A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620).
DNA damage
PARP
Pharmacokinetics
Phase 1 study
Solid tumors
Triple negative breast cancer
Veliparib
Journal
Breast cancer research and treatment
ISSN: 1573-7217
Titre abrégé: Breast Cancer Res Treat
Pays: Netherlands
ID NLM: 8111104
Informations de publication
Date de publication:
Apr 2023
Apr 2023
Historique:
received:
22
09
2022
accepted:
08
02
2023
pmc-release:
01
04
2024
pubmed:
1
3
2023
medline:
28
3
2023
entrez:
28
2
2023
Statut:
ppublish
Résumé
Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC). Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%. Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.
Sections du résumé
BACKGROUND
BACKGROUND
Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC).
METHODS
METHODS
Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m
RESULTS
RESULTS
Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%.
CONCLUSION
CONCLUSIONS
Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.
Identifiants
pubmed: 36853577
doi: 10.1007/s10549-023-06889-0
pii: 10.1007/s10549-023-06889-0
pmc: PMC10710035
mid: NIHMS1947592
doi:
Substances chimiques
Carboplatin
BG3F62OND5
Paclitaxel
P88XT4IS4D
veliparib
01O4K0631N
Types de publication
Clinical Trial, Phase I
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
487-498Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001857
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA186690
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA047904
Pays : United States
Organisme : NCI NIH HHS
ID : P30CA047904
Pays : United States
Organisme : NCI NIH HHS
ID : U01CA099168
Pays : United States
Organisme : NCI NIH HHS
ID : UM1CA186690
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA099168
Pays : United States
Organisme : NCI NIH HHS
ID : U24CA247643
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA247643
Pays : United States
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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