Study of the Pan-DAC Inhibitor AR-42 and Pazopanib in Advanced Sarcoma and Kidney Cancer

Inclusion Criteria:

* Recurrent, unresectable, or metastatic Renal Cell Carcinoma (RCC) or Soft Tissue Sarcoma (STS) (any histologic type) for which pazopanib was an appropriate therapy
* Measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
* Age ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Adequate bone marrow function as defined below:

  * Absolute neutrophil count (ANC) ≥ 1200/mm3
  * Platelets ≥ 120,000/mm3
  * Hemoglobin ≥ 9.5 g/dL
* Adequate renal function as defined below:

  * Creatinine ≤ 1.5 x upper limit of normal (ULN) for the laboratory or calculated or actual creatinine clearance ≥ 60 mL/min
  * Proteinuria ≤ 2+ \[100 mg/dL\] (using a random urine sample or \< 3.0 gm using a 24-hour sample) (Note: If urine sample indicates ≥ 2+ \[100 mg/dL\]), a 24-hour urine sample must be collected and tested; urine protein in the 24-hour sample must be \< 3.0 gm/24 hours.)
* Adequate hepatic function as defined below:

  * Total bilirubin ≤ 1.5 x ULN for the laboratory (Note: Patients with known Gilbert's Syndrome were not eligible for this study)
  * Aspartate aminotransferase (AST) ≤ 2.5 x ULN for the laboratory
  * Alanine aminotransferase (ALT) ≤ 2.5 x ULN for the laboratory
* Non-hematologic toxicities from previous cancer therapies resolved to ≤ grade 1
* International normalized ratio (INR) ≤ 1.5
* Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN for the laboratory
* Left ventricular ejection fraction (LVEF) assessment (eg, echocardiogram, MUGA scan, first-pass technique) performed within 3 months prior to initiation of study treatment indicates an LVEF of ≥ 50%
* A woman of childbearing potential (WCBP), defined as a woman who was \< 60 years of age and had not had a hysterectomy, must have had a documented negative serum pregnancy test within 7 days prior to initiating study treatment
* A WCBP and a male patient with a partner who was a WCBP must have agreed to use a medically accepted method for preventing pregnancy for the duration of study treatment and for 2 months following completion of study treatment
* Ability to have understood and willingness to have signed the consent form

Exclusion Criteria:

* Symptomatic or untreated brain metastasis
* Leptomeningeal metastasis
* Any investigational agent within 4 weeks prior to initiating study treatment
* Previous therapy with pazopanib
* Inability to swallow medication
* Known or suspected malabsorption condition or obstruction
* Contraindication to antiangiogenic agents, including:

  * Serious non-healing wound, non-healing ulcer, or bone fracture
  * Major surgical procedure or significant traumatic injury within 4 weeks prior to initiating study treatment; other surgical procedures within 2 weeks prior to initiating study treatment
  * Pulmonary hemorrhage/bleeding event ≥ grade 2 within 12 weeks prior to initiating study treatment
  * Any other hemorrhage/bleeding event ≥ grade 3 within 12 weeks prior to initiating study treatment
* History of organ allograft including corneal transplant
* Evidence of bleeding diathesis or coagulopathy
* Documented Gilbert's Syndrome
* Resting systolic blood pressure (BP) \< 100 mmHg
* Hypertension defined as systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg despite optimal medical management
* QTc interval \> 450 ms on screening 12-lead electrocardiogram (ECG)

  * If baseline QTc on screening ECG met exclusion criteria:

    * Check calcium, potassium, and magnesium serum levels.
    * Correct any identified hypocalcemia, hypokalemia, and/or hypomagnesemia and repeat ECG to reconfirm exclusion of patient due to prolonged QTc interval.
  * For patients with heart rate (HR) 60-100 bpm, manual read of QTc was not required.
  * For patients with a baseline HR \< 60 bpm or \> 100 bpm, manual read of the QT interval by a cardiologist was required, with Fridericia correction applied to determine QTc (ie, QTcF).
* Active or clinically significant cardiac disease including any of the following:

  * Unstable angina (eg, anginal symptoms at rest) or onset of angina within 3 months prior to initiating study treatment
  * Myocardial infarction within 6 months prior to initiating study treatment
  * Cardiac arrhythmias currently requiring anti-arrhythmic therapy other than beta blockers
* Any documented history of clinically significant thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or pulmonary embolism necessitating therapeutic anticoagulation within 6 months prior to initiating study treatment (Note: Patients with a tumor-associated thrombus of locally-involved vessels were not excluded from participating in the study.)
* Active infection requiring treatment or chronic infection requiring suppressive therapy
* Chronic or active hepatitis B or C infection requiring treatment with antiviral therapy
* Pleural effusion or ascites that caused respiratory compromise (eg, ≥ grade 2 dyspnea)
* Required ongoing treatment with other drugs thought to potentially have adverse interactions with either of the medications included in the study treatment; if such medications have been used, patients must have discontinued these agents at least 1 week prior to initiating study treatment. Examples include:

  * Strong CYP3A4 inhibitors and/or strong CYP3A4 inducers; the reference list of CYP isozymes and classification of strong, moderate, and weak interactions are available through the Food and Drug Administration (FDA website.
  * Strong inhibitors of P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP); the reference list of strong inhibitors of P-gp and BCRP.
  * Simvastatin and other HMG-CoA reductase inhibitors (ie, statins)
  * Drugs that raise gastric pH including proton pump inhibitors and H2-blockers (Note: Short-acting antacids, in place of PPIs and H2-blockers, are permitted.)
  * HDAC inhibitors
* Pregnancy or breastfeeding
* Medical, psychological, or social condition that, in the opinion of the investigator, may have increased the patient's risk or limit the patient's adherence with study requirement