VEGFR/PDGFR Dual Kinase Inhibitor X-82 and Docetaxel 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