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

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Summary

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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Funding

D.E.R. received funding and drug supply from Millenium Pharmaceuticals to support this trial. K.B. is a recipient of an American Society of Clinical Oncology Young Investigator Award and is funded by a National Cancer Institute training grant (T32CA009515) and a Pilot and Feasibility Studies Program grant funded by the Co-operative Center for Excellence in Hematology. B.S.C. is funded by 1R01 CA182503-01A1. T.L.L. was funded in part by a Transformative Impact Award from the CDMRP (W81XWH-12-PCRP-TIA). A.C.H. is a V Foundation Scholar and is funded by a NextGen Grant for Transformative Cancer Research from the American Association for Cancer Research, a Fred Hutchinson Cancer Research Center/University of Washington Cancer Center Support Grant, a National Institutes of Health Career Development Award (1K08CA175154–01), and the Burroughs Wellcome Fund. D.E.R., Y.C., and H.I.S. received support through the NIH/NCI Cancer Center Support Grant P30 CA008748. B.S.C, Y.C, A.C.H., and D.E.R. are recipients of a Movember-Prostate Cancer Foundation Challenge Award. NCI P50CA092629 (B.S.C., Y.C., H.I.S., D.E.R), NCI P30CA008748 (B.S.C., Y.C., H.I.S., D.E.R).

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Authors and Affiliations

  1. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

    Laura Graham, Kalyan Banda & Andrew C. Hsieh

  2. School of Medicine and Genome Sciences, University of Washington, Seattle, WA, 98195, USA

    Laura Graham, Kalyan Banda & Andrew C. Hsieh

  3. Departments of Pathology and Oncology, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA

    Alba Torres & Tamara L. Lotan

  4. Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Brett S. Carver

  5. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Brett S. Carver & Yu Chen

  6. Department of Urology, Weill Cornell Medical College, New York, NY, 10065, USA

    Brett S. Carver

  7. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Yu Chen, Katie Pisano, Greg Shelkey, Tracy Curley, Howard I. Scher & Dana E. Rathkopf

  8. Department of Medicine, Weill Cornell Medical College, New York, NY, 10065, USA

    Yu Chen, Howard I. Scher & Dana E. Rathkopf

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  1. Laura Graham
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Correspondence to Andrew C. Hsieh or Dana E. Rathkopf.

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Conflict of interest

D.E.R. is a consultant for Janssen (uncompensated) and receives research funding from Astellas, Astra-Zeneca, Celgene, Genentech, Janssen, Medivation, Novartis, Taiho, Tracon. L.G. declares that she has no conflicts of interest. K.B. declares that he has no conflicts of interest. A.T. declares that she has no conflicts of interest. B.S.R. declares that he has no conflicts of interest., Y.C. declares that he has no conflicts of interest. K.P. declares that she has no conflicts of interest. G.S. declares that he has no conflicts of interest. H.I.S. declares that he has no conflicts of interest. T.L.L. declares that she has no conflicts of interest. A.C.H. declares that he has no conflicts of interest.

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Graham, L., Banda, K., Torres, A. et al. A phase II study of the dual mTOR inhibitor MLN0128 in patients with metastatic castration resistant prostate cancer. Invest New Drugs 36, 458–467 (2018). https://doi.org/10.1007/s10637-018-0578-9

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