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A Phase I Dose-Escalation Study of LY3405105, a Covalent Inhibitor of Cyclin-Dependent Kinase 7, Administered to Patients With Advanced Solid Tumors.
- Source :
- Oncologist; Jan2024, Vol. 29 Issue 1, pe131-e140, 10p
- Publication Year :
- 2024
-
Abstract
- Background This study aimed to evaluate the safety, pharmacokinetics (PKs), and preliminary activity of LY3405105, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), in patients with advanced solid tumors. Materials and Methods LY3405105 monotherapy was given once daily (QD; part A1) or thrice weekly (TIW; part A2) starting at 1 and 2 mg orally, respectively, and escalated per a Bayesian design in adult patients. The primary endpoint was safety, and secondary endpoints included PKs and antitumor activity. Results Fifty-four patients were enrolled: 43 in part A1 and 11 in part A2. Seven patients had dose-limiting toxicities, all in part A1 (45 mg: n = 3; 35 mg: n = 3; 25 mg: n = 1). Thirty-five patients (64.8%) reported at least one treatment-related adverse event (TRAE). TRAEs (≥10%) were diarrhea, nausea, fatigue, vomiting, abdominal pain, anemia, asthenia, and decreased platelet count. QD dosing showed sustained exposure with less peak-trough fluctuation compared to TIW dosing. Median time to maximum concentration was 1-2 hours and half-life was 15-19 hours. CDK7-target occupancy in skin and peripheral blood on day 15 was dose-dependent and reached near maximal occupancy of 75% at ≥15 mg QD. The maximum tolerated dose (MTD) was 20 mg QD. Twelve patients in part A1 (27.9%) and 5 patients in part A2 (45.5%) had a best overall response of stable disease. No complete response or partial response was observed. Conclusion The MTD of LY3405105 monotherapy was 20 mg QD. The most common toxicities were gastrointestinal adverse events, myelosuppression, fatigue, and asthenia. Limited clinical activity was observed in this phase I trial, and there are no plans for further development. ClinicalTrials.gov Identifier NCT03770494. [ABSTRACT FROM AUTHOR]
- Subjects :
- THERAPEUTIC use of antineoplastic agents
DRUG efficacy
DRUG dosage
DRUG tolerance
CLINICAL trials
DIARRHEA
NAUSEA
PROTEIN kinase inhibitors
ANTINEOPLASTIC agents
GASTROINTESTINAL diseases
CANCER patients
VOMITING
ASTHENIA
CELL cycle
RESEARCH funding
DESCRIPTIVE statistics
ANEMIA
PLATELET count
GENE expression profiling
TUMORS
FATIGUE (Physiology)
ABDOMINAL pain
PATIENT safety
DRUG toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 10837159
- Volume :
- 29
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Oncologist
- Publication Type :
- Academic Journal
- Accession number :
- 174668700
- Full Text :
- https://doi.org/10.1093/oncolo/oyad215