Date: 2014-06-01
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the 50th American Society of Clinical Oncology (ASCO) Annual Meeting, May 30 to June 3, 2014, in Chicago
Company: Novartis (Switzerland)
Product: sonidegib - LDE225
Action
mechanism: hedgehog signaling inhibitor. LDE225 (sonidegib) is an oral, investigational, selective smoothened inhibitor being studied in a variety of cancers. Smoothened (SMO receptor) is a molecule that regulates the hedgehog (Hh) signaling pathway, which plays a critical role in stem cell maintenance and tissue repair. This GPCR-like (G protein-coupled receptor) molecule is currently being investigated in Phase II/III trials in patients with advanced solid tumors, myelofibrosis, leukemia.
Disease: advanced basal cell carcinoma
Therapeutic area: Cancer - Oncology
Country:
Trial
details: The Phase II, randomized, double-blind BOLT (Basal cell carcinoma Outcomes in LDE225 Trial) study was designed to assess the safety and efficacy of two oral dose levels of LDE225 (200 mg and 800 mg) in patients with locally advanced or metastatic basal cell carcinoma, which are subtypes of advanced basal cell carcinoma.
Latest
news: * On June 1, 2014, Novartis announced the results of a pivotal Phase II trial demonstrating that patients with locally advanced (laBCC) or metastatic basal cell carcinoma (mBCC) taking the investigational oral compound LDE225 (sonidegib) had marked and sustained tumor shrinkage after a median follow-up of 13.9 months1. The data were revealed for the first time in an oral presentation at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago (abstract #9009a). The trial assessed the efficacy and safety of two oral doses of LDE225, 200 mg and 800 mg, in patients with laBCC or mBCC[6]. The primary endpoint was the objective response rate (ORR), defined as the proportion of patients with complete or partial tumor response, or shrinkage, as measured by a central review committee. The study met the primary endpoint in both treatment arms with ORRs of 41.8% (95% confidence interval [CI]: 30.8, 53.4) in the 200 mg arm and 32.5% (95% CI: 25.1, 40.5) in the 800 mg arm. More specifically, 47.0% of patients with laBCC and 15.4% of patients with mBCC, in the 200 mg arm, and 35.2% of patients with laBCC and 17.4% of patients with mBCC in the 800 mg arm, achieved an objective response. Secondary endpoints included duration of response (DoR), progression-free survival (PFS) and time to tumor response (TTR), a measure of how quickly the tumor responded to treatment. Median DoR for patients with laBCC in both treatment arms could not be estimated since the majority of patients who had a response had no event at the time of the analysis (an event is defined as progression or death due to any cause). Median DoR was 8.3 months for patients with mBCC treated with LDE225 800 mg; however, it could not be estimated for patients with mBCC in the 200 mg arm because they had no event at the time of the analysis. The median PFS for patients with laBCC in both treatment arms could not be estimated since the majority of patients had no event at the time of the analysis. The median PFS per central review for patients with mBCC was 13.1 months in the 200 mg arm and 7.6 months in the 800 mg arm. Median TTR per central review for patients with laBCC was 3.9 months (95% CI: 3.6, 4.2) in the 200 mg arm and 3.7 months (95% CI: 2.6, 3.8) in the 800 mg arm, and 4.6 months (95% CI: 1.8, 7.4) and 1.0 month (95% CI: 1.0, 2.1) for patients with mBCC in the 200 mg and 800 mg arms, respectively. The most common Grade 3/4 adverse events (AEs) reported in >=2% of patients receiving treatment with the 200 mg dose were elevated levels of creatine phosphokinase (6.3%), increased lipase (5.1%), hypertension (2.5%), asthenia, or weakness (2.5%) and muscle spasms (2.5%). The most common Grade 3/4 AEs, reported in >=2% of patients receiving treatment with the 800 mg dose were elevated levels of creatine phosphokinase (12.7%), increased lipase (5.3%), muscle spasms (5.3%), decreased weight (5.3%), decreased appetite (4.0%), rhabdomyolysis, or the breakdown of muscle fibers (3.3%), nausea (2.7%), hypertension (2.7%), increased alanine aminotransferase (2.7%), increased aspartate aminotransferase (2.7%), fatigue (2.0%), syncope, or fainting (2%), anemia (2%), dehydration (2%), hyperkalemia (2%) and myalgia, or muscle pain (2.0%). Overall, Grade 3/4 events were observed less frequently in the 200 mg group (30.4%) than in the 800 mg group (56.0%). The data from this pivotal trial will serve as the basis for worldwide regulatory filings for the 200 mg dose of LDE225 in advanced basal cell carcinoma. * On February 19, 2014, Novartis has announced that the pivotal trial of LDE225 (sonidegib) in advanced basal cell carcinoma met its primary endpoint of demonstrating an objective response rate among patients within six months of treatment. Objective response included complete response (clinically significant tumor response with complete absence of disease) and partial response (clinically significant tumor shrinkage). The primary endpoint was the proportion of patients achieving an objective response rate, defined as a confirmed complete response and partial response as their best overall response per modified RECIST criteria, within six months of starting treatment with LDE225. Key secondary endpoints of the study included assessing the duration of tumor responseand the rate of complete response. Other secondary endpoints included progression-free survival, time to tumor response and overall survival. Full study results will be presented at a future scientific meeting.
