bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066
Authors: Kwak E. L. , Camidge D. R. , Clark J. , Shapiro G. I. , Maki R. G. , Ratain M. J. , Solomon B. , Bang Y. , Ou S. , Salgia R. 
Published: August 2020

3509 Background: PF-02341066 (PF) is a selective, ATP-competitive, small molecule oral inhibitor of the c-Met/HGFR and ALK receptor tyrosine kinases that has not previously been tested in humans. A Phase 1 dose-escalation trial evaluating PF as an oral single agent was conducted to investigate safety, PK and PD in patients (pts) with advanced cancer (excluding leukemias). Methods: PF was administered under fasting conditions QD or BID on a continuous schedule to pts in successive dose-escalating cohorts at doses ranging from 50 mg QD to 300 mg BID. Pts with advanced cancer were enrolled in the study. Results: Thirty-seven pts were enrolled into the dose escalation part of the study. Tumor types included colorectal, pancreatic, sarcoma, ALCL and NSCLC. The MTD was 250 mg BID. Three DLTs were observed: grade 3 increase in ALT (1 pt at 200 mg QD) and grade 3 fatigue (2 pts at 300 mg BID). The most common AEs were nausea, emesis, fatigue and diarrhea. Nausea and emesis were independent of dose or duration of treatment. Mean AUC (30–57% CV) and Cmax (36–69% CV) increased proportionally with dose from 100 mg QD to 300 mg BID. The median terminal half-life was 46 hours. A 2- to 4-fold increase in the oral midazolam (MDZ) AUC was observed following 28-days of PF dosing at 100 mg QD (n = 3) and 300 mg BID (n = 2), respectively, suggesting PF to be an inhibitor of CYP3A. Ten pts have entered an enriched RP2D cohort of pts with tumors harboring c-Met amplification/gene mutation or ALK fusion genes. There has been 1 confirmed PR in a sarcoma pt with ALK rearrangement (inflammatory myofibroblastic tumor). Among 10 NSCLC pts whose tumors harbor EML4-ALK rearrangement, 1 pt has had a PR, 2 pts have achieved unconfirmed PR and 4 pts have had SD (3 have experienced reduction in tumor burden by ∼20% in measurable lesions and 1 has been treated for 28 weeks). Conclusions: The MTD of PF is 250 mg BID. The major AEs were fatigue or GI-related, and all AEs were manageable and reversible. There was no evidence of non-linear PK at PF doses >100 QD. Treatment with PF-02341066 resulted in promising clinical activity against tumors carrying activating ALK gene rearrangements. Further study of PF in pts with ALK-dependent tumors is warranted. [Table: see text]
A phase I study of XL228, a potent IGF1R/AURORA/SRC inhibitor, in patients with solid tumors or hematologic malignancies
Authors: Smith D. C. , Britten C. , Clary D. O. , Nguyen L. T. , Woodard P. , Hurwitz H. I. 
Published: August 2020

3512 Background: XL228 is a protein kinase inhibitor targeting IGF1R, the AURORA kinases, FGFR1–3, ABL and SRC family kinases. It is being evaluated in a phase 1 trial in patients (pts) with advanced malignancies. Methods: XL228 is administered as weekly 1-hour IV infusions. Cohorts of pts with refractory solid tumors or lymphoma are evaluated for determination of the maximum tolerated dose, pharmacokinetics, and pharmacodynamic effects using FDG-PET, signal pathway analysis in tumor and normal tissue biopsies, and plasma marker analysis. MTD expansion cohorts will include pts with multiple myeloma and colorectal cancer. Results: Thirty-six pts have been treated at doses ranging from 0.45 to 8.0mg/kg. The maximum administered dose was defined as 8.0mg/kg as a result of the dose limiting toxicities of Grade (Gr) 4 neutropenia, and Gr 3 neutropenia requiring dose skipping. XL228 is generally well tolerated; one serious adverse event of drug-related Gr 3 vomiting has been observed. Common drug-related adverse events include Gr 1 nausea, fatigue, decreased appetite, and flushing, and Grade 1–2 hyperglycemia (fasting) lasting up to 4 hours post- infusion. XL228 exposure was approximately dose-proportional; the mean terminal half-life (t1/2, z) ranged from 27 to 54 hours. Low accumulation was observed after weekly administration. Protein phosphorylation measurements in skin, hair, and blood samples demonstrate inhibition of IGF1R, SRC and FGFR1 signaling by XL228, including reductions in hair follicle phospho-IGF1R and phospho-FAK1 of 39% and 42%, respectively, in a pt dosed at 5.4mg/kg. Evidence of clinical activity includes one non-small cell lung cancer pt with an unconfirmed partial response (confirmation pending) and 9 additional pts (of 30 evaluable) with stable disease (SD) lasting >3 months, including a small cell lung cancer pt on study for 13.3+ months after failing carboplatin/etoposide. For pts with SD, the median time on study is currently 5.9 months (range 3.3+ to 13.3+). Conclusions: XL228 is generally well tolerated and has shown encouraging preliminary clinical and pharmacodynamic activity. [Table: see text]
First-in-human phase I study of the novel structure proteasome inhibitor NPI-0052
Authors: Hamlin P. A. , Aghajanian C. , Younes A. , Hong D. S. , Palladino M. A. , Longenecker A. M. , Lloyd G. K. , Hannah A. L. , Spear M. A. , Kurzrock R. 
Published: August 2020

