Clinical trial NCT01769508: Study of 5-FU, Oxaliplatin, & Lapatinib Combined With Radiation Therapy to Treat HER2 Positive Esophagogastric Cancer
Official title: A Phase II Study With Lead-in Safety Cohort of 5-Fluorouracil, Oxaliplatin and Lapatinib in Combination With Radiation Therapy as Neoadjuvant Treatment for Patients With Localized HER2 Positive Esophagogastric Adenocarcinomas
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: HER2 Positive Esophagogastric Cancer
Keywords: Esophagogastric Adenocarcinoma
5-Fluorouracil
Oxaliplatin
Lapatinib
Radiation Therapy
Surgery
Lead sponsor: SCRI Development Innovations, LLC
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2013-01-16
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: With improvements in response rate and survival seen for HER2 positive patients treated with HER2 blockade in the metastatic setting, the use of HER2 blockade in the neoadjuvant setting to increase antitumor effect shows promise. Patients with previously untreated localized HER2 positive esophageal, GE junction and gastric adenocarcinomas will be enrolled. Patients meeting all inclusion/exclusion criteria will receive neoadjuvant treatment with concurrent chemotherapy and radiation therapy beginning on day 1 of treatment. During the lead-in safety portion, the optimal dose of lapatinib will be determined.

Detailed description: This is an open-label, non-randomized, Phase II study with a lead-in safety cohort. The study will evaluate the combination of 5-Fluorouracil, Oxaliplatin and Lapatinib with radiation therapy as neoadjuvant treatment for patients with previously untreated localized HER2 positive esophagogastric adenocarcinomas. Approximately 12 patients will be enrolled in the lead-in cohort to evaluate the safety of the combination. Following the lead-in cohort, Phase II will commence and up to 30 additional patients may be treated. The starting doses will be administered as follows:

5-FU 225 mg/mg2 continuous intravenous (IV) infusion Days 1 - 42 during XRT; Oxaliplatin 85 mg/m2 Days 1, 15 and 29, given by IV infusion, per institutional standard; Lapatinib Continuous PO daily dosing during XRT (final dose determined during lead-in cohort).

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed Stage I, II, or III adenocarcinoma of the esophagus (lower ⅓), GE junction, or gastric cardia.
* Clinical stage I, II, or III as assessed by required baseline staging. In addition, patients with celiac node involvement (stage IVa) are eligible.
* Patients must be surgical candidates based on stage and location of disease as well as other medical conditions and risk factors.
* Positive HER2 status (overexpression and/or amplification of HER2 in primary tumor) as defined by FISH (HER2 FISH positivity).
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.
* Patient must be able to swallow and absorb oral medication.
* Patients must have an indwelling central venous access catheter.
* Adequate hematologic, renal, and hepatic function:
* Known brain or leptomeningeal metastases.
* Male patients willing to use adequate contraceptive measures.
* Female patients who are not of child-bearing potential, and female patients of child-bearing potential who agree to use adequate contraceptive measures, who are not breastfeeding, and who have a negative serum or urine pregnancy test within 72 hours prior to start of treatment.
* Life expectancy ≥ 12 weeks.
* Age ≥18 years of age.
* Willingness and ability to comply with trial and follow-up procedures.
* Ability to understand the nature of this trial and give written informed consent.

Exclusion Criteria:

* Patients with evidence of distant metastases are ineligible, as are patients who are not potential surgical candidates based on location or extent of local disease. Patients with celiac nodal disease (Stage IVa) will be allowed on study.
* Previous anti-cancer treatment for esophageal, GE junction, or gastric cancer.
* Any other investigational agents within the 28 days prior to day 1 of the study.
* Known active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).
* Concurrent treatment with drugs known to be strong inhibitors or inducers of isoenzyme CYP3A that cannot be discontinued or switched to different medication prior to starting study drug.
* Concurrent use of St. John's wort and grapefruit /grapefruit juice ≤7 days prior to starting study drug is not allowed.
* Ongoing treatment with full-dose warfarin or its equivalent. Prophylactic treatment with 1 mg daily of warfarin and/or low molecular weight heparin is allowed.
* History of any other disease, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of a novel regimen, or that might affect interpretation of the results of this study or render the subject at high-risk for treatment complications.
* Active gastrointestinal (GI) disease or other condition that in the opinion of the investigator will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (e.g. ulcerative disease, uncontrolled nausea, or vomiting).
* Poorly controlled or clinically significant atherosclerotic vascular disease
* A serious active infection at the time of treatment, or another serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.
* Known diagnosis of human immunodeficiency virus (HIV), Hepatitis B (HBV) or Hepatitis C (HCV).
* Presence of other active cancers, or history of treatment for invasive cancer ≤5 years. Patients with stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e. non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.
* Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
* Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol.

Primary outcomes:
measure: Pathologic Complete Response Rate (pCR Rate)
timeFrame: 18 months
measure: Safety and Optimal Dose of Regimen
timeFrame: 18 months
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 18 months
measure: Toxicity Profile for Treated Patients
timeFrame: 18 months
measure: Time to Progression (TTP)
timeFrame: 18 months
measure: Overall Survival (OS)
timeFrame: 18 months
Other outcomes:
Locations:
city: Fort Myers
country: United States
facility: Florida Cancer Specialists - South
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Cancer Institute
state: Florida
city: Pensacola
country: United States
facility: Woodlands Medical Specialists
state: Florida
city: St. Petersburg
country: United States
facility: Florida Cancer Specialists-North
state: Florida
city: Gainesville
country: United States
facility: Northeast Georgia Medical Center
state: Georgia
city: Grand Rapids
country: United States
facility: Grand Rapids Oncology Program
state: Michigan
city: Cincinnati
country: United States
facility: Oncology Hematology Care
state: Ohio
city: Chattanooga
country: United States
facility: Chattanooga Oncology and Hematology Associates
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
Study officials:
affiliation: SCRI Development Innovations, LLC
name: Johanna C Bendell, MD
role: STUDY_CHAIR
References:
citation: Shepard G, Arrowsmith ER, Murphy P, Barton JH Jr, Peyton JD, Mainwaring M, Blakely L, Maun NA, Bendell JC. A Phase II Study with Lead-In Safety Cohort of 5-Fluorouracil, Oxaliplatin, and Lapatinib in Combination with Radiation Therapy as Neoadjuvant Treatment for Patients with Localized HER2-Positive Esophagogastric Adenocarcinomas. Oncologist. 2017 Oct;22(10):1152-e98. doi: 10.1634/theoncologist.2017-0186. Epub 2017 Aug 1.