Clinical Trials /

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

NCT03783936

Description:

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.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial of mFOLFOX6 + Trastuzumab + Avelumab in Gastric and Esophageal Adenocarcinomas
  • Official Title: A Single Arm, Multi-center Phase 2 Trial of mFOLFOX6 + Trastuzumab + Avelumab in First-line, Metastatic, HER2-amplified Gastric and Esophageal Adenocarcinomas

Clinical Trial IDs

  • ORG STUDY ID: HCRN GI17-319
  • NCT ID: NCT03783936

Conditions

  • Gastric Adenocarcinoma
  • Esophageal Adenocarcinoma
  • Metastasis
  • HER-2 Gene Amplification

Interventions

DrugSynonymsArms
OxaliplatinInduction and Maintenance
LeucovorinInduction and Maintenance
5 fluorouracilInduction and Maintenance
TrastuzumabInduction and Maintenance
AvelumabInduction and Maintenance

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Induction and MaintenanceOtherCycles 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 10 mg/kg IV Day 1 Cycles 10 and subsequent; Maintenance; Cycle = 14 days Trastuzumab 4 mg/kg Day 1 and Avelumab 10 mg/kg Day 1
  • Oxaliplatin
  • Leucovorin
  • 5 fluorouracil
  • Trastuzumab
  • Avelumab

Eligibility Criteria

        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 3 months 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best Objective Response Rate (bORR)
Time Frame:24 weeks
Safety Issue:
Description: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

Measure:Progression Free Survival (PFS)
Time Frame:2 years
Safety Issue:
Description: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.
Measure:Progression Free Survival (iPFS)
Time Frame:2 years
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:2 years
Safety Issue:
Description: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.
Measure:Disease Control Rate (DCR)
Time Frame:24 weeks
Safety Issue:
Description: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
Measure:Assess adverse events
Time Frame:2 years
Safety Issue:
Description:Adverse events will be summarized by frequency and severity using CTCAE version 5.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Michael Sangmin Lee

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