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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Buparlisib (BKM120), developed by Novartis and licensed by Adlai Nortye in 2018, is an orally available small molecule with pan-class I PI3K inhibitory activity. In 2018 buparlisib received fast track status from the FDA for head and neck squamous cell carcinoma. It is believed to work by interfering with microtubule assembly, thereby inducing cell-cycle arrest at G2–M phase. In early-phase clinical trials, buparlisib had an encouraging tolerability profile but only modest efficacy as a single agent, and so further development was halted in 2017.
Multiple Comparisons, Multiple Primary Endpoints and Subpopulation Analysis
Published in Susan Halabi, Stefan Michiels, Textbook of Clinical Trials in Oncology, 2019
Ekkehard Glimm, Dong Xi, Paul Gallo
In the following, we will use the BELLE-4 study [7] to illustrate various aspects of multiplicity adjustment arising in oncology trials. BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study. The study compared the therapy of advanced HER2-positive breast cancer by the experimental treatment paclitaxel + burparlisib versus the standard of care by paclitaxel + placebo. Buparlisib is an oral PI3 K inhibitor and thus it was expected that its effect would be stronger in patients with strong PI3 K activation. Consequently, the study used stratified randomization according to PI3 K activation (active or non-active) and also stratified patients by hormone-receptor status (HR+ or HR−).
Systemic therapy of advanced/metastatic gastrointestinal stromal tumors: an update on progress beyond imatinib, sunitinib, and regorafenib
Published in Expert Opinion on Investigational Drugs, 2021
Mahmoud Mohammadi, Hans Gelderblom
The hypothesis that buparlisib has potential activity in GIST is based on the activation of alternative signaling pathways such as phosphoinositide 3-kinase (PI3K) in imatinib resistant GIST [31,32]. Buparlisib, an inhibitor of the PI3K pathway, had demonstrated anti-growth effects in patient-derived GIST xenograft models [33]. In a multicenter, phase 1b study [34], a combination of imatinib with buparlisib was given in patients with resistance to both imatinib and sunitinib. In the dose-escalation phase, 35 patients received the maximum-tolerated dose of 80 mg buparlisib along with 400 mg imatinib. The best overall response observed was in 54.3% of the patients a stable disease, while none of the patients achieved a partial response or complete response. The median PFS was 3.5 months. The toxicity profile showed, besides the common side effects of imatinib (nausea, diarrhea), neuropsychiatric adverse events, probably due to blood-barrier penetration of buparlisib. Overall the combination of imatinib and buparlisib has limited activity.
Biologic therapy for advanced breast cancer: recent advances and future directions
Published in Expert Opinion on Biological Therapy, 2020
Paolo Tarantino, Stefania Morganti, Giuseppe Curigliano
Buparlisib is a highly selective pan-class I PI3K inhibitor tested in combination with several ET. Preliminary results from the phase 2 BELLE-2 trial [26] showed a significant PFS improvement from the combination of buparlisib plus fulvestrant versus fulvestrant alone (6.9 vs 5 months; HR 0.78; 95% CI 0.67–0.89; p < 0.001), with a favorable trend in OS (HR 0.87; 95% CI 0.74–1.02; p = 0.045) [27]. These results were confirmed in phase 3 BELLE-3 study [28], where mPFS was significantly higher in the combination arm (3.9 vs 1.8 months; HR 0.67, 95% CI 0.53–0.84; p < 0.01). Despite these results, the clinical development of buparlisib was stopped because of excessive toxicities. As high as 61% of patients in the buparlisib group experienced ≥G3 AEs, with elevated aminotransferases, hyperglycemia, and hypertension being the most frequent.
Treating central nervous system lymphoma in the era of precision medicine
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ytel Garcilazo-Reyes, Maria-José Ibáñez-Juliá, Isaias Hernández-Verdin, Ludovic Nguyen-Them, Nadia Younan, Caroline Houillier, Khê Hoang-Xuan, Agusti Alentorn
On the other hand, it has been suggested the interest in blocking the PI3 K/mammalian target of rapamycin (PI3 K/mTOR) pathway to overcome resistance in CD79B mutated tumors. The PI3 K signaling pathway plays a critical role in oncogene-mediated tumor growth and proliferation and has regulatory functions in cell survival, apoptosis, protein synthesis, and glucose metabolism [35,36]. Down in this signalization pathway, it is found a serine-threonine protein kinase, mTOR. Temsirolimus is an mTOR inhibitor, that has been studied in R/R PCNSL, mTOR is now recognized as a unique and important target for cancer therapeutics. There is only one prospective study that investigated the mTOR inhibition in R/R PCNSL using temsirolimus. This phase II nonrandomized, open-label study used temsirolimus as a single-agent with a two-stage design. In the first stage, patients were treated with temsirolimus 25 mg intravenously once per week, if no common toxicity criteria grades 3 to 4 were observed, all following patients were treated with 75 mg once per week. Korfel and colleagues demonstrated a high radiographic response of 54%, but a low median PFS of only 2.1 months, suggesting a transient effect [37]. Even less encouraging results were reported with buparlisib. Buparlisib is an oral pan-PI3 K inhibitor that had shown antitumor activity in lymphoma cell lines and induced apoptosis in DLBCL [38]. However, in a phase II trial, there was a response rate of 25% a median PFS of 39 days an 100% of relapses [39].