VEGFR/PDGFR Dual Kinase Inhibitor X-82 and Docetaxel in Treating Patients With Solid Tumors
VEGFR/PDGFR Dual Kinase Inhibitor X-82 and Docetaxel in Treating Patients With Solid Tumors
This partially randomized phase I trial studies the side effects and how well sequential
 dosing of vascular endothelial growth factor receptor (VEGFR)/platelet derived growth factor
 receptor (PDGFR) dual kinase inhibitor X-82 and docetaxel works in treating patients with
 solid tumors. VEGFR/PDGFR dual kinase inhibitor X-82 may stop the growth of tumor cells by
 blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as
 docetaxel, work in different ways to stop the growth of tumor cells, either by killing the
 cells, by stopping them from dividing, or by stopping them from spreading. Giving VEGFR/PDGFR
 dual kinase inhibitor X-82 and docetaxel one at a time instead of concurrently may work in
 treating patients with solid tumors.
PRIMARY OBJECTIVES:

 I. To evaluate the safety and tolerability of intermittent X-82 (VEGFR/PDGFR dual kinase
 inhibitor X-82) when administered in a 2 week on, 1 week off schedule (Cycle #1).

 II. To evaluate the safety and tolerability of intermittent X-82 administered in combination
 with docetaxel every 3 weeks (Cycle #2).

 III. To determine the change in vascular parameters using 3'Deoxy-3'-fluorothymidine (FLT)
 positron emission tomography (PET)/computed tomography (CT) to X-82 alone (Cycle #1).

 IV. To determine the change in vascular parameters using FLT PET/CT to X-82 in combination
 with docetaxel (Cycle #2).

 SECONDARY OBJECTIVES:

 I. To determine the objective response using Response Evaluation Criteria In Solid Tumors
 (RECIST) 1.1 of intermittent X-82 with docetaxel.

 II. To measure the change in plasma vascular endothelial growth factor (VEGF) levels with
 changes on FLT PET/CT.

 III. To measure changes in X-82 pharmacokinetics with changes on FLT PET/CT.

 TERTIARY OBJECTIVES:

 I. To evaluate the safety and tolerability of sequential X-82 with docetaxel in disease
 sub-populations. (Dose expansion cohort) II. To evaluate the objective response rate of
 sequential X-82 with docetaxel in these disease sub-populations. (Dose expansion cohort)

 OUTLINE: Patients are randomized to 1of 2 treatment arms.

 ARM I: Patients receive high dose VEGFR/PDGFR dual kinase inhibitor X-82 orally (PO) once
 daily (QD) on days 2-15. Beginning course 2, patients also receive docetaxel intravenously
 (IV) over 60 minutes on day 1.

 ARM II: Patients receive low dose VEGFR/PDGFR dual kinase inhibitor X-82 PO QD on days 2-15
 and docetaxel IV as in Arm I.

 In both arms, courses repeat every 21 days in the absence of disease progression or
 unacceptable toxicity.

 EXPANSION COHORT: Patients receive VEGFR/PDGFR dual kinase inhibitor X-82 as in Arm I and
 docetaxel IV over 60 minutes on day 1. Courses repeat every 21 days in the absence of disease
 progression or unacceptable toxicity.
Inclusion Criteria:

 -  For the pharmacodynamic (PD) cohort, patients must have histologically or
 cytologically confirmed solid malignancy (excluding lymphoma) that is metastatic or
 unresectable; all patients will need to be approved by the principal investigator [PI]
 as certain diseases may not be appropriate for the imaging assessments)

 -  For the dose expansion cohort, patients with histologically or cytologically confirmed
 solid malignancy are eligible for treatment as long as insurance approval for
 docetaxel is obtained.

