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

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

Tracking Information
First Submitted Date  ICMJE December 19, 2018
First Posted Date  ICMJE December 21, 2018
Last Update Posted Date February 27, 2020
Actual Study Start Date  ICMJE January 24, 2019
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 19, 2018)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 19, 2018)
  • 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.
  • 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.
  • 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.
  • 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
  • Assess adverse events [ Time Frame: 2 years ]
    Adverse events will be summarized by frequency and severity using CTCAE version 5.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Trial of mFOLFOX6 + Trastuzumab + Avelumab in Gastric and Esophageal Adenocarcinomas
Official Title  ICMJE A Single Arm, Multi-center Phase 2 Trial of mFOLFOX6 + Trastuzumab + Avelumab in First-line, Metastatic, HER2-amplified Gastric and Esophageal Adenocarcinomas
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Gastric Adenocarcinoma
  • Esophageal Adenocarcinoma
  • Metastasis
  • HER-2 Gene Amplification
Intervention  ICMJE
  • 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
Study Arms  ICMJE Induction and Maintenance

Cycles 1-9; Induction; Cycle = 14 days

mFOLFOX6

  • 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

Interventions:
  • Drug: Oxaliplatin
  • Drug: Leucovorin
  • Drug: 5 fluorouracil
  • Drug: Trastuzumab
  • Drug: Avelumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 19, 2018)
63
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2022
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Michael Lee, MD 919-966-3856 michael_s_lee@med.unc.edu
Contact: Robyn Lillie, BSN (317) 634-5842 ext 60 rlillie@hoosiercancer.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03783936
Other Study ID Numbers  ICMJE HCRN GI17-319
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Michael Sangmin Lee, Hoosier Cancer Research Network
Study Sponsor  ICMJE Michael Sangmin Lee
Collaborators  ICMJE
  • EMD Serono
  • University of North Carolina, Chapel Hill
Investigators  ICMJE
Principal Investigator: Michael Lee, MD University of North Carolina, Chapel Hill
PRS Account Hoosier Cancer Research Network
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP