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

• Status: Terminated
• Trial end date: 2019-03-14
• Target enrollment: 0
• Participant gender: All

Summary

This phase 1 study was developed to identify recommended phase 2 doses (RP2Ds) of AR-42 and pazopanib when given in combination for subsequent clinical trials and may have potentially identified candidate pharmacodynamic and predictive biomarkers.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Virginia Commonwealth University
• Collaborators: Arno Therapeutics; National Cancer Institute (NCI)

Criteria

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