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