •EUS =\< 21 days prior to registration
- •NOTE: Patients may have regional adenopathy including para-esophageal, gastric, gastrohepatic and celiac nodes; if celiac adenopathy is present, it must be \< 2 cm
Exclusion Criteria
- •Tumor characteristics - any of the following are excluded:
- •Evidence of distant metastases
- •Tumors whose location is restricted to the tubular esophagus (i.e., without involvement of the GEJ or cardia)
- •Tumors whose proximal end are at the level of the carina or higher
- •Invasion of the tracheobronchial tree or presence of tracheoesophageal fistula
- •Palpable supraclavicular nodes, biopsy-proven involvement of supraclavicular nodes, or radiographically involved supraclavicular nodes (\> 1.5 cm in greatest dimension)
- •T1N0M0, T4Nany, or in situ carcinoma
- •Tumor must not extend 5 or more cm into the stomach
- •Received prior treatment or receiving current treatment for this malignancy
- •Prior radiation to chest or abdomen, or to \> 30% of the marrow cavity
Arms & Interventions
Treatment (pembrolizumab, chemotherapy, radiation, surgery)
See Detailed Description
Intervention: Carboplatin
Treatment (pembrolizumab, chemotherapy, radiation, surgery)
See Detailed Description
Intervention: Computed Tomography
Treatment (pembrolizumab, chemotherapy, radiation, surgery)
See Detailed Description
Intervention: Fluorouracil
Treatment (pembrolizumab, chemotherapy, radiation, surgery)
See Detailed Description
Intervention: Laboratory Biomarker Analysis
Treatment (pembrolizumab, chemotherapy, radiation, surgery)
See Detailed Description
Intervention: Leucovorin Calcium
Treatment (pembrolizumab, chemotherapy, radiation, surgery)
See Detailed Description
Intervention: Oxaliplatin
Treatment (pembrolizumab, chemotherapy, radiation, surgery)
See Detailed Description
Intervention: Paclitaxel
Treatment (pembrolizumab, chemotherapy, radiation, surgery)
See Detailed Description
Intervention: Pembrolizumab
Treatment (pembrolizumab, chemotherapy, radiation, surgery)
See Detailed Description
Intervention: Positron Emission Tomography
Treatment (pembrolizumab, chemotherapy, radiation, surgery)
See Detailed Description
Intervention: Radiation Therapy
Treatment (pembrolizumab, chemotherapy, radiation, surgery)
See Detailed Description
Intervention: Therapeutic Conventional Surgery
Outcomes
Primary Outcomes
Pathological Complete Response (PathCR) Rate
Time Frame: Up to 3 years
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.
Secondary Outcomes
- Complete Resection With no Tumor Within 1 mm of the Resection Margins (R0) Rate(Up to 3 years)
- Disease-free Survival (DFS)(Up to 3 years)
- Time to Relapse (TTR)(Up to 3 years)
- Overall Survival (OS) at Two Years(2 years)
- Progression-free Survival (PFS) Rate at Two Years(2 years)
- Number of Patients Experiencing Dose-limiting Toxicities (DLTs)(Up to 3 years)