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

This study is a single-arm, open-label, phase 1 trial to determine the RP2Ds of AR-42 and
pazopanib when given in combination to patients with advanced Renal Cell Carcinoma (RCC) or
Soft Tissue Sarcoma (STS). Eligible patients will have recurrent, unresectable, or metastatic
RCC or STS for which pazopanib is an appropriate therapy.

AR-42 will be taken orally once per day on 3 non-consecutive days each week during the first
3 weeks of each 4-week cycle. Pazopanib will be taken by mouth once daily continuously during
each cycle.

A modified 3+3 dose-escalation design will be followed until the maximum tolerated doses
(MTDs) have been determined. Additional patients will be enrolled until a total of 12
patients have been treated at the MTDs. The maximum number of patients needed is 51 with an
expected sample size of 29-35 patients enrolled over a period of about 15-35 months.

Correlative studies will be conducted using samples of tumor that were archived following the
most recent surgery or biopsy.

Inclusion Criteria:

- Recurrent, unresectable, or metastatic Renal Cell Carcinoma (RCC) or Soft Tissue
Sarcoma (STS) (any histologic type) for which pazopanib is 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 are 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 is < 60 years of age
and has not had a hysterectomy, must have a documented negative serum pregnancy test
within 7 days prior to initiating study treatment

- A WCBP and a male patient with a partner who is a WCBP must agree 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 understand and willingness to sign 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 meets exclusion criteria:

- Check calcium, potassium, and magnesium serum levels.

- Correct any identified hypocalcemia, hypokalemia, and/or hypomagnesemia and
repeat ECG to confirm exclusion of patient due to prolonged QTc interval.

- For patients with heart rate (HR) 60-100 bpm, manual read of QTc is not required.

- For patients with a baseline HR < 60 bpm or > 100 bpm, manual read of the QT
interval by a cardiologist is 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 should not be 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 causes 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 increase the patient's risk or limit the patient's adherence with study
requirement