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) signaling pathway is aberrantly activated in several cancers. Notch signaling 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 tumors. No intrapatient dose escalation was permitted. Results 28 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 8 evaluable patients receiving ridaforolimus 30 mg, three DLTs were reported (1 each grade 3 stomatitis, grade 3 diarrhea, 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, diarrhea, decreased appetite, hyperglycemia, thrombocytopenia, asthenia, and rash. Two of 15 (13%) patients with head and neck squamous cell carcinoma (HNSCC) had responses: one with complete response (CR) and one with partial response (PR). 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.

Activation of multiple angiogenic signaling pathways in hemangiopericytoma

“…Further studies showed an association of Notch signaling activation with a poor prognosis in several cancers [37,38]. Thus, anti-DLL4/Notch signaling has become a new concept implicated in anti-angiogenic therapy of tumors [27,29]. The present study demonstrated the upregulation of Notch signaling core-components in HPC, suggesting a possible crucial role of this signaling pathway in hyper-angiogenesis in this tumor.…”

New Opportunities and Challenges to Defeat Cancer Stem Cells

“…Early staged clinical trials assessing the efficacy of MK-0752 in combination with other drugs, such as MTOR inhibitors or chemotherapies, demonstrate that while gamma secretase inhibitors can limit CSC populations in preclinical studies, it is still challenging to completely eradicate CSC subgroups in clinical settings of head and neck squamous cell carcinoma (HNSCC) and pancreatic ductal adenocarcinoma (PDAC) [82, 83]. Complete response in these studies was only observed in 1 out of 15 patients with HNSCC (Table 3) [82]. Partial response was observed in 1 out of the 15 patients with HNSCC and 11 out of 18 patients with PDAC [82, 83].…”

“…Complete response in these studies was only observed in 1 out of 15 patients with HNSCC (Table 3) [82]. Partial response was observed in 1 out of the 15 patients with HNSCC and 11 out of 18 patients with PDAC [82, 83]. While partial response was promising for the PDAC patients, time to subsequent disease progression was only 38 weeks, suggesting the need for more effective therapies.…”

A unified model of the hierarchical and stochastic theories of gastric cancer

“…However, only a few solid tumour patients have experienced complete responses to selected drugs, including MK0752 (Krop et al , 2012; Piha-Paul et al , 2015) and PF03084014 (Messersmith et al , 2015). Moreover, many drugs induce a variety of severe adverse events such as intractable diarrhoea, vomiting, skin disorders and hypophosphatemia (Takebe et al , 2014), perhaps due to the wide distribution of the Notch pathway in normal tissues, especially NSCs.…”