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Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research, vol 27, iss 12, Clin Cancer Res
- Publication Year :
- 2021
- Publisher :
- American Association for Cancer Research (AACR), 2021.
-
Abstract
- Purpose: To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma. Patients and Methods: This two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden. Results: Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12–24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value. Conclusions: Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.
- Subjects :
- 0301 basic medicine
Oncology
Cancer Research
medicine.medical_specialty
Maximum Tolerated Dose
Clinical Trials and Supportive Activities
Oncology and Carcinogenesis
Astrocytoma
Neutropenia
Article
03 medical and health sciences
Rare Diseases
0302 clinical medicine
Pharmacokinetics
Clinical Research
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
Temozolomide
medicine
Humans
Oncology & Carcinogenesis
Dosing
Survival rate
Cancer
Brain Neoplasms
business.industry
Evaluation of treatments and therapeutic interventions
Bayes Theorem
medicine.disease
Discontinuation
Dacarbazine
030104 developmental biology
6.1 Pharmaceuticals
030220 oncology & carcinogenesis
Absolute neutrophil count
Patient Safety
Digestive Diseases
business
medicine.drug
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....cd007dd58b16e9df20e3282c3e7efd57