3516 Background: NPI-0052 is a second-generation proteasome inhibitor that has a novel structure with preclinical studies suggesting unique proteasome inhibition (PI), signal transduction, efficacy and toxicology profiles, and activities in a broad range of models including bortezomib (BZ) resistant models. Methods: Patients were treated with NPI-0052 IV weekly x 3 in 4-week cycles in a 3+3 design dose escalation to a Recommended Phase 2 Dose (RP2D). PI was assayed in whole blood (PWB) and in PBMCs. Up to 10 patients each (lymphoma and solid tumors) are treated at the RP2D. Results: 39 patients have been treated between 0.0125 mg/m2 to 0.8 mg/m2 for up to 12 cycles. The RP2D was 0.8 mg/m2 and has been well tolerated in this study, with the most notable drug-related adverse events being N/V, fatigue, diarrhea, dizziness, headache, decreases in hemoglobin, and insomnia. Thrombocytopenia or neuropathy did not appear to be induced by NPI-0052. Escalation was halted at 0.8 mg/m2, as DLT of transient “hallucinations” (visual imprints when eyes closed) and dizziness/unsteady gait were reported in another study at 0.9 mg/m2. PK data indicate T1/2 ∼4–10 minutes, with clearance at 3–15 L/min and Vz of 35–85L. PI (chymotrypsin-like activity) in PWB and PBMC were dose dependent (mean D1 and D15 PI in PWB at 0.8 mg/m2 was 75 and 100%) (efficacious doses of BZ have been reported to result in a range of ∼40–70% PI). PI in PBMC returned to ∼baseline within one week of each dose, while inhibition remained in PWB. Stable disease was observed in patients with cervical carcinoma (11 months; maximum response was 24%; PI increased with dose escalation), colorectal, hepatocellular, adenoid cystic, melanoma, granulosis cell and ovarian. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects, with equal to greater PI seen than reported with therapeutic doses of BZ. At the RP2D toxicity is mild-to-moderate, without the toxicity profile associated with BZ. Together with preclinical data this suggests NPI-0052 may have utility in treating patients who are not candidates for BZ as well as in indications and combinations that have not supported BZ use. Additional trials have been initiated including combinations with other targeted agents. [Table: see text]
Phase I study of enzastaurin (ENZ) and bevacizumab (BV) in patients with advanced cancer: Safety, pharmacokinetics (PK), and response assessment
Authors: Carducci M. A. , Armstrong D. K. , Collins C. , Wang T. , Schaefer S. , Ermisch S. , Musib L. C. , Nicol S. , Thornton D. E. , Zhang Z. 
Published: August 2020

