Dasatinib in Treating Patients With Recurrent or Metastatic Malignant Salivary Gland Tumors

Phase 2

Completed

Conditions: Salivary Gland Adenoid Cystic Carcinoma
Stage IV Major Salivary Gland Cancer AJCC v7
Malignant Salivary Gland Neoplasm
Recurrent Salivary Gland Carcinoma

Interventions: Drug: Dasatinib
Other: Laboratory Biomarker Analysis

Registration Number: NCT00859937

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial is studying how well dasatinib works in treating patients with malignant salivary gland tumors that have come back after treatment or have spread to other parts of the body. Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description: PRIMARY OBJECTIVES:

I. Determine the objective response rate (complete response plus partial response) of dasatinib in adenoid cystic carcinoma (ACC).

II. Determine the progression-free survival of dasatinib in ACC.

SECONDARY OBJECTIVES:

I. Determine the duration of response. II. Determine the stable disease rate and duration of stable disease. III. Determine progression-free survival. IV. Determine the median survival. V. Determine the overall survival. VI. Determine the safety and tolerability.

TERTIARY OBJECTIVES:

I. To examine biomarkers that relate to SRC proto-oncogene, non-receptor tyrosine kinase (Src) signal transduction and to correlate these biomarkers with clinical response to dasatinib in ACC and non-ACC malignant salivary gland tumors (MSGT).

II. Determine if activating mutations in platelet-derived growth factor alpha polypeptide (PDGFA) and KIT are associated with response in ACC.

OUTLINE:

Patients receive dasatinib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed at 8 weeks.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 55

Inclusion Criteria

Histologically or cytologically confirmed malignant salivary gland tumor (MSGT), including one of the following histologic subtypes:
- Adenoid cystic carcinoma (ACC) with c v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (Kit) overexpression or non-ACC MSGT that is not amenable to potentially curable surgery or radiation
  - c-KIT overexpression in ACC patients is defined as cluster of differentiation (CD) 117 staining by immunohistochemistry (IHC) in 25% of tumor cells
  - No stipulation for c-KIT overexpression is not required for non-ACC MSGT patients
Patients must have radiographically measurable disease; radiographically measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan
Patients must have evidence of disease progression (objective growth of existing tumors) within 4 months of study entry
No known brain metastases, unless patient meets both of the following criteria:
- Neurologic status stable for >= 8 weeks after completion of definitive local therapy (surgery or radiotherapy)
- No neurologic dysfunction that would confound study results
Life expectancy greater than 12 weeks
Eastern Cooperative Oncology Group (ECOG) performance status 0-2 OR Karnofsky performance status (PS) >= 60%
Leukocytes >= 3,000/mcL
Absolute neutrophil count (ANC) >= 1,500/mcL
Platelet >= 100,000/mcL
Hemoglobin >= 9 g/dL
Serum calcium =< 12.0 mg/dL
Total serum bilirubin within normal institutional limits
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x institutional upper limit of normal
Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; all women of childbearing potential must have a negative pregnancy test prior to receiving dasatinib; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; at least 4 weeks must have elapsed since any major surgery
Patients may not be receiving any other investigational agents
No prior treatment with any other targeted agents that inhibit vascular endothelial growth factor receptor (VEGFR), Breakpoint cluster region (BCR) ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL), c-Src, c-KIT, platelet-derived growth factor (PDGF) beta receptor, or ephrin type-A receptor 2 (EPHA2) (e.g., imatinib mesylate)
History of allergic reactions attributed to compounds of similar chemical or biologic composition to dasatinib
Patients with corrected QT interval (QTc) prolongation (defined as a QTc interval equal to or greater than 500 msec), serious ventricular arrhythmia (ventricular fibrillation or ventricular tachycardia greater than or equal to 3 beats in a row) or other significant echocardiogram (ECG) abnormalities are excluded
Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication, requirement for intravenous [IV] alimentation, or active peptic ulcer disease) that impairs their ability to swallow and retain dasatinib tablets are excluded
Patients with any of the following conditions are excluded:
- Serious or non-healing wound, ulcer, or bone fracture
- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscesses within the past 28 days
- Any history of cerebrovascular accident (CVA) or transient ischemic attack within the past 12 months
- History of myocardial infraction, cardiac arrhythmia, stable/unstable angina, symptomatic congestive heart failure, or coronary/peripheral artery bypass graft or stenting within the past 6 months
- History of pulmonary embolism within the past 12 months
- Ejection fraction less than institutional normal by echocardiograph (only required for patients with a known history of congestive heart failure, low ejection fraction, or clinical symptoms/findings consistent with congestive heart failure)
Patients taking medications that are potent inducers or inhibitors of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) liver enzyme will be determined following a review of their case by the Principal Investigator; every effort should be made to switch patients taking such agents or substances to other medications
Patients with known brain metastases should be excluded; patients with brain metastases with stable neurologic status following local therapy (surgery or radiation) for at least 8 weeks from definitive therapy and without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events are eligible for participation; patients cannot be receiving enzyme inducing anti-convulsants including carbamazepine, phenobarbital, and phenytoin
Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infections or psychiatric illness/social situations that would limit compliance with study requirements are ineligible
Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with dasatinib
Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
Patients who have an active pleural or pericardial effusion of any grade
Diagnosis of any second malignancy within the last 5 years; basal cell carcinoma, squamous cell skin cancer, stage I carcinoma fully treated, or in situ carcinoma that have been adequately treated with no evidence of recurrent disease for 12 months will be eligible

