Safety & 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

Jung Min Lee, Ashley M Cimino-Mathews, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Maria I. Harrell, Elizabeth M. Swisher, Nicole Houston, Dana Adriana Botesteanu, Janis M Taube, Elizabeth Thompson, Aleksandra Ogurtsova, Haiying Xu, Jeffers Nguyen, Tony W. Ho, William D. Figg, Elise C. Kohn

Research output: Contribution to journalArticle

Abstract

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 andMay 2016, 26womenwere enrolled. The RP2Dwas durvalumab 1,500mg 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$4months (median, 8 months [4 to 14.5months]) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses ($ 5 to $ 8 months) and three stable diseases $ 4months (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.

Original languageEnglish (US)
Pages (from-to)2193-2202
Number of pages10
JournalJournal of Clinical Oncology
Volume35
Issue number19
DOIs
StatePublished - Jul 1 2017

Fingerprint

Vascular Endothelial Growth Factor Receptor-3
Vascular Endothelial Growth Factor Receptor-1
Ligands
Safety
Neoplasms
Appointments and Schedules
Pulmonary Embolism
Pulmonary Hypertension
Hypertension
olaparib
cediranib
Poly(ADP-ribose) Polymerase Inhibitors
Lymphopenia
Vascular Endothelial Growth Factor Receptor
Poly(ADP-ribose) Polymerases
Vascular Endothelial Growth Factor A
Tablets
DNA Damage
Area Under Curve
Fatigue

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Safety & 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. / Lee, Jung Min; Cimino-Mathews, Ashley M; Peer, Cody J.; Zimmer, Alexandra; Lipkowitz, Stanley; Annunziata, Christina M.; Cao, Liang; Harrell, Maria I.; Swisher, Elizabeth M.; Houston, Nicole; Botesteanu, Dana Adriana; Taube, Janis M; Thompson, Elizabeth; Ogurtsova, Aleksandra; Xu, Haiying; Nguyen, Jeffers; Ho, Tony W.; Figg, William D.; Kohn, Elise C.

In: Journal of Clinical Oncology, Vol. 35, No. 19, 01.07.2017, p. 2193-2202.

Research output: Contribution to journalArticle

Lee, Jung Min ; Cimino-Mathews, Ashley M ; Peer, Cody J. ; Zimmer, Alexandra ; Lipkowitz, Stanley ; Annunziata, Christina M. ; Cao, Liang ; Harrell, Maria I. ; Swisher, Elizabeth M. ; Houston, Nicole ; Botesteanu, Dana Adriana ; Taube, Janis M ; Thompson, Elizabeth ; Ogurtsova, Aleksandra ; Xu, Haiying ; Nguyen, Jeffers ; Ho, Tony W. ; Figg, William D. ; Kohn, Elise C. / Safety & 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. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 19. pp. 2193-2202.
@article{a22d66e030964768b8d00919cd779ba6,
title = "Safety & 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",
abstract = "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 andMay 2016, 26womenwere enrolled. The RP2Dwas durvalumab 1,500mg 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$4months (median, 8 months [4 to 14.5months]) were seen in patients who received durvalumab plus olaparib, yielding an 83{\%} disease control rate. Six partial responses ($ 5 to $ 8 months) and three stable diseases $ 4months (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.",
author = "Lee, {Jung Min} and Cimino-Mathews, {Ashley M} and Peer, {Cody J.} and Alexandra Zimmer and Stanley Lipkowitz and Annunziata, {Christina M.} and Liang Cao and Harrell, {Maria I.} and Swisher, {Elizabeth M.} and Nicole Houston and Botesteanu, {Dana Adriana} and Taube, {Janis M} and Elizabeth Thompson and Aleksandra Ogurtsova and Haiying Xu and Jeffers Nguyen and Ho, {Tony W.} and Figg, {William D.} and Kohn, {Elise C.}",
year = "2017",
month = "7",
day = "1",
doi = "10.1200/JCO.2016.72.1340",
language = "English (US)",
volume = "35",
pages = "2193--2202",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "19",

}

TY - JOUR

T1 - Safety & 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

T2 - A dose-escalation, phase I study

AU - Lee, Jung Min

AU - Cimino-Mathews, Ashley M

AU - Peer, Cody J.

AU - Zimmer, Alexandra

AU - Lipkowitz, Stanley

AU - Annunziata, Christina M.

AU - Cao, Liang

AU - Harrell, Maria I.

AU - Swisher, Elizabeth M.

AU - Houston, Nicole

AU - Botesteanu, Dana Adriana

AU - Taube, Janis M

AU - Thompson, Elizabeth

AU - Ogurtsova, Aleksandra

AU - Xu, Haiying

AU - Nguyen, Jeffers

AU - Ho, Tony W.

AU - Figg, William D.

AU - Kohn, Elise C.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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 andMay 2016, 26womenwere enrolled. The RP2Dwas durvalumab 1,500mg 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$4months (median, 8 months [4 to 14.5months]) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses ($ 5 to $ 8 months) and three stable diseases $ 4months (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.

AB - 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 andMay 2016, 26womenwere enrolled. The RP2Dwas durvalumab 1,500mg 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$4months (median, 8 months [4 to 14.5months]) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses ($ 5 to $ 8 months) and three stable diseases $ 4months (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.

UR - http://www.scopus.com/inward/record.url?scp=85021746571&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021746571&partnerID=8YFLogxK

U2 - 10.1200/JCO.2016.72.1340

DO - 10.1200/JCO.2016.72.1340

M3 - Article

C2 - 28471727

AN - SCOPUS:85021746571

VL - 35

SP - 2193

EP - 2202

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 19

ER -