Study of Dovitinib (TKI258) in Adenoid Cystic Carcinoma

Inclusion Criteria:

Patients eligible for inclusion in this study have to meet all of the following criteria:

1. Patients must have histology or cytology studies that confirm the diagnosis of adenoid cystic carcinoma. (Note: Subsequent central review of the pathology slides will be provided by Drs. Christopher Moskaluk or Henry Frierson, Department of Pathology at the University of Virginia Health Sciences Center).

2. Patients must have recurrent and/or metastatic disease that is not amenable to potentially curative surgical resection or radiotherapy.

3. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >10 mm with spiral CT scan (or >20 mm with conventional techniques). Pathologic lymph nodes are measured by shortest diameter as per RECIST.

4. Patients must have serial imaging that allows measurement of tumor growth rates by change point analysis:

1. The remote baseline study scan must be within six calendar months of the immediate pre-study scan.

2. The remote baseline scan must have measurable disease ≥ 10 mm for non-pulmonary lesions or ≥ 4 mm for pulmonary metastases that show subsequent progression.

3. Comparison of the remote baseline and subsequent studies must show progressive disease in 1-5 selected target lesions based on the following:

1. Modified RECIST criteria (i.e. proportional increase of 1.2 or the appearance of new lesions) AND/OR

2. Progression by change point analysis with an increase in the slope of the average tumor measurements of at least 0.22 b

a = "remote baseline scan" refers to scan done prior to pre-study scan which is used to determine pre-treatment tumor growth rate.

b = the estimated mean minus one standard deviation based on analysis of progressive tumors from untreated patients with ACC.

5. Life expectancy > 16 weeks.

6. ECOG (WHO) performance status 0-2

7. Age ≥ 18 years old

8. Patients must have the following laboratory values:

- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

- Platelets ≥ 100 x 109/L

- Hemoglobin (Hgb) > 9 g/dL

- Serum total bilirubin: ≤ 1.5 x ULN

- ALT and AST ≤ 3.0 x ULN

- Serum creatinine ≤ 1.5 x ULN or serum creatinine >1.5 - 3 x ULN if calculated creatinine clearance (CrCl) is ≥ 30 mL/min using the Cockroft-Gault equation, see formula below:

CrCl = [140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)] (if patient is female multiply the above by 0.85)

9. Patients who give a written informed consent obtained according to local guidelines

Exclusion Criteria:

Patients are ineligible for this study if he or she has any of the following:

1. Patients with brain metastases

2. Patients with another primary malignancy within 3 years prior to starting study drug, with the exception of adequately treated in-situ carcinoma of the uterine cervix, or skin cancer (such as basal cell carcinoma, squamous cell carcinoma, or non-melanomatous skin cancer)

3. Patients who have received the last administration of an anticancer therapy including chemotherapy, immunotherapy, hormonal therapy and monoclonal antibodies (but excluding nitrosurea, mitomycin-C, targeted therapy and radiation) ≤ 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy

4. Patients who have received the last administration of nitrosurea or mitomycin-C ≤ 6 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy

5. Patients who have received targeted therapy (e.g. sunitinib, sorafenib, pazopanib) ≤ 2 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy

6. Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug or ≤ 2 weeks prior to starting study drug in the case of localized radiotherapy (e.g. for analgesic purpose or for lytic lesions at risk of fracture), if the measurable lesions are outside the radiation field. Also excluded would be those who have not recovered from toxicity radiotherapy.

7. Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury

8. Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:

- Impaired cardiac function or clinically significant cardiac diseases, including any of the following:

- History or presence of serious uncontrolled ventricular arrhythmias

- Clinically significant resting bradycardia

- LVEF assessed by 2-D echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) < 45%

- Any of the following within 6 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism (PE)

- Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication(s)

1. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of dovitinib (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)

2. Cirrhosis, chronic active hepatitis or chronic persistent hepatitis

3. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)

4. Patients who are currently receiving anticoagulation treatment with therapeutic doses of warfarin

5. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol

9. Pregnant or breast-feeding women

10. Women of child-bearing potential not employing an effective method of birth control. Two birth control methods must be used throughout the trial and one month after the last dose of study drug (e.g. condom with spermicidal jelly, foam suppository or film; diaphragm with spermicide; male condom and diaphragm with spermicide). Contraceptives that are affected by cytochrome P450 interactions (e.g. oral, implantable, injectable, or intrauterine hormonal contraceptives) are not considered effective for this study. Women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 7 days prior to starting study drug.

11. Fertile males not willing to use contraception, as stated above

12. Patients unwilling or unable to comply with the protocol