Clinical trial NCT02962063: Durvalumab, an Anti-PDLI Antibody, and Tremelimumab, an Anti-CTLA4 Antibody, and Chemoradiation Before Surgery for Esophageal Cancer
Official title: Phase Ib/II Study of Induction Chemotherapy and Durvalumab (MEDI4736) and Tremelimumab With Chemoradiation for Esophageal and Gastroesophageal Junction Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Esophageal Adenocarcinoma
Gastroesophageal Junction Adenocarcinoma
Keywords: Durvalumab
Anti-PD-L1 Antibody
Tremelimumab
16-1405
Lead sponsor: Memorial Sloan Kettering Cancer Center
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2016-11-11
Enrollment: 79
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 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.
Primary purpose: TREATMENT

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).

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
* 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
* Adequate organ function defined at baseline as:

  * WBC ≥3,000/ L
  * ANC ≥1,500/ L
  * Platelets ≥100,000/ L
  * Hb ≥9 g/dl
  * Calculated creatinine clearance \>40 ml/min using Cockcroft-Gault method:

Males:

Creatinine CL = Weight (kg) x (140 - Age) . (mL/min) 72 x serum creatinine (mg/dL)

Females:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)

* Total serum bilirubin ≤1.5 mg/dL
* AST/ALT ≤2.5× upper limit of normal

  * Mean QT interval corrected for heart rate (QTc) \<470 ms calculated from 3 ECGs using Frediricia's Correction
  * Able to provide written informed consent
  * Subject willing to provide informed consent for MSKCC IRB#12-245 for IMPACT testing
  * 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 HIV positivity
* Chronic Hepatitis B or known Hepatitis C infection (e.g. Hepatitis B surface 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 outcomes:
measure: unacceptable toxicity
timeFrame: 1 year
measure: pathologic complete response rate
timeFrame: 1 year
Secondary outcomes:
measure: overall survival (OS)
timeFrame: 3 years
Other outcomes:
Locations:
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Basking Ridge
state: New Jersey
city: Montvale
country: United States
facility: Memorial Sloan Kettering Bergen
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Commack
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Westchester
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Rockville Centre
country: United States
facility: Memorial Sloan Kettering Rockville Centre
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Nassau
state: New York
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Geoffrey Ku, MD
role: PRINCIPAL_INVESTIGATOR
References: