A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575)

Abstract

SummaryPurpose To establish the recommended phase II dose of the oral γ-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity. Methods Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg. RO was administered orally, once daily on days 1–3, 8–10, 15–17, 22–24. Gemcitabine was administered at 1,000 mg/m2 on d1, 8, and 15 in 28 d cycles. Dose limiting toxicities (DLTs) were assessed by CTCAE v4. Serial plasma was collected for RO (total and unbound) and gemcitabine pharmacokinetic analysis. Biomarkers of Notch signaling were assessed by immunohistochemistry in archival tissue. Antitumor activity was evaluated (RECIST 1.1). Results A total of 18 patients were enrolled to establish the recommended phase II dose. Of these, 3 patients received 20 mg RO, 7 patients received 30 mg RO, 6 patients received 45 mg RO and 2 patients received 90 mg RO. DLTs were grade 3 transaminitis (30 mg RO), grade 3 transaminitis and maculopapular rash (45 mg RO), and grade 3 transaminitis and failure to receive 75 % of planned RO doses secondary to prolonged neutropenia (90 mg); all were reversible. The maximum tolerated dose was exceeded at 90 mg RO. Pharmacokinetic analysis of both total and free RO confirmed the presence of autoinduction at 45 and 90 mg. Median levels of Notch3 staining were higher in individuals who received fewer than 4 cycles (p = 0.029). Circulating angiogenic factor levels did not correlate with time to progression or ≥ grade 3 adverse events. Best response (RECIST 1.1) was partial response (nasopharyngeal cancer) and stable disease > 4 months was observed in 3 patients (pancreas, tracheal, and breast primary cancers). Conclusions RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m2. Although RO exposure was limited by the presence of autoinduction, RO levels achieved exceeded the area under the concentration-time curve for 0–24 h (AUC0–24) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified.

Notch1 pathway in adrenocortical carcinomas: correlations with clinical outcome

“…This discrepancy with the JAG1 findings may reflect the profound dysregulation of the Notch pathway in ACCs and the role of additional influences downstream of Notch. The demonstration of Notch activation and the overexpression of its target genes in patients with advanced ACCs may become therapeutically relevant, considering the potential use of Notch-inhibiting drugs that act downstream of JAG1, such as g-secretase inhibitors, which are currently under investigation alone and in combination in clinical trials for Notch-dependent solid tumors (Richter et al 2014, Lee et al 2015, LoConte et al 2015, Messersmith et al 2015, or more innovative compounds, such as receptor-blocking monoclonal antibodies (Supplementary Figure S1, see section on supplementary data given at the end of this article) (Hernandez Tejada et al 2014).…”

“…Several clinical trials with these compounds alone or in combination are currently ongoing or have been recently completed (ClinicalTrials. gov) (Richter et al 2014, Lee et al 2015, LoConte et al 2015, Messersmith et al 2015. Moreover, inhibiting Notch signaling (i.e., by pretreatment) has been shown to sensitize tumors to platinum compounds or other cytotoxic drugs, such as gemcitabine (Meng et al 2009, Wang et al 2010, McAuliffe et al 2012.…”

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

“…Some clinical trials have also established the efficacy of combination therapies. For example, when combined GSIs with cytotoxic chemotherapy, clinical benefits, such as PR and prolonged SD, are observed in solid cancer patients (73,151,152). Encouraging antitumor activity is noticed in a Notch2/3-specific antibody study.…”

Inhibition of γ-secretase activity synergistically enhances tumour necrosis factor-related apoptosis-inducing ligand induced apoptosis in T-cell acute lymphoblastic leukemia cells via upregulation of death receptor 5

“…was the best outcome (23)(24)(25), whilst other studies noted a partial clinical response (22). Pre-clinical research continues to aspire to identify suitable anti-cancer agents to combine with GSIs, with the aim of further improving clinical outcome.…”