J Bendell1, E M O'Reilly2, M R Middleton3, I Chau4, H Hochster5, A Fielding6, W Burke7, H Burris8. 1. Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, Nashville. Electronic address: jbendell@tnonc.com. 2. Memorial Sloan Kettering Cancer Center, New York, USA. 3. Department of Oncology, University of Oxford, Oxford. 4. Department of Medicine, Royal Marsden Hospital, Sutton, UK. 5. Yale Cancer Center, Yale School of Medicine, New Haven, USA. 6. Global Medicines Development, AstraZeneca. 7. Clinical Pharmacology, AstraZeneca, Macclesfield, UK. 8. Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, Nashville.
Abstract
BACKGROUND: Olaparib (Lynparza) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects. PATIENTS AND METHODS: In this phase I, dose-escalation trial, patients with advanced solid tumours received olaparib (50-200 mg capsules b.i.d.) continuously or intermittently (days 1-14, per 28-day cycle) plus gemcitabine [i.v. 600-800 mg/m(2); days 1, 8, 15, and 22 (cycle 1), days 1, 8, and 15 (subsequent cycles)] to establish the maximum tolerated dose. A separate dose-escalation phase evaluated olaparib in tablet formulation (100 mg o.d./b.i.d.; days 1-14) plus gemcitabine (600 mg/m(2)). In an expansion phase, patients with genetically unselected locally advanced or metastatic pancreatic cancer were randomised 2 : 1 to the tolerated olaparib capsule combination dose or gemcitabine alone (1000 mg/m(2)). RESULTS: Sixty-six patients were treated [dose-escalation phase, n = 44 (tablet cohort, n = 12); dose-expansion phase, n = 22 (olaparib plus gemcitabine, n = 15; gemcitabine alone, n = 7)]. In the dose-escalation phase, four patients (6%) experienced dose-limiting toxicities (raised alanine aminotransferase, n = 2; neutropenia, n = 1; febrile neutropenia, n = 1). Grade ≥3 adverse events were reported in 38/47 patients (81%) treated with olaparib capsules plus gemcitabine; most common were haematological toxicities (55%). Tolerated combinations were olaparib 100 mg b.i.d. capsule (intermittently, days 1-14) plus gemcitabine 600 mg/m(2) and olaparib 100 mg o.d. tablet (intermittently, days 1-14) plus gemcitabine 600 mg/m(2). There were no differences in efficacy observed during the dose-expansion phase. CONCLUSIONS: Olaparib 100 mg b.i.d. (intermittent dosing; capsules) plus gemcitabine 600 mg/m(2) is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m(2) was not considered to have an acceptable tolerability profile for further study. CLINICALTRIALSGOV: NCT00515866.
BACKGROUND: Olaparib (Lynparza) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects. PATIENTS AND METHODS: In this phase I, dose-escalation trial, patients with advanced solid tumours received olaparib (50-200 mg capsules b.i.d.) continuously or intermittently (days 1-14, per 28-day cycle) plus gemcitabine [i.v. 600-800 mg/m(2); days 1, 8, 15, and 22 (cycle 1), days 1, 8, and 15 (subsequent cycles)] to establish the maximum tolerated dose. A separate dose-escalation phase evaluated olaparib in tablet formulation (100 mg o.d./b.i.d.; days 1-14) plus gemcitabine (600 mg/m(2)). In an expansion phase, patients with genetically unselected locally advanced or metastatic pancreatic cancer were randomised 2 : 1 to the tolerated olaparib capsule combination dose or gemcitabine alone (1000 mg/m(2)). RESULTS: Sixty-six patients were treated [dose-escalation phase, n = 44 (tablet cohort, n = 12); dose-expansion phase, n = 22 (olaparib plus gemcitabine, n = 15; gemcitabine alone, n = 7)]. In the dose-escalation phase, four patients (6%) experienced dose-limiting toxicities (raised alanine aminotransferase, n = 2; neutropenia, n = 1; febrile neutropenia, n = 1). Grade ≥3 adverse events were reported in 38/47 patients (81%) treated with olaparib capsules plus gemcitabine; most common were haematological toxicities (55%). Tolerated combinations were olaparib 100 mg b.i.d. capsule (intermittently, days 1-14) plus gemcitabine 600 mg/m(2) and olaparib 100 mg o.d. tablet (intermittently, days 1-14) plus gemcitabine 600 mg/m(2). There were no differences in efficacy observed during the dose-expansion phase. CONCLUSIONS: Olaparib 100 mg b.i.d. (intermittent dosing; capsules) plus gemcitabine 600 mg/m(2) is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m(2) was not considered to have an acceptable tolerability profile for further study. CLINICALTRIALSGOV: NCT00515866.
