Phase I Trial of Debio 1143, an Antagonist of Inhibitor of Apoptosis Proteins, Combined with Cisplatin Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck.
Adolescent
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Azocines
/ administration & dosage
Benzhydryl Compounds
/ administration & dosage
Chemoradiotherapy
/ methods
Cisplatin
/ administration & dosage
Female
Follow-Up Studies
Head and Neck Neoplasms
/ pathology
Humans
Inhibitor of Apoptosis Proteins
/ antagonists & inhibitors
Male
Maximum Tolerated Dose
Middle Aged
Prognosis
Retrospective Studies
Squamous Cell Carcinoma of Head and Neck
/ pathology
Young Adult
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 12 2020
15 12 2020
Historique:
received:
03
02
2020
revised:
25
06
2020
accepted:
24
09
2020
pubmed:
1
10
2020
medline:
15
12
2021
entrez:
30
9
2020
Statut:
ppublish
Résumé
Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported. Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment. Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3-4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%. The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.
Identifiants
pubmed: 32994295
pii: 1078-0432.CCR-20-0425
doi: 10.1158/1078-0432.CCR-20-0425
doi:
Substances chimiques
Azocines
0
Benzhydryl Compounds
0
Inhibitor of Apoptosis Proteins
0
N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide
0
Cisplatin
Q20Q21Q62J
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6429-6436Informations de copyright
©2020 American Association for Cancer Research.
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