Phase 1 study of the HSP90 inhibitor onalespib in combination with AT7519, a pan-CDK inhibitor, in patients with advanced solid tumors
PURPOSE: We conducted a phase 1 trial of the HSP90 inhibitor onalespib in combination with the CDK inhibitor AT7519, in patients with advanced solid tumors to determine the safety profile and maximally tolerated dose, pharmacokinetics, preliminary antitumor activity, and to assess the pharmacodynamic (PD) effects on HSP70 expression in patient-derived PBMCs and plasma.
METHODS: This study followed a 3 + 3 trial design with 1 week of intravenous (IV) onalespib alone, followed by onalespib/AT7519 (IV) on days 1, 4, 8, and 11 of a 21-days cycle. PK and PD samples were collected at baseline, after onalespib alone, and following combination therapy.
RESULTS: Twenty-eight patients were treated with the demonstration of downstream target engagement of HSP70 expression in plasma and PBMCs. The maximally tolerated dose was onalespib 80 mg/m2 IV + AT7519 21 mg/m2 IV. Most common drug-related adverse events included Grade 1/2 diarrhea (79%), fatigue (54%), mucositis (57%), nausea (46%), and vomiting (50%). Partial responses were seen in a palate adenocarcinoma and Sertoli-Leydig tumor; a colorectal and an endometrial cancer patient both remained on study for ten cycles with stable disease as the best response. There were no clinically relevant PK interactions for either drug.
CONCLUSIONS: Combined onalespib and AT7519 is tolerable, though below monotherapy RP2D. Promising preliminary clinical activity was seen. Further benefit may be seen with the incorporation of molecular signature pre-selection. Further biomarker development will require the assessment of the on-target impact on relevant client proteins in tumor tissue.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:86 |
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| Enthalten in: |
Cancer chemotherapy and pharmacology - 86(2020), 6 vom: 01. Dez., Seite 815-827 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Do, Khanh T [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.05.2021 Date Revised 14.07.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00280-020-04176-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM316641561 |
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| 100 | 1 | |a Do, Khanh T |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Phase 1 study of the HSP90 inhibitor onalespib in combination with AT7519, a pan-CDK inhibitor, in patients with advanced solid tumors |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 21.05.2021 | ||
| 500 | |a Date Revised 14.07.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a PURPOSE: We conducted a phase 1 trial of the HSP90 inhibitor onalespib in combination with the CDK inhibitor AT7519, in patients with advanced solid tumors to determine the safety profile and maximally tolerated dose, pharmacokinetics, preliminary antitumor activity, and to assess the pharmacodynamic (PD) effects on HSP70 expression in patient-derived PBMCs and plasma | ||
| 520 | |a METHODS: This study followed a 3 + 3 trial design with 1 week of intravenous (IV) onalespib alone, followed by onalespib/AT7519 (IV) on days 1, 4, 8, and 11 of a 21-days cycle. PK and PD samples were collected at baseline, after onalespib alone, and following combination therapy | ||
| 520 | |a RESULTS: Twenty-eight patients were treated with the demonstration of downstream target engagement of HSP70 expression in plasma and PBMCs. The maximally tolerated dose was onalespib 80 mg/m2 IV + AT7519 21 mg/m2 IV. Most common drug-related adverse events included Grade 1/2 diarrhea (79%), fatigue (54%), mucositis (57%), nausea (46%), and vomiting (50%). Partial responses were seen in a palate adenocarcinoma and Sertoli-Leydig tumor; a colorectal and an endometrial cancer patient both remained on study for ten cycles with stable disease as the best response. There were no clinically relevant PK interactions for either drug | ||
| 520 | |a CONCLUSIONS: Combined onalespib and AT7519 is tolerable, though below monotherapy RP2D. Promising preliminary clinical activity was seen. Further benefit may be seen with the incorporation of molecular signature pre-selection. Further biomarker development will require the assessment of the on-target impact on relevant client proteins in tumor tissue | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
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| 650 | 7 | |a HSP90 Heat-Shock Proteins |2 NLM | |
| 650 | 7 | |a Isoindoles |2 NLM | |
| 650 | 7 | |a Piperidines |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Pyrazoles |2 NLM | |
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| 700 | 1 | |a O'Sullivan Coyne, Geraldine |e verfasserin |4 aut | |
| 700 | 1 | |a Hays, John L |e verfasserin |4 aut | |
| 700 | 1 | |a Supko, Jeffrey G |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Stephen V |e verfasserin |4 aut | |
| 700 | 1 | |a Beebe, Kristin |e verfasserin |4 aut | |
| 700 | 1 | |a Neckers, Len |e verfasserin |4 aut | |
| 700 | 1 | |a Trepel, Jane B |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Min-Jung |e verfasserin |4 aut | |
| 700 | 1 | |a Smyth, Tomoko |e verfasserin |4 aut | |
| 700 | 1 | |a Gannon, Courtney |e verfasserin |4 aut | |
| 700 | 1 | |a Hedglin, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Muzikansky, Alona |e verfasserin |4 aut | |
| 700 | 1 | |a Campos, Susana |e verfasserin |4 aut | |
| 700 | 1 | |a Lyons, John |e verfasserin |4 aut | |
| 700 | 1 | |a Ivy, Percy |e verfasserin |4 aut | |
| 700 | 1 | |a Doroshow, James H |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Alice P |e verfasserin |4 aut | |
| 700 | 1 | |a Shapiro, Geoffrey I |e verfasserin |4 aut | |
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