A phase II study of the dual mTOR inhibitor MLN0128 in patients with metastatic castration resistant prostate cancer Journal Article

Authors: Graham, L.; Banda, K.; Torres, A.; Carver, B. S.; Chen, Y.; Pisano, K.; Shelkey, G.; Curley, T.; Scher, H. I.; Lotan, T. L.; Hsieh, A. C.; Rathkopf, D. E.
Article Title: A phase II study of the dual mTOR inhibitor MLN0128 in patients with metastatic castration resistant prostate cancer
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. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.
Keywords: prostate cancer; mtor; mln0128
Journal Title: Investigational New Drugs
Volume: 36
Issue: 3
ISSN: 0167-6997
Publisher: Springer  
Date Published: 2018-06-01
Start Page: 458
End Page: 467
Language: English
DOI: 10.1007/s10637-018-0578-9
PROVIDER: scopus
PUBMED: 29508246
PMCID: PMC6050986
Notes: Article -- Export Date: 1 June 2018 -- Source: Scopus
Citation Impact
MSK Authors
  1. Yu Chen
    104 Chen
  2. Dana Elizabeth Rathkopf
    222 Rathkopf
  3. Brett Stewart Carver
    133 Carver
  4. Howard Scher
    1081 Scher
  5. Katherine Pisano
    2 Pisano