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Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer
- Source :
- Scientia, British Journal of Cancer
- Publication Year :
- 2020
- Publisher :
- Springer Nature, 2020.
-
Abstract
- Background This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. Methods Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). Results Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. Conclusions Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer. Clinical trial registration ClinicalTrials.gov, NCT01058707.
- Subjects :
- Male
Cancer Research
Cancer therapy
Other subheadings::Other subheadings::/drug therapy [Other subheadings]
0302 clinical medicine
Renal cell carcinoma
Neoplasms
Medicine
Carcinoid tumour
Aged, 80 and over
0303 health sciences
TOR Serine-Threonine Kinases
Càncer - Tractament
Middle Aged
Kidney Neoplasms
Oncology
Tolerability
030220 oncology & carcinogenesis
técnicas de investigación::pruebas de toxicidad::dosis máxima tolerada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS]
Female
Adult
medicine.medical_specialty
Maximum Tolerated Dose
Urology
Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores]
Antineoplastic Agents
Urological cancer
Article
neoplasias [ENFERMEDADES]
03 medical and health sciences
Pharmacokinetics
Carcinoma
Humans
Carcinoma, Renal Cell
Protein Kinase Inhibitors
Aged
030304 developmental biology
Gynaecological cancer
Bladder cancer
business.industry
Endometrial cancer
Investigative Techniques::Toxicity Tests::Maximum Tolerated Dose [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT]
medicine.disease
Endometrial Neoplasms
Neoplasms [DISEASES]
Pyrimidines
Urinary Bladder Neoplasms
Pharmacodynamics
Pyrazoles
Medicaments - Administració
business
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Scientia, British Journal of Cancer
- Accession number :
- edsair.doi.dedup.....04304289ca3485f1a4178792263b5785