Clinical Trials /

Durvalumab, an Anti-PD-L1 Antibody, and Chemoradiation Before Surgery for Esophageal Cancer

NCT02962063

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab, an Anti-PD-L1 Antibody, and Chemoradiation Before Surgery for Esophageal Cancer
  • Official Title: Phase II Study of Induction Chemotherapy and Durvalumab (MEDI4736) With Chemoradiation for Esophageal and Gastroesophageal Junction Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: 16-1405
  • NCT ID: NCT02962063

Conditions

  • Esophageal Adenocarcinoma
  • Gastroesophageal Junction Adenocarcinoma

Interventions

DrugSynonymsArms
durvalumab(MEDI4736)Esophageal Cancer
carboplatin AUC 2/paclitaxelEsophageal Cancer

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Esophageal CancerExperimentalPts will get a baseline PET/CT scan prior to getting mFOLFOX6 chemo (bolus 5-fluorouracil or -FU 400 mg/m2, leucovorin 400 mg/m2, oxaliplatin 70-85 mg/m2 & infusional 5-FU 1,200 mg/m2/day ×46 hours) q14 days ×2, followed by repeat PET scan. 2 weeks after the 2nd dose of mFOLFOX6, pts get 1 dose of durvalumab 1,500 mg. 2 weeks later, all pts will start radiation (1.8 Gy/fraction ×28 fractions Monday to Friday total dose of 50.4 Gy). PET responders get concurrent chemo 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 to Friday thru the radiation period. PET non-responders get concurrent carboplatin AUC 2/paclitaxel 50 mg/m2 weekly ×5 with concurrent. All pts get a 2nd dose of durvalumab 1,500 mg q28 days after 1st dose. Pts undergo surgical resection 6-8 weeks after the end of chemoradiation. Adjuvant setting, pts who have undergone R0 resections will get durvalumab 1,500 mg every 4 weeks ×6 doses.
  • durvalumab
  • carboplatin AUC 2/paclitaxel

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 ≥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. 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 PD1 or PD-L1 inhibitor, including durvalumab

          -  History of hypersensitivity to durvalumab 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:unacceptable toxicity
Time Frame:1 year
Safety Issue:
Description:"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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Durvalumab
  • Anti-PD-L1 Antibody
  • 16-1405

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