Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : ckbsupport@jax.org
Ref Type | |||||||||||||
PMID | |||||||||||||
Authors | A. Italiano, J.R. Infante, G. Shapiro, K.N. Moore, P. Lorusso, S. Postel-Vinay, S. Cousin, M. Toulmonde, C. Lucchesi, E. Blackwood, S. Mahrus, X. Lu, M. Tagen, J. Schutzman, J. Lauchle, J-C. Soria | ||||||||||||
Title | Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine (gem) in patients (pts) with refractory solid tumors | ||||||||||||
|
|||||||||||||
URL | https://www.annalsofoncology.org/article/S0923-7534(20)37795-4/fulltext | ||||||||||||
Abstract Text | Background: Checkpoint kinase 1 (Chk1) inhibition following chemotherapy overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. Methods: This Phase I trial enrolled pts with refractory solid tumors and ECOG 0-1 status. Patients received IV gem 1000 mg/m2 followed ∼24 hours later by GDC-0575 (15-60 mg) PO, or IV gem 500 mg/m2 followed ∼24 hours later by GDC-0575 (45-105 mg) PO, weekly for 2 of 3-week cycles. TP53 was evaluated in archival tumor tissue by gene sequencing. Safety, pharmacokinetics (PK), pharmacodynamics, and tumor response by RECIST v1.1 were investigated. Results: Of 81 pts treated, 73% were female, the median age was 56 years (range 27-75), and 48% were ECOG PS 0. The most common tumor types were breast (46%), and soft tissue sarcoma and NSCLC (both 7%). Dose escalation was halted at GDC-0575 60 mg and 105 mg with gem 1000 mg/m2 and gem 500 mg/m2, respectively, as pts experienced Grade 4 thrombocytopenia and Grade 3-4 febrile neutropenia as dose-limiting toxicities. The most frequent adverse events (all grades) related to GDC-0575 and/or gem were neutropenia (80%), anemia (56%), fatigue (47%), nausea (46%), and thrombocytopenia (40%). Maximum concentrations of GDC-0575 were achieved within 2 hours of dosing, and its half-life was ∼23 hours. No PK drug-drug interaction was observed between GDC-0575 and gem. Among pts treated with GDC-0575 and gem 500 mg/m2, there were 4 cPRs (2x sarcoma, NSCLC, TNBC) and 3 SDs (TNBC, NSCLC, SCLC) for ≥ 6 months. Exome sequencing data from tumor samples obtained at progression did not reveal mutations in Chk1 but identified mutations in genes known to regulate apoptosis. Conclusions: The Chk1 inhibitor GDC-0575 can be safely combined with a standard or modified dose and schedule of gem. Hematological toxicities were frequent but manageable. Preliminary anti-tumor activity was observed in patients with a variety of refractory solid tumors treated with GDC-0575 in combination with gem 500 mg/m2. Clinical trial identification: NCT01564251 |
Molecular Profile | Treatment Approach |
---|
Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
---|
Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
---|
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
---|
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
---|
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|