Authors: Bella Kaufman; Ronnie Shapira-Frommer; Rita K Schmutzler; M William Audeh; Michael Friedlander; Judith Balmaña; Gillian Mitchell; Georgeta Fried; Salomon M Stemmer; Ayala Hubert; Ora Rosengarten; Mariana Steiner; Niklas Loman; Karin Bowen; Anitra Fielding; Susan M Domchek Journal: J Clin Oncol Date: 2014-11-03 Impact factor: 44.544
Authors: Arun Rajan; Corey A Carter; Ronan J Kelly; Martin Gutierrez; Shivaani Kummar; Eva Szabo; Mary Ann Yancey; Jiuping Ji; Baskar Mannargudi; Sukyung Woo; Shawn Spencer; William Douglas Figg; Giuseppe Giaccone Journal: Clin Cancer Res Date: 2012-02-27 Impact factor: 12.531
Authors: M Goggins; M Schutte; J Lu; C A Moskaluk; C L Weinstein; G M Petersen; C J Yeo; C E Jackson; H T Lynch; R H Hruban; S E Kern Journal: Cancer Res Date: 1996-12-01 Impact factor: 12.701
Authors: Patrick J Loehrer; Yang Feng; Higinia Cardenes; Lynne Wagner; Joanna M Brell; David Cella; Patrick Flynn; Ramesh K Ramanathan; Christopher H Crane; Steven R Alberts; Al B Benson Journal: J Clin Oncol Date: 2011-10-03 Impact factor: 44.544
Authors: Cherrie K Donawho; Yan Luo; Yanping Luo; Thomas D Penning; Joy L Bauch; Jennifer J Bouska; Velitchka D Bontcheva-Diaz; Bryan F Cox; Theodore L DeWeese; Larry E Dillehay; Debra C Ferguson; Nayereh S Ghoreishi-Haack; David R Grimm; Ran Guan; Edward K Han; Rhonda R Holley-Shanks; Boris Hristov; Kenneth B Idler; Ken Jarvis; Eric F Johnson; Lawrence R Kleinberg; Vered Klinghofer; Loren M Lasko; Xuesong Liu; Kennan C Marsh; Thomas P McGonigal; Jonathan A Meulbroek; Amanda M Olson; Joann P Palma; Luis E Rodriguez; Yan Shi; Jason A Stavropoulos; Alan C Tsurutani; Gui-Dong Zhu; Saul H Rosenberg; Vincent L Giranda; David J Frost Journal: Clin Cancer Res Date: 2007-05-01 Impact factor: 12.531
Authors: Ruth Plummer; Christopher Jones; Mark Middleton; Richard Wilson; Jeffrey Evans; Anna Olsen; Nicola Curtin; Alan Boddy; Peter McHugh; David Newell; Adrian Harris; Patrick Johnson; Heidi Steinfeldt; Raz Dewji; Diane Wang; Lesley Robson; Hilary Calvert Journal: Clin Cancer Res Date: 2008-12-01 Impact factor: 12.531
Authors: Peter C Fong; David S Boss; Timothy A Yap; Andrew Tutt; Peijun Wu; Marja Mergui-Roelvink; Peter Mortimer; Helen Swaisland; Alan Lau; Mark J O'Connor; Alan Ashworth; James Carmichael; Stan B Kaye; Jan H M Schellens; Johann S de Bono Journal: N Engl J Med Date: 2009-06-24 Impact factor: 91.245
Authors: Jonathan Ledermann; Philipp Harter; Charlie Gourley; Michael Friedlander; Ignace Vergote; Gordon Rustin; Clare L Scott; Werner Meier; Ronnie Shapira-Frommer; Tamar Safra; Daniela Matei; Anitra Fielding; Stuart Spencer; Brian Dougherty; Maria Orr; Darren Hodgson; J Carl Barrett; Ursula Matulonis Journal: Lancet Oncol Date: 2014-05-31 Impact factor: 41.316
Authors: Ronald Stoller; John C Schmitz; Fei Ding; Shannon Puhalla; Chandra P Belani; Leonard Appleman; Yan Lin; Yixing Jiang; Salah Almokadem; Daniel Petro; Julianne Holleran; Brian F Kiesel; R Ken Czambel; Benedito A Carneiro; Emmanuel Kontopodis; Pamela A Hershberger; Madani Rachid; Alice Chen; Edward Chu; Jan H Beumer Journal: Cancer Chemother Pharmacol Date: 2017-08-02 Impact factor: 3.333
Authors: Masaya Suenaga; Jun Yu; Koji Shindo; Koji Tamura; Jose Alejandro Almario; Christopher Zaykoski; P Dane Witmer; Shahriar Fesharakizadeh; Michael Borges; Anne-Marie Lennon; Eun-Ji Shin; Marcia Irene Canto; Michael Goggins Journal: Clin Cancer Res Date: 2018-01-04 Impact factor: 12.531
Authors: Anne L van de Ven; Shifalika Tangutoori; Paige Baldwin; Ju Qiao; Codi Gharagouzloo; Nina Seitzer; John G Clohessy; G Mike Makrigiorgos; Robert Cormack; Pier Paolo Pandolfi; Srinivas Sridhar Journal: Mol Cancer Ther Date: 2017-05-12 Impact factor: 6.261