Phase I Study of Rucaparib in Combination with Bevacizumab in Ovarian Cancer Patients: Maximum Tolerated Dose and Pharmacokinetic Profile

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.

Trial registration: ClinicalTrials.gov identifier NCT03462212; registered March 2018.

Conflict of interest statement

Domenica Lorusso has served in a consulting or advisory role for Clovis Oncology, Amgen, AstraZeneca, ImmunoGen, Genmab, Merck, PharmaMar, Roche, Takeda, and Tesaro; received support for travel or accommodation from AstraZeneca, PharmaMar, Roche, and Tesaro; has served as a principal investigator of trials for Clovis Oncology, AstraZeneca, Immunogen, Genmab, Merck, PharmaMar, Roche, and Tesaro; and her institution has received research grants from Clovis Oncology, Merck, PharmaMar, Roche, and Tesaro. Maurizio D’Incalci has served in a consulting or advisory role for Tesaro and PharmaMar. Filippo de Braud has served in a consulting or advisory role for Regione Toscana and Servier; received support for travel or accommodation from Amgen, BMS, Celgene, and Roche; received fees for review activities such as data monitoring boards from BMS, Daiichi Sankyo, EMD Serono, Incyte, Ignyta, Nerviano Medical Science (NMS), OCTIMET Oncology, Pfizer, Pharma Research Associates; Pierre Fabre, Roche, Sanofi, and Teofarma; and reports other support (e.g., writing assistance, administrative support) from AccuMed, Bayer, Biotechspert, BMS, Celgene, Dephaforum, Healthcare Research & Pharmacoepidemiology, Ignyta, Loxo Oncology, Merck, MSD, Pfizer, prIME Oncology, Roche, Sanofi, and Servier. Giuseppa Maltese, Ilaria Sabatucci, Sara Cresta, Cristina Matteo, Tommaso Ceruti, , Massimo Zucchetti, Francesco Raspagliesi, Cristina Sonetto, Valentina Sinno, Dominique Ronzulli, and Serena Giolitto have no conflicts of interest that are directly relevant to the content of this article.

Figures

Fig. 1

Concentration–time profiles of patients treated with rucaparib (a) 400 mg, (b) 500 mg, and (c) 600 mg twice daily. Colored dots represent the rucaparib concentration measured for each individual; the data in black represent the mean rucaparib concentration. Pt patient

Fig. 2

Comparison of mean concentration–time profiles of patients treated with rucaparib 400 mg, 500 mg, and 600 mg twice daily. Error bars represent standard deviation