Phase 1b study to assess the safety, tolerability, and clinical activity of pamiparib in combination with temozolomide in patients with locally advanced or metastatic solid tumors.
Humans
Temozolomide
/ administration & dosage
Female
Middle Aged
Male
Aged
Neoplasms
/ drug therapy
Adult
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Maximum Tolerated Dose
Benzimidazoles
/ administration & dosage
Aged, 80 and over
Poly(ADP-ribose) Polymerase Inhibitors
/ administration & dosage
Drug Administration Schedule
Fluorenes
DNA repair
biomarkers
clinical trials
target therapy
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
Jul 2024
Jul 2024
Historique:
revised:
24
05
2024
received:
16
10
2023
accepted:
28
05
2024
medline:
6
7
2024
pubmed:
6
7
2024
entrez:
6
7
2024
Statut:
ppublish
Résumé
Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.
Sections du résumé
BACKGROUND
BACKGROUND
Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors.
METHODS
METHODS
Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed.
RESULTS
RESULTS
Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics.
CONCLUSIONS
CONCLUSIONS
Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.
Substances chimiques
Temozolomide
YF1K15M17Y
pamiparib
8375F9S90C
Benzimidazoles
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Fluorenes
0
Types de publication
Journal Article
Clinical Trial, Phase I
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
e7385Subventions
Organisme : BeiGene, Ltd
Informations de copyright
© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.
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