bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I trial of the HSP90 inhibitor, alvespimycin (17-DMAG) administered weekly, intravenously, to patients with advanced, solid tumours
Authors: Pacey S. C. , Wilson R. , Walton M. , Eatock M. , Zetterlund A. , Arkenau H. , Beecham R. , Raynaud F. , Workman P. , Judson I. 
Published: August 2020

3534 Background: alvespimycin (17-dimethylaminoethylamino-17-demethoxygeldanamycin, 17-DMAG) inhibits N-terminal ATPase activity of Heat Shock Protein 90 (HSP90). Chaperone interactions are altered such that client proteins are targeted for degradation. The plethora of HSP90 client proteins offers the potential of simultaneous blockade across multiple, oncogenic signalling pathways. Methods: the maximum tolerated dose, at which ≤ 1/6 patients experienced dose limiting toxicity (DLT) was determined by dose-doubling (3+3) design. PK and PD biomarker data were used to define a biologically effective dose (BED). PK (LC/MS/MS) and PD (western blot) assays were validated and compliant with European clinical trial legislation. Cancer Research UK and the NCI were co-sponsors. Results: twenty five patients, median age 58 (range 38–78) years, received 475 infusions at doses between 2.5 and 106 mg/m2. Dose doubling was possible to 80mg/m2 when grade 2 toxicity, including dry eye and blurred vision (2/5 patients) occurred. At 106mg/m2 DLT were observed (grade 3 fatigue, diarrhoea, dehydration and grade 4 hypotension, AST rise) in 2/4 patients, one patient died from cardiac arrest. PK data were as follows; plasma t = 24.6 ± 8.6 hr, Vss 468 ± 383 L (mean ± SD) and clearance 27.7 L/hr (range 8.26 - 153). Maximum plasma concentration increased proportionally with alvespimycin dose, area under the curve was only linear ≤ 80 mg/m2. PD changes (HSP72 induction) in peripheral blood mononuclear cells were detected ≥ 20 mg/m2. HSP90 inhibition (client protein depletion and HSP72 induction) was not readily detected until 106 mg/m2. Tumour samples confirmed HSP90 inhibition 24 hours after 17-DMAG in 1/1 and 2/4 patients given 106 and 80 mg/m2, respectively. Two partial responses one, confirmed, in a patient with hormone refractory prostate cancer and one, investigator assessed, in a patient with melanoma occurred. Both remain on study after 27 and 18 months, respectively. Nine patients (36%) have been on trial ≥16 weeks. Conclusions: The recommended phase II dose of alvespimycin is 80 mg/m2 weekly. PK and PD data support this as a BED. No significant financial relationships to disclose.
A phase I study evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of the oral pan-phosphoinositide-3 kinase (PI3K) inhibitor GDC-0941
Authors: Sarker D. , Kristeleit R. , Mazina K. E. , Ware J. A. , Yan Y. , Dresser M. , Derynck M. K. , De-Bono J. 
Published: August 2020

3538 Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent and selective oral inhibitor of class I PI3K and demonstrates activity in a broad range of preclinical models (breast, ovarian, lung, and prostate). Methods: Patients (pts) with histologically confirmed advanced solid tumors and ECOG PS 0–1 were treated with GDC-0941 using a 3+3 escalation design at a single institution. Treatment was a single dose with 1wk washout, followed by GDC-0941 qd on a 3wk on, 1wk off schedule. Objectives were to determine MTD and DLT, evaluate PD endpoints in surrogate (pAKT in platelet rich plasma) and tumor (pAKT and pS6 in paired tumor biopsies and FDG uptake via PET imaging) tissues, and describe anti-tumor activity. Results: Thirteen patients have been enrolled in 4 successive cohorts (15–60 mg qd). GDC-0941 was generally well-tolerated with no drug related Grade 3 or 4 AEs or DLTs to date. Grade 1 diarrhea, nausea, dysgeusia, peripheral sensory neuropathy, dry mouth, thrombocytopenia, and increased aspartate aminotransferase have been observed. Preliminary PK data suggest dose-proportional increases in fasting mean Cmax and AUC. Preliminary PD data show decreased levels of pAKT in platelet rich plasma correlated with GDC-0941 plasma concentrations. GDC-0941 effects on FDG-PET imaging is being assessed, with 1 patient with HER2+ metastatic breast cancer showing a reduction in FDG uptake and improvement of a chest wall lesion (dose level 60 mg qd). Evaluation of PI3K pathway modulation from paired tumor biopsies is underway. Conclusions: GDC-0941 is generally well tolerated when administered qd at doses associated with inhibition of pAKT in surrogate tissues. Evidence of PD activity in tumor tissue has also been observed. Dose-escalation continues and updated PK/PD data will be presented. [Table: see text]
Phase I and pharmacokinetic (PK) study of dasatinib (D) and cetuximab (C) in patients (pts) with advanced solid malignancies
Authors: Feinstein T. M. , Agrawal S. , Stoller R. G. , Egorin M. J. , Argiris A. 
