A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK525762 in Subjects With NUT Midline Carcinoma (NMC) and Other Cancers

Summary

This study is divided into two parts; Part 1 of the study is a dose escalation phase to select the recommended dose for Part 2 based on the safety, pharmacokinetic, and pharmacodynamic profiles observed after oral administration of GSK525762 in the following subjects: NMC, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), neuroblastoma (NB), castration resistant prostate cancer (CRPC), triple negative breast cancer (TNBC), estrogen receptor positive (ER positive) breast cancer, and MYCN driven solid tumor subjects. Part 2 of the study will explore the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of the recommended dose from Part 1 in cohorts comprised of NMC, small cell lung cancer (SCLC), castration resistant prostate cancer (CRPC), triple negative breast cancer (TNBC), and estrogen receptor positive (ER positive) breast cancer subjects. Approximately 60 subjects will be enrolled in the Part 1 and approximately 150 subjects will be enrolled in Part 2. A sub-study will be opened in Part 1 to approximately 10-12 subjects in the United States to investigate the relative bioavailability of the besylate tablet compared to the amorphous free-base tablet at the maximum tolerated dose (MTD) or recommended phase 2 dosing (RP2D), the effect of high-fat high-calorie meal on the bioavailability of the besylate tablet at the MTD or RP2D and the dose proportionality of 2 doses of GSK525762 administered as besylate tablet.

Timeline

Start

2012-03-28

Primary completion

2018-04-13

Completion

2019-07-29

Publications

• Background Piha-Paul SA, Hann CL, French CA, Cousin S, Brana I, Cassier PA, Moreno V, de Bono JS, Harward SD, Ferron-Brady G, Barbash O, Wyce A, Wu Y, Horner T, Annan M, Parr NJ, Prinjha RK, Carpenter CL, Hilton J, Hong DS, Haas NB, Markowski MC, Dhar A, O'Dwyer PJ, Shapiro GI. Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma and Other Solid Tumors. JNCI Cancer Spectr. 2019 Nov 6;4(2):pkz093. doi: 10.1093/jncics/pkz093. eCollection 2020 Apr.
• Cousin S, Blay JY, Garcia IB, de Bono JS, Le Tourneau C, Moreno V, Trigo J, Hann CL, Azad AA, Im SA, Cassier PA, French CA, Italiano A, Keedy VL, Plummer R, Sablin MP, Hemming ML, Ferron-Brady G, Wyce A, Khaled A, Datta A, Foley SW, McCabe MT, Wu Y, Horner T, Kremer BE, Dhar A, O'Dwyer PJ, Shapiro GI, Piha-Paul SA. Safety, pharmacokinetic, pharmacodynamic and clinical activity of molibresib for the treatment of nuclear protein in testis carcinoma and other cancers: Results of a Phase I/II open-label, dose escalation study. Int J Cancer. 2022 Mar 15;150(6):993-1006. doi: 10.1002/ijc.33861. Epub 2021 Nov 26.
• Krishnatry AS, Voelkner A, Dhar A, Prohn M, Ferron-Brady G. Population pharmacokinetic modeling of molibresib and its active metabolites in patients with solid tumors: A semimechanistic autoinduction model. CPT Pharmacometrics Syst Pharmacol. 2021 Jul;10(7):709-722. doi: 10.1002/psp4.12639. Epub 2021 Jun 4.
• Parikh SA, French CA, Costello BA, Marks RS, Dronca RS, Nerby CL, Roden AC, Peddareddigari VG, Hilton J, Shapiro GI, Molina JR. NUT midline carcinoma: an aggressive intrathoracic neoplasm. J Thorac Oncol. 2013 Oct;8(10):1335-8. doi: 10.1097/JTO.0b013e3182a00f41.

Drugs

Indications