A phase II study of the dual mTOR inhibitor MLN0128 in patients with metastatic castration resistant prostate cancer.
Invest New Drugs
; 36(3): 458-467, 2018 06.
Article
em En
| MEDLINE
| ID: mdl-29508246
ABSTRACT
Background MLN0128 is a first-in-class, dual mTOR inhibitor with potential to outperform standard rapalogs through inhibition of TORC1 and TORC2. This phase II study was designed to assess antitumor activity of MLN0128 in metastatic castration-resistant prostate cancer (mCRPC). Methods Eligible patients had mCRPC previously treated with abiraterone acetate and/or enzalutamide. Five patients started MLN0128 at 5 mg once daily, subsequently dose reduced to 4 mg because of toxicity. Four subsequent patients started MLN0128 at 4 mg daily. Primary endpoint was progression-free survival at 6 months. Results Nine patients were enrolled and median time on treatment was 11 weeks (range 3-30). Best response was stable disease. All patients had a rise in PSA on treatment, with a median 159% increase from baseline (range 12-620%). Median baseline circulating tumor cell count was 1 cell/mL (range 0-40); none had a decrease in cell count posttreatment. Grade ≤ 2 adverse events included fatigue, anorexia, and rash. The most common serious adverse events were grade 3 dyspnea and maculopapular rash. Eight patients discontinued treatment early because of radiographic progression (n = 1), grade 3 toxicity (n = 5), or investigator discretion (n = 2). Four patients had immediate PSA decline following drug discontinuation, suggesting MLN0128 could cause compensatory increase of androgen receptor (AR) activity. Correlative studies of pretreatment and posttreatment biopsy specimens revealed limited inhibition of AKT phosphorylation, 4EBP1 phosphorylation, and eIF4E activity. Conclusions Clinical efficacy of MLN0128 in mCRPC was limited likely due to dose reductions secondary to toxicity, PSA kinetics suggesting AR activation resulting from mTOR inhibition, and poor inhibition of mTOR signaling targets.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
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Benzoxazóis
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Serina-Treonina Quinases TOR
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Neoplasias de Próstata Resistentes à Castração
Limite:
Aged
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Invest New Drugs
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos