A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors

Abstract

This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5–300 mg/day; Arm A), BI 860585 (40–220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80–220 mg/day; Arm C) with 60–80 mg/m2/week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash (n = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash (n = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel.

Sophoridine Derivatives Induce Apoptosis and Autophagy to Suppress the Growth of Triple‐Negative Breast Cancer through Inhibition of mTOR Signaling

“…One reason for the limited clinical benefit of rapalogs is that by only targeting mTORC1 (partial inhibition of p4EBP1), they cannot abrogate mTORC2‐mediated phosphorylation of AKT at Ser 473 and thus cannot completely shut down AKT signaling, which attenuate the signaling effect on tumor cell proliferation [35] . Recently, a number of dual inhibitors targeting both mTORC1 and mTORC2 have been developed and are currently being tested in TNBC clinical trials, [36] e. g. NCT02208375 and NCT02719691. In this case, we show here that our sophoridine derivatives blocked AKT phosphorylation at Ser 473; in addition, the phosphorylation of mTORC1 substrates (p70S6K and 4EBP1) was also inhibited in MDA‐MB‐231 cells, although not as potently as AKT Ser473.…”

Uterine Tumor Resembling Sex-Cord Tumors of the Ovary (Utrosct): A Case of Long-Term Response to Pazopanib

“…On December 2015 the patient was enrolled in a phase I clinical trial at our Institution evaluating the combination of BI860585 (mTORC1 and mTORC2 serine/threonine kinase inhibitor) and exemestane 25 mg/die [19]. The treatment was well tolerated except for grade-2 stomatitis.…”