TY - JOUR
T1 - Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer
T2 - a dose-escalation and dose-expansion phase 1b trial
AU - Konstantinopoulos, Panagiotis A.
AU - Barry, William T.
AU - Birrer, Michael
AU - Westin, Shannon N.
AU - Cadoo, Karen A.
AU - Shapiro, Geoffrey I.
AU - Mayer, Erica L.
AU - O'Cearbhaill, Roisin E.
AU - Coleman, Robert L.
AU - Kochupurakkal, Bose
AU - Whalen, Christin
AU - Curtis, Jennifer
AU - Farooq, Sarah
AU - Luo, Weixiu
AU - Eismann, Julia
AU - Buss, Mary K.
AU - Aghajanian, Carol
AU - Mills, Gordon B.
AU - Palakurthi, Sangeetha
AU - Kirschmeier, Paul
AU - Liu, Joyce
AU - Cantley, Lewis C.
AU - Kaufmann, Scott H.
AU - Swisher, Elizabeth M.
AU - D'Andrea, Alan D.
AU - Winer, Eric
AU - Wulf, Gerburg M.
AU - Matulonis, Ursula A.
N1 - Funding Information:
This investigator-initiated trial was supported by a translational research grant from the Stand Up To Cancer-Ovarian Cancer Research Alliance-National Ovarian Cancer Coalition Ovarian Cancer Dream Team ( SU2C-AACR-DT16-15 ). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of Stand Up To Cancer. This trial was also supported by the Breast Cancer Research Foundation. We thank Novartis for providing funding and alpelisib and AstraZeneca for providing olaparib. We thank all the patients and their families for participation in this trial.
Funding Information:
PAK reports institutional research funding from AstraZeneca and Novartis during the conduct of the study. PAK also reports serving in advisory boards at AstraZeneca, Pfizer, and Merck outside the submitted work. WTB reports institutional research support from Pfizer, outside the submitted work. SNW reports grants and personal fees from AstraZeneca, Clovis, Tesaro, Merck, and Genentech (Roche); grants from Bayer, Cotinga Pharmaceuticals, and Novartis; and personal fees from Pfizer and MediVation, outside the submitted work. KAC reports serving in advisory boards at AstraZeneca and Syndax Pharmaceuticals, outside the submitted work. GIS reports grants and personal fees from Eli Lilly, Pfizer, Merck/EMD Serono, and Sierra Oncology; and personal fees from Roche, Bicycle Therapeutics, Fusion Pharmaceuticals, G1 Therapeutics, Cybrexa Therapeutics, Bayer, Ipsen, Astex, and Almac, outside the submitted work. ELM reports institutional research funding from Pfizer and Myriad. ELM also reports serving as consultant at Eisai, Pfizer, Eli Lilly, and Context Therapeutics. REO'C reports personal fees from Clovis and Tesaro, outside the submitted work. RLC reports grants and personal fees from Genentech (Roche), Clovis, AstraZeneca, Janssen, Oncomed, Novartis, and Genmab; grants from Merck, Abbvie, and Esperance; and personal fees from Tesaro, Agenus, Eisai, Gamamab, and Incyte, outside the submitted work. CA reports personal fees from Tesaro, Immunogen, Clovis, Mateon Therapeutics, and Cerulean Pharma, outside the submitted work. GBM reports grants and personal fees from AstraZeneca, Critical Outcome Technologies, ImmunoMET, Takeda/Millennium Pharmaceuticals, and Pfizer; grants from Adelson Medical Research Foundation, Breast Cancer Research Foundation, Komen Research Foundation, Nanostring, Ovarian Cancer Research Foundation, and Prospect Creek Foundation; personal fees from PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda, and Spindle Top Ventures; and research funding from Ionis and Catena Pharmaceuticals, during the conduct of the study. GBM also has a patent licensed to Nanostring, and a patent licensed to Myriad Genetics. SP reports serving in advisory boards at Elstar Therapeutics outside the submitted work. JL reports personal fees from AstraZeneca, Tesaro, Mersana Therapeutics, and Clovis Oncology, outside the submitted work. LCC is a founder and member of the senior advisory board of Agios Pharmaceuticals and Petra Pharmaceuticals. These companies are developing novel therapies for cancer. His laboratory also receives some financial support from Petra Pharmaceuticals. No drugs from these companies are discussed in this manuscript. SHK reports grants from Stand Up To Cancer during the conduct of the study. EMS reports grants from Stand Up To Cancer during the conduct of the study and personal fees from Johnson & Johnson, outside the submitted work. EW reports personal fees from