Published: August 2020

3540 Background: D is a small molecule inhibitor of several kinases, including SRC. SRC can potentiate Epidermal Growth Factor Receptor (EGFR) signaling and is implicated in resistance to EGFR inhibitors. Combined inhibition of EGFR and SRC may lead to improved therapeutic effect. We evaluated the combination of D and C, a chimeric IgG1 monoclonal anti-EGFR antibody. Methods: Eligible pts had advanced solid malignancies treated with any number of prior regimens but without EGFR or SRC inhibitors, ECOG performance status 0–2, QTc interval on baseline EKG <450 msec, and adequate laboratory parameters. C was administered i.v as a loading dose of 400 mg/m2 on cycle 1, day 1 and then weekly at 250 mg/m2 on days 1, 8 and 15. D was administered orally, once daily, on a continuous schedule, on days 1–21. We used a standard up-and-down dose escalation scheme to assign pts on 3 dose levels (DL): 1- 100 mg QD, 2- 150 mg, 3- 200 mg. PK studies of D were performed on days 0 (prior to starting C) and 15 of cycle 1. Results: 25 pts (DL 1, 3 pts; DL 2; 19 pts; DL 3; 3 pts) were enrolled; 15 male; median age 62; median prior regimens: 2 (range: 0–5). Pts received a median of 2 cycles of D plus C (range: 1–15). 3 pts developed dose-limiting toxicities (DLT): 1 at DL 2 (headache; HA) and 2 at DL 3 (HA and nausea). Thus, MTD was reached at DL 2. DL 2 was expanded by an additional 12 pts to obtain further clinical and PK data. PK parameters (AUC and T-1/2) of D were comparable when given alone or in combination with C. Grade 3–4 toxicities in > 2 pts included: dyspnea (4), vomiting (4), nausea (3), allergic reactions (3), HA (3) and anemia (3). 21 pts developed HA (grade 1, 8 pts; grade 2, 10 pts). HA occurred after the loading of C, and took a median of 2 days to resolve. Pleural effusion developed in 4 pts (grade 2, 3 pts; grade 3, 1 pt) after 2–5 months of treatment. In 17 evaluable pts, there were no objective responses; 9 pts had stable disease: salivary gland cancer (3), thyroid (2), sarcoma (1), unknown primary (1), esophagus (1), and NSCLC (1). Conclusions: D 150 mg plus C was well tolerated, but early-onset HA was frequent. C administration did not affect D PK. We plan to treat 6 additional pts starting D 3 days after the C loading dose in an attempt to ameliorate early-onset HA. A phase II trial of C plus D in head and neck cancer is planned. [Table: see text]
Phase I evaluation of lapatinib and everolimus in patients with advanced malignancies: Southwest Oncology Group trial S0528
Authors: Hoban C. J. , Hoering A. , Synold T. W. , Chung V. , Gandara D. R. , Schott A. F. , Kingsbury L. , Lew D. , LoRusso P. M. , Gadgeel S. M. 
