Perceptions of Race Concordance and Cultural Mindfulness in Dermatology amongst People of Color in the United States

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Preliminary activity in adrenocortical tumor (ACC) in phase I dose escalation study of intermittent oral dosing of OSI-906, a small-molecule insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor in patients with advanced solid tumors

3544 Background: IGF-1R is overexpressed in various malignancies, and implicated in proliferation, survival, and metastasis. IGF-1R blockade increases apoptosis and reduces tumor growth in preclinical models. OSI-906 is an oral small molecule tyrosine kinase IGR-1R inhibitor. Methods: Patients (pt) with advanced solid tumours were enrolled to determine safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity. Results: 26 pt have been treated (14M:12F, median age 61 yrs) at 10, 20, 40, 80, 150, 300, and 450 mg on days (d) 1–3 q14 d. No dose-limiting toxicities have been observed to date. Drug-related toxicities include grade 1 fatigue, nausea, rash, diarrhea, tachycardia, proteinuria, pruritis and peripheral oedema. Linear PK was observed, with median terminal t1/2 3.5 hr; AUC0-∞ 25.8 μg.hr/mL; Cmax 3.20 μg/ml at 450mg. Plasma OSI-906 concentrations above the estimated efficacious concentration (1 μM) were attained at doses &gt; 40mg. Glucose did not increase with rising OSI-906 concentration, but plasma insulin levels showed an upward trend, indicating potential PD effects. PD data on IGFR phosphorylation were analyzed. In total, 11 pt were treated for &gt; 12 weeks (w). Of 3 pt with ACC, 1 pt had a partial response (43% reduction in primary and multiple lung metastases) and remains on treatment after 16 w, 1 pt was treated for 32 w, and 1 pt progressed after 4 w at 40mg. In addition, 1 pt with heavily pretreated NSCLC was treated for 43 w and 1 pt with progressive myxoid chondrosarcoma remains on treatment after 38 w. Conclusions: OSI 906 had minimal toxicity, dose proportional PK at dose levels up to 450mg tested d 1–3 q14 d, with preliminary antitumor activity seen, particularly in ACC. Dose escalation with 5 and 7 d schedules q14 d continues. [Table: see text] </jats:p

Final results of a dose escalation (DE), pharmacokinetic (PK), and pharmacodynamic (PD) study of two schedules of OSI-930 in patients (pts) with advanced solid tumors

3564 Background: OSI-930 is an oral TKI with potent activity against Kit, VEGFR2, and PDGFR. Preclinical studies demonstrate tumor regression with long-term remissions across multiple xenograft models. Methods: Sequential cohorts of pts with advanced solid tumors received continuous daily OSI-930 to determine the maximum tolerated dose (MTD) and to evaluate safety, PK/PD and efficacy of OSI-930 with both QD and BID dosing. An expansion cohort was enrolled for detailed PD analysis including sVEGFR2 plasma levels, PET imaging in GIST pts or DCE-MRI in selected pts. Results: A total of 58 pts were treated (20M/38F; median 60 years (range 19–83)). OSI-930 was dosed up to 1600 mg QD without reaching MTD. 46 pts received BID dosing [mg(# pts treated)]; 400(7), 500 (31) and 600(8). DLT's were seen in 3/8 pts at 600 mg BID; G3 rash (2 pts) and G4 GGT; and 3/31 at 500 mg BID; G3 myalgia, G3 fatigue and G3 lipase. G3 hypertension was noted in 3/46 pts but not dose-limiting. Common G1/2 toxicities were fatigue (37%), diarrhea (27%), nausea (31%), and rash (24%). Objective (CA125) responses were seen in platinum-resistant ovarian cancer (2 PR/8) while in heavily pretreated GIST (median 4 prior therapies including imatinib/sunitinib), 8/18 pts achieved SD ≥12 w. Median therapy duration in the BID arm was 9 w and 18/46 pts with SD ≥12 w. PK indicated that Css were achieved after ∼7d with BID dosing. PET scans showed reduction in glycolytic activity in 4/9 pts and DCE-MRI response was seen in 4/6 pts. A trend in decreased sVEGFR levels was seen at higher doses. Conclusions: At the MTD level of 500 mg BID OSI-930 is an active, well-tolerated compound with clinically relevant antitumor activity and exposure levels consistent with antitumor activity in preclinical models. PD data indicate mechanistic proof of concept for OSI-930. OSI-930/erlotinib combination phase I study is currently enrolling. [Table: see text] </jats:p

A dose escalation (DE), pharmacokinetic (PK), and pharmacodynamic (PD) study of OSI-930 and erlotinib (E) in patients (pts) with advanced solid tumors