 -  Patients must have no available therapies that will confer clinical benefit and
 docetaxel is a reasonable treatment option for their malignancy

 -  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 >
 20 mm with conventional techniques or as > 2 times the slice width with spiral CT scan
 (i.e. 10 mm if the CT slice width is 5 mm, 14 mm if the CT slice width is 7 mm)

 -  Life expectancy of greater than 12 weeks

 -  Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1

 -  Leukocytes >= 3,000/mcL

 -  Absolute neutrophil count >= 1,500/mcL

 -  Platelets >= 100,000/mcL

 -  Hemoglobin >= 9 g/dL

 -  Serum calcium =< 12.0 mg/dL

 -  Total serum bilirubin =< institutional upper limit of normal

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 =< 2.5 x institutional upper limit of normal

 -  Creatinine =< 1.5 mg/dL OR creatinine clearance (measured) >= 50 mL/min

 -  Urinary protein =< 2+ by urine analysis; if urine protein is > 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

 -  All patients need to be willing to undergo planned pharmacodynamic assessments,
 including serial PET imaging and pharmacokinetic sampling

 -  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 X-82; 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, radiotherapy, experimental therapy or major
 surgery within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the
 study or those who have not recovered (to grade =< 1 or baseline) from clinically
 significant adverse events due to agents administered more than 4 weeks earlier
 (alopecia and fatigue excluded); clinical significance to be determined by
 investigator

 -  Patients may not be receiving any other investigational agents

 -  Prior anti-VEGF directed therapy may be allowed only if approved by the PI

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to X-82 or docetaxel

 -  Patients with poorly controlled hypertension (systolic blood pressure of 140 mmHg or
 higher or diastolic blood pressure of 90 mmHg or higher) are ineligible; patients with
 a history of hypertension (HTN) and stable blood pressure (BP) < 140/90 on anti-HTN
 regimen are eligible

 -  Patients will be required to have a baseline electrocardiogram (EKG) prior to the
 start of treatment; patients with a corrected QT (QTc) > 480 millisecond (ms) are
 excluded from the study

 -  Patients with any condition (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) that impairs their
 ability to swallow and retain X-82 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
 abscess within 28 days of treatment

 -  Any history of cerebrovascular accident (CVA) or transient ischemic attack within
 12 months prior to study entry

 -  History of myocardial infarction, ventricular arrhythmia, stable/unstable angina,
 symptomatic congestive heart failure, coronary/peripheral artery bypass graft or
 stenting or other significant cardiac disease within 12 months prior to study
 entry

 -  Any history of arterial or venous thrombosis/thromboembolic event, including
 pulmonary embolism within the past 12 months

 -  Any episode of atrial fibrillation in the prior 12 months

 -  Patients without appropriate lesion on CT scan for fluorothymidine (FLT)-PET/CT
 imaging will be excluded

 -  The eligibility of patients taking medications that are potent inducers or inhibitors
 of the 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; any identified agent needs to be stopped at least 2 weeks prior to
 study registration

 -  Patients with known brain metastases should be excluded; patients who had definitive
 treatment for their brain metastases which includes surgical resection/stereotactic
 body radiation therapy (SBRT) with whole brain radiation therapy (WBRT) > 6 months ago
 will be eligible

 -  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
 prior to starting study treatment

 -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
 therapy are ineligible

 -  Patients taking herbal supplements (St. John's Wort, gingko balboa, etc.) should
 discontinue these supplements two weeks prior to study registration

 -  Patients cannot be receiving concomitant chemotherapy, radiotherapy, experimental
 therapy or any other therapy for the purposes of anti-cancer treatment

 -  Subjects must not have clinically significant bleeding (i.e. GI bleed, intracranial
 bleeding) whtin 6 months or have had major surgery within 4 weeks. Minor surgeries
 (i.e. port placement, cataract surgery) are allowed if completed more than within 2
 weeks from the start of treatment.

 -  Any brain metastases must be stable and not progressing prior to study entry

 -  Patients with prior malignancy except for the following:

 -  Adequately treated basal cell or squamous cell skin cancer

 -  In situ cervical cancer

 -  Adequately treated Stage I or II cancer from which the patient is currently in
 complete remission and has been disease free for the past 2 years

 -  Any other cancer from which the patient has been disease-free for 5 years