Gottfried E Konecny1, Amit M Oza2, Anna V Tinker3, Ana Oaknin4, Ronnie Shapira-Frommer5, Isabelle Ray-Coquard6, Carol Aghajanian7, Robert L Coleman8, David M O'Malley9, Alexandra Leary10, Lee-May Chen11, Diane Provencher12, Ling Ma13, James D Brenton14, Cesar Castro15, Michelle Green16, Andrew D Simmons17, Jeri Beltman18, Thomas Harding17, Kevin K Lin17, Sandra Goble19, Lara Maloney20, Rebecca S Kristeleit21, Iain A McNeish22, Elizabeth M Swisher23, Jim J Xiao24. 1. Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: GKonecny@mednet.ucla.edu. 2. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. 3. Medical Oncology, BC Cancer Agency, Vancouver, BC, Canada. 4. Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain. 5. Department of Oncology, Chaim Sheba Medical Center, Tel HaShomer, Israel. 6. Medical Oncology Department, Centre Léon Bérard and University Claude Bernard and Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), Lyon, France. 7. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 8. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 9. Division of Gynecologic Oncology, The Ohio State University, James Cancer Center, Columbus, OH, USA. 10. Gynecological Unit, Gustave Roussy Cancer Center, INSERM U981, GINECO, Villejuif, France. 11. Gynecologic Oncology Division, University of California San Francisco, San Francisco, CA, USA. 12. Institut du Cancer de Montréal, Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montreal, QC, Canada. 13. Medical Oncology, Rocky Mountain Cancer Centers, Lakewood, CO, USA. 14. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. 15. Cancer Center, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. 16. Integrated Drug Development, Certara Strategic Consulting, Menlo Park, CA, USA. 17. Molecular Diagnostics, Clovis Oncology, Inc., Boulder, CO, USA. 18. Regulatory Affairs, Clovis Oncology, Inc., Boulder, CO, USA. 19. Biostatistics, Clovis Oncology, Inc., Boulder, CO, USA. 20. Clinical Development, Clovis Oncology, Inc., Boulder, CO, USA. 21. Department of Oncology, University College London (UCL) Cancer Institute, UCL Hospitals, London, UK. 22. Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. 23. Division of Gynecologic Oncology, University of Washington, Seattle, WA, USA. 24. Clinical Pharmacology, Clovis Oncology, Inc., Boulder, CO, USA.
Abstract
OBJECTIVE: To evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2. METHODS: Efficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUCss) and maximum concentration (Cmax,ss) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUCavg,ss and Cmax,avg,ss) using a previously developed population pharmacokinetic model. RESULTS: Rucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUCavg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. Cmax,ss was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p < 0.05). CONCLUSION: The exposure-response analyses provide support for the approved starting dose of rucaparib 600 mg BID for maximum clinical benefit with subsequent dose modification only following the occurrence of a treatment-emergent adverse event in patients with BRCA-mutated recurrent ovarian carcinoma.
OBJECTIVE: To evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2. METHODS: Efficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUCss) and maximum concentration (Cmax,ss) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUCavg,ss and Cmax,avg,ss) using a previously developed population pharmacokinetic model. RESULTS: Rucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUCavg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. Cmax,ss was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p < 0.05). CONCLUSION: The exposure-response analyses provide support for the approved starting dose of rucaparib 600 mg BID for maximum clinical benefit with subsequent dose modification only following the occurrence of a treatment-emergent adverse event in patients with BRCA-mutated recurrent ovarian carcinoma.
Authors: Kathryn P Pennington; Tom Walsh; Maria I Harrell; Ming K Lee; Christopher C Pennil; Mara H Rendi; Anne Thornton; Barbara M Norquist; Silvia Casadei; Alexander S Nord; Kathy J Agnew; Colin C Pritchard; Sheena Scroggins; Rochelle L Garcia; Mary-Claire King; Elizabeth M Swisher Journal: Clin Cancer Res Date: 2013-11-15 Impact factor: 12.531
Authors: J S Berek; U A Matulonis; U Peen; P Ghatage; S Mahner; A Redondo; A Lesoin; N Colombo; I Vergote; O Rosengarten; J Ledermann; M Pineda; S Ellard; J Sehouli; A Gonzalez-Martin; D Berton-Rigaud; R Madry; A Reinthaller; S Hazard; W Guo; M R Mirza Journal: Ann Oncol Date: 2018-08-01 Impact factor: 32.976
Authors: Geoffrey I Shapiro; Rebecca S Kristeleit; Howard A Burris; Patricia LoRusso; Manish R Patel; Yvette Drew; Heidi Giordano; Lara Maloney; Simon Watkins; Sandra Goble; Sarah Jaw-Tsai; Jim J Xiao Journal: Clin Pharmacol Drug Dev Date: 2018-05-25
Authors: Amit M Oza; Anna V Tinker; Ana Oaknin; Ronnie Shapira-Frommer; Iain A McNeish; Elizabeth M Swisher; Isabelle Ray-Coquard; Katherine Bell-McGuinn; Robert L Coleman; David M O'Malley; Alexandra Leary; Lee-May Chen; Diane Provencher; Ling Ma; James D Brenton; Gottfried E Konecny; Cesar M Castro; Heidi Giordano; Lara Maloney; Sandra Goble; Kevin K Lin; James Sun; Mitch Raponi; Lindsey Rolfe; Rebecca S Kristeleit Journal: Gynecol Oncol Date: 2017-09-04 Impact factor: 5.482
Authors: Michelle L Green; Shu Chin Ma; Sandra Goble; Heidi Giordano; Lara Maloney; Andrew D Simmons; Jeri Beltman; Thomas C Harding; Jim J Xiao Journal: Cancer Chemother Pharmacol Date: 2022-04-10 Impact factor: 3.288