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

NCT ID: NCT03783936

Last Updated: 2023-12-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-24
• Study Completion Date: 2022-08-30

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: OTHER

Oxaliplatin

Intervention Type: DRUG

Oxaliplatin 85 mg/m2

Leucovorin

Intervention Type: DRUG

Leucovorin 400 mg/m2

5 fluorouracil

Intervention Type: DRUG

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

Trastuzumab

Intervention Type: DRUG

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

Avelumab

Intervention Type: DRUG

Avelumab 800 mg

Interventions

Oxaliplatin

Oxaliplatin 85 mg/m2

Intervention Type: DRUG

Leucovorin

Leucovorin 400 mg/m2

Intervention Type: DRUG

5 fluorouracil

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

Intervention Type: DRUG

Trastuzumab

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

Intervention Type: DRUG

Avelumab

Avelumab 800 mg

Intervention Type: DRUG

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 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

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

EMD Serono

INDUSTRY

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: collaborator

Ashwin Somasundaram

OTHER

Sponsor Role: lead

Responsible Party

Ashwin Somasundaram

Sponsor-Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Ashwin Somasundaram, MD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Locations

City of Hope

Duarte, California, United States

Winship Cancer Insititute of Emory University

Atlanta, Georgia, United States

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

University of Iowa Hospital and Clinics

Iowa City, Iowa, United States

Atlantic Health System

Morristown, New Jersey, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 40571483 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

HCRN GI17-319

Identifier Type: -

Identifier Source: org_study_id