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

Metastatic Disease, Renal Cell Carcinoma, Soft Tissue Sarcoma

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.

This study was a single-arm, open-label, dose escalation 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 had recurrent, unresectable, or metastatic RCC or STS for which pazopanib was an appropriate therapy. AR-42 was taken orally once per day on 3 non-consecutive days each week during the first 3 weeks of each 4-week cycle. Pazopanib was taken by mouth once daily continuously during each cycle. A modified 3+3 dose-escalation design was to be followed until the maximum tolerated doses (MTDs) were determined. The initial cohort of patients were assigned to an AR-42 dose of 20 mg taken once per day on 3 non-consecutive days during the first 3 weeks of each 4-week cycle and a pazopanib dose of 600 mg once daily continuously. Additional patients would be enrolled until a total of 12 patients were treated at the MTDs. The protocol specifies a dose escalation plan that initially impacts only the pazopanib dose. The starting dose of pazopanib (600 mg) was planned to be escalated early so that the FDA-approved full dose of pazopanib (800 mg) would be reached before escalating the AR-42 dose. In subsequent dose-escalation steps, the dose of AR-42 was planned to be increased in 10-mg increments from a starting dose of 20 mg to a maximum dose of 40 mg. If the number of Dose-Limiting Toxicities (DLT) showed that the MTD was exceeded with a pazopanib dose of 800 mg , the pazopanib dose was planned to be decreased to 600 mg and the AR-42 dose increased in 10-mg increments regardless of relationship of the DLT to one or both study medications. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0). The DLT evaluation period was the first treatment cycle. A minimum of 6 doses of AR-42 and 21 doses of pazopanib were required for a patient to be DLT-evaluable (if DLT was not observed with the delivered dose). DLT was defined as any ≥ grade 3 toxicity occurring during the DLT evaluation period and attributed to one or both of the study medications EXCEPT the following: * The first incidence of grade 3 PPE at any dose level (subsequent incidences of grade 3 PPE will be considered DLT) * Grade 3 nausea and vomiting in the absence of adequate prophylaxis and/or responsive to medical management within 48 hours * Grade 3 diarrhea in the absence of adequate prophylaxis and/or responsive to medical management within 48 hours * Grade 3 fatigue responsive to medical management • Grade 3 asymptomatic hypertension lasting ≤ 7 days * Grade 3 electrolyte abnormalities that are corrected within 48 hours and, when corrected, can be maintained * Grade 3 asymptomatic lipase elevation lasting ≤ 7 days * Grade 3 decrease in platelet count if no clinically significant hemorrhage has occurred * Grades 3 and 4 decrease in white blood cell count * Grade 3 decrease in neutrophil count * Grade 4 decrease in neutrophil count lasting ≤ 7 days * Grades 3 and 4 decrease in lymphocyte count Dose escalation was planned to continue until the maximum-tolerated dose (MTD), defined as one dose level below the dose in which dose-limiting toxicities (DLTs) are observed in \>1 of the participants (e.g., in at least 2 participants in a cohort of at least 3). In the cohort of 12 patients at the MTD, no more than 3 DLTs were allowed to confirm the MTD. The RP2D was defined as equal to or less than the MTD, with an allowance to consider an RP2D below the MTD given the overall tolerability of the regimen including the frequency of AEs that were not DLTs and the frequency of dose modifications.

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