Phase Ib/II Study of Induction Chemotherapy and Durvalumab (MEDI4736) and Tremelimumab With Chemoradiation for Esophageal and Gastroesophageal Junction Adenocarcinoma
Overview
- Phase
- Phase 1
- Intervention
- durvalumab
- Conditions
- Esophageal Adenocarcinoma
- Sponsor
- Memorial Sloan Kettering Cancer Center
- Enrollment
- 64
- Locations
- 7
- Primary Endpoint
- unacceptable toxicity
- Status
- Active, not recruiting
- Last Updated
- 7 months ago
Overview
Brief Summary
The purpose of this study is to test the safety of adding a new drug, durvalumab (also called MEDI4736), to chemoradiation with either FOLFOX/Capeox or carboplatin and paclitaxel, following initial chemotherapy with FOLFOX. The investigators want to find out what effects, good and/or bad, this combination has on the patient and cancer.
Detailed Description
Patients will undergo a baseline PET/CT scan prior to receiving mFOLFOX6 chemotherapy (bolus 5-fluorouracil or -FU 400 mg/m2, leucovorin 400 mg/m2, oxaliplatin 70-85 mg/m2 and infusional 5-FU 1,200 mg/m2/day ×46 hours) q14 days ×2, followed by repeat PET scan. Two weeks after the second dose of mFOLFOX6, patients receive 1 dose of durvalumab 1,500 mg. and tremelimumab 300 mg. Two weeks later, all patients will initiate radiation (1.8 Gy/fraction ×23 fractions Monday through Friday for total dose of 41 Gy). PET responders receive concurrent chemotherapy with oxaliplatin 70-85 mg/m2 q14 days ×3 doses with either infusional 5-FU 300 mg/m2/day ×96 hours or capecitabine 825 mg/m2 BID Monday through Friday throughout the radiation period. PET non-responders receive concurrent carboplatin AUC 2/paclitaxel 50 mg/m2 weekly ×5 with concurrent. All patients receive a second dose of durvalumab 1,500 mg q28 days after the first dose. Patients undergo surgical resection 6-10 weeks after the completion of chemoradiation. In the adjuvant setting, patients who have undergone R0 resections will receive tremelimiumab 300 mg ×1 and durvalumab 1,500 mg every 4 weeks ×6 doses starting within 12 weeks of surgery. Radiation will be administered starting ≥14 days after the first durvalumab treatment; it will commence on a Monday or Tuesday and continue weekly from Monday through Friday (except for public holidays).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically or cytologically confirmed adenocarcinoma of the esophagus or gastroesophageal junction (GEJ). Pathology must be confirmed at Memorial Sloan Kettering Cancer Center
- •Tumors that are Her2 positive are eligible
- •Availability of archived tumor tissue for banking
- •TanyN+M0 or T3-4NanyM0 tumors
- •Disease must be clinically limited to the esophagus or GEJ. GEJ tumors must be Siewert Type I-III
- •No prior chemotherapy
- •Prior radiation is permitted, provided it does not limit the ability to deliver per-protocol radiation in the opinion of the treating radiation oncologist
- •Patients must have surgically resectable disease treatable by esophagectomy, as assessed by a thoracic surgeon
- •mSUV in the primary tumor must be ≥5.0
- •Patients must be ≥18 years of age
Exclusion Criteria
- •Carcinoma in-situ and tumors determined to be T1-2N0
- •Tumors with significant involvement of the proximal stomach which, in the opinion of the treating thoracic surgeon, would require an esophagogastrectomy
- •Patients with evidence of metastatic disease, including:
- •Positive malignant cytology of the pleural, pericardium or peritoneum
- •Radiographic evidence of distant organ involvement
- •Non-regional lymph nodes that cannot be contained within a radiation field
- •Biopsy-proven tumor invasion of the tracheobronchial tree or presence of tracheoesophageal fistula. Recurrent laryngeal or phrenic nerve paralysis
- •Grade 2 ≥ peripheral neuropathy
- •Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease; systemic lupus erythematosus; Wegener syndrome \[granulomatosis with polyangiitis\]; myasthenia gravis; Graves' disease; rheumatoid arthritis, hypophysitis, uveitis) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
- •Subjects with vitiligo or alopecia
Arms & Interventions
Esophageal Cancer
This is a phase Ib/II trial of durvalumab (MEDI4736), a monoclonal antibody against programmed death ligand-1 (PD-L1)), and tremelimumab, an anti-CTLA-4 antibody, in combination with chemoradiation for patients with locally advanced (TanyN+M0 or T3-4NanyM0) esophageal or gastroesophageal (GE) junction adenocarcinoma.
Intervention: durvalumab
Esophageal Cancer
This is a phase Ib/II trial of durvalumab (MEDI4736), a monoclonal antibody against programmed death ligand-1 (PD-L1)), and tremelimumab, an anti-CTLA-4 antibody, in combination with chemoradiation for patients with locally advanced (TanyN+M0 or T3-4NanyM0) esophageal or gastroesophageal (GE) junction adenocarcinoma.
Intervention: carboplatin AUC 2/paclitaxel
Esophageal Cancer
This is a phase Ib/II trial of durvalumab (MEDI4736), a monoclonal antibody against programmed death ligand-1 (PD-L1)), and tremelimumab, an anti-CTLA-4 antibody, in combination with chemoradiation for patients with locally advanced (TanyN+M0 or T3-4NanyM0) esophageal or gastroesophageal (GE) junction adenocarcinoma.
Intervention: External beam radiation (EBRT)
Esophageal Cancer
This is a phase Ib/II trial of durvalumab (MEDI4736), a monoclonal antibody against programmed death ligand-1 (PD-L1)), and tremelimumab, an anti-CTLA-4 antibody, in combination with chemoradiation for patients with locally advanced (TanyN+M0 or T3-4NanyM0) esophageal or gastroesophageal (GE) junction adenocarcinoma.
Intervention: esophagogastrectomy
Esophageal Cancer
This is a phase Ib/II trial of durvalumab (MEDI4736), a monoclonal antibody against programmed death ligand-1 (PD-L1)), and tremelimumab, an anti-CTLA-4 antibody, in combination with chemoradiation for patients with locally advanced (TanyN+M0 or T3-4NanyM0) esophageal or gastroesophageal (GE) junction adenocarcinoma.
Intervention: Tremelimumab
Outcomes
Primary Outcomes
unacceptable toxicity
Time Frame: 1 year
"Unacceptable toxicity" is defined as any of the following toxicities: \>1 episode of grade 3/4 neutropenia or thrombocytopenia \<75,000/μL (despite prior dose reduction) during chemoradiation any toxicity that results in \>2 week cumulative delay in chemoradiation any toxicity that is attributed to durvalumab which results in a delay of \>8 weeks in surgery, i.e. surgery \>16 weeks from the end of radiation, for a potentially operable patient any reason that is attributed to durvalumab which leads to death within 30 days of surgery. All toxicity will be graded according to the National Cancer Institute (NCI) Common Toxicity Criteria, version 4.0.3.
pathologic complete response rate
Time Frame: 1 year
Secondary Outcomes
- overall survival (OS)(3 years)