Sunitinib in Treating Patients With Relapsed or Refractory Esophageal or Gastroesophageal Junction Cancer

A Mechanistic Radiographic and Biologic Phase 2 Single Agent Study of Sunitinib Malate in Relapsed/Refractory Esophageal and Gastroesophageal Cancers

RATIONALE: Sunitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PURPOSE: This phase II trial is studying how well sunitinib works in treating patients with relapsed or refractory esophageal or gastroesophageal junction cancer.

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer
• Intervention / Treatment: Drug: sunitinib malate

Detailed Description

OBJECTIVES:

Primary

• To determine the progression-free survival rate (complete response, partial response, and stable disease as defined by RECIST criteria [Response Evaluation Criteria in solid Tumors]) at 24 weeks in patients with relapsed or refractory esophageal or gastroesophageal junction cancer treated with sunitinib malate.

Secondary

• To explore the predictive role of a hybrid imaging protocol that combines PET/CT (Positron emission tomography) scan simultaneously with dynamic contrast-enhanced MRI.
• Correlate quantitative changes in mean vessel density, alterations in tumor cell proliferation, and apoptosis in tumor biopsy specimens with clinical outcome in these patients.
• To evaluate the objective response as defined by RECIST criteria, median overall survival, and median progression-free survival of these patients.
• To evaluate the toxicities of sunitinib malate in these patients.

OUTLINE: Patients receive oral sunitinib malate once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood and tumor tissue sample collection periodically for correlative laboratory studies. Tumor tissue samples are assessed by immunohistochemistry and TUNEL for detection and quantitation of mean vessel density, proliferating tumor cells, and apoptosis. Tumor tissue samples are also assessed by immunohistochemistry for MAPK levels. Blood samples are analyzed by ELISA for VEGF, PlGF, sVEGFR2, and sVEGFR3 levels. Patients also undergo PET/CT scan and dynamic contrast-enhanced MRI periodically for correlative studies.

After completion of study treatment, patients are followed for at least 6 months.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed esophageal or gastroesophageal junction carcinoma that is not amenable to curative surgery or other curative therapy

  • Advanced, relapsed or refractory disease
• Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by conventional techniques or as ≥ 10 mm by spiral CT scan
• No known brain metastases

PATIENT CHARACTERISTICS:

• ECOG (Eastern Cooperative Oncology Group) performance status 0-1
• Life expectancy > 12 weeks
• WBC ≥ 3,000/μL
• Absolute neutrophil count ≥ 1,500/μL
• Platelet count ≥ 100,000/μL
• Serum calcium ≤ 12.0 mg/dL
• Total bilirubin normal
• AST (aspartate aminotransferase) and ALT (Alanine Aminotransferase) ≤ 2.5 times upper limit of normal
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception prior to, during, and for 28 days after completion of study treatment
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to sunitinib malate
• No ongoing cardiac dysrhythmias ≥ grade 2, atrial fibrillation of any grade, or prolongation of the QTc (corrected QT interval) interval to > 450 msec (for males) or > 470 msec (for females)
• No hypertension that cannot be controlled by medications (i.e., systolic/diastolic blood pressure > 150/100 mm Hg despite optimal medical therapy)
• No myocardial infarction, cardiac arrhythmia, stable/unstable angina, symptomatic congestive heart failure, or coronary/peripheral artery bypass graft or stenting within the past 12 months
• No cerebrovascular accident or transient ischemic attack within the past 12 months
• No pulmonary embolism within the past 12 months
• No condition that would impair the ability to swallow and retain sunitinib malate tablets (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease)
• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days
• No serious or nonhealing wound, ulcer, or bone fracture
• No pre-existing thyroid abnormality that cannot be maintained in the normal range with medication
• No concurrent uncontrolled illness including, but not limited to, ongoing or active infection or psychiatric illness/social situation that would limit compliance with study requirements

PRIOR CONCURRENT THERAPY:

• Recovered from prior therapy
• At least 4 weeks since prior radiotherapy or major surgery
• At least 4 weeks since prior chemotherapy (6 weeks for mitomycin C, carmustine, or alkylating agents)
• No more than 6 prior courses of an alkylating agent
• No more than 450 mg/m² of prior doxorubicin hydrochloride or 900 mg/m² of prior epirubicin hydrochloride
• No more than 2 lines of prior therapy in the metastatic setting
• No prior anti-VEGF monoclonal antibodies, such as bevacizumab or aflibercept
• No prior tyrosine kinase inhibitors with similar targets (e.g., sorafenib tosylate or axitinib)
• No other concurrent investigational agents

