A Phase 2 Trial of Neoadjuvant Chemoradiation With Pembrolizumab Followed by Pembrolizumab With Lenvatinib in Esophageal/Gastroesophageal Junction Squamous Cell and Adenocarcinomas
Overview
- Phase
- Phase 2
- Intervention
- Carboplatin
- Conditions
- Clinical Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8
- Sponsor
- City of Hope Medical Center
- Enrollment
- 3
- Locations
- 1
- Primary Endpoint
- Clinical complete response (CR)
- Status
- Active, not recruiting
- Last Updated
- 8 months ago
Overview
Brief Summary
This phase II trial studies the effect of chemoradiation and pembrolizumab followed by pembrolizumab and lenvatinib before surgery in treating patients with esophageal or esophageal/gastroesophageal junction cancer that has not spread to other places in the body (non-metastatic). Pembrolizumab is an immunotherapy drug that works by harnessing the immune system to attack cancer. Lenvatinib is an anti-cancer drug that works by stopping or slowing down the growth of cancer cells. Chemotherapy drugs, such as carboplatin and paclitaxel, 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 chemoradiation and pembrolizumab followed by pembrolizumab and lenvatinib before surgery may kill more tumor cells.
Detailed Description
PRIMARY OBJECTIVE: I. To evaluate pathologic complete response rate (path CR) and complete clinical response rate (clinical CR) at 14 weeks after starting chemoradiotherapy. SECONDARY OBJECTIVES: I. To assess safety and tolerability of pembrolizumab and lenvatinib in this patient population. II. To establish that pembrolizumab + lenvatinib will increase immune response via increased expression of the 18 gene pro-immune response signature measured using the Nanostring platform on tumor tissue biopsies. III. To evaluate disease-free survival (DFS) and overall survival (OS) in this study population. EXPLORATORY OBJECTIVES: I. To identify through an integrated genomic sequencing approach (MHC-PepSeq) the presence of tumor mutations able to elicit neo-antigen-specific immunity in this population expected to be predominated by microsatellite stability (MSS) tumors. II. To correlate temporal variations in circulating tumor deoxyribonucleic acid (ctDNA) representing immunogenic and non-immunogenic mutations as pharmacodynamic immune markers. III. To correlate diversity in the gut microbiome with path CR and clinical CR in this study population. OUTLINE: CHEMORADIATION PHASE: Patients receive carboplatin intravenously (IV) and paclitaxel IV once a week (QW) for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo external beam radiation therapy (EBRT) over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate orally (PO) once daily (QD) at weeks 3-6 in the absence of disease progression or unacceptable toxicity. SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy. After completion of study treatment, patients are followed up at 90 days, then for up to 3 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Documented informed consent of the participant and/or legally authorized representative
- •Agreement to allow the use of archival tissue from diagnostic tumor biopsies
- •If unavailable, exceptions may be granted only with study principal investigator (PI) approval
- •Age \>= 18 years
- •Eastern Cooperative Oncology Group (ECOG) =\< 1
- •Non-metastatic cancer of the esophagus OR esophagus and gastroesophageal junction (GEJ; tumor extending =\< 2 cm into the stomach)
- •Confirmed stage I (T1N1 only)-IVA diagnosis of one of the following:
- •Squamous cell; OR
- •Adenocarcinoma; OR
- •Mixed adenosquamous carcinoma
Exclusion Criteria
- •Immune checkpoint inhibitor(s) (e.g. anti-PD-1, anti-CTLA4)
- •Multi-tyrosine kinase inhibitor(s) (e.g. lenvatinib)
- •Radiotherapy within 21 days prior to day 1 of study participation
- •Investigational agent within 21 days prior to day 1 of study participation
- •Live-virus vaccination within 30 days prior to day 1 of study participation
- •Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery within 21 days of study participation
- •Chronic systemic steroid therapy or on any other form of immunosuppressive medication
- •Coumarin-based anticoagulants
- •Unstable or untreated brain/leptomeningeal metastasis
- •Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation)
Arms & Interventions
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity. SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
Intervention: Carboplatin
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity. SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
Intervention: Endoscopic Biopsy
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity. SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
Intervention: External Beam Radiation Therapy
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity. SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
Intervention: Lenvatinib Mesylate
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity. SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
Intervention: Paclitaxel
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity. SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
Intervention: Pembrolizumab
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity. SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
Intervention: Resection
Outcomes
Primary Outcomes
Clinical complete response (CR)
Time Frame: At 14 weeks after starting protocol chemoradiotherapy
Defined as no radiographic evidence of disease on positron emission tomography /computed tomography or CT imaging. Clinical CR rate will be estimated by the proportion of patients achieving clinical CR, along with the 95% exact binomial confidence interval.
Pathological complete response (CR)
Time Frame: At 14 weeks after starting protocol chemoradiotherapy
Defined as no residual cancer cells, including lymph nodes under pathologic examination of the surgically resected specimen and/or a Tumor Regression Score of 0 by the College of American Pathologist (CAP) Cancer Protocol for Esophageal Carcinoma. Pathological CR rate will be estimated by the proportion of patients achieving pathological CR, along with the 95% exact binomial confidence interval.
Secondary Outcomes
- Incidence of adverse events(Up to 90 days post-treatment)
- Disease-free survival (DFS)(Up to 3 years)
- Overall survival (OS)(Up to 3 years)
- Immune-mediated tumor cytotoxicity(Up to 3 years)