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

Sponsor

Autumn McRee, MD (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03783936

Collaborator

EMD Serono (Industry), University of North Carolina, Chapel Hill (Other)

Enrollment

Locations

Arm

35.3

Anticipated Duration (Months)

2.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

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

Study Design

Study Type:

Interventional

Actual Enrollment :

18 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 :

Jan 24, 2019

Actual Primary Completion Date :

Sep 11, 2020

Anticipated Study Completion Date :

Jan 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Other: 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	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

Arm

Intervention/Treatment

Other: 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

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

Outcome Measures

Primary Outcome Measures

Best Objective Response Rate (bORR) [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

Progression Free Survival (PFS) [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) [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) [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) [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 [2 years]
Adverse events will be summarized by frequency and severity using CTCAE version 5.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

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 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

Left ventricular ejection fraction (LVEF) ≥ 50% or above the lower limit of the institutional normal range, whichever is lower.
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.
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.
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:

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

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).
Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
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.
Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines.
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).
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.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Winship Cancer Insititute of Emory University	Atlanta	Georgia	United States	30322
3	Northwestern University Feinberg School of Medicine	Chicago	Illinois	United States	60611
4	University of Iowa Hospital and Clinics	Iowa City	Iowa	United States	52242
5	Atlantic Health System	Morristown	New Jersey	United States	07960
6	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
7	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599