Genentech (Roche), Infinite MD, Eli Lilly, Leap Therapeutics, Carrick Therapeutics, and GlaxoSmithKline, outside the submitted work. EW also reports serving in the advisory board at Verastem. GMW reports grants from Mary Kay Ash Foundation, Ovarian Cancer Research Foundation, Breast Cancer Alliance, Breast Cancer Research Foundation, and Merck & Co during the conduct of the study. GMW also reports the Cancer Dream Team Translational Research Grant ( SU2C-AACR-DT0209 ) and National Institutes of Health Research Project Grant ( 1R01CA226776-01 ) awarded to Beth Israel Deaconess Medical Center. Additionally, GMW has patent application 14/348810 pending, “Compositions and methods for the treatment of proliferative diseases”, and patent US 20090258352 A1,”Pin1 as a marker for abnormal cell growth” licensed to Cell Signaling (R&D Systems). The other authors declare no competing interests.
PY - 2019/4
Y1 - 2019/4
N2 - Background: Based on preclinical work, we found that combination of poly (ADP-ribose) polymerase (PARP) inhibitors with drugs that inhibit the homologous recombination repair (HRR) pathway (such as PI3K inhibitors) might sensitise HRR-proficient epithelial ovarian cancers to PARP inhibitors. We aimed to assess the safety and identify the recommended phase 2 dose of the PARP inhibitor olaparib in combination with the PI3K inhibitor alpelisib in patients with epithelial ovarian cancer and in patients with breast cancer. Methods: In this multicentre, open-label, phase 1b trial following a 3 + 3 dose-escalation design, we recruited patients aged 18 years or older with the following key eligibility criteria: confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of high-grade serous histology; confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of any histology with known germline BRCA mutations; confirmed diagnosis of recurrent breast cancer of triple-negative histology; or confirmed diagnosis of recurrent breast cancer of any histology with known germline BRCA mutations. Additional patients with epithelial ovarian cancer were enrolled in a dose-expansion cohort. Four dose levels were planned: the starting dose level of alpelisib 250 mg once a day plus olaparib 100 mg twice a day (dose level 0); alpelisib 250 mg once a day plus olaparib 200 mg twice a day (dose level 1); alpelisib 300 mg once a day plus olaparib 200 mg twice a day (dose level 2); and alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Both drugs were administered orally, in tablet formulation. The primary objective was to identify the maximum tolerated dose and the recommended phase 2 dose of the combination of alpelisib and olaparib for patients with epithelial ovarian cancer and patients with breast cancer. Analyses included all patients who received at least one dose of the study drugs. The trial is active, but closed to enrolment; follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov, number NCT01623349. Findings: Between Oct 3, 2014, and Dec 21, 2016, we enrolled 34 patients (28 in the dose-escalation cohort and six in the dose-expansion cohort); two in the dose-escalation cohort were ineligible at the day of scheduled study initiation. Maximum tolerated dose and recommended phase 2 dose were identified as alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Considering all dose levels, the most common treatment-related grade 3–4 adverse events were hyperglycaemia (five [16%] of 32 patients), nausea (three [9%]), and increased alanine aminotransferase concentrations (three [9%]). No treatment-related deaths occurred. Dose-limiting toxic effects included hyperglycaemia and fever with decreased neutrophil count. Of the 28 patients with epithelial ovarian cancer, ten (36%) achieved a partial response and 14 (50%) had stable disease according to Response Evaluation Criteria in Solid Tumors 1.1. Interpretation: Combining alpelisib and olaparib is feasible with no unexpected toxic effects. The observed activity provides preliminary clinical evidence of synergism between olaparib and alpelisib, particularly in epithelial ovarian cancer, and warrants further investigation. Funding: Ovarian Cancer Dream Team (Stand Up To Cancer, Ovarian Cancer Research Alliance, National Ovarian Cancer Coalition), Breast Cancer Research Foundation, Novartis.
