The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved..
The treatment of metastatic uveal melanoma remains a major clinical challenge. Procaspase-3, a proapoptotic protein and precursor to the key apoptotic executioner caspase-3, is overexpressed in a wide range of malignancies, and the drug PAC-1 leverages this overexpression to selectively kill cancer cells. Herein, we investigate the efficacy of PAC-1 against uveal melanoma cell lines and report the synergistic combination of PAC-1 and entrectinib. This preclinical activity, tolerability data in mice, and the known clinical effectiveness of these drugs in human cancer patients led to a small Phase 1b study in patients with metastatic uveal melanoma. The combination of PAC-1 and entrectinib was tolerated with no treatment-related grade ≥3 toxicities in these patients. The pharmacokinetics of entrectinib were not affected by PAC-1 treatment. In this small and heavily pretreated initial cohort, stable disease was observed in four out of six patients, with a median progression-free survival of 3.38 months (95% CI 1.6-6.5 months). This study is an initial demonstration that the combination of PAC-1 and entrectinib may warrant further clinical investigation. Clinical trial registration: Clinical Trials.gov: NCT04589832.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:33 |
|---|---|
| Enthalten in: |
Melanoma research - 33(2023), 6 vom: 01. Dez., Seite 514-524 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Boudreau, Matthew W [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Clinical Trial, Phase I |
|---|
| Anmerkungen: |
Date Completed 30.10.2023 Date Revised 07.12.2023 published: Print-Electronic ClinicalTrials.gov: NCT04589832 Citation Status MEDLINE |
|---|
| doi: |
10.1097/CMR.0000000000000927 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM362345562 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM362345562 | ||
| 003 | DE-627 | ||
| 005 | 20231226091038.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1097/CMR.0000000000000927 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1207.xml |
| 035 | |a (DE-627)NLM362345562 | ||
| 035 | |a (NLM)37738028 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Boudreau, Matthew W |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma |
| 264 | 1 | |c 2023 | |
| 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 30.10.2023 | ||
| 500 | |a Date Revised 07.12.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT04589832 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved. | ||
| 520 | |a The treatment of metastatic uveal melanoma remains a major clinical challenge. Procaspase-3, a proapoptotic protein and precursor to the key apoptotic executioner caspase-3, is overexpressed in a wide range of malignancies, and the drug PAC-1 leverages this overexpression to selectively kill cancer cells. Herein, we investigate the efficacy of PAC-1 against uveal melanoma cell lines and report the synergistic combination of PAC-1 and entrectinib. This preclinical activity, tolerability data in mice, and the known clinical effectiveness of these drugs in human cancer patients led to a small Phase 1b study in patients with metastatic uveal melanoma. The combination of PAC-1 and entrectinib was tolerated with no treatment-related grade ≥3 toxicities in these patients. The pharmacokinetics of entrectinib were not affected by PAC-1 treatment. In this small and heavily pretreated initial cohort, stable disease was observed in four out of six patients, with a median progression-free survival of 3.38 months (95% CI 1.6-6.5 months). This study is an initial demonstration that the combination of PAC-1 and entrectinib may warrant further clinical investigation. Clinical trial registration: Clinical Trials.gov: NCT04589832 | ||
| 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, Non-U.S. Gov't | |
| 650 | 7 | |a entrectinib |2 NLM | |
| 650 | 7 | |a L5ORF0AN1I |2 NLM | |
| 700 | 1 | |a Tonogai, Emily J |e verfasserin |4 aut | |
| 700 | 1 | |a Schane, Claire P |e verfasserin |4 aut | |
| 700 | 1 | |a Xi, Min X |e verfasserin |4 aut | |
| 700 | 1 | |a Fischer, James H |e verfasserin |4 aut | |
| 700 | 1 | |a Vijayakumar, Jayanthi |e verfasserin |4 aut | |
| 700 | 1 | |a Ji, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Tarasow, Theodore M |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Timothy M |e verfasserin |4 aut | |
| 700 | 1 | |a Hergenrother, Paul J |e verfasserin |4 aut | |
| 700 | 1 | |a Dudek, Arkadiusz Z |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Melanoma research |d 1997 |g 33(2023), 6 vom: 01. Dez., Seite 514-524 |w (DE-627)NLM012645702 |x 1473-5636 |7 nnns |
| 773 | 1 | 8 | |g volume:33 |g year:2023 |g number:6 |g day:01 |g month:12 |g pages:514-524 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1097/CMR.0000000000000927 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 33 |j 2023 |e 6 |b 01 |c 12 |h 514-524 | ||