BERIL-1: A phase II, placebo-controlled study of buparlisib (BKM120) plus paclitaxel in patients with platinum-pretreated recurrent/metastatic head and neck squamous cell carcinoma (HNSCC).

Soulières, Denis; Faivre, Sandrine; Mesı́a, Ricard; Remenár, Éva; Li, Shau-Hsuan; Karpenko, Andrey; Dechaphunkul, Arunee; Keilholz, Ulrich; Kiss, Laura; Lin, Jin‐Ching; Nagarkar, Rajnish; Tamás, László; Kim, Sung‐Bae; Erfán, József; Turri, Sabine; Dey, Debdeep; Chakravartty, Arunava; Aimone, Paola; Massacesi, Cristian; Licitra, Lisa

doi:10.1200/jco.2016.34.15_suppl.6008

Cited by 10 publications

(7 citation statements)

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“…In HPV(−) tumors, mutations in PIK3CA are relatively rare (7–11%), whereas there are dominant hot spot genomic mutations in about 30% of in HPV (+) disease [79]. Currently available small molecule inhibitors of PI3K block production of PIP 3 , leading to suppression of Akt, inhibition of cell growth, and induction of apoptosis [80] The PI3K inhibitors BKM120 (Buparlisib), PX-866, BYL719 (Alpelisib), and copanlisib are being actively investigated in HNSCC clinical trials. Buparlisib is an orally bioavailable pan-class I PI3K inhibitor with known adverse effects that include gastrointestinal side effects, hyperglycemia, skin reactions, and stomatitis.…”

Section: Scientific Rationalementioning

confidence: 99%

“…Buparlisib is an orally bioavailable pan-class I PI3K inhibitor with known adverse effects that include gastrointestinal side effects, hyperglycemia, skin reactions, and stomatitis. A phase II clinical trial in platinum-resistant R/M HNSCC demonstrated improved outcomes with buparlisib plus paclitaxel versus paclitaxel alone [80]. Median PFS was 4.6 months vs. 3.5 months and median OS was 10.4 months vs. 6.5 months.…”

Section: Scientific Rationalementioning

confidence: 99%

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An update: emerging drugs to treat squamous cell carcinomas of the head and neck

Lee

Johnson

Grandis

2018

Expert Opinion on Emerging Drugs

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Introduction: Subsequent to the 2006 FDA approval of cetuximab, a variety of molecular targeting agents have been evaluated in head and neck squamous cell carcinoma (HNSCC). The treatment outcomes of recurrent and/or metastatic (R/M) HNSCC, in particular, remain dismal. The 2016 FDA approval of PD-1 immune checkpoint inhibitors has expanded the treatment options for R/M HNSCC, and highlights the potential for immune-based therapies. Areas covered: We will review the clinical application of EGFR-targeted agents, alone and in combination with other drugs. Molecular targeting agents directed against the IL6/PI3K/STAT3 signaling pathway will be covered. In addition, evaluation of immune checkpoint inhibitors in HNSCC, along with ongoing combination trials incorporating these agents, will be discussed. The expanded indications of emerging drugs and the potential clinical benefit of new drugs and treatment combinations will be summarized. Expert opinion: In recent years, there has been a major shift towards immunotherapy-based approaches for the treatment of HNSCC, leading to significant improvements in outcomes for a subset of patients. Leveraging the increased understanding of the genetic alterations that characterize individual HNSCC tumors will facilitate precision medicine approaches using targeted agents, immunotherapies, as well as standard chemotherapy and radiation.

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Section: Scientific Rationalementioning

confidence: 99%

Section: Scientific Rationalementioning

confidence: 99%

An update: emerging drugs to treat squamous cell carcinomas of the head and neck

Lee

Johnson

Grandis

2018

Expert Opinion on Emerging Drugs

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“…Dies wäre insbesondere für palliative Therapieansätze von Bedeutung, da die oral verfügbaren TKIs die Frequenz von Hospitalisierungen deutlich reduzieren könnten. kante Verbesserung der Ansprechrate, des progressionsfreien und des medianen Gesamtüberlebens durch Buparlisib in Kombination mit Paclitaxel im Vergleich zu einer Monotherapie mit Paclitaxel gezeigt werden [97].…”

Section: Pi3k-inhibitorenunclassified

Aktuelle Entwicklung der molekular zielgerichteten Therapie von Kopf-Hals-Karzinomen

Strieth¹

2017

Laryngo-Rhino-Otol

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Primärtherapie von Kopf-Hals-Tumoren Die konventionelle Chemotherapie hat seit Jahrzehnten keinen Stellenwert bei der kurativen Primärtherapie von Kopf-Hals-Karzinomen. Während in der palliativen Chemotherapie in den 1970er Jahren zunächst Therapien mit Methotrexat und Bleomycin dominierten, avancierte Cisplatin in den 1980er Jahren zum Goldstandard als Kombination im Rahmen sog. Platin-Doubletten [1-10].

