Journal
INVESTIGATIONAL NEW DRUGS
Volume 36, Issue 3, Pages 458-467Publisher
SPRINGER
DOI: 10.1007/s10637-018-0578-9
Keywords
mTOR; Prostate cancer; MLN0128
Categories
Funding
- Millenium Pharmaceuticals
- American Society of Clinical Oncology Young Investigator Award
- National Cancer Institute [T32CA009515]
- Pilot and Feasibility Studies Program by Co-operative Center for Excellence in Hematology
- Transformative Impact Award from CDMRP [W81XWH-12-PCRP-TIA]
- NextGen Grant for Transformative Cancer Research from American Association for Cancer Research
- Fred Hutchinson Cancer Research Center/University of Washington Cancer Center Support Grant
- National Institutes of Health [1K08CA175154-01]
- Burroughs Wellcome Fund
- NIH/NCI Cancer Center [P30 CA008748]
- Movember-Prostate Cancer Foundation Challenge Award
- NCI [P50CA092629, P30CA008748]
- [1R01 CA182503-01A1]
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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.
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