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
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
|---|---|
| Enthalten in: |
Journal for immunotherapy of cancer - 7(2019), 1 vom: 25. Juli, Seite 197 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zimmer, Alexandra S [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.06.2020 Date Revised 04.11.2023 published: Electronic ClinicalTrials.gov: NCT02484404 Citation Status MEDLINE |
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| doi: |
10.1186/s40425-019-0680-3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM299571378 |
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| 041 | |a eng | ||
| 100 | 1 | |a Zimmer, Alexandra S |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a 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 |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 24.06.2020 | ||
| 500 | |a Date Revised 04.11.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT02484404 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02484404. Registered June 29, 2015 | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, N.I.H., Intramural | |
| 650 | 4 | |a Immune checkpoint inhibitor | |
| 650 | 4 | |a Ovarian cancer | |
| 650 | 4 | |a PARP inhibitor | |
| 650 | 4 | |a VEGF inhibition | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a B7-H1 Antigen |2 NLM | |
| 650 | 7 | |a CD274 protein, human |2 NLM | |
| 650 | 7 | |a Phthalazines |2 NLM | |
| 650 | 7 | |a Piperazines |2 NLM | |
| 650 | 7 | |a Quinazolines |2 NLM | |
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| 700 | 1 | |a Nichols, Erin |e verfasserin |4 aut | |
| 700 | 1 | |a Cimino-Mathews, Ashley |e verfasserin |4 aut | |
| 700 | 1 | |a Peer, Cody |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Liang |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Min-Jung |e verfasserin |4 aut | |
| 700 | 1 | |a Kohn, Elise C |e verfasserin |4 aut | |
| 700 | 1 | |a Annunziata, Christina M |e verfasserin |4 aut | |
| 700 | 1 | |a Lipkowitz, Stanley |e verfasserin |4 aut | |
| 700 | 1 | |a Trepel, Jane B |e verfasserin |4 aut | |
| 700 | 1 | |a Sharma, Rajni |e verfasserin |4 aut | |
| 700 | 1 | |a Mikkilineni, Lekha |e verfasserin |4 aut | |
| 700 | 1 | |a Gatti-Mays, Margaret |e verfasserin |4 aut | |
| 700 | 1 | |a Figg, William D |e verfasserin |4 aut | |
| 700 | 1 | |a Houston, Nicole D |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Jung-Min |e verfasserin |4 aut | |
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