AB - Background: Based on preclinical work, we found that combination of poly (ADP-ribose) polymerase (PARP) inhibitors with drugs that inhibit the homologous recombination repair (HRR) pathway (such as PI3K inhibitors) might sensitise HRR-proficient epithelial ovarian cancers to PARP inhibitors. We aimed to assess the safety and identify the recommended phase 2 dose of the PARP inhibitor olaparib in combination with the PI3K inhibitor alpelisib in patients with epithelial ovarian cancer and in patients with breast cancer. Methods: In this multicentre, open-label, phase 1b trial following a 3 + 3 dose-escalation design, we recruited patients aged 18 years or older with the following key eligibility criteria: confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of high-grade serous histology; confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of any histology with known germline BRCA mutations; confirmed diagnosis of recurrent breast cancer of triple-negative histology; or confirmed diagnosis of recurrent breast cancer of any histology with known germline BRCA mutations. Additional patients with epithelial ovarian cancer were enrolled in a dose-expansion cohort. Four dose levels were planned: the starting dose level of alpelisib 250 mg once a day plus olaparib 100 mg twice a day (dose level 0); alpelisib 250 mg once a day plus olaparib 200 mg twice a day (dose level 1); alpelisib 300 mg once a day plus olaparib 200 mg twice a day (dose level 2); and alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Both drugs were administered orally, in tablet formulation. The primary objective was to identify the maximum tolerated dose and the recommended phase 2 dose of the combination of alpelisib and olaparib for patients with epithelial ovarian cancer and patients with breast cancer. Analyses included all patients who received at least one dose of the study drugs. The trial is active, but closed to enrolment; follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov, number NCT01623349. Findings: Between Oct 3, 2014, and Dec 21, 2016, we enrolled 34 patients (28 in the dose-escalation cohort and six in the dose-expansion cohort); two in the dose-escalation cohort were ineligible at the day of scheduled study initiation. Maximum tolerated dose and recommended phase 2 dose were identified as alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Considering all dose levels, the most common treatment-related grade 3–4 adverse events were hyperglycaemia (five [16%] of 32 patients), nausea (three [9%]), and increased alanine aminotransferase concentrations (three [9%]). No treatment-related deaths occurred. Dose-limiting toxic effects included hyperglycaemia and fever with decreased neutrophil count. Of the 28 patients with epithelial ovarian cancer, ten (36%) achieved a partial response and 14 (50%) had stable disease according to Response Evaluation Criteria in Solid Tumors 1.1. Interpretation: Combining alpelisib and olaparib is feasible with no unexpected toxic effects. The observed activity provides preliminary clinical evidence of synergism between olaparib and alpelisib, particularly in epithelial ovarian cancer, and warrants further investigation. Funding: Ovarian Cancer Dream Team (Stand Up To Cancer, Ovarian Cancer Research Alliance, National Ovarian Cancer Coalition), Breast Cancer Research Foundation, Novartis.
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UR - http://www.scopus.com/inward/citedby.url?scp=85063575195&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(18)30905-7
DO - 10.1016/S1470-2045(18)30905-7
M3 - Article
C2 - 30880072
AN - SCOPUS:85063575195
VL - 20
SP - 570
EP - 580
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 4
ER -