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