A phase 1 dose-escalation study of intraperitoneal cisplatin, intravenous/intraperitoneal paclitaxel, bevacizumab, and olaparib for newly diagnosed ovarian cancer Journal Article
| Authors: | Cadoo, K. A.; Grisham, R. N.; O'Cearbhaill, R. E.; Boucicaut, N. N.; Henson, M.; Iasonos, A.; Zhou, Q.; Sarasohn, D. M.; Gallagher, J.; Kravetz, S.; Zamarin, D.; Makker, V.; Sabbatini, P. J.; Tew, W. P.; Aghajanian, C.; Konner, J. A. |
| Article Title: | A phase 1 dose-escalation study of intraperitoneal cisplatin, intravenous/intraperitoneal paclitaxel, bevacizumab, and olaparib for newly diagnosed ovarian cancer |
| Abstract: | Objective: We assessed the safety and maximum tolerated dose (MTD) of the poly ADP-ribose polymerase (PARP) inhibitor olaparib with intravenous (IV)/intraperitoneal (IP) cisplatin/paclitaxel and IV bevacizumab, followed by olaparib and bevacizumab maintenance, in patients with newly diagnosed ovarian cancer who had undergone primary debulking surgery. Methods: Treatment included: (Cycles 1–6) Day 1, IV paclitaxel 135 mg/m2/3 h + (from Cycle 2 onward) bevacizumab 15 mg/kg; Day 2, IP cisplatin 75 mg/m2; Days 2–8, olaparib (50/100/200 mg BID); Day 8, IP paclitaxel 60 mg/m2 of a 21-day cycle. Maintenance (Cycles 7–22) included: olaparib 300 mg BID and bevacizumab 15 mg/kg Day 1. The primary endpoint was MTD of olaparib, chemotherapy, and bevacizumab. Results: Seventeen women were treated (Cohort 1 [50 mg olaparib], 8 patients; Cohort 2 [100 mg], 3 patients; and Cohort 3 [200 mg], 6 patients). Median age was 57 years (47–73); 94% had stage III disease; 29% had a germline BRCA mutation. Two of 6 patients in Cohort 3 experienced a dose-limiting toxicity (DLT). Grade 3/4 toxicities included: neutropenia (56%), lymphopenia (31%), anemia (25%), and fatigue (19%). Most patients started (88%, 81%) and completed (75%, 50%) maintenance olaparib and bevacizumab, respectively; 36% of patients on olaparib maintenance required a dose reduction. Median PFS was 33 months (26.2-NA). Conclusions: The MTD of intermittently dosed olaparib with concurrent IV/IP cisplatin/paclitaxel and bevacizumab is 100 mg BID. Non-hematologic toxicities were predominantly low grade. One-third of patients on olaparib maintenance required dose reduction. © 2020 Elsevier Inc. |
| Keywords: | adult; clinical article; aged; constipation; fatigue; neutropenia; postoperative period; bevacizumab; cisplatin; diarrhea; drug dose reduction; drug safety; drug withdrawal; hypertension; side effect; paclitaxel; nuclear magnetic resonance imaging; outcome assessment; anorexia; ovarian cancer; cytoreductive surgery; gene; carboplatin; progression free survival; computer assisted tomography; multiple cycle treatment; nephrotoxicity; ovary cancer; pain; sensory neuropathy; anemia; leukopenia; nausea; neuropathy; thrombocytopenia; vomiting; myalgia; peripheral neuropathy; tinnitus; maintenance therapy; cohort analysis; dexamethasone; docetaxel; abdominal pain; arthralgia; backache; coughing; drug dose escalation; dyspnea; febrile neutropenia; hyperglycemia; hypomagnesemia; lymphocytopenia; rash; lung embolism; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; acute kidney failure; hyperkalemia; hypoalbuminemia; hypokalemia; hyponatremia; insomnia; maculopapular rash; depression; add on therapy; kidney injury; peripheral edema; sepsis; headache; maximum tolerated dose; phase 1 clinical trial; gastroesophageal reflux; drug substitution; epistaxis; skin infection; small intestine obstruction; phase 1; bladder disease; electrolyte disturbance; platelet count; antihistaminic agent; olaparib; hypocalcemia; nose obstruction; enterocolitis; myositis; kidney dysfunction; hypersensitivity; device infection; germline mutation; activated partial thromboplastin time; estimated glomerular filtration rate; human; female; priority journal; article; parp inhibitors; brca gene; epitaxis |
| Journal Title: | Gynecologic Oncology |
| Volume: | 157 |
| Issue: | 1 |
| ISSN: | 0090-8258 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2020-04-01 |
| Start Page: | 214 |
| End Page: | 221 |
| Language: | English |
| DOI: | 10.1016/j.ygyno.2020.01.018 |
| PUBMED: | 31959492 |
| PROVIDER: | scopus |
| PMCID: | PMC7127949 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2020 -- Source: Scopus |
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