Published: August 2020

3553 Background: Anti-tumor activity of Her inhibitors including lapatinib, an oral inhibitor of Her1 and Her 2, appears to correlate with their ability to down regulate PI3/Akt pathway. Everolimus, an oral inhibitor of mTOR, a serine/threonine kinase downstream of Akt, has shown enhanced efficacy when combined with Her inhibitors in pre-clinical studies. This phase I study is being conducted to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of the combination of lapatinib and everolimus. Methods: Pts with advanced tumors, for which there was no effective therapy, were eligible. The study consists of two parts. In Part I dose escalation to define MTD was performed with both drugs being given together. MTD was defined by dose limiting toxicities (DLT) in the first cycle (each cycle is of 4 weeks duration). In Part II, PK of both drugs are being analyzed in patients treated at MTD and randomized to either cohort A- everolimus alone for a week followed by both drugs, or cohort B- lapatinib alone for a week followed by both drugs. 12 PK eligible pts will be accrued to each cohort to detect the influence of one drug over the other drug's PK. Results: 26 pts were enrolled in Part I of the study, 23 were evaluable for DLT. Median age- 63 (29–76); males/females- 20/6. Common tumors were breast (4), lung cancer (3), adenoid cystic (3). 79 cycles (median 2, range 1–15) have been administered to date. 6 pts developed DLTs: pneumonitis, rash, diarrhea, stomatitis (2), and fatigue (2). The MTD of the combination is lapatinib 1250mg and everolimus 5mg, daily. None of the pts had a response but 11 pts (2 liver, 1 breast, 1 renal, 1 sarcoma, 2 adenoid cystic, 1 melanoma, 1 bladder, 1 NSCLC, 1 colorectal) had stable disease for 8 weeks or longer. Conclusions: The MTD of the combination is lapatinib 1250 mg and everolimus 5 mg. The dose limiting toxicities observed were diarrhea, stomatitis and fatigue. Accrual to Part II is ongoing and pharmacokinetic analysis is pending. [Table: see text] [Table: see text]
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies: A phase I/II dose finding and biomarker study
Authors: Angevin E. , Lopez J. A. , Pande A. , Moldovan C. , Shi M. , Soria J. C. , Wang X. , Harzstark A. , Saro J. , Escudier B. 
Published: August 2020

3563 Background: TKI258 is a potent receptor tyrosine kinase inhibitor (TKI) that selectively targets VEGFR, PDGFR, FGFR, CSF1R, c-KIT, RET, TrKA, and FLT3. Compared to other TKI agents, TKI258 additionally targets FGFR. FGF has been reported as an important escape mechanism of anti-VEGFR therapies. Methods: The primary objective of this phase I was to determine the maximum tolerated dose (MTD) of TKI258, administered orally on a 5 days on / 2 days off schedule in repeated 28 day cycles, in mRCC pts refractory to standard therapies. A two-parameter Bayesian logistic regression model and safety data for at least 21 pts will be used to determine MTD. Results: A phase I study is ongoing. As of December 2008, 11 pts (9 m, 2 f), median age: 55 (29–66 yrs) have been enrolled. Four pts have been treated at 500 mg/day (start dose): 2 are ongoing at cycle (C) 7; 1 pt discontinued due to PD and 1 due to sinus bradycardia. Five pts received 600 mg/day: 2 DLTs (G4 hypertension and G3 fatigue - pts discontinued) leading to dose reduction of all patients to 500mg/day; 2 pts in C5 and C4, 1 pt discontinued for PD. Two pts just entered the extension cohort at 500 mg. Other toxicities ≥G2 included fatigue, nausea, vomiting, diarrhea, neutropenia, folliculitis and dizziness. PK data showed CMax range (180–487 ng/mL, n = 8), and AUC range (2200–8251 ng/mL*h). Preliminary biomarker data indicated pts had high baseline VEGF (506 ± 203 pg/ml, n=6) and bFGF (220 ± 185 pg/ml, n = 6) levels, which may reflect failure of previous anti-VEGF agents. Induction of plasma FGF23 levels, a pharmacodynamic biomarker of FGFR1 inhibition, was observed in pts from the first 500 mg/day dosing cohort. Preliminary evidence of efficacy is observed with one minor response (-17% at C4), 4 stable disease and 1 dramatic shrinkage/necrosis of some target lesions (lymph node & suprarenal mass). Conclusions: TKI258 500mg/day seems a feasible schedule in heavily pre-treated mRCC patients with some indications of clinical benefit. These preliminary findings will be confirmed in the extension cohort. [Table: see text]
Phase I evaluation of orally-administered CYT997, a novel cytotoxic vascular-disrupting agent, in patients with advanced cancer
Authors: Francesconi A. , Kotasek D. , Burge M. , Smith G. , Lickliter J. 
