Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer

被引：171

作者：

Matulonis, U. A. ^{[1
]}

Wulf, G. M. ^{[2
]}

Barry, W. T. ^{[1
]}

Birrer, M. ^{[3
]}

Westin, S. N. ^{[4
]}

Farooq, S. ^{[1
]}

Bell-McGuinn, K. M. ^{[5
]}

Obermayer, E. ^{[1
]}

Whalen, C. ^{[1
]}

Spagnoletti, T. ^{[1
]}

Luo, W. ^{[1
]}

Liu, H. ^{[2
]}

Hok, R. C. ^{[2
]}

Aghajanian, C. ^{[6
]}

Solit, D. B. ^{[6
]}

Mills, G. B. ^{[7
]}

Taylor, B. S. ^{[6
]}

Won, H. ^{[6
]}

Berger, M. F. ^{[6
]}

Palakurthi, S. ^{[1
]}

Liu, J. ^{[1
]}

Cantley, L. C. ^{[8
]}

Winer, E. ^{[1
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Div Hematol & Oncol, Beth Israel Deaconess Med Ctr, Boston, MA USA

[3] Massachusetts Gen Hosp, Dept Hematol & Oncol, Boston, MA USA

[4] Dept Gynecol Oncol, MD Anderson Canc Ctr, Houston, TX USA

[5] Eli Lilly, Indianapolis, IN USA

[6] Mem Sloan Kettering Canc Ctr, New York, NY USA

[7] Univ Texas MD Anderson Canc Ctr, Div Basic Sci Res, Dept Syst Biol, Houston, TX USA

[8] Weill Cornell Med Coll, New York, NY USA

来源：

ANNALS OF ONCOLOGY | 2017年 / 28卷 / 03期

基金：

美国国家卫生研究院;

关键词：

BKM120; olaparib; ovarian cancer; breast cancer; PARP-inhibitors; PI3K INHIBITOR; BUPARLISIB BKM120; MUTATION;

D O I：

10.1093/annonc/mdw672

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3+3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results: In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100mg b.i.d.). The MTD was determined to be BKM120 50mg q.d. and olaparib 300mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAmand gBRCA wild-type (gBRCAwt) patients. Conclusions: BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone.

引用

页码：512 / 518

页数：7

共 17 条

[1] Phase I dose- escalation study of buparlisib ( BKM120), an oral pan- class I PI3K inhibitor, in Japanese patients with advanced solid tumors [J].

Ando, Yuichi ;

Inada-Inoue, Megumi ;

Mitsuma, Ayako ;

Yoshino, Takayuki ;

Ohtsu, Atsushi ;

Suenaga, Naoko ;

Sato, Masahiko ;

Kakizume, Tomoyuki ;

Robson, Matthew ;

Quadt, Cornelia ;

Doi, Toshihiko .

CANCER SCIENCE, 2014, 105 (03) :347-353

[2] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[3] Phase I, Dose-Escalation Study of BKM120, an Oral Pan-Class I PI3K Inhibitor, in Patients With Advanced Solid Tumors [J].

Bendell, Johanna C. ;

Rodon, Jordi ;

Burris, Howard A. ;

de Jonge, Maja ;

Verweij, Jaap ;

Birle, Diana ;

Demanse, David ;

De Buck, Stefan S. ;

Ru, Qinhua C. ;

Peters, Malte ;

Goldbrunner, Michael ;

Baselga, Jose .

JOURNAL OF CLINICAL ONCOLOGY, 2012, 30 (03) :282-290

[4] Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology [J].

Cheng, Donavan T. ;

Mitchell, Talia N. ;

Zehir, Ahmet ;

Shah, Ronak H. ;

Benayed, Ryma ;

Syed, Aijazuddin ;

Chandramohan, Raghu ;

Liu, Zhen Yu ;

Won, Helen H. ;

Scott, Sasinya N. ;

Brannon, A. Rose ;

O'Reilly, Catherine ;

Sadowska, Justyna ;

Casanova, Jacklyn ;

Yannes, Angela ;

Hechtman, Jaclyn F. ;

Yao, Jinjuan ;

Song, Wei ;

Ross, Dara S. ;

Oultache, Alifya ;

Dogan, Snjezana ;

Borsu, Laetitia ;

Hameed, Meera ;

Nafa, Khedoudja ;

Arcila, Maria E. ;

Ladanyi, Marc ;

Berger, Michael F. .

