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

Abstract B10: A phase I, dose-escalation and PK study of IV aflibercept (VEGF Trap) in combination with docetaxel (D), cisplatin (C), and 5-fluorouracil (F) administered every 3 weeks in patients with advanced solid malignancies

Abstract Background: Aflibercept (AF) is a recombinant fusion protein of the human vascular endothelial growth factor (VEGF) receptor combining the Fc portion of human IgG1 with the extracellular ligand-binding domains of human VEGFR1 and VEGFR2. AF binds and neutralizes all VEGF-A isoforms plus placental growth factor. This study was designed to assess the safety, dose-limiting toxicities (DLTs)/ recommended dose (RD), and PK of AF + DCF. Methods: This phase I combination trial explored escalating IV doses of AF given on day 1 followed by DCF (fixed dose of D 75mg/m2, C 75mg/m2 both on day 1 and F 750 mg/m2/day from day 1 to 5), every 3 weeks. G-CSF and fluoroquinolone were given as primary prophylaxis. Patient characteristics: 44 pts (M/F 29/15, median age 53 [range: 33–74], baseline ECOG-PS 0/1/2: 16/27/1) were enrolled in 3 AF dose cohorts: 2 (n = 9), 4 (n = 14) and 6 (n = 21) mg/kg. Primary tumors were mostly gastro-intestinal (28, including 22 gastro-esophageal, 3 pancreas, 2 liver, 1 cholangiocarcinoma), 4 breast, 3 lung, 3 utero-vaginal, 2 thyroid, and 4 others. Sixteen (36%) pts received prior chemotherapy, median number of lines 2 (range 1–6). Preliminary Results: Pts received a median number of 6, 4, and 7 cycles respectively for each dose group of 2, 4, and 6 mg/kg (range 1–19). One AF-related DLT of pulmonary embolism was observed at the 6 mg/kg AF dose level. Most common Gr ≥ 3 adverse events included: fatigue/asthenia (46%), mucosal inflammation/stomatitis (41%), anorexia (18%), and febrile neutropenia (16%). Mild to moderate arterial hypertension and proteinuria were reported. Grade 1 or 2 epistaxis (61%) and dysphonia (41%) also were reported. Two fatal events were observed: gastrointestinal haemorrhage after C2 (cholangiocarcinoma, AF 6 mg/kg), pulmonary haemorrhage with bronchial necrosis after C12 (NSCL cancer, AF 6 mg/kg). Thirteen (35%) partial responses (PR) in various tumor types, and 20 stable disease (SD) including 14 pts with SD≥2 months were noted. PK analysis will be presented once available. Conclusions: AF 6 mg/kg combined with DCF q3wks was selected for further investigation, based on DLTs and overall safety profile. This dose is consistent with results from other aflibercept phase 1 studies. Encouraging signs of anti-tumor activity and disease control have been seen. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B10.</jats:p

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)