Dovitinib Lactate, Gemcitabine Hydrochloride, and Capecitabine in Treating Patients With Advanced or Metastatic Solid Tumors, Pancreatic Cancer and Biliary Cancers

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose and recommended phase II dose of dovitinib
(dovitinib lactate) when administered concurrently with gemcitabine (gemcitabine
hydrochloride) and capecitabine in patients with advanced solid malignancies.

II. To characterize the safety profile of dovitinib, gemcitabine and capecitabine
combination in patients with advanced solid malignancies.

SECONDARY OBJECTIVES:

I. To characterize the pharmacokinetic profile of dovitinib, capecitabine, gemcitabine and
their metabolites when administered concurrently in patients with advanced solid
malignancies.

II. To determine the preliminary efficacy of the study combination in patients with advanced
adenocarcinoma of the pancreas or biliary tract.

III. To explore serum and tumor biomarkers predictive of efficacy to the study combination.

OUTLINE: This is a dose-escalation study of dovitinib lactate.

Patients receive dovitinib lactate orally (PO) on days 1-5, 8-12, and 15-19, gemcitabine
hydrochloride intravenously (IV) over 30 minutes on days 1 and 8, and capecitabine PO twice
daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks and then every 3
months for 1 year.

Inclusion Criteria:

- Part A: histologically or cytologically confirmed solid tumors that ale advanced or
metastatic that the gemcitabine combination is considered standard therapy or a
rational option

- Part B: histologically or cytologically confirmed adenocarcinoma of the pancreas or
the biliary tract (cholangiocarcinoma)that is advanced or metastatic

- Part B: must have tumor lesions amenable to safe biopsy and willing to consent to
tumor biopsies

- Patients with at least one measurable site of disease as defined by Response
Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 that have not been
previously irradiated

- Eastern Cooperative Oncology Group (ECOG) Performance Status =< 1

- Life expectancy >= 3 months

- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3

- Platelets >= 100,000 cells/mm^3

- Hemoglobin >= 9.0 g/dL

- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) =< 1.5 x
Upper Limit of Normal (ULN)

- Bilirubin =< 1.5 x ULN

- Serum creatinine =< 1.5 x ULN

- International normalized ratio (INR) =< 1.5 (anticoagulation is allowed if target INR
=< 1.5 on a stable dose of warfarin or on a stable dose of low-molecular-weight
heparin (LMW) heparin for > 2 weeks at the first dose of study agent);if urinalysis
shows proteinuria, 24 hour urine collection is to be performed and the 24 hour urine
protein is to be < 2 grams to be eligible

- Willing and able to take oral medication, comply with scheduled visits, treatment
plan and laboratory tests

- Ability to understand and willingness to sign a written informed consent, a signed
informed consent must be obtained prior to any specific procedures

Exclusion Criteria:

- Part B: Patients with history of another malignancy within the last three years prior
to study entry, with 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)

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

- Patients who have received the last administration of nitrosourea or mitomycin-C =< 6
weeks prior to starting study drug, or who have not recovered from the side effects
of such therapy

- 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

- Patients who have had radiotherapy =< 4 weeks prior to starting study drug, or =<
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), or who have not
recovered from radiotherapy toxicities

- 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

- History or presence of serious uncontrolled ventricular arrhythmias or presence of
serious uncontrolled atrial fibrillation

- Clinically significant resting bradycardia

- Known left ventricular ejection fraction (LVEF) assessed by 2-D echocardiogram (ECHO)
< 50% or lower limit of normal (whichever is higher) or multiple gated acquisition
scan (MUGA) < 45% or lower limit of normal (whichever is higher)

- Any of the following within 6 months prior to study entry: 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 systolic blood pressure (SBP) of >= 160 mm Hg
and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without anti-hypertensive
medication

- Previous pericarditis; clinically significant pleural effusion in the previous 12
months or current ascites requiring two or more interventions/month

- Any active gastrointestinal (GI) impairment which, in the opinion of the
investigator, would impair or alter the absorption of dovitinib (e.g. ulcerative
colitis, or Crohn's disease)

- Positive hemoccult test result within 14 days prior to the start of study treatment

- Cirrhosis, chronic active hepatitis or chronic persistent hepatitis

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

- Patients who are currently receiving oral anticoagulation treatment with therapeutic
doses of warfarin with goal INR >= 1.5; patients receiving anticoagulation by
subcutaneous injection such as heparin, enoxaparain, fondaparinix that are not
expected to interact with study medications will be eligible

- History of alcoholism, drug addiction, or any psychiatric or psychological condition
which, in the opinion of the investigator, would impair study compliance

- Uncontrolled diarrhea >= Common Terminology Criteria for Adverse Events (CTCAE) grade
2

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

- Pregnant or breast-feeding women

- 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 (e.g., who has had menses any time in the preceding 12
consecutive months), must have a negative serum pregnancy test =< 3 days prior to
starting study treatment

- Women of child-bearing potential, who are biologically able to conceive, not
employing two forms of highly effective contraception; male not using at least at
least one form of highly effective contraception will be excluded; highly effective
contraception (e.g. male condom with spermicide, diaphragm with spermicide,
intra-uterine device) must be used by both sexes during the study and must be
continued for 8 weeks after the end of study treatment; oral, implantable, or
injectable contraceptives may be affected by cytochrome P450 interactions, and are
therefore not considered effective for this study

- Patients with known brain metastases or who have signs/symptoms attributable to brain
metastases and have not been assessed with radiologic imaging to rule out the
presence of brain metastases