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

NCT03783936 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: HCRN GI17-319
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 7

Brief Summary

The initial intent of the study was to be a multi-center single-arm open-label Simon's two-stage Phase II clinical trial of first-line mFOLFOX6 + trastuzumab + avelumab in metastatic HER2-amplified gastric and esophageal adenocarcinomas. Accrual will halt after completion of Stage I (enrollment of 18 patients). This decision is not due to safety issues. Subjects currently on treatment will continue until criteria as defined in the protocol is met.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Best Objective Response Rate (bORR)

  Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter(LD) of target lesions; Progressive Disease (PD): \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. The bORR will be defined as the percentage of subjects whose best response by 24 weeks are either a CR or PR according to RECIST 1.1. For confirmed response, PR or CR need to be confirmed by repeat assessments that should be performed no less than 4 weeks. Otherwise, it will be considered as an unconfirmed response.

  24 weeks

Secondary Outcomes (5)

• Progression Free Survival (PFS)

  Time of treatment start until the criteria for disease progression or death, up to a maximum of 11 months.

• Progression Free Survival by iRECIST(iPFS)

  Time of treatment start until the criteria for disease progression or death, up to a maximum of 11 months.

• Overall Survival (OS)

  Time of treatment start until death or date of last contact, up to a maximum of 20 months

• Disease Control Rate (DCR)

  Up to a maximum of 11 months.

• Number of Participants With Grade 3-4 Treatment Related Adverse Events

  AE had been recorded from time of signed informed consent until 30 days after discontinuation of study drug(s) and/or until a new anti-cancer treatment starts, whichever occurs first, up to a maximum of 20 months.

Study Arms (1)

Induction and Maintenance

OTHER

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

Drug: Oxaliplatin; Drug: Leucovorin; Drug: 5 fluorouracil; Drug: Trastuzumab; Drug: Avelumab

Interventions

Oxaliplatin DRUG

Oxaliplatin 85 mg/m2

Induction and Maintenance

Leucovorin DRUG

Leucovorin 400 mg/m2

Induction and Maintenance

5 fluorouracil DRUG

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

Induction and Maintenance

Trastuzumab DRUG

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

Induction and Maintenance

Avelumab DRUG

Avelumab 800 mg

Induction and Maintenance

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent and HIPAA authorization for release of personal health information prior to registration.
• Age ≥ 18 years at the time of consent.
• ECOG Performance Status of 0 or 1.
• Histologically confirmed esophageal, gastroesophageal junction, or gastric adenocarcinoma, with unresectable or metastatic disease documented on diagnostic imaging studies.
• 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).
• Radiographically measurable disease according to RECIST 1.1 within 28 days prior to registration.
• 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 10\^9/L
• Hemoglobin (Hgb) ≥ 9 g/dL (may have been transfused)
• Platelets ≥ 100 x 10\^9/L OR ≥ 75 x 10\^9/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
• Left ventricular ejection fraction (LVEF) ≥ 50% or above the lower limit of the institutional normal range, whichever is lower.

You may not qualify if:

• 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.
• Active infection requiring intravenous systemic therapy.
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
• Treatment with any investigational drug within 28 days prior to registration.
• Prior immune checkpoint inhibitor therapy (i.e. anti-CTLA-4, anti-PD-L1, anti-PD-1), or HER2-directed therapy (including trastuzumab)
• Evidence of interstitial lung disease or active, non-infectious pneumonitis
• Untreated brain metastasis or brain metastasis treated within 4 weeks prior to enrollment.
• 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.
• 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.
• History of organ allograft or allogeneic stem cell transplantation
• 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

Sponsors & Collaborators

• Ashwin Somasundaram: lead
• EMD Serono: collaborator
• University of North Carolina, Chapel Hill: collaborator

Study Sites (7)

City of Hope

Duarte, California, 91010, United States

Location

Winship Cancer Insititute of Emory University

Atlanta, Georgia, 30322, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

University of Iowa Hospital and Clinics

Iowa City, Iowa, 52242, United States

Location

Atlantic Health System

Morristown, New Jersey, 07960, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Related Publications (1)

• Lee MS, Chao J, Mulcahy MF, Kasi PM, Alistar AT, Mukherjee S, Akce M, Moore DT, McRee AJ, Somasundaram A. Phase II study of avelumab and trastuzumab with FOLFOX chemotherapy in previously untreated HER2-amplified metastatic gastroesophageal adenocarcinoma. Oncologist. 2025 Jul 4;30(7):oyaf195. doi: 10.1093/oncolo/oyaf195.

  PMID: 40571483 DERIVED

MeSH Terms

Conditions

Adenocarcinoma Of Esophagus; Neoplasm Metastasis

Interventions

Oxaliplatin; Leucovorin; Fluorouracil; Trastuzumab; avelumab

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Fauzia Sharmin
• Organization: Hoosier Cancer Research Network

fsharmin@hoosiercancer.org

(317) 921-2050

Study Officials

• Ashwin Somasundaram, MD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: December 19, 2018
• First Posted: December 21, 2018
• Study Start: January 24, 2019
• Primary Completion: September 11, 2020
• Study Completion: August 30, 2022
• Last Updated: December 19, 2023
• Results First Posted: December 19, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)