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Trial of mFOLFOX6 + Trastuzumab + Avelumab in Gastric and Esophageal Adenocarcinomas

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. Identifier: NCT03783936
Recruitment Status : Recruiting
First Posted : December 21, 2018
Last Update Posted : February 27, 2020
EMD Serono
University of North Carolina, Chapel Hill
Information provided by (Responsible Party):
Michael Sangmin Lee, Hoosier Cancer Research Network

Brief Summary:
This study will be a prospective, open-label, single arm, multi-center phase 2 clinical trial of mFOLFOX6 + trastuzumab + avelumab in first-line, metastatic, HER2-amplified gastric and esophageal adenocarcinomas. The primary objective of this study is to estimate the best objective response rate (CR or PR, ORR) in these patients within 24 weeks by RECIST 1.1 criteria. Secondary objectives include; estimating PFS by both RECIST 1.1 and iRECIST criteria, estimating OS, estimating the disease control rate (DCR) at 24 weeks by RECIST 1.1 and iRECIST, and characterizing the safety issues associated with this regimen.

Condition or disease Intervention/treatment Phase
Gastric Adenocarcinoma Esophageal Adenocarcinoma Metastasis HER-2 Gene Amplification Drug: Oxaliplatin Drug: Leucovorin Drug: 5 fluorouracil Drug: Trastuzumab Drug: Avelumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 63 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single Arm, Multi-center Phase 2 Trial of mFOLFOX6 + Trastuzumab + Avelumab in First-line, Metastatic, HER2-amplified Gastric and Esophageal Adenocarcinomas
Actual Study Start Date : January 24, 2019
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Induction and Maintenance

Cycles 1-9; Induction; Cycle = 14 days


  • oxaliplatin 85 mg/m2 IV Day 1 and
  • leucovorin 400 mg/m2 IV Day 1 and
  • 5 fluorouracil 400 mg/m2 IV bolus and 2400 mg/m2 IV over 46 hours Day 1 and

Trastuzumab 6 mg/kg IV loading dose C1D1 then Trastuzumab 4 mg/kg IV Day 1 and

Avelumab 800 mg IV Day 1

Cycles 10 and subsequent; Maintenance; Cycle = 14 days

Trastuzumab 4 mg/kg Day 1 and Avelumab 800 mg Day 1

Drug: Oxaliplatin
Oxaliplatin 85 mg/m2

Drug: Leucovorin
Leucovorin 400 mg/m2

Drug: 5 fluorouracil
5 fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion

Drug: Trastuzumab
Trastuzumab 6 mg/kg loading dose C1D1 then 4 mg/kg Day 1

Drug: Avelumab
Avelumab 800 mg

Primary Outcome Measures :
  1. Best Objective Response Rate (bORR) [ Time Frame: 24 weeks ]
    The best objective response rate will be defined as the total number of patients whose best response by 24 weeks are either a CR or PR divided by the number of response evaluable patients

Secondary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: 2 years ]
    Progression Free Survival (PFS) by RECIST 1.1 will be defined as the time from the start date of treatment to the date of documented progression as determined by RECIST 1.1 or death from any cause.

  2. Progression Free Survival (iPFS) [ Time Frame: 2 years ]
    Progression Free Survival by iRECIST (iPFS) will be defined as the time from the start date of treatment to the date of documented progression as determined by iRECIST criteria or death from any cause.

  3. Overall Survival (OS) [ Time Frame: 2 years ]
    Overall Survival (OS) will be defined as the time from start of treatment to the date of death. If the patient has not died, survival will be censored on last date the patient was known to be alive.

  4. Disease Control Rate (DCR) [ Time Frame: 24 weeks ]
    Disease Control Rate (DCR) used to help determine clinical benefit will be defined as the total number of patients whose best responses are either a CR, PR, or SD divided by the number of response evaluable patients. Patients with best response of SD will need to maintain SD by 24 weeks to be considered to have received clinical benefit from the treatment regimen

  5. Assess adverse events [ Time Frame: 2 years ]
    Adverse events will be summarized by frequency and severity using CTCAE version 5.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

Inclusion Criteria:

  1. Written informed consent and HIPAA authorization for release of personal health information prior to registration.
  2. Age ≥ 18 years at the time of consent.
  3. ECOG Performance Status of 0 or 1.
  4. Histologically confirmed esophageal, gastroesophageal junction, or gastric adenocarcinoma, with unresectable or metastatic disease documented on diagnostic imaging studies.
  5. HER2 amplification confirmed by standard of care testing of tumor specimen (3+ by immunohistochemistry, or 2+ on IHC with ISH with HER2/CEP17 ratio ≥2).
  6. Radiographically measurable disease according to RECIST 1.1 within 28 days prior to registration.
  7. Adequate organ function as defined in the table below. All screening labs to be obtained within 28 days prior to registration.

