Phase I Study of Rucaparib in Combination with Bevacizumab in Ovarian Cancer Patients: Maximum Tolerated Dose and Pharmacokinetic Profile
Open Access
- 1 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Targeted Oncology
- Vol. 16 (1), 59-68
- https://doi.org/10.1007/s11523-020-00780-4
Abstract
Background Targeted agents, such as antiangiogenic drugs (e.g., bevacizumab) and poly(ADP-ribose) polymerase inhibitors (e.g., rucaparib), have been shown to improve outcomes in patients with newly diagnosed or recurrent ovarian cancer. Evidence suggests that combinations of these two classes of targeted agents may result in synergistic antitumor activity. Objective The phase I portion of MITO 25 was designed to determine the maximum tolerated dose, pharmacokinetics, and the safety profile of rucaparib when administered in combination with bevacizumab as maintenance treatment for patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Methods This was a single-arm, phase I dose-escalation study. Cohorts of three patients were recruited to receive increasing rucaparib doses of 400 mg, 500 mg, or 600 mg twice daily for 28 days. Bevacizumab 15 mg/kg was administered at day 1 every 21 days. Results We enrolled nine patients. Two patients in the rucaparib 600-mg group had four grade 3 treatment-emergent adverse events: increased in alanine aminotransferase and aspartate aminotransferase levels, depression, and hallucinations. These were deemed to be dose-limiting toxicities related to rucaparib. Because these dose-limiting toxicities occurred in the 600-mg group and affected more than one in three patients, the maximum tolerated dose for rucaparib was considered 500 mg twice daily when combined with bevacizumab 15 mg/kg at day 1 every 21 days. There were no new safety concerns from using the combination. No substantial difference in pharmacokinetic parameters was found between the cohorts or in the pharmacokinetic profiles of rucaparib administered alone or with bevacizumab with respect to historical controls. Conclusions The maximum tolerated dose of rucaparib is 500 mg twice daily when co-administered with bevacizumab. The plasma concentration-time profiles of rucaparib in combination with bevacizumab suggest no pharmacokinetic interactions between the drugs. The randomized phase II portion of MITO 25 will further investigate rucaparib maintenance treatment with or without bevacizumab in patients with newly diagnosed stage III-IV ovarian cancer who responded to carboplatin-paclitaxel chemotherapy with or without bevacizumab.Funding Information
- Clovis Oncology
- Università Cattolica del Sacro Cuore
This publication has 33 references indexed in Scilit:
- Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancerGynecologic Oncology, 2015
- Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 studyThe Lancet Oncology, 2014
- Stereospecific PARP Trapping by BMN 673 and Comparison with Olaparib and RucaparibMolecular Cancer Therapeutics, 2014
- Liquid chromatography–tandem mass spectrometric assay for the PARP inhibitor rucaparib in plasmaJournal of Pharmaceutical and Biomedical Analysis, 2013
- Trapping of PARP1 and PARP2 by Clinical PARP InhibitorsCancer Research, 2012
- Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian CancerThe New England Journal of Medicine, 2012
- Hypoxia-Induced Down-regulation of BRCA1 Expression by E2FsCancer Research, 2005
- Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymeraseNature, 2005
- Down-Regulation of Rad51 and Decreased Homologous Recombination in Hypoxic Cancer CellsMolecular and Cellular Biology, 2004
- Part I: Chemotherapy for epithelial ovarian cancer–treatment at first diagnosisThe Lancet Oncology, 2002