Axitinib (AG-013736) in Patients With Progressive, Recurrent/Metastatic Adenoid Cystic Carcinoma

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to find out what effects, good and/or bad, a new treatment called axitinib has on the patient and adenoid cystic carcinoma. This type of cancer study is called a phase II study. Axitinib is an oral medication that can interfere with cancer cell growth and reduce the growth of blood vessels around tumors. This study will help find out if axitinib is a useful drug for treating patients with adenoid cystic carcinomas. Axitinib is an experimental drug that has not yet been approved by the Food and Drug Administration for use in adenoid cystic carcinoma.

Official Title
-----------------
A Phase II Study of Axitinib (AG-013736) in Patients With Progressive, Recurrent/Metastatic Adenoid Cystic Carcinoma

Conditions
-----------------
Adenoid Cystic Carcinoma

Intervention / Treatment
-----------------
* Drug: AG-013736 (AXITINIB)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have MSKCC pathologically confirmed adenoid cystic carcinoma. Cancers arising from non-salivary gland primary sites are allowed. Patients must have locally advanced and/or recurrent and/or metastatic disease not amenable to potentially curative surgery or radiotherapy. At least 2 weeks must have elapsed since the end of prior systemic treatment (4 weeks for bevacizumab- containing regimens), radiotherapy, or surgical procedure with resolution of all treatment-related toxicity to NCI CTCAE Version 4.0 grade ≤1 (or tolerable grade 2) or back to baseline except for alopecia or hypothyroidism. Patients must have RECIST v1.1 measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as > or = to 20 mm with conventional techniques or as > or = to 10 mm with spiral CT scan. Patients must have documentation of a new or progressive lesion on a radiologic imaging study performed within 6 months prior to study enrollment (progression of disease over any interval is allowed) and/or new/worsening disease related symptoms. Note: This assessment will be performed by the treating investigator. Evidence of progression by RECIST criteria is not required. Patients must have archival tissue from the primary tumor or metastases available for correlative studies. Either a paraffin block or twenty unstained slides containing 5μm sections are acceptable. If twenty slides are not available, a lesser amount may be acceptable after discussion with the study Principal Investigator, Dr. Alan L. Ho. Male or female, age > or = to 18 years. ECOG performance status < or = to 2 (Karnofsky > or = to 60%, see Appendix A). Life expectancy of ≥ 12 weeks. Adequate organ function as defined by the following criteria: absolute neutrophil count (ANC) > 1000 cells/mm3 platelets > or = to 75,000 cells/mm3 Hemoglobin > or = to 9.0 g/dL AST and ALT < or = to 2.5 x upper limit of normal (ULN), unless there are liver metastases in which case AST and ALT < 5.0 x ULN Total bilirubin < or = to 1.5 x ULN Serum creatinine < or = to 1.5 x ULN or calculated creatinine clearance > or = to 60 ml/min Urinary protein < 2+ by urine dipstick. If dipstick is > or = to 2+ then a 24-hour urine collection can be done and the patient may enter only if urinary protein is < 2 g per 24 hours. Women of child-bearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 6 months after discontinuing study treatment. Exclusion Criteria: Major surgery < 2 weeks or radiation therapy < 2 weeks of starting the study treatment. Gastrointestinal abnormalities including: inability to take oral medication; malabsorption syndromes. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (i.e., grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine) Current use or anticipated need for treatment with drugs that are known CYP3A4 or CYP1A2 inducers (i.e., carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and St. John's wort) Requirement for anticoagulant therapy with oral vitamin K antagonists. Low-dose anticoagulants for maintenance of patency of central venous access devise or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is allowed. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis. A serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment. Any of the following within the 12 months prior to study drug administration: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack and 6 months for deep vein thrombosis or pulmonary embolism. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol. Female patients who are pregnant or lactating. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AG-013736 (AXITINIB)<br>This is a single-arm phase II study evaluating the clinical efficacy of axitinib in the treatment of patients with progressive, recurrent/metastatic adenoid cystic carcinoma (ACC). | Drug: AG-013736 (AXITINIB)<br>* All eligible patients will receive a starting axitinib dose of 5 mg twice daily (BID) taken orally in 4-week (28-day) cycles. Patients who tolerate axitinib with no adverse events related to study drug above CTCAE v. 4.0 Grade 2 for a consecutive 2-week period may have their dose increased by one dose level according to the discretion of the treating physician (NOT allowed for patients with blood pressure (BP) > 150/90 mm Hg or who are receiving antihypertensive medication). This dose escalation is not mandatory. RECIST v1.1 tumor assessments will be made at baseline (CT or MRI) and then approximately every 2 cycles (or every 8 weeks (+/- 1 week)). After 10 months, imaging will be done every 3 cycles (or every 12 weeks (+/- 1 week)). Patients may remain on study until progression of disease or unacceptable toxicity.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Best overall response rate documented by RECIST v1.1 criteria of patients with progressive, recurrent/metastatic ACC treated with axitinib. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI and/or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease (POD); POD, 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; Complete Response (CR), Disappearance of all target lesions | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival (PFS). | Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 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 | 2 years | 
| MYB Immunohistochemistry (IHC) |  | 2 years | 
| Number of Participants With Next Generation Sequencing (NGS) | Next generation sequencing the t(6;9) translocation (MYBNFIB gene product) status will be analyzed by Fluorescent In-Situ Hybridization (FISH) assay and correlated to clinical response. The number of participants with NGS will be recorded. | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
axitinib (AG-013736), recurrent, metastatic, 12-004