From Revolutionary to Palace Guard: The Role and Requirements of Intermediaries Under Proposed Regulation Crowdfunding

Intermediaries in securities crowdfunding face significant requirements as a result of the statutory mandates of Title III of the JOBS Act. The SEC, in its proposed rules, provided structure to these requirements. The proposed rules would create strict requirements for intermediaries regarding their relationships with investors and how they undertake crowdfunding transactions under Section 4(a)(6) of the Securities Act. The proposed rules would also create and establish the guidelines for funding portals, a new type of limited purpose securities broker. While some commentators decry the SEC for placing undue burdens and legal liabilities on intermediaries in securities crowdfunding, the SEC had limited discretion in the proposed rules in regards to those issues. It is unclear what type of market will develop as a result of these rules as market participants work through the challenges and opportunities of securities crowdfunding

Futibatinib, an irreversible FGFR1-4 inhibitor, in patients with advanced solid tumors harboring FGF/FGFR aberrations: a phase I dose-expansion study

Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, was evaluated in a large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, with responses in a broad spectrum of tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer) bearing both known and previously uncharacterized FGFR1-3 aberrations. The greatest activity was observed in FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some patients with acquired resistance to a prior FGFR inhibitor also experienced responses with futibatinib. Futibatinib demonstrated a manageable safety profile. The most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%). These results formed the basis for ongoing futibatinib phase II/III trials and demonstrate the potential of genomically selected early-phase trials to help identify molecular subsets likely to benefit from targeted therapy

From Revolutionary to Palace Guard: The Role and Requirements of Intermediaries Under Proposed Regulation Crowdfunding

Intermediaries in securities crowdfunding face significant requirements as a result of the statutory mandates of Title III of the JOBS Act. The SEC, in its proposed rules, provided structure to these requirements. The proposed rules would create strict requirements for intermediaries regarding their relationships with investors and how they undertake crowdfunding transactions under Section 4(a)(6) of the Securities Act. The proposed rules would also create and establish the guidelines for funding portals, a new type of limited purpose securities broker. While some commentators decry the SEC for placing undue burdens and legal liabilities on intermediaries in securities crowdfunding, the SEC had limited discretion in the proposed rules in regards to those issues. It is unclear what type of market will develop as a result of these rules as market participants work through the challenges and opportunities of securities crowdfunding

Phase I, first-in-human study of futibatinib, a highly selective, irreversible FGFR1-4 inhibitor in patients with advanced solid tumors.

BACKGROUND: Futibatinib is an oral, irreversible, highly selective fibroblast growth factor receptor (FGFR)1-4 inhibitor with potent preclinical activity against tumors harboring FGFR aberrations. This first-in-human, phase I dose-escalation trial (NCT02052778) evaluates the safety and pharmacokinetics/pharmacodynamics of futibatinib in advanced solid tumors. PATIENTS AND METHODS: Following a standard 3+3 dose-escalation design, eligible patients with advanced solid tumors refractory to standard therapies received 8-200 mg futibatinib three times a week (t.i.w.) or 4-24 mg once daily (q.d.). RESULTS: A total of 86 patients were enrolled in the nine t.i.w. (n = 42) and five q.d. cohorts (n = 44); 71 patients (83%) had tumors harboring FGF/FGFR aberrations. Three of nine patients in the 24-mg q.d. cohort experienced dose-limiting toxicities, including grade 3 increases in alanine transaminase, aspartate transaminase, and blood bilirubin (n = 1 each). The maximum tolerated dose (MTD) was determined to be 20 mg q.d.; no MTD was defined for the t.i.w. schedule. Across cohorts (n = 86), the most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (59%), diarrhea (37%), and constipation (34%); 48% experienced grade 3 TEAEs. TEAEs led to dose interruptions, dose reductions, and treatment discontinuations in 55%, 14%, and 3% of patients, respectively. Pharmacokinetics were dose proportional across all q.d. doses but not all t.i.w. doses evaluated, with saturation observed between 80 and 200 mg t.i.w. Serum phosphorus increased dose dependently with futibatinib on both schedules, but a stronger exposure-response relationship was observed with q.d. dosing, supporting 20 mg q.d. as the recommended phase II dose (RP2D). Overall, partial responses were observed in five patients [FGFR2 fusion-positive intrahepatic cholangiocarcinoma (n = 3) and FGFR1-mutant primary brain tumor (n = 2)], and stable disease in 41 (48%). CONCLUSIONS: Futibatinib treatment resulted in manageable safety, pharmacodynamic activity, and preliminary responses in patients with advanced solid tumors. The results of this phase I dose-escalation trial support 20 mg q.d. futibatinib as the RP2D. CLINICAL TRIAL REGISTRATION: FOENIX-101 (ClinicalTrials.gov, NCT02052778)

Molecular guided therapy for advanced pancreatic cancer patients with PI3K activated mutation: vision or illusion?

Anas Gazzah,1 Daniel Barrios Gonzales,1 Antonin Levy,1 Rastislav Bahleda,1 Michel Ducreux,2 Ludovic Lacroix,3 Jean Charles Soria11SITEP (Service des Innovations Therapeutiques Précoces), Department of Medicine, Institut Gustave Roussy, Paris XI University, Villejuif, France; 2Department of Medicine, Institut Gustave Roussy, Paris XI University, Villejuif, France; 3Department of Biology, Institut Gustave Roussy, Paris XI University, Villejuif, FranceAbstract: Despite a modern validated regimen of chemotherapy, advanced pancreatic adenocarcinoma remains the fourth most common cause of cancer-related death worldwide. The phosphoinositide 3-kinase pathway (PI3K)/Akt/mammalian target of rapamycin (mTOR) is a major signaling pathway that may be activated in advanced pancreatic cancer. To highlight the potential interest of this targetable pathway in selected advanced pancreatic cancer patients, we report herein a patient with an activated PI3K mutation who was treated in a phase I trial evaluating a treatment combination including an mTOR inhibitor.Keywords: pancreatic cancer, PI3K, targeted therapy, molecular profilin