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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02962063
Recruitment Status : Recruiting
First Posted : November 11, 2016
Last Update Posted : June 22, 2020
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

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.

Condition or disease Intervention/treatment Phase
Esophageal Adenocarcinoma Gastroesophageal Junction Adenocarcinoma Biological: durvalumab Drug: carboplatin AUC 2/paclitaxel Radiation: External beam radiation (EBRT) Procedure: esophagogastrectomy Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Induction Chemotherapy and Durvalumab (MEDI4736) With Chemoradiation for Esophageal and Gastroesophageal Junction Adenocarcinoma
Study Start Date : November 2016
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : November 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Esophageal Cancer
Pts receive fluorouracil intravenously (IV) over 46-48 hours, oxaliplatin IV over up to 6 hours & 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 2nd cycle of induction chemotherapy, pts receive durvalumab IV over 60 minutes on day 29 before & during the 3rd week of chemoradiation. Pts also receive carboplatin IV over 30 minutes & paclitaxel IV over 60 minutes once per week for 5 weeks. Pts undergo EBRT 5 days per week for 5.5 weeks starting ≥14 days after durvalumab in the absence of progression or unacceptable toxicity. Beginning 6-8 weeks following chemoradiation therapy, pts undergo esophagectomy. Beginning approximately 6-12 weeks following surgery, pts who have had complete removal of the tumor receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Biological: durvalumab
Durvalumab can be given irrespective of CBC, at the discretion of the treating physician.
Other Name: (MEDI4736)

Drug: carboplatin AUC 2/paclitaxel
Radiation: External beam radiation (EBRT)
Procedure: esophagogastrectomy



Primary Outcome Measures :
  1. 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.

  2. pathologic complete response rate [ Time Frame: 1 year ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02962063


Contacts
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Contact: Geoffrey Ku, MD 646-888-4588
Contact: David Ilson, MD, PhD 646-888-4183

Locations
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United States, New Jersey
Memorial Sloan Kettering Basking Ridge Recruiting
Basking Ridge, New Jersey, United States, 07920
Contact: Geoffrey Ku, MD    646-888-4588      
Memorial Sloan Kettering Bergen Recruiting
Montvale, New Jersey, United States, 07645
Contact: Geoffrey Ku, MD    646-888-4588      
United States, New York
Memorial Sloan Kettering Commack Recruiting
Commack, New York, United States, 11725
Contact: Geoffrey Yu, MD    646-888-4588      
Memorial Sloan Kettering Westchester Recruiting
Harrison, New York, United States, 10604
Contact: Geoffrey Yu, MD    646-888-4588      
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Geoffrey Ku, MD    646-888-4588      
Principal Investigator: Geoffrey Ku, MD         
Memorial Sloan Kettering Rockville Centre Recruiting
Rockville Centre, New York, United States, 11570
Contact: Geoffrey Yu, MD    646-888-4588      
Memorial Sloan Kettering Nassau Recruiting
Uniondale, New York, United States, 11553
Contact: Geoffrey Ku, MD    646-888-4588      
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
AstraZeneca
Investigators
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Principal Investigator: Geoffrey Ku, MD Memorial Sloan Kettering Cancer Center
Additional Information:
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Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT02962063    
Other Study ID Numbers: 16-1405
First Posted: November 11, 2016    Key Record Dates
Last Update Posted: June 22, 2020
Last Verified: June 2020
Keywords provided by Memorial Sloan Kettering Cancer Center:
Durvalumab
Anti-PD-L1 Antibody
16-1405
Additional relevant MeSH terms:
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Adenocarcinoma
Esophageal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Paclitaxel
Carboplatin
Durvalumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological