A Phase I Trial of IGF-1R Inhibitor Cixutumumab and mTOR Inhibitor Temsirolimus in Metastatic Castration-resistant Prostate Cancer

Deaglan J. McHugh, Jay Chudow, Mia DeNunzio, Susan F. Slovin, Daniel C. Danila, Michael J. Morris, Howard I. Scher, Dana E. Rathkopf

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)171-178.e2
JournalClinical Genitourinary Cancer
Volume18
Issue number3
DOIs
StatePublished - Jun 2020
Externally publishedYes

Keywords

  • Akt
  • AR
  • FDHT
  • PTEN
  • Reciprocal feedback

ASJC Scopus subject areas

  • Oncology
  • Urology

Fingerprint

Dive into the research topics of 'A Phase I Trial of IGF-1R Inhibitor Cixutumumab and mTOR Inhibitor Temsirolimus in Metastatic Castration-resistant Prostate Cancer'. Together they form a unique fingerprint.

Cite this