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• W2955003497 abstract "Abstract Background: PAC-1 is a small molecule that directly activates procaspase-3 and induces apoptosis of cancer cells. PAC-1 crosses the blood-brain-barrier. This first-in-human, phase I, multicenter study consists of 2 components. Component 1 evaluated safety, pharmacokinetics (PK), and preliminary clinical activity of single agent PAC-1 in patients with solid tumors or lymphoma. Component 2 combines PAC-1 with temozolomide in patients with refractory high-grade astrocytomas. Methods: Patients with metastatic solid tumors or lymphomas were enrolled in component 1 and patients with refractory high-grade astrocytomas were enrolled in component 2. A modified- Fibonacci dose-escalation 3+3 design was used in both components. The primary objective was to assess maximum tolerated dose (MTD). In component 1, PAC-1 was dosed from 75 to 750 mg daily orally (7 dose levels (DL)) on days 1-21 on 28 days cycle. For all dose cohorts, PAC-1 PK was assessed following doses administered on days 1 and 21 of the first cycle. In component 2, PAC-1 is dosed from 375 to 750 mg daily (up to 4 DL) plus temozolomide orally 150 mg/m2 daily for 5 days. PAC-1 PK was assessed following doses administered on days 7 and 12 and temozolomide PK is performed on Day 12 of the first cycle. Disease assessment was done every 2 cycles. Neurologic and neurocognitive function (NNCF) tests were performed throughout the study due to concern for neurotoxicity. Results: Forty-four patients were enrolled in part 1 and 12 in component 2. In part 1, at DL 1-5 no dose-limiting toxicities (DLTs) were observed. DL 6 was expanded to 6 patients due to one episode of intracranial bleed that occurred during cycle 4 of treatment, assessed initially as possibly related to study drug, but later attributed to new brain metastasis and unrelated to PAC-1. Grade 1 and 2 neurological adverse events such as ataxia and hallucinations were noted in DL 7 and this DL was expanded to 9 patients to assure safety. All other serious adverse events were determined to be unrelated or unlikely related to the study drug. Eleven patients (25%) did not complete 2 cycles of treatment due to rapid progression or withdrawal. Eight patients (18%) had stable disease for at least 2 cycles. One patient (2%) had partial response. In component 2 treating refractory high-grade astrocytomas, 7 patients were accrued to DL 1, and 5 patients to DL 2. No DLT was observed. Nine patients were evaluable for response. Five patients (42 %) had disease progression. Two patients (16%) had stable disease for at least 2 cycles, and two (16%) had partial response. Review of NNCF testing showed a consistent pattern of stable neurologic and cognitive evaluations. The PK data demonstrated satisfactory systemic delivery of PAC-1 following oral administration and acceptable absorption and elimination profiles. Conclusions: Single agent PAC-1 is well tolerated and 750 mg was determined to be the MTD. The combination of PAC-1 plus temozolomide continues to enroll patients in this study. Citation Format: Oana C. Danciu, M. Kelly Nicholas, Matthias Holdhoff, Richard A. Peterson, Neeta Venepalli, Rozina Chowdhery, Paul J. Hergenrother, Theodore M. Tarasow, Arkadiusz Z. Dudek. Phase I study of procaspase activating compound -1 (PAC-1) in the treatment of advanced malignancies and in combination with temozolomide in refractory high-grade astrocytomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT027." @default.
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• W2955003497 date "2019-07-01" @default.
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• W2955003497 title "Abstract CT027: Phase I study of procaspase activating compound -1 (PAC-1) in the treatment of advanced malignancies and in combination with temozolomide in refractory high-grade astrocytomas" @default.
• W2955003497 doi "https://doi.org/10.1158/1538-7445.am2019-ct027" @default.
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