Phase I study of procaspase activating compound -1 (PAC-1) in the treatment of advanced malignancies.

Authors

null

Oana Cristina Danciu

University of Illinois at Chicago, Chicago, IL

Oana Cristina Danciu , Martin Kelly Nicholas , Matthias Holdhoff , Neeta K. Venepalli , Paul J. Hergenrother , Theodore M Tarasow , Arkadiusz Z. Dudek

Organizations

University of Illinois at Chicago, Chicago, IL, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, Vanquish Oncology Inc, Champaign, IL

Research Funding

Pharmaceutical/Biotech Company

Background: Members of the caspase family of cysteine proteases are key players in both the initiation and execution of apoptosis; the activation of procaspase-3 to caspase-3 is a critical event in the apoptotic cascade. Procaspase-3 levels are elevated in: glioblastoma, breast cancer, colon cancer, lung cancer, lymphoma, neuroblastoma, melanoma, and liver cancer. As a consequence, caspase-3 levels are abnormally low in these tumors, allowing the tumors to avoid apoptosis. PAC-1 is a small molecule that directly activates procaspase-3 and induces apoptosis of cancer cells in culture. PAC-1 showed efficacy across a wide range of cancer cell lines, as well as in animal models of cancer, including brain cancer. This novel compound potently synergizes with chemotherapy agents (e.g.doxorubicin, temozolomide, etoposide, carboplatin). Methods: This is a Phase I dose escalation study with a modified- Fibonacci 3+3 design, consisting of two parts: to determine the maximum tolerated dose (MTD) of PAC-1 in advanced malignancies, and to determine the MTD of PAC-1 when combined with temozolomide in patients with primary brain tumors. For both parts the MTD dose level will expand to a total of 9 patients to ensure safety. Primary objectives: establish MTD, tolerability and toxicity. Secondary and correlative objectives: pharmacokinetics, pharmacodynamics, preliminary antitumor activity correlation with procaspase-3 expression in tumor, clinical response and adverse effects. Neurological symptoms of CNS toxicity will be assessed throughout the trial. Inclusion criteria: diagnoses of advanced malignancies (for part 1) and high grade glioma (for part 2), ECOG PS 0-2, adequate organ function. Exclusion criteria: received prior cytotoxic therapy in the last 3-6 weeks (duration based on prior therapy) or uncontrolled chronic illness. Administration and design: Part 1, PAC-1 (PO) is dosed at 75-450 mg daily (up to 5 dose levels) on days 1-21 on 28 days cycle. In Part 2, the first PAC-1 dose will be 1 dose lower than the PAC-1 MTD established in Part 1 (up to 3 dose levels).Temozolomide (PO) will be dosed at 150 mg/m2 daily for 5 days starting on day 8 of each cycle. The study is currently enrolling patients in Part 1, NCT02355535. Clinical trial information: NCT02355535

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Abstract Details

Meeting

2016 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics

Track

Developmental Therapeutics and Translational Research

Sub Track

Small Molecules

Clinical Trial Registration Number

NCT02355535

Citation

J Clin Oncol 34, 2016 (suppl; abstr TPS2605)

DOI

10.1200/JCO.2016.34.15_suppl.TPS2605

Abstract #

TPS2605

Poster Bd #

298a

Abstract Disclosures

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