• No concurrent therapeutic doses of coumarin-derivative anticoagulants, such as warfarin

  • Warfarin at doses of ≤ 2 mg daily are allowed for prophylaxis of thrombosis
  • Low molecular weight heparin allowed provided PT/INR (Prothrombin time and international normalized ratio) is ≤ 1.5
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent agents with proarrhythmic potential (e.g., terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide, and flecainide)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Sunitinib; Sunitinib 37.5 mg daily for a 4 week cycle	Drug: sunitinib malate; Sunitinib 37.5 mg daily for a 4 week cycle; Other Names: Sutent; SU011248; SU010398; PHA-290940AD; SU011248 L-Malate salt

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival Rate	Complete response, partial response, and stable disease) as assessed by RECIST criteria at 24 weeks	up to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	The Overall Response Rate (ORR) was assessed using Partial Response + Complete Response for patients. Response and progression was evaluated in this study using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.	up to 4 years
Median Overall Survival Time	The median overall survival time will be reported using the 95% confidence intervals for the parameters.	up to 4 years
Median Progression-free Survival Time	Progression free survival was measured as the time from start of treatment to the first measurement of tumor growth.	up to 4 years
Frequency and Severity of Adverse Events	The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was utilized for adverse event reporting.	up to 4 years
Change in Mean Vessel Density	Quantitative assessment of proliferating tumor cells, and apoptosis, of the laboratory and radiographic correlates, the analyses will be purely explorative.	up to 4 years
Quantitative Assessment of Proliferating Tumor Cells and Apoptosis	Biopsy sample taken from patients before and after treatment Apoptosis measures using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, which measures 3' nicked DNA. DNA is degraded in the early steps of apoptosis into low molecular weight (LMW) fragments and the production of single strand breaks in the high molecular weight DNA.Both of these features of apoptosis can be detected by labeling free 3'-OH termini with modified nucleotides, in our case this will be biotin-labeled dUTP. Terminal deoxynucleotidyl transferase (TdT) is an enzyme that labels blunt-ends of DNA breaks and can catalyze polymerization of nucleotides to free 3'-OH DNA ends in a template-independent manner. The newly incorporated nucleotides are detected by a secondary antibody, avidin-peroxidase. After substrate reaction, the stained cells can be detected and counted under a light microscope. Apoptotic cells will be fixed with formaldehyde which links LMW DNA	up to 4 years

Collaborators and Investigators

• Sponsor: Tony Bekaii-Saab
• Collaborators: Pfizer
• Investigators: Principal Investigator: Tanios Bekaii-Saab, MD, Ohio State University

Publications and helpful links

General Publications

• Wu C, Mikhail S, Wei L, Timmers C, Tahiri S, Neal A, Walker J, El-Dika S, Blazer M, Rock J, Clark DJ, Yang X, Chen JL, Liu J, Knopp MV, Bekaii-Saab T. A phase II and pharmacodynamic study of sunitinib in relapsed/refractory oesophageal and gastro-oesophageal cancers. Br J Cancer. 2015 Jul 14;113(2):220-5. doi: 10.1038/bjc.2015.197. Epub 2015 Jul 7.

Helpful Links

• Jamesline

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 30, 2008
• Primary Completion (ACTUAL): September 17, 2013
• Study Completion (ACTUAL): December 30, 2013

Study Registration Dates

• First Submitted: June 19, 2008
• First Submitted That Met QC Criteria: June 19, 2008
• First Posted (ESTIMATE): June 20, 2008

Study Record Updates

• Last Update Posted (ACTUAL): March 21, 2017
• Last Update Submitted That Met QC Criteria: January 31, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: stage IIIA esophageal cancer; stage IIIB esophageal cancer; stage IIIC esophageal cancer; recurrent esophageal cancer; stage IV esophageal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Esophageal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Sunitinib
• Other Study ID Numbers: OSU-07121; NCI-2011-03148 (REGISTRY: Clinical Trials Reporting Program (CTRP))