PMID- 28471727
OWN - NLM
STAT- MEDLINE
DCOM- 20170825
LR  - 20220331
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Print)
IS  - 0732-183X (Linking)
VI  - 35
IP  - 19
DP  - 2017 Jul 1
TI  - Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor 
      Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or 
      Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's 
      Cancers: A Dose-Escalation, Phase I Study.
PG  - 2193-2202
LID - 10.1200/JCO.2016.72.1340 [doi]
AB  - Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition 
      and/or reduced vascular endothelial growth factor signaling by vascular 
      endothelial growth factor receptor inhibition may complement antitumor activity 
      of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 
      (PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable 
      and active in recurrent women's cancers. Patients and Methods This phase I study 
      tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was 
      administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either 
      olaparib tablets twice daily or cediranib on two schedules. The primary end point 
      was the recommended phase II dose (RP2D). Response rate and pharmacokinetic 
      analysis were secondary end points. Results Between June 2015 and May 2016, 26 
      women were enrolled. The RP2D was durvalumab 1,500 mg every 4 weeks with olaparib 
      300 mg twice a day, or cediranib 20 mg, 5 days on/2 days off. No dose-limiting 
      toxicity was recorded with durvalumab plus olaparib. The cediranib intermittent 
      schedule (n = 6) was examined because of recurrent grade 2 and non-dose-limiting 
      toxicity grade 3 and 4 adverse events (AEs) on the daily schedule (n = 8). 
      Treatment-emergent AEs included hypertension (two of eight), diarrhea (two of 
      eight), pulmonary embolism (two of eight), pulmonary hypertension (one of eight), 
      and lymphopenia (one of eight). Durvalumab plus intermittent cediranib grade 3 
      and 4 AEs were hypertension (one of six) and fatigue (one of six). Exposure to 
      durvalumab increased cediranib area under the curve and maximum plasma 
      concentration on the daily, but not intermittent, schedules. Two partial 
      responses (>/=15 months and >/= 11 months) and eight stable diseases >/= 4 months 
      (median, 8 months [4 to 14.5 months]) were seen in patients who received 
      durvalumab plus olaparib, yielding an 83% disease control rate. Six partial 
      responses (>/= 5 to >/= 8 months) and three stable diseases >/= 4 months (4 to >/= 8 
      months) were seen in 12 evaluable patients who received durvalumab plus 
      cediranib, for a 50% response rate and a 75% disease control rate. Response to 
      therapy was independent of PD-L1 expression. Conclusion To our knowledge, this is 
      the first reported anti-PD-L1 plus olaparib or cediranib combination therapy. The 
      RP2Ds of durvalumab plus olaparib and durvalumab plus intermittent cediranib are 
      tolerable and active. Phase II studies with biomarker evaluation are ongoing.
FAU - Lee, Jung-Min
AU  - Lee JM
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Cimino-Mathews, Ashley
AU  - Cimino-Mathews A
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Peer, Cody J
AU  - Peer CJ
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Zimmer, Alexandra
AU  - Zimmer A
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Lipkowitz, Stanley
AU  - Lipkowitz S
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Annunziata, Christina M
AU  - Annunziata CM
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Cao, Liang
AU  - Cao L
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Harrell, Maria I
AU  - Harrell MI
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Swisher, Elizabeth M
AU  - Swisher EM
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Houston, Nicole
AU  - Houston N
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Botesteanu, Dana-Adriana
AU  - Botesteanu DA
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Taube, Janis M
AU  - Taube JM
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Thompson, Elizabeth
AU  - Thompson E
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Ogurtsova, Aleksandra
AU  - Ogurtsova A
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Xu, Haiying
AU  - Xu H
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Nguyen, Jeffers
AU  - Nguyen J
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Ho, Tony W
AU  - Ho TW
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Figg, William D
AU  - Figg WD
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
FAU - Kohn, Elise C
AU  - Kohn EC
AD  - Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. 
      Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, 
      William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer 
      Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, 
      Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, 
      Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell 
      and Elizabeth M. Swisher, University of Washington, Seattle, WA.
LA  - eng
GR  - ZIA BC011525/ImNIH/Intramural NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20170504
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (B7-H1 Antigen)
RN  - 0 (CD274 protein, human)
RN  - 0 (Phthalazines)
RN  - 0 (Piperazines)
RN  - 0 (Poly(ADP-ribose) Polymerase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0 (durvalumab)
RN  - EC 2.7.10.1 (FLT1 protein, human)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1)
RN  - NQU9IPY4K9 (cediranib)
RN  - WOH1JD9AR8 (olaparib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal/administration & dosage/adverse effects/pharmacokinetics
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - B7-H1 Antigen/antagonists & inhibitors/biosynthesis/immunology
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Genital Neoplasms, Female/*drug therapy/immunology/metabolism/pathology
MH  - Humans
MH  - Lymphocytes, Tumor-Infiltrating/immunology
MH  - Middle Aged
MH  - Phthalazines/administration & dosage/adverse effects/pharmacokinetics
MH  - Piperazines/administration & dosage/adverse effects/pharmacokinetics
MH  - Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage
MH  - Protein Kinase Inhibitors/administration & dosage/adverse effects
MH  - Quinazolines/administration & dosage/adverse effects/pharmacokinetics
MH  - Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors
PMC - PMC5493052
EDAT- 2017/05/05 06:00
MHDA- 2017/08/26 06:00
PMCR- 2018/07/01
CRDT- 2017/05/05 06:00
PHST- 2017/05/05 06:00 [pubmed]
PHST- 2017/08/26 06:00 [medline]
PHST- 2017/05/05 06:00 [entrez]
PHST- 2018/07/01 00:00 [pmc-release]
AID - 721340 [pii]
AID - 10.1200/JCO.2016.72.1340 [doi]
PST - ppublish
SO  - J Clin Oncol. 2017 Jul 1;35(19):2193-2202. doi: 10.1200/JCO.2016.72.1340. Epub 
      2017 May 4.