Published: August 2020

3568 Background: CYT997 is a novel, small-molecule vascular disrupting agent which binds tubulin and inhibits microtubule assembly. The compound demonstrates potent antitumour and vascular-disrupting activity in preclinical models. A phase I study of CYT997 given by intravenous infusion showed favourable safety and tolerability, pharmacokinetics and preliminary evidence of pharmacodynamic activity. Unlike most other VDAs, CYT997 is orally available and a phase I dose-ranging study with oral capsule dosing is underway. Methods: CYT997 was administered orally every 2 weeks to patients with advanced solid tumours. Doses were escalated using an accelerated phase I design to cohort 6 and thereafter with a standard 3+3 design. Pharmacodynamic effects on tumour vasculature were assessed with DCE-MRI scans, circulating endothelial cell (CEC) assays and von Willebrand factor (vWF) plasma levels. Results: 21 patients (M/F: 16/5; median age 63, range 48–77) have been treated on study. A total of 56 cycles of CYT997 have been administered (median 2/patient, range 1–7) over 8 dose levels (15 - 164 mg/m2). Doses up to 118 mg/m2 were well tolerated. However, dose-limiting toxicities were observed at 164 mg/m2, consisting of grade 3 hypoxia in one patient and grade 3–4 asthenia in two patients. The grade 3 hypoxia was reversible. PK profiles revealed favourable oral absorption which was generally dose-linear. DCE-MRI assessments indicating significant changes in tumour Ktrans values consistent with vascular disruption were observed in 6 of 10 currently evaluated patients. No objective tumour responses were seen; however, disease stabilisation for six weeks or greater was observed in 13 patients. vWf and CEC analysis is currently ongoing. Conclusions: Orally-administered CYT997 is well tolerated at doses associated with vascular targeting activity. Moreover, its good oral bioavailability suggests the potential for novel administration schedules, including metronomic dosing. [Table: see text]
Phase I trial of NPI-2358 (a novel vascular disrupting agent) plus docetaxel
Authors: Millward M. , Mita A. , Spear M. A. , Federico K. C. , Lloyd G. K. , Cropp G. , Mita M. , Mainwaring P. 
Published: August 2020

3571 Background: NPI-2358 is a vascular disrupting agent (VDA) that destabilizes tumor vascular endothelial cell architecture resulting in selective collapse of established tumor vasculature. In murine tumor models NPI-2358 produces tumor regression alone and synergistically with agents such as paclitaxel, docetaxel (TXT) and irinotecan, often with decreased toxicity. Methods: The objective was to determine the Recommended Phase 2 Dose (RP2D) of NPI-2358 in combination with TXT. Patients with previously treated advanced NSCLC or other malignancies where TXT use was appropriate were enrolled. Patients received 75 mg/m2 TXT every 21 days. NPI-2358 was administered IV 2 hours after TXT on Day 1, and alone on Day 8. The dose of NPI-2358 was escalated from the single agent biologic effect dose (BED) of 13.5 mg/m2 to the single agent RP2D of 30 mg/m2 using a 3+3 design. PK was assessed on Days 1 and 8. Results: 13 patients were enrolled of whom 10 had NSCLC. At all dose levels adverse events were consistent with those of both agents given alone. Adverse events commonly associated with NPI-2358 were seen, including nausea, vomiting, fatigue, fever, tumor pain and transient blood pressure elevations. One DLT of nausea, vomiting, dehydration and neutropenia occurred at 30mg/m2. PK analysis did not indicate a drug-drug interaction. Of the patients with NSCLC, 8 had measureable disease of which 2 demonstrated a partial response (PR), with 4 others having lesser regressions. The RP2D was thus 30 mg/m2 of NPI-2358 with 75 mg/m2 TXT. Conclusions: The combination of full dose NPI-2358 and TXT is tolerable. Although a limited data set, activity appears favorable relative to the 5–10% response rate reported with TXT alone in this population. Based on these results, efficacy is now being assessed in Phase 2 (the ADVANCE study), a randomized comparison of TXT ± 30 mg/m2 of NPI-2358 in 2nd- line NSCLC. Of note, entry criteria allow patients with squamous cell carcinoma, as VDAs do not appear to result in unfavorable outcomes associated with some other agents in this sub-population. [Table: see text]
A phase Ib trial of Bcl-2 inhibitor obatoclax in combination with carboplatin and etoposide for previously untreated patients with extensive-stage small cell lung cancer (ES-SCLC)
Authors: Chiappori A. , Schreeder M. T. , Moezi M. M. , Stephenson J. , Blakely J. L. , Salgia R. , Chu Q. S. , Malik S. M. , Modiano M. M. , Berger M. S. 
