A phase I trial of IGF-1R inhibitor cixutumumab and mTOR inhibitor temsirolimus in metastatic castration-resistant prostate cancer Journal Article
| Authors: | McHugh, D. J.; Chudow, J.; DeNunzio, M.; Slovin, S. F.; Danila, D. C.; Morris, M. J.; Scher, H. I.; Rathkopf, D. E. |
| Article Title: | A phase I trial of IGF-1R inhibitor cixutumumab and mTOR inhibitor temsirolimus in metastatic castration-resistant prostate cancer |
| Abstract: | Background: Despite frequent PTEN (phosphatase and tensin homologue) loss and Akt/mammalian target of rapamycin (mTOR) signaling in prostate cancer, the disease is insensitive to single-agent mTOR inhibition. Insulin-like growth factor-1 receptor inhibition might mitigate the feedback inhibition by Torc1 inhibitors, suppressing downstream Akt activation and, thus, potentiating the antitumor activity of mTOR inhibition. Patients and Methods: In the present phase I study, patients with metastatic castration-resistant prostate cancer received 6 mg/kg cixutumumab and 25 mg temsirolimus intravenously each week. The primary objective was safety and tolerability. Temsirolimus was decreased if ≥ 2 dose-limiting toxicities (DLTs) were observed in 6 patients. The correlative analyses included measurement of circulating tumor cells, [18F]-fluoro-2-deoxyglucose positron emission tomography, 16β-[18F]-fluoro-α-dihydrotestosterone positron emission tomography, and tumor biopsy. Results: A total of 16 patients were enrolled across 3 cohorts (1, −1, −2). Two DLTs (grade 3 oral mucositis) were observed in cohort 1 (temsirolimus, 25 mg), and 1 DLT (grade 3 lipase) in cohort −1 (temsirolimus, 20 mg). The most common adverse events included hyperglycemia (100%; 31% grade 3), oral mucositis (63%; 19% grade 3), and diarrhea (44%; 0 grade 3). Low-grade pneumonitis occurred in 7 of 11 patients (44%; 0 grade 3), prompting the opening of a 3-weekly cohort (temsirolimus, 20 mg/kg), without pneumonitis events. No patient had a >50% decline in prostate-specific antigen from baseline. The best radiographic response was stable disease, with median study duration of 22 weeks (range, 7-63 weeks). Conclusions: Despite a strong scientific rationale for the combination, temsirolimus plus cixutumumab demonstrated limited antitumor activity and a greater than expected incidence of toxicity, including low-grade pneumonitis and hyperglycemia. Hence, the trial was stopped in favor of alternative androgen receptor/phosphatidylinositol 3-kinase–directed combinatorial therapies. © 2019 In metastatic castration-resistant prostate cancer, poor single-agent response to Torc1 inhibition has been postulated to be, in part, due to release of negative feedback on the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway. The present phase I study of 16 patients aimed to overcome resistance to Torc1 inhibition monotherapy with concurrent insulin-like growth factor-1 receptor inhibition. The results showed limited antitumor activity and greater than anticipated toxicity. The trial was stopped in favor of alternative androgen receptor/phosphatidylinositol 3-kinase-directed combinatorial therapies. © 2019 |
| Keywords: | akt; pten; fdht; ar; reciprocal feedback |
| Journal Title: | Clinical Genitourinary Cancer |
| Volume: | 18 |
| Issue: | 3 |
| ISSN: | 1558-7673 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2020-06-01 |
| Start Page: | 171 |
| End Page: | 178.e2 |
| Language: | English |
| DOI: | 10.1016/j.clgc.2019.10.013 |
| PUBMED: | 32057715 |
| PROVIDER: | scopus |
| PMCID: | PMC8394788 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 August 2020 -- Source: Scopus |
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