JOURNAL OF MOLECULAR DIAGNOSTICS, 2015, 17 (03) :251-264

[5] Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers. [J].

Fong, Peter C. ;

Boss, David S. ;

Yap, Timothy A. ;

Tutt, Andrew ;

Wu, Peijun ;

Mergui-Roelvink, Marja ;

Mortimer, Peter ;

Swaisland, Helen ;

Lau, Alan ;

O'Connor, Mark J. ;

Ashworth, Alan ;

Carmichael, James ;

Kaye, Stan B. ;

Schellens, Jan H. M. ;

de Bono, Johann S. .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (02) :123-134

[6] Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study [J].

Gelmon, Karen A. ;

Tischkowitz, Marc ;

Mackay, Helen ;

Swenerton, Kenneth ;

Robidoux, Andre ;

Tonkin, Katia ;

Hirte, Hal ;

Huntsman, David ;

Clemons, Mark ;

Gilks, Blake ;

Yerushalmi, Rinat ;

Macpherson, Euan ;

Carmichael, James ;

Oza, Amit .

LANCET ONCOLOGY, 2011, 12 (09) :852-861

[7] Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton [J].

Hu, Hai ;

Juvekar, Ashish ;

Lyssiotis, Costas A. ;

Lien, Evan C. ;

Albeck, John G. ;

Oh, Doogie ;

Varma, Gopal ;

Hung, Yin Pun ;

Ullas, Soumya ;

Lauring, Josh ;

Seth, Pankaj ;

Lundquist, Mark R. ;

Tolan, Dean R. ;

Grant, Aaron K. ;

Needleman, Daniel J. ;

Asara, John M. ;

Cantley, Lewis C. ;

Wulf, Gerburg M. .

CELL, 2016, 164 (03) :433-446

[8] PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition [J].

Ibrahim, Yasir H. ;

Garcia-Garcia, Celina ;

Serra, Violeta ;

He, Lei ;

Torres-Lockhart, Kristine ;

Prat, Aleix ;

Anton, Pilar ;

Cozar, Patricia ;

Guzman, Marta ;

Grueso, Judit ;

Rodriguez, Olga ;

Teresa Calvo, Maria ;

Aura, Claudia ;

Diez, Orland ;

Rubio, Isabel T. ;

Perez, Jose ;

Rodon, Jordi ;

Cortes, Javier ;

Ellisen, Leif W. ;

Scaltriti, Maurizio ;

Baselga, Jose .

CANCER DISCOVERY, 2012, 2 (11) :1036-1047

[9] Combining a PI3K Inhibitor with a PARP Inhibitor Provides an Effective Therapy for BRCA1-Related Breast Cancer [J].

Juvekar, Ashish ;

Burga, Laura N. ;

Hu, Hai ;

Lunsford, Elaine P. ;

Ibrahim, Yasir H. ;

Balmana, Judith ;

Rajendran, Anbazhagan ;

Papa, Antonella ;

Spencer, Katherine ;

Lyssiotis, Costas A. ;

Nardella, Caterina ;

Pandolfi, Pier Paolo ;

Baselga, Jose ;

Scully, Ralph ;

Asara, John M. ;

Cantley, Lewis C. ;

Wulf, Gerburg M. .

CANCER DISCOVERY, 2012, 2 (11) :1048-1063

[10] Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation [J].

Kaufman, Bella ;

Shapira-Frommer, Ronnie ;

Schmutzler, Rita K. ;

Audeh, M. William ;

Friedlander, Michael ;

Balmana, Judith ;

Mitchell, Gillian ;

Fried, Georgeta ;

Stemmer, Salomon M. ;

Hubert, Ayala ;

Rosengarten, Ora ;

Steiner, Mariana ;

Loman, Niklas ;

Bowen, Karin ;

Fielding, Anitra ;

Domchek, Susan M. .

JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (03) :244-250

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