3517 Background: ENZ, an oral kinase inhibitor, suppresses tumor growth through PKC and PI-3 kinase/AKT. BV binds VEGF and inhibits angiogenesis. Since ENZ and BV are complementary in inhibiting angiogenesis, we conducted a Phase I study of ENZ / BV. Methods: Eligible patients (pts) had advanced cancer, adequate organ function and no co-morbidities for increased risk of drug-related toxicities. Six pts were enrolled per cohort; if ≤1 DLT the next cohort opened. A loading dose of ENZ 1125 mg was given on Day 1, C1. After 1 cohort combining ENZ 500 mg/QD and BV at 5mg/kg IV q 2 wks, subsequent cohorts alternated pts between BV 10 mg/kg IV q 2 wks and BV 15 mg/kg IV q 3wks with escalating doses of ENZ (500 mg/QD, 250 mg/BID, and 375 mg/BID) for a total of 7 cohorts. DLT was defined as C1: Grade (G)4 neutropenia ≥7 days, febrile neutropenia, G3 thrombocytopenia with bleeding or G4 thrombocytopenia; G3/G4 non-hematological toxicities, and toxicities associated with BV. ENZ PK was performed at steady-state on Day 1, C2. Results: 43 pts (21 with ovarian cancer) are evaluable for toxicity. Two DLTs (G3 elevated aminotransferase and intraparenchymal hemorrhage) occurred at different dose levels. No apparent increase in ENZ or BV toxicity was seen. Two SAEs (DVT and myocardial ischemia) in two pts occurred at DL 3 after 3 cycles and 13 cycles, respectively. Common toxicities included fatigue, chromaturia, dry/sore mouth, nausea and diarrhea. Nine of 43 pts (21%) had a response (CR, PR), 6 responses were in the ovarian subset (29%). Median time to progression was 3.9 mos (range 0–19.2 mos) and 7.7 mos for ovarian pts (range 0.3–19.2 mos). Overall, 43% remained on study without disease progression for >6 mos (51% of ovarian pts remained on study for >6 mos). Mean steady-state ENZ concentrations (%CV) at 500 mg/QD, 250mg/BID and 375mg/BID were 1080 nmol/L (82.8 %), 516 nmol/L (102%) and 1120 nmol/L (93.3%), respectively. Conclusions: The addition of ENZ to BV in any of the currently approved BV dosing schedules is well tolerated and clinically active in advanced cancer pts. ENZ exposures are highly variable and comparable across the three dose groups. The combination of ENZ / BV demonstrates encouraging activity, specifically in our population of ovarian cancer pts. [Table: see text]
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of PF-00337210, a highly selective VEGFR inhibitor
Authors: Liu G. , LoRusso P. M. , Goncalves P. , Holen K. , Traynor A. , Zhang J. , Hee B. , Tortorici M. , Shalinsky D. R. , Ricart A. D. 
Published: August 2020

3519 Background: PF-00337210 potently inhibits VEGFR2 phosphorylation and is >10-fold more selective, based on IC50, for VEGFR2 than other kinases (eg, KIT and PDGFRs). In vitro, PF-00337210 inhibits VEGF-mediated HUVEC survival (IC50 = 0.53 nM). In vivo, it inhibits tumor angiogenesis and human xenograft growth. Methods: The primary objectives were to determine the safety profile and MTD of PF-00337210. PK and PD (DCE-MRI at baseline and cycle [C] 1, day [D] 2) were also evaluated. The volume rate transfer constant (Ktrans) assessed VEGFR inhibitory effects on vascular permeability and perfusion. Results: To date, 29 patients (pts) with advanced solid tumors were treated with PF-00337210 at doses of 0.67–9 mg QD, 13 of whom (45%) had received prior VEGF/VEGFR inhibitors. No dose-limiting toxicities (DLTs) occurred at 0.67–8 mg QD. Two DLTs occurred at 9 mg QD: one pt had chest pain, G3 troponin I, and G3 myocardial ischemia; a second pt had significant hypertension (HTN) at the anticipated Tmax after the first dose (systolic ≥180 mmHg over 3 hrs). HTN and fatigue were the most common treatment-related adverse events (AEs). HTN occurred in 8 pts (28%); incidence and intensity corresponded with dose, but was well controlled with antihypertensive agents. Fatigue was reported in 9 pts (31%) and occurred most frequently in pts receiving ≥6 mg QD. Other AEs included nausea, anorexia, proteinuria, and diarrhea. PK data indicated that mean (%CV) t1/2 at 8 mg QD was 8.60 (81) h (n=4) and AUC0–24 was 309 (45) ng.h/mL at steady-state (SS) on C1D15. Exposures (AUC0–24) were generally linear and variability ranged from 21 to 44% across doses. The observed accumulation ratio (Rac) at SS was 1.22 (15) (n=21), which was predicted by t1/2. PF-00337210 decreased mean Ktrans (1/min) values by 22.5±11.8 (n=2), 15.2 (n=1), 5.4±4.8 (n=3), and 25.3±8.5% (n=4) at 4, 6, 8, and 9 mg QD, respectively. No objective responses were observed but 7/29 pts (24%) had stable disease. Conclusions: PF-00337210 was well tolerated with the DLTs being HTN and myocardial ischemia. The QD MTD was determined to be 8 mg. Preliminary evidence of VEGFR inhibition was shown by DCE-MRI at ≥4 mg QD. The trial is now evaluating BID dosing which may allow increased drug exposures and fewer hypertensive effects that may be related to Cmax. [Table: see text]
Phase II trial of pazopanib in progressive, metastatic, iodine-insensitive differentiated thyroid cancers
Authors: Bible K. C. , Smallridge R. C. , Maples W. J. , Molina J. R. , Menefee M. E. , Suman V. J. , Burton J. K. , Bieber C. C. , Ivy S. P. , Erlichman C. 
Published: August 2020

