Durvalumab, an Anti-PDLI Antibody, Tremelimumab, an Anti-CTLA4 Antibody, and Chemoradiation before Surgery for Esophageal Cancer

This phase Ib / II trial studies the side effects of durvalumab when given together with chemotherapy and radiation therapy in treating patients with esophageal or gastroesophageal junction cancer. Both durvalumab and tremelimumab are antibodies (proteins) which bind to cells involved in the immune system. Antibodies are normally made by the body to destroy germs, like bacteria and viruses. The antibodies in this study are designed to boost the body’s immune system, by allowing immune cells to be more active and fight the cancer. Durvalumab works by interacting with an immune molecule called PD-L1, located on the tumor cells and white blood cells. Tremelimumab works by interacting with an immune molecule called CTLA-4, located on white blood cells. Both durvalumab and tremelimumab may help strengthen the immune system. Drugs used in chemotherapy, such as fluorouracil, leucovorin calcium, oxaliplatin, 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 durvalumab together with chemotherapy and radiation therapy before surgery may work better at treating patients with esophageal or gastroesophageal junction cancer.

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 T3-4N any M0 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
• Maximum standard uptake value (mSUV) in the primary tumor must be >= 5.0
• Eastern Cooperative Oncology Group performance status of 0-1
• Female subjects must either be of non-reproductive potential (i.e. post-menopausal by history: >= 60 years old and no menses for >= 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry
• White blood cells (WBC) >= 3,000/uL
• Absolute neutrophil count (ANC) >= 1,500/uL
• Platelets >= 100,000/uL
• Hemoglobin (Hb) >= 9 g/dl
• Calculated creatinine clearance > 40 ml/min using Cockcroft-Gault method
• Total serum bilirubin =< 1.5 mg/dL
• Aspartame aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal
• Mean QT interval corrected for heart rate (QTc) < 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's correction
• Able to provide written informed consent
• Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up

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 * Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment
• History of pneumonitis
• The use of immunosuppressive medication within 28 days prior to the first dose of durvalumab/tremelimumab; the following are exceptions to this criterion: * Intranasal, topical, inhaled corticosteroids or local steroid injections (e.g. intraarticular injection) * Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent * Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
• Known human immunodeficiency virus (HIV) positivity
• Chronic hepatitis B or known hepatitis C infection (e.g. hepatitis B surface antigen [Ag] positive or detectable viral load for hepatitis B); patients with prior evidence of hepatitis B or C without active infection are eligible
• Known history of previous clinical diagnosis of tuberculosis
• Uncontrolled seizures
• Pregnant or breast-feeding women; women of childbearing potential (WOCBP) must undergo a negative pregnancy test (either serum or urine) prior to study entry; male and female patients of reproductive potential need to employ two highly effective and acceptable forms of contraception throughout their participation in the study and for 90 days after last dose of study drug; WOCBP include: * Any woman who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or oophorectomy) or who is not post-menopausal (defined as amenorrheic >= 12 consecutive months) * Women on hormone replacement therapy with documented serum follicle stimulating hormone level > 35 mIU/ml * Women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as intrauterine device or barrier methods to prevent pregnancy or are practicing abstinence of where the partner is sterile
• Prior malignancy (other than basal cell/squamous cell carcinoma of the skin, in-situ cervical carcinoma or superficial transitional cell bladder carcinoma) diagnosed and/or treated within three years of study entry
• Connective tissue disorders, e.g. scleroderma, that in the opinion of the treating physicians is a contraindication to radiation therapy
• History of primary immunodeficiency
• History of allogenic organ transplant
• Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab; for example, the intramuscular influenza vaccine can be administered but the intranasal vaccine is a live attenuated virus that cannot be given
• Any previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab, or a CTLA-4 inhibitor, including tremelimumab
• History of hypersensitivity to durvalumab or tremelimumab or any excipient uncontrolled intercurrent illness including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease, active bleeding diatheses or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent

PRIMARY OBJECTIVE:

I. Assess the pathologic complete response rate of durvalumab/tremelimumab with positron emission tomography (PET)-directed chemotherapy and radiation followed by surgery.

SECONDARY OBJECTIVES:

I. Assess the safety of durvalumab/tremelimumab with positron emission tomography (PET)-directed chemotherapy and radiation followed by surgery.

II. Determine the progression-free (PFS) and overall survival (OS) of durvalumab/tremelimumab with PET-directed chemotherapy and radiation followed by surgery and adjuvant durvalumab/tremelimumab for patients with completely resected disease.

EXPLORATORY OBJECTIVE:

I. Correlate outcomes - pathologic complete response (pCR), PFS and OS - with immune correlative assays and Memorial Sloan Kettering (MSK)-Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT) profiles.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients receive fluorouracil intravenously (IV) over 46-48 hours, oxaliplatin IV over up to 6 hours and leucovorin calcium IV over 2 hours. Treatment repeats every 14 days for 2 cycles in the absence of disease progression or unacceptable toxicity.

Beginning 2 weeks after second cycle of induction chemotherapy, patients receive durvalumab IV over 60 minutes and tremelimumab IV over 1 hour on day 29 before and during the third week of chemoradiation. Patients also receive carboplatin IV over 30 minutes and paclitaxel IV over 60 minutes once per week for 5 weeks. Patients undergo external beam radiation therapy (EBRT) 5 days per week for 5.5 weeks starting >= 14 days after durvalumab in the absence of disease progression or unacceptable toxicity. Beginning 6-8 weeks following chemoradiation therapy, patients undergo esophagectomy. Beginning approximately 6-12 weeks following surgery, patients who have had complete removal of the tumor receive durvalumab IV over 60 minutes and tremelimumab IV over 1 hour on day 1. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

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

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Geoffrey Yuyat Ku

• Primary ID 16-1405
• Secondary IDs NCI-2016-01758
• Clinicaltrials.gov ID NCT02962063