Study of the Pan-DAC Inhibitor AR-42 and Pazopanib in Advanced Sarcoma and Kidney Cancer
Condition: Renal Cell Carcinoma; Soft Tissue Sarcoma; Metastatic Disease
MeSH terms: Carcinoma; Sarcoma; Carcinoma, Renal Cell; Neoplasm Metastasis
Intervention: AR-42; Pazopanib
Intervention description: AR-42 tablets were taken orally once per day on 3 non-consecutive days during the first 3 weeks of each 4-week cycle. If treatment was interrupted during the cycle, the cycle was to be extended; Pazopanib tablets were taken orally once daily continuously during each 4-week treatment cycle. There were no scheduled breaks in pazopanib therapy
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility 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