    • Absolute Neutrophil Count ≥ 1.5 x 109/L
    • Hemoglobin (Hgb) ≥ 9 g/dL (may have been transfused)
    • Platelets ≥ 100 x 109/L OR ≥ 75 x 109/L for patients who received Cycle 1 of mFOLFOX6 +/- trastuzumab prior to registration
    • Calculated creatinine clearance1 ≥ 30 mL/min OR creatinine ≤ 1.5 × upper limit of normal (ULN)
    • Bilirubin ≤ 1.5 × upper limit of normal (ULN) (Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level >1.5 mg/dL, if their conjugated bilirubin is < 1.5× ULN)
    • Aspartate aminotransferase (AST) ≤ 2.5 × ULN OR ≤ 5x ULN in patients with known liver metastases
    • Alanine aminotransferase (ALT) ≤ 2.5 × ULN OR ≤ 5x ULN in patients with known liver metastases
  8. Left ventricular ejection fraction (LVEF) ≥ 50% or above the lower limit of the institutional normal range, whichever is lower.
  9. Females of childbearing potential must have a negative serum pregnancy test at screening. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
  10. Females of childbearing potential and males must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 210 days after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method.
  11. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.

Exclusion Criteria:

  1. Previous systemic therapy for stage IV disease - EXCEPT that patient may have received one cycle of mFOLFOX6 +/- trastuzumab within the 4 weeks prior to registration.
  2. Active infection requiring intravenous systemic therapy.
  3. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
  4. Treatment with any investigational drug within 28 days prior to registration.
  5. Prior immune checkpoint inhibitor therapy (i.e. anti-CTLA-4, anti-PD-L1, anti-PD-1), or HER2-directed therapy (including trastuzumab)
  6. Evidence of interstitial lung disease or active, non-infectious pneumonitis
  7. Untreated brain metastasis or brain metastasis treated within 4 weeks prior to enrollment.
  8. Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years.
  9. Serious cardiovascular event within 6 months prior to study entry, including myocardial infarction, malignant hypertension, severe/unstable angina, symptomatic congestive heart failure (≥ New York Heart Association Classification Class II), cerebral vascular accident, transient ischemic attack, or serious cardiac arrhythmia requiring medication.
  10. History of organ allograft or allogeneic stem cell transplantation
  11. Active autoimmune disease requiring systemic treatment in the past 3 months (for example with disease modifying agents, corticosteroids, or immunosuppressive drugs).

    Exceptions Include:

    • Subjects with endocrine diseases stable on replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) or hormone suppression.
    • Subjects that require intermittent use of bronchodilators, local steroid injections, or inhaled or topical steroids
    • Subjects with vitiligo, psoriasis, Sjogren's syndrome, or resolved childhood asthma/atopy
  12. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
  13. Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
  14. Known history of Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection will be permitted.
  15. Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines.
  16. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5 Grade ≥ 3).
  17. Persisting toxicity related to prior therapy (NCI CTCAE v5 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.
  18. Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with informed consent, the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

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 identifier (NCT number): NCT03783936

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Contact: Michael Lee, MD 919-966-3856
Contact: Robyn Lillie, BSN (317) 634-5842 ext 60

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United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Tina Zhang    626-218-0867   
Principal Investigator: Joseph Chao, MD         
United States, Georgia
Winship Cancer Insititute of Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Kim Nguyen    404-778-5680   
Principal Investigator: Mehmet Akce, MD         
United States, Illinois
Northwestern University Feinberg School of Medicine Recruiting
Chicago, Illinois, United States, 60611
Contact: Rita Staples    312-695-4781   
Principal Investigator: Victoria Villaflor, MD         
United States, Iowa
University of Iowa Hospital and Clinics Recruiting
Iowa City, Iowa, United States, 52242
Contact: Marian Anderson    319-353-4578   
Principal Investigator: Pashtoon M. Kasi, MD         
United States, New Jersey
Atlantic Health System Recruiting
Morristown, New Jersey, United States, 07960
Contact: Batbara Peloquin    973-971-6298   
Principal Investigator: Angela Alistar, MD         
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Deeponpaul Singh    716-845-8270   
Principal Investigator: Sarbajit Mukherjee, MD         
United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Jessica Ghidorzi    919-962-8569   
Principal Investigator: Michael Sangmin Lee, MD         
Sponsors and Collaborators
Michael Sangmin Lee
EMD Serono
University of North Carolina, Chapel Hill
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Principal Investigator: Michael Lee, MD University of North Carolina, Chapel Hill
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Responsible Party: Michael Sangmin Lee, Sponsor-Investigator, Hoosier Cancer Research Network Identifier: NCT03783936    
Other Study ID Numbers: HCRN GI17-319
First Posted: December 21, 2018    Key Record Dates
Last Update Posted: February 27, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Esophageal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Protective Agents
Vitamin B Complex