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	Laboratory Biomarker Analysis	Patients receive dasatinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm I	Dasatinib	Patients receive dasatinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival	up to 5 years	Progression-free survival from start of treatment to the time of disease progression or death from any cause was estimated using the Kaplan-Meier method.
Response Rate	Up to 2 months	Response rate is percentage of the best overall response which recoded from the start of the treatment until diseases progression/recurrence. Response criteria are defined using the international criteria proposed by the Response Evaluation Criteria In Solid Tumors (RECIST) Committee: Complete Response, Disappearance of all target lesions; Partial Response, \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease, neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, no occurrence of progression disease for non-target lesions, and no new lesions.

Secondary Outcome Measures

Name	Time	Method
Changes in Laboratory Correlates	Baseline and 4 weeks	Changes in laboratory correlates pre-post therapy will be analyzed using paired t-tests. The association between RET gene rearrangements/mutations and tumor response, as well as the association between germ-line polymorp response, will be analyzed using Fisher's exact test. The correlative and genetic data will also be entered as cova only due to the small sample size) in a Cox regression model of progression-free survival.
Overall Survival	Up to 5 years	Kaplan-Meier curves will be generated and 90% confidence intervals will be derived.

Trial Locations

Locations (34): Tower Cancer Research Foundation
🇺🇸
Beverly Hills, California, United States
Joliet Oncology-Hematology Associates Limited
🇺🇸
Joliet, Illinois, United States
Ingalls Memorial Hospital
🇺🇸
Harvey, Illinois, United States
City of Hope Comprehensive Cancer Center
🇺🇸
Duarte, California, United States
Mount Sinai Hospital
🇺🇸
New York, New York, United States
Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States
Illinois CancerCare-Peoria
🇺🇸
Peoria, Illinois, United States
Mercy Hospital Saint Louis
🇺🇸
Saint Louis, Missouri, United States
Montefiore Medical Center-Wakefield Campus
🇺🇸
Bronx, New York, United States
Oncology Care Associates PLLC
🇺🇸
Saint Joseph, Michigan, United States
Central Illinois Hematology Oncology Center
🇺🇸
Springfield, Illinois, United States
USC / Norris Comprehensive Cancer Center
🇺🇸
Los Angeles, California, United States
Fort Wayne Medical Oncology and Hematology Inc-Parkview
🇺🇸
Fort Wayne, Indiana, United States
Emory University Hospital/Winship Cancer Institute
🇺🇸
Atlanta, Georgia, United States
Decatur Memorial Hospital
🇺🇸
Decatur, Illinois, United States
NorthShore University HealthSystem-Evanston Hospital
🇺🇸
Evanston, Illinois, United States
Loyola University Medical Center
🇺🇸
Maywood, Illinois, United States
Northern Indiana Cancer Research Consortium
🇺🇸
South Bend, Indiana, United States
University of Maryland/Greenebaum Cancer Center
🇺🇸
Baltimore, Maryland, United States
University of Pittsburgh Cancer Institute (UPCI)
🇺🇸
Pittsburgh, Pennsylvania, United States
M D Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University Health Network-Princess Margaret Hospital
🇨🇦
Toronto, Ontario, Canada
Vanderbilt University/Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Mercy UC Davis Cancer Center
🇺🇸
Merced, California, United States
CHUM-Hotel Dieu de Montreal
🇨🇦
Montreal, Quebec, Canada
Fox Chase Cancer Center
🇺🇸
Philadelphia, Pennsylvania, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
University of Michigan Comprehensive Cancer Center
🇺🇸
Ann Arbor, Michigan, United States
Froedtert and the Medical College of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
London Regional Cancer Program
🇨🇦
London, Ontario, Canada
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States