Published: August 2020

3576 Background: Obatoclax (Ob) is a small-molecule antagonist of all the Bcl-2 prosurvival proteins. In vitro it enhances the effects of the drugs cisplatin and etoposide. Bcl-2 family proteins are frequently expressed in SCLC, and SCLC cell lines are sensitive to Ob. Methods: This study was designed to find the maximal tolerated doses (MTD) of oOb when given on a 21 day (D) cycle together with carboplatin (AUC 5 D1) and etoposide (100 mg/m2 D1–3), in separate dose escalations using Ob as a 3-hr infusion D1–3 and as a 24-hr infusion D1–3. Eligible patients had ES-SCLC, measurable disease, ≤1 prior therapy, ECOG PS ≤1, and adequate hematological, renal and hepatic function. 3- 6 patients were enrolled into ascending dose cohorts with standard DLT rules evaluating safety in C1 to determine dose escalation. Results: 24 patients were enrolled into 5 dosing cohorts (14 males; median age 67). A total of 66 cycles (C) have been administered to date. There were no DLTs in the initial cohorts using Ob 15 mg over 3 hr or Ob 30 mg over 24 hr. Two DLTs occurred in the Ob 30 mg over 3 hr cohort - both due to myelosuppression in previously treated patients. As a result, the trial was amended to exclude previously treated patients. 5 previously untreated patients receiving Ob 30 over 3 hr had no DLTs. There were no DLTs in the Ob 45 mg over 24 hr cohort but 2 patients in the Ob 24-hr infusion cohorts had infusion pump malfunctions while at home. There were 2 DLTs in the Ob 45 mg over 3 hr cohort (somnolence, euphoria, & disorientation) establishing MTD of Ob 30 mg over 3 hr daily x 3. After C2 the 6 previously untreated patients on Ob 24-hr infusion cohorts had 3 PRs, 1 SD, 1 PD, and 1 Unk; the 2 previously treated patients had PRs. After C2 all 7 previously-untreated patients at 15 or 30 mg in the 3-hr infusion cohorts have PR; the 3 previously treated patients had SD. Conclusions: Ob can be combined with carboplatin and etoposide using either a 3-hr or a 24-hr infusion, and both regimens are associated with high early response rates in ES-SCLC, perhaps due to inhibition of mcl-1. Due to practical issues with the 24-hr infusion arm, the 3-hr 30 mg MTD dose will be utilized in a randomized phase II versus carboplatin and etoposide alone. [Table: see text]
AT-101 or placebo (P) with docetaxel (D) in second-line NSCLC with gene signature biomarker development
Authors: Ready N. , Potti A. , Karaseva N. , Orlov S. , Luft A. , Popovych O. , Liu P. Y. , Holmlund J. T. , Wood B. A. , Leopold L. 