3521 Background: Systemic therapies have had little impact on the outcomes of patients with advanced differentiated thyroid cancers. Methods: A three-outcome one-stage Phase II trial was conducted to assess the anti-tumor activity and toxicities of the orally bioavailable VEGF/tyrosine kinase inhibitor pazopanib (800 mg daily) in patients with advanced and progressive radioiodine-insensitive differentiated thyroid cancers. Up to 2 prior therapies were allowed, with measurable disease required. Design: at the 0.10 significance level, there would be a 90% chance of detecting a RECIST response rate of >20% given a true response rate of >5%; with the regimen considered promising if >4 confirmed responses observed. Results: From February to November 2008, 32 patients (53% male) aged 23–79 years (median: 63 years) were enrolled. Common sites of metastases were: lung (100%), nodes (52%), and bone (39%). Measurement data are available for 26 patients, with the median number of cycles administered thus far 4 (range: 1–8, total: 101). Overall, therapy has been well tolerated. Six patients (23%) required dose reduction due to: grade 2+ ALT (3 pts), grade 3 mucositis (1 pt); grade 3 diarrhea and dehydration (1 pt), and grade 3 abdominal pain (1 pt.). Other serious toxicities included grade 3 colon perforation and grade 3 chest pain (1 pt). No thyroglobulin antibody (TGA) negative patient has become TGA positive, and 11 of 16 patients (69%) with initially elevated thyroglobulin levels experienced a decline in thyroglobulin of >50%. Five RECIST partial responses have been confirmed to date (19%). Two patients are alive with disease progression and another has died from disease progression. Conclusions: Pazopanib appears to have both a favorable toxicity profile and promising clinical activity in patients with advanced and progressive differentiated thyroid cancers. Supported in part by NCI CA15083 and CM62205. No significant financial relationships to disclose.
Circulating tumor and endothelial cells as pharmacodynamic biomarkers in a phase I clinical trial of intravenous bevacizumab in combination with escalating doses of oral cediranib for patients with advanced malignancies
Authors: Davis D. W. , Liu W. , Kurzrock R. , Naing A. , Wheler J. , Ricks L. W. , Ivy S. , Hong D. 
Published: August 2020

3525 Background: Rare circulating tumor cells (CTCs) and endothelial cells (CECs) offer a feasible approach for studying the pharmacodynamic effects of investigational agents. We investigated the effects of bevacizumab (B) and cediranib (C) on inhibition of the VEGFR pathway and correlated these changes with dose and clinical response. Methods: Peripheral blood was obtained at baseline, 24hrs and at C2D26–30 post-treatment from patients (n=14) undergoing dose escalation of intravenous B and oral C. CTCs and CECs (CD31+ or CD105+) were isolated and immunofluorescently stained. Laser scanning cytometry (LSC) was used to quantify phosphorylated and total-VEGFR2 (pVEGFR2/VEGFR2), pERK/ERK, and apoptosis in each phenotype. Changes in each biomarker were correlated with partial response (PR) or stable disease and progression > 2 months, evaluated using RECIST. Results: Overall, immature CECs (CD105+) enumerated by CellSearch™ revealed a dose-dependent significant decrease (p=0.0001). A 3-fold induction in apoptosis was observed at 24 hrs compared to baseline in the CD105+ CECs. Mature CD31+ cells assessed for VEGFR2 activity revealed an 83% and 1.9% significant (p=0.019) inhibition in pVEGFR2 expression at low (B;3mg/kg) and high (B;5mg/kg) doses, respectively. In the non-responders, mature CECs revealed a dose-dependent significant increase (-6.8% to 63%;p=0.031) in pERK/ERK expression levels. No significant changes were observed in CTC enumeration by CellSearch™. LSC-mediated CTC enumeration revealed a 4.77 % and 2.33% increase in CTCs following treatment in the non- responders and responder (p=0.809), respectively. Analysis of pVEGFR2 in CTCs revealed a 58% inhibition in the responder versus a 163% increase in expression in the non-responders (p=0.63). Conclusions: Inhibition of pVEGFR2 and induction of apoptosis in CECs confirmed the target therapy. An increase in CD105+ CECs is consistent with the hypothesis that anti-angiogenic efficacy induces endothelial cell shedding. Assessment of CECs indicates that B and C are more biologically active at lower doses, and resistance may be attributed to ERK activity. Support: UO1 CA062461 (RK) No significant financial relationships to disclose.
Pharmacodynamics and pharmacokinetics of AUY922 in a phase I study of solid tumor patients
Authors: Ide S. , Motwani M. , Jensen M. R. , Wang J. , Huseinovic N. , Stiegler P. , Wang X. , Quadt C. 
Published: August 2020