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“…All of the inhibitors, except buparlisib, were active against the class II PI3K enzymes PIK3C2B and PIK3C2G (10 μM only for SN32976 and pictilisib), which despite a limited understanding can regulate cellular processes, such as invasion and migration and their inhibition may contribute to the anticancer activity of these agents, rather than just off-target toxicity [ 34 , 35 ]. It is notable that the pan PI3K inhibitor that has shown the greatest clinical activity, buparlisib [ 17 , 18 , 19 ], was the only agent other than SN32976 to show kinase selectivity and greatest potency against PI3Kα, yet it was >10-fold less potent against PI3Kα than SN32976 and showed only 1.8, 3.6 and 3.7-fold selectivity over mTOR, PI3Kδ and PI3Kβ, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…This drug is being tested in a large number of clinical trials (88 trials registered with the NIH; 37 ongoing), both as a single agent and part of combination therapy, on the basis of promising preclinical activity [ 15 ]. Despite showing limited single agent activity [ 16 ], improved patient outcomes have been observed to date in hormone receptor-positive breast cancer [ 17 , 18 ] and head and neck squamous cell carcinoma [ 19 ] in combination with other therapies, but treatment has been associated with serious adverse effects, including a rise in liver enzymes and severe anxiety and depression [ 18 ]. Several other pan PI3K and PI3K/mTOR inhibitors have entered clinical development including pictilisib, copanlisib, ZSTK474, omipalisib and dactolisib, but many of these have now been discontinued due to toxicity and limited efficacy.…”

Section: Introductionmentioning

confidence: 99%

Biological characterization of SN32976, a selective inhibitor of PI3K and mTOR with preferential activity to PI3Kα, in comparison to established pan PI3K inhibitors

et al. 2017

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Multiple therapeutic agents have been developed to target the phosphatidylinositol 3-kinase (PI3K) signaling pathway, which is frequently dysregulated in cancer promoting tumor growth and survival. These include pan PI3K inhibitors, which target class Ia PI3K isoforms and have largely shown limited single agent activity with narrow therapeutic windows in clinical trials. Here, we characterize SN32976, a novel pan PI3K inhibitor, for its biochemical potency against PI3K isoforms and mTOR, kinase selectivity, cellular activity, pharmacokinetics, pharmacodynamics and antitumor efficacy relative to five clinically-evaluated pan PI3K inhibitors: buparlisib, dactolisib, pictilisib, omipalisib and ZSTK474. SN32976 potently inhibited PI3K isoforms and mTOR, displaying preferential activity for PI3Kα and sparing of PI3Kδ relative to the other inhibitors, while showing less off-target activity than the clinical inhibitors in a panel of 442 kinases. The major metabolites of SN32976 were also potent PI3K inhibitors with similar selectivity for PI3Kα as the parent compound. SN32976 compared favorably with the clinically-evaluated PI3K inhibitors in cellular assays, inhibiting pAKT expression and cell proliferation at nM concentrations, and in animal models, inducing a greater extent and duration of pAKT inhibition in tumors than pictilisib, dactolisib and omipalisib at similarly tolerated dose levels and inhibiting tumor growth to a greater extent than dactolisib and ZSTK474 and with similar efficacy to pictilisib and omipalisib. These results suggest that SN32976 is a promising clinical candidate for cancer therapy with enhanced kinase selectivity and preferential inhibition of PI3Kα compared to first generation pan PI3K inhibitors, while retaining comparable anticancer activity.

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BERIL-1: A phase II, placebo-controlled study of buparlisib (BKM120) plus paclitaxel in patients with platinum-pretreated recurrent/metastatic head and neck squamous cell carcinoma (HNSCC).

Cited by 10 publications

References 0 publications

An update: emerging drugs to treat squamous cell carcinomas of the head and neck

An update: emerging drugs to treat squamous cell carcinomas of the head and neck

Aktuelle Entwicklung der molekular zielgerichteten Therapie von Kopf-Hals-Karzinomen

Biological characterization of SN32976, a selective inhibitor of PI3K and mTOR with preferential activity to PI3Kα, in comparison to established pan PI3K inhibitors

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