A phase i study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women's cancers with biomarker analyses

Alexandra S. Zimmer, Erin Nichols, Ashley M Cimino-Mathews, Cody Peer, Liang Cao, Min Jung Lee, Elise C. Kohn, Christina M. Annunziata, Stanley Lipkowitz, Jane B. Trepel, Rajni Sharma, Lekha Mikkilineni, Margaret Gatti-Mays, William D. Figg, Nicole D. Houston, Jung Min Lee

Research output: Contribution to journalArticle

Abstract

Background: Strategies to improve activity of immune checkpoint inhibitors are needed. We hypothesized enhanced DNA damage by olaparib, a PARP inhibitor, and reduced VEGF signaling by cediranib, a VEGFR1-3 inhibitor, would complement anti-tumor activity of durvalumab, a PD-L1 inhibitor, and the 3-drug combination would be tolerable. Methods: This phase 1 study tested the 3-drug combination in a 3 + 3 dose escalation. Cediranib was taken intermittently (5 days on/2 days off) at 15 or 20 mg (dose levels 1 and 2, respectively) with durvalumab 1500 mg IV every 4 weeks, and olaparib tablets 300 mg twice daily. The primary end point was the recommended phase 2 dose (RP2D). Response rate, pharmacokinetic (PK), and correlative analyses were secondary endpoints. Results: Nine patients (7 ovarian/1 endometrial/1 triple negative breast cancers, median 3 prior therapies [2-6]) were treated. Grade 3/4 adverse events include hypertension (1/9), anemia (1/9) and lymphopenia (3/9). No patients experienced dose limiting toxicities. The RP2D is cediranib, 20 mg (5 days on/2 days off) with full doses of durvalumab and olaparib. Four patients had partial responses (44%) and 3 had stable disease lasting ≥6 months, yielding a 67% clinical benefit rate. No significant effects on olaparib or cediranib PK parameters from the presence of durvalumab, or the co-administration of cediranib or olaparib were identified. Tumoral PD-L1 expression correlated with clinical benefit but cytokines and peripheral immune subsets did not. Conclusions: The RP2D is tolerable and has preliminary activity in recurrent women's cancers. A phase 2 expansion study is now enrolling for recurrent ovarian cancer patients. Trial registration: ClinicalTrials.gov identifier: NCT02484404. Registered June 29, 2015.

Original languageEnglish (US)
Article number197
JournalJournal for immunotherapy of cancer
Volume7
Issue number1
DOIs
StatePublished - Jul 25 2019

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Tumor Biomarkers
Complement Inactivating Agents
Drug Combinations
Pharmacokinetics
Triple Negative Breast Neoplasms
Lymphopenia
Ovarian Neoplasms
Vascular Endothelial Growth Factor A
Tablets
DNA Damage
Anemia
Neoplasms
Poly(ADP-ribose) Polymerase Inhibitors
cediranib
olaparib
Cytokines
Hypertension
Therapeutics

Keywords

  • Immune checkpoint inhibitor
  • Ovarian cancer
  • PARP inhibitor
  • VEGF inhibition

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

A phase i study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women's cancers with biomarker analyses. / Zimmer, Alexandra S.; Nichols, Erin; Cimino-Mathews, Ashley M; Peer, Cody; Cao, Liang; Lee, Min Jung; Kohn, Elise C.; Annunziata, Christina M.; Lipkowitz, Stanley; Trepel, Jane B.; Sharma, Rajni; Mikkilineni, Lekha; Gatti-Mays, Margaret; Figg, William D.; Houston, Nicole D.; Lee, Jung Min.

In: Journal for immunotherapy of cancer, Vol. 7, No. 1, 197, 25.07.2019.

Research output: Contribution to journalArticle

Zimmer, AS, Nichols, E, Cimino-Mathews, AM, Peer, C, Cao, L, Lee, MJ, Kohn, EC, Annunziata, CM, Lipkowitz, S, Trepel, JB, Sharma, R, Mikkilineni, L, Gatti-Mays, M, Figg, WD, Houston, ND & Lee, JM 2019, 'A phase i study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women's cancers with biomarker analyses', Journal for immunotherapy of cancer, vol. 7, no. 1, 197. https://doi.org/10.1186/s40425-019-0680-3
Zimmer, Alexandra S. ; Nichols, Erin ; Cimino-Mathews, Ashley M ; Peer, Cody ; Cao, Liang ; Lee, Min Jung ; Kohn, Elise C. ; Annunziata, Christina M. ; Lipkowitz, Stanley ; Trepel, Jane B. ; Sharma, Rajni ; Mikkilineni, Lekha ; Gatti-Mays, Margaret ; Figg, William D. ; Houston, Nicole D. ; Lee, Jung Min. / A phase i study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women's cancers with biomarker analyses. In: Journal for immunotherapy of cancer. 2019 ; Vol. 7, No. 1.
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T1 - A phase i study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women's cancers with biomarker analyses

AU - Zimmer, Alexandra S.

AU - Nichols, Erin

AU - Cimino-Mathews, Ashley M

AU - Peer, Cody

AU - Cao, Liang

AU - Lee, Min Jung

AU - Kohn, Elise C.

AU - Annunziata, Christina M.

AU - Lipkowitz, Stanley

AU - Trepel, Jane B.

AU - Sharma, Rajni

AU - Mikkilineni, Lekha

AU - Gatti-Mays, Margaret

AU - Figg, William D.

AU - Houston, Nicole D.

AU - Lee, Jung Min

PY - 2019/7/25

Y1 - 2019/7/25

N2 - Background: Strategies to improve activity of immune checkpoint inhibitors are needed. We hypothesized enhanced DNA damage by olaparib, a PARP inhibitor, and reduced VEGF signaling by cediranib, a VEGFR1-3 inhibitor, would complement anti-tumor activity of durvalumab, a PD-L1 inhibitor, and the 3-drug combination would be tolerable. Methods: This phase 1 study tested the 3-drug combination in a 3 + 3 dose escalation. Cediranib was taken intermittently (5 days on/2 days off) at 15 or 20 mg (dose levels 1 and 2, respectively) with durvalumab 1500 mg IV every 4 weeks, and olaparib tablets 300 mg twice daily. The primary end point was the recommended phase 2 dose (RP2D). Response rate, pharmacokinetic (PK), and correlative analyses were secondary endpoints. Results: Nine patients (7 ovarian/1 endometrial/1 triple negative breast cancers, median 3 prior therapies [2-6]) were treated. Grade 3/4 adverse events include hypertension (1/9), anemia (1/9) and lymphopenia (3/9). No patients experienced dose limiting toxicities. The RP2D is cediranib, 20 mg (5 days on/2 days off) with full doses of durvalumab and olaparib. Four patients had partial responses (44%) and 3 had stable disease lasting ≥6 months, yielding a 67% clinical benefit rate. No significant effects on olaparib or cediranib PK parameters from the presence of durvalumab, or the co-administration of cediranib or olaparib were identified. Tumoral PD-L1 expression correlated with clinical benefit but cytokines and peripheral immune subsets did not. Conclusions: The RP2D is tolerable and has preliminary activity in recurrent women's cancers. A phase 2 expansion study is now enrolling for recurrent ovarian cancer patients. Trial registration: ClinicalTrials.gov identifier: NCT02484404. Registered June 29, 2015.

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