3533 Background: AUY922 is a synthetic inhibitor of Heat Shock Protein 90. Disruption of the HSP90 chaperone hetero- complex results in the loss of repression of heat shock factor-1 (HSF1), and subsequent induction of HSP70. We evaluated HSP70 as a pharmacodynamic (PD) marker of AUY922 activity in a phase I/II clinical trial in patients (pts) with solid tumors. Methods: Single agent AUY922 was administered by IV infusion once a week to pts with advanced solid malignancies. HSP70 levels in PBMC were quantitated by ELISA in samples taken at baseline and multiple time-points post the 1st and 5th treatments over two cycles. Fold change of HSP70 induction was calculated and compared to dose level and AUY922 blood exposure obtained within the first week of treatment (single dose) at 6, 24, 48, and 168 hours post-treatment. Results: Of the 40 pts treated to date, HSP70 levels in PBMC has been evaluated in 36, encompassing seven dose levels ranging from 2 mg/m2 to 40mg/m2. Baseline levels of HSP70 in PBMC ranged from 26.0 to 95.1 ng/mg protein, with a median of 42.5ng/mg. The highest level of HSP70 induction obtained over two cycles was increasing with dose from 2 to 40 mg/m2, with a range of 1.4 to 12.1 fold, and the amount of HSP70 induction was frequently higher in the second cycle of treatment. In the first cycle of treatment, HSP70 induction is correlated to blood AUC. The degree of HSP70 upregulation in PBMCs at 40 mg/m2 exceeds the 8-fold upregulation seen in BT474 xenograft tumor tissue when treated with efficacious doses of AUY922. Conclusions: PK/PD analyses show that the highest level of HSP70 achieved post-treatment increases with dose, and at the highest dose tested thus far (40mg/m2), this pharmacodynamic effect has not yet reached a maximum response. Additionally, our analysis suggests that in humans, the PD effect of AUY922 is reaching the level corresponding to that required for anti-tumor effect in the BT474 xenograft model. [Table: see text]
Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors
Authors: Galsky M. D. , Von Hoff D. D. , Neubauer M. , Anderson T. , Fleming M. , Sweetman R. W. , Mahoney J. , Midwinter D. , Vocila L. , Zaks T. Z. 
Published: August 2020

3541 Background: The current paradigm of histology-specific drug development may not be optimal in the era of targeted therapeutics. We sought to explore the activity of lapatinib, an oral tyrosine kinase inhibitor of HER2, with a trial design focused on the target rather than on tumor-type. Methods: Patients (pts) with HER2-amplified treatment-refractory metastatic gastro- esophageal (G/E), bladder (B), ovarian (O), or uterine (U) tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1500 mg PO daily (malignancies selected based on reported frequencies of HER2 amplification). The planned sample size was 250 HER2+ pts, with the goal of then randomizing 100 pts with SD at week (wk) 12 to either lapatinib or placebo until progressive disease (PD). Pts who responded at wk 12 (CR or PR) continued on lapatinib; those who progressed were discontinued from study. Primary objectives were response rate at 12 wks and percentage of pts who remain progression free at 24 wks. Secondary objectives were duration of response, progression free survival (PFS) after randomization, and determination of the incidence of HER2 amplification in multiple tumor types. Futility analyses were preplanned to ensure feasibility of screening and of randomization (i.e. a sufficient rate of non- progression at 12 wks). Results: A total of 145 pts were screened (G/E=47, B=35, O=58, U=5); 42 were HER2-amplified (G/E=16, B=13, O=13, U=0) and 32 (G/E=13, B=9, O=10) were enrolled. At wk 12, 1 (3%) patient had a CR, 10 (31%) had SD, 19 (59%) had PD, and 2 (6%) were unknown. Median time to progression during open-label lapatinib was 78 days, 95% CI (42, 92). Only 7 pts with SD underwent randomization. Two pts with esophageal cancer remain on study; one (CR at wk 12) remains a CR at wk 60 and the other (SD at wk 12) remains with SD at wk 36. Low response rate coupled with slow screening and enrollment led to early study closure. Conclusions: Basing trial eligibility on a target, versus histologic classification, is challenging. While HER2 amplifications appear to be prevalent in select non-breast tumors, lapatinib monotherapy in refractory disease is associated with a low level of objective responses. [Table: see text]