Results of a phase 1 trial combining ridaforolimus and MK-0752 in patients with advanced solid tumours

Abstract

Background: The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K-AKT-mTOR) signalling pathway is aberrantly activated in several cancers. Notch signalling maintains cell proliferation, growth and metabolism in part by driving the PI3K pathway. Combining the mTOR inhibitor ridaforolimus with the Notch inhibitor MK-0752 may increase blockade of the PI3K pathway.

Methods: This phase I dose-escalation study (NCT01295632) aimed to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of combination oral ridaforolimus (rising doses starting at 20 mg, 5 days/week) and oral MK-0752 (1800 mg once weekly) in patients with solid tumours. No intrapatient dose escalation was permitted.

Results: Twenty eight patients were treated on study. Ridaforolimus doses were escalated from 20 to 30 mg/day. Among 14 evaluable patients receiving ridaforolimus 20 mg, one DLT (grade 2 stomatitis, second episode) was reported. Among eight evaluable patients receiving ridaforolimus 30 mg, three DLTs were reported (one each grade 3 stomatitis, grade 3 diarrhoea, and grade 3 asthenia). The MTD was 20 mg daily ridaforolimus 5 days/week+1800 mg weekly MK-0752. The most common drug-related adverse events included stomatitis, diarrhoea, decreased appetite, hyperglycaemia, thrombocytopenia, asthenia and rash. Two of 15 (13%) patients with head and neck squamous cell carcinoma (HNSCC) had responses: one with complete response and one with partial response. In addition, one patient experienced stable disease ⩾6 months.

Conclusions: Combined ridaforolimus and MK-0752 showed activity in HNSCC. However, a high number of adverse events were reported at the MTD, which would require careful management during future clinical development.

Keywords: Head and neck cancer; MK-0752; Notch inhibitor; Phase I; Ridaforolimus; mTOR inhibitor.

Conflict of interest statement

Conflict of Interest Statement

S.A. Piha-Paul, A. Hollebecque, G. Argilés, O. Dajani, and S. Gupta have nothing to disclose. P.N. Munster received research support from Merck & Co., Inc. J.D. Cheng, R. Wang, A. Swift, and A. Tosolini are employees of Merck & Co., Inc.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Fig. 1

Rationale for mTOR inhibitor + NOTCH inhibitor combination. The PI3K/AKT/mTOR signaling pathway is aberrantly activated in a variety of cancers. Notch signaling has been shown to maintain cell proliferation, growth, and metabolism in part by driving PI3K pathway signaling. The combination of mTOR inhibitor ridaforolimus and Notch inhibitor MK-0752 may lead to complementary blockade of the PI3K pathway. Abbreviations: AKT, protein kinase-B; DLL4, Delta-like ligand 4; HES1, Hairy/enhancer of split 1; HIF, hypoxia-inducible factor; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; rida, ridaforolimus; RTK, receptor tyrosine kinase; VEGFR, vascular endothelial growth factor receptor.

Fig. 2

Maximum change from baseline in the size of target lesions in patients evaluable for response (at least 1 postbaseline scan available) as assessed per RECIST v1.1 by investigator review. A. All patients (n = 18). B. Patients with HNSCC (n =10). Abbreviations: HNSCC, head and neck squamous cell carcinoma; RECIST v1.1, Response Evaluation Criteria in Solid Tumors, version 1.1.

Fig. 3

Imaging results for a patient with recurrent HNSCC obtained at baseline (5/2/2012), cycle 4, day 27 (9/10/12) and cycle 20, day 35 (1/7/14). The patient developed a contrast allergy, and CT of the neck done at baseline was later changed to PET-CT. The patient exhibits no evidence of disease and continues on therapy. Abbreviations: CT, computed tomography; HNSCC, head and neck squamous cell carcinoma; PET, positron emission tomography.

Fig. 4

Imaging results for a patient with recurrent HNSCC obtained at baseline (3/2/11) and cycle 8, day 26 (10/28/11). The best response per RECIST v1.1 by local assessment was a decrease in target lesions of 46%. Abbreviations: HNSCC, head and neck squamous cell carcinoma; RECIST v1.1, Response Evaluation Criteria in Solid Tumors, version 1.1.