Published: August 2020

3577 Background: AT-101 inhibits the Bcl-2 protein family (Bcl-2, Bcl-xL, Mcl-1, Bcl-W) with broad preclinical activity including synergy with D. Methods: We conducted a randomized, double-blind, P-controlled phase 2 study. Patients had received 1 prior chemotherapy regimen for advanced NSCLC. Patients received AT-101 (40 mg b.i.d. days 1–3) or P with D (75 mg/m2 day 1) Q 21 days. Primary endpoint was progression-free survival (PFS) by independent review (IR). Secondary endpoints were overall survival (OS) and investigator determined PFS. 102 patients were planned for 70 events (80% power, HR 0.6, 1-sided alpha 0.1). A biomarker of AT-101 activity was developed by treating 55 NSCLC cell lines with AT-101 and using the corresponding gene expression data to identify a genomic predictor of sensitivity to AT-101. Results: 106 patients were randomized. Baseline factors were balanced. Median OS for patients on AT-101+D was 7.3 months versus 5.6 months for P + D arm (HR 0.60, p = 0.05). The median investigator determined PFS was 12.6 weeks and 10.7 weeks for AT-101+D and P+D arms respectively (HR 1.0, p = 0.49); IR is ongoing. Common adverse events were fatigue (18%), anemia (18%), and dyspnea (18%). Grade 1/2 headaches occurred more frequently in the AT-101 arm. Analysis of gene expression data by Bayesian regression revealed a robust 500 gene predictor of sensitivity to AT-101 that was cross validated in a leave one out analysis and in an independent cohort of 32 NSCLC cell lines. Validation of the predictor in patient samples from the trial is ongoing. Conclusions: In this phase II trial AT-101, an oral pan Bcl-2 family inhibitor, had favorable OS compared to placebo when combined with docetaxel in previously treated NSCLC and was well tolerated. A genomic predictor of AT-101 sensitivity is likely to enrich for responders and identify novel therapeutic combinations for future [Table: see text]
Microdosing imaging pharmacokinetic (PK) study of the antisense oligonucleotide (ASO) to survivin (LY2181308) using positron emission tomography (PET): A novel paradigm in clinical drug development
Authors: Saleem A. , Ranson M. , Callies S. , Lahn M. , Prenant C. , Brown G. , Matthews J. C. , Dence C. S. , McMahon A. , Price P. 
Published: August 2020

3578 Background: Survivin, an inhibitor of an apoptosis protein, widely overexpressed in cancer is associated with poor clinical outcome. We performed the first worldwide human microdosing imaging PK study of an ASO with LY2181308, a specific, second generation antisense inhibitor of Survivin using carbon-11 radiolabelled LY2181308 ([11C]LY2181308). Methods: LY2181308 was administered at the recommended phase II dose (750 mg over 3 hours IV daily x 3, then once weekly). [11C]LY2181308 was manufactured to GMP standard by random [11C]methylation with [11C]methyl iodide of LY2181308 using a GE Tracerlab FXc molecule. [11C]LY2181308-PET scans were performed at baseline and during treatment infusion. [11C]LY2181308 uptake in normal tissue and tumour was quantified. Results: Three pts (2 female Caucasian/1 male Asian) were scanned after administering [11C]LY2181308 which delivered (135–376 μg) of LY2181308. Despite its large size (6778 amu), [11C]LY2181308 rapidly distributed to tissues, with maximal uptake in kidney followed by liver, spleen, vertebral body, tumour, spinal cord, lung, and muscle at baseline. Although renal uptake was high, urinary elimination (bladder activity) was low suggesting renal trapping of [11C]LY2181308 at baseline. For a normalised injected dose of 1 mg, mean (range) tumour concentrations of 31 (4–41) ng/ml were observed at baseline, consistent with that predicted from the preclinical PK/PD model. In a pt with mesothelioma who also had a second [11C]LY2181308-PET scan during LY2181308 treatment infusion, there was about 2-fold increase in [11C]LY2181308 tumour uptake, in contrast to markedly reduced uptake in kidneys, liver, and spleen and similar aortic (circulatory) [11C]LY2181308 levels. In this patient, tumour [18F]FDG- PET uptake at 28 days was reduced by up to 40% after treatment, suggesting drug activity. Conclusions: [11C]LY2181308 pharmacokinetics suggest biologically active human tumour drug concentrations can be attained. LY2181308 therapy saturated normal tissue kinetics and increased tumour uptake of [11C]LY2181308. Data uniquely obtained from fully regulated microdosing studies may rationalise and hasten drug development. [Table: see text]