3550 Background: EGFR and VEGFR are important targets in a number of human cancers with common downstream signalling pathways. Combined blockade of EGFR-VEGFR with E and OSI-930 has shown additional antitumor activity compared to either agent alone with long-term remissions in multiple xenograft models. Methods: Sequential cohorts of pts with advanced refractory solid tumors were treated with OSI-930 BID with addition of E QD from Day 8 and beyond to determine the maximum tolerated dose (MTD) and to evaluate safety, PK and efficacy of the combination. Escalation followed a standard 3+3 design until dose-limiting toxicity (DLT) was observed in ≥ 2/6 pts. PK of OSI-930, E and its metabolite OSI-420 were determined. Levels of soluble VEGFR2 (sVEGFR2) in plasma were also measured. Results: 16 pts have been entered (13M/3F); median age 63 years (range 41–78), PS ≤2 and 38% pts with mCRC. OSI-930/E were administered at 3 levels [mg(pts entered/evaluable)]; 200 BID/100 QD (7/6), 200 BID/150 QD (4/3), and 300 BID/150 QD (5/5). Median duration of therapy was 8 weeks (range 1–22). DLT was seen in 1/6 pts at 200 BID/100 QD (&gt;5 day interruption due to G4 neutropenia); and 1/5 at 300 BID/150 QD (G3 Asthenia/lethargy). Other common related toxicities (% all grades:% g3/4) were: skin-related (rash, HFS etc) (85:23), Asthenia/lethargy/fatigue (69:15), diarrhea (77:8), anorexia (92:0), and transaminitis (31:15). Reduction and/or interruptions of one or both study drugs during or beyond the initial 28 days were required in 8/14 pts. Six of 11 pts evaluable for response achieved SD ≥12 weeks. Median plasma Cmax (and AUCTau) of OSI -930 for Cohort 3 (300 BID/150 QD) were: 0.826 (6.08), 0.947 (5.57), and 1.66 (14.3) μg/mL (μg.hr/mL) on Days 7, 8 and 22, respectively. Exposure of OSI-930 increased approximately 2-fold upon co-administration with E at steady-state. OSI-930 appeared not to alter the PK properties of E or the ratio of OSI-420 to E. Decreases in plasma sVEGFR2 were observed, indicating a PD effect of OSI-930. Conclusions: Additional patients are being added to confirm the MTD of the combination. PK data indicate a drug-drug interaction with doubling of the OSI-930 exposure on co-administration with E. [Table: see text] </jats:p

Phase I dose escalation study of Linsitinib (OSI-906) and Erlotinib in patients with advanced solid tumors

Cross-talk between type 1 IGF receptor (IGF-1R), insulin receptor (INSR) and epidermal growth factor receptor (EGFR) mediates resistance to individual receptor blockade. This study aimed to determine the MTD, safety, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of linsitinib, a potent oral IGF-1R/INSR inhibitor, with EGFR inhibitor erlotinib.This open-label, dose-escalation study investigated linsitinib schedules S1: once-daily (QD) intermittent (days 1-3 weekly); S2, QD continuous; S3, twice-daily (BID) continuous; each with erlotinib 100-150mg QD; and a non-small cell lung cancer (NSCLC) expansion cohort.Ninety-five patients were enrolled (S1, 44; S2, 24; S3, 12; expansion cohort, 15) and 91 treated. Seven experienced dose-limiting toxicities: QTc prolongation (3), abnormal liver function (2), hyperglycemia (1), anorexia (1). Common adverse events included drug eruption (84%), diarrhea (73%), fatigue (68%), nausea (58%), vomiting (40%). MTDs for linsitinib/erlotinib were 450/150mg (S1), 400/100mg (S2). Based on prior monotherapy data, S3 dosing at 150mg BID/150mg QD was the recommended phase II dose for the expansion cohort. There was no evidence of drug-drug interaction. Pharmacodynamic data showed IGF-1 elevation and reduced IGF-1R/INSR phosphorylation, suggesting pathway inhibition. Across schedules, 5/75 (7%) evaluable patients experienced partial responses: spinal chordoma (268+ weeks), rectal cancer (36 weeks), three NSCLCs including 2 adenocarcinomas (16, 72 weeks), 1 squamous wild-type EGFR NSCLC (36 weeks). Disease control (CR+PR+SD) occurred in 38/75 (51%), and 28/91 (31%) patients were on study >12 weeks.The linsitinib/erlotinib combination was tolerable with preliminary evidence of activity, including durable responses in cases unlikely to respond to erlotinib monotherapy