bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive biomarker discovery and validation for the targeted chemotherapeutic ixabepilone
Authors: Lee H. , Xu L. , Wu S. , Paul B. , Baselga J. , Llombart A. , Steger G. G. , Galbraith S. , Clark E. 
Published: March 2020

3011 Background: Ixabepilone is a microtubule stabilizing agent with significant therapeutic value in breast cancer (BC) patients. To identify predictive biomarkers capable of identifying patients likely to receive optimal benefit from ixabepilone treatment, preclinical and clinical studies were carried out. Several biomarkers discovered using preclinical models were validated in a neoadjuvant BC clinical study ( CA163080 ) and one, estrogen receptor 1 (ER), was shown to double the pathological complete response (pCR) rate in patients treated with ixabepilone. To identify candidate sets of biomarkers that could further increase the pCR rate we have performed post-hoc analyses of the preclinical and clinical data. Methods: Eighteen BC cell lines were classified as sensitive or resistant (S/R) based on the IC50 values for ixabepilone treatment. Gene expression profiling of the BC cell lines was conducted and genes correlated with the S/R classification were identified using a k-Nearest Neighbors algorithm. Patients in clinical study CA163080 underwent a pretreatment core needle biopsy from which RNA was isolated and gene expression profiles generated (data available on 134 patients). Analyses using the preclinical and clinical markers were conducted using various statistical tools. Results: Several markers used in combination with ER were found to be capable of tripling the pCR to ixabepilone in CA163080. In addition to ER other predictive markers were identified that were as predictive as ER, including several genes whose expression is anti-correlated with ER and are part of the ER pathway. Finally, various sub-group analyses were performed and manifested the importance of clinical sample variation that needs to be considered for the analysis. Conclusions: Several single biomarkers identified from preclinical studies were validated in the clinical study CA163080 , demonstrating the utility of this approach. Such markers can be used in combination to better identify patients likely to respond to ixabepilone in future clinical trials. Furthermore, molecular response markers that can be tied to the mechanism of drug resistance can be used for further developing chemotherapy in drug development. [Table: see text]
Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, dose finding study of rapamycin in adult patients with solid tumors
Authors: Jimeno A. , Kulesza P. , Cusatis G. , Howard A. , Khan Y. , Messersmith W. , Laheru D. , Garrett-Mayer E. , Baker S. D. , Hidalgo M. 
Published: March 2020

3020 Background: Pharmacodynamic (PD) studies, using either surrogate or tumor tissues, are frequently incorporated in Phase I trials. However, it has been less common to base dose selection, the primary endpoint in Phase I trials, in PD effects. We conducted a PD-based dose selection study with rapamycin (Rap). Methods: We used the modified continuous reassessment method (mCRM), a computer-based dose escalation algorithm, and adapted the logit function from its classic toxicity-based input data to a PD-based input. We coupled this design to a Phase I trial of Rap with 2 parts: a dose estimation phase where PD endpoints are measured in normal tissues and a confirmation phase where tumor tissue is assessed. Patients (pts) had solid tumors refractory to standard therapy. Rap was given starting at 2 mg/day continuously in 3-pt cohorts. The PD endpoint was pP70S6K in skin and tumor. Biopsies were done on days 0 and 28 of cycle 1, and a PD effect was defined as ≥ 80% inhibition from baseline. The first 2 dose levels (2 and 3 mgs) were evaluated before implementing the mCRM. The data was then fed to the computer that based on the PD effect calculated the next dose level. The mCRM was set so escalation continued until a dose level elicited a PD effect and the mCRM assigned the same dose to 8 consecutive pts, at which point the effect of that dose will be confirmed in tumor biopsies. Other correlates were PET-CT and pharmacokinetics. Results: Ten pts were enrolled at doses of 2 mg (n = 4), 3 mg (n = 3) and 6 mg (n = 3). Toxicity was anemia (4 G1, 1 G2), leucopenia (1 G1, 2 G2), low ANC (2 G2), hyperglycemia (2 G1, 1 G2), hyperlipidemia (4 G1), and mucositis (1 G1, 1 G2). PD responses were seen in 2 and 1 pt at 2 and 3 mg dose levels. Input of data to the mCRM selected a dose of 6 mg for the third cohort, where PD effect was seen in 1 pt, and thus a fourth dose around 9 mg will be tested. No responses by RECIST occurred, but 2 pts had a response by PET. The PK was consistent with prior data (t1/2 24.6 ± 10.2 h, CL 31.4 ± 12.0 L/h, vol of distribution 235 ± 65 L), and exposure increased with dose. Steady-state concentration were in the 5–20 nM range. Conclusions: mCRM-based dose escalation based on real-time PD assessment is feasible and permits the exploitation of PD effects for dose selection in a rational manner. No significant financial relationships to disclose.
A phase I study of IMC-11F8, a fully human anti-epidermal growth factor receptor (EGFR) IgG1 monoclonal antibody in patients with solid tumors. Interim results
Authors: Kuenen B. , Witteveen E. , Ruijter R. , Ervin-Haynes A. , Tjin-A-ton M. , Fox F. , Ding C. , Giaccone G. , Voest E. E. 
Published: March 2020

3024 Background: This ongoing phase I study is being conducted to determine the safety profile and recommended dose of IMC-11F8, a fully-human IgG1 monoclonal antibody that targets the EGFR. Methods: Patients (pts) with advanced solid tumors who are refractory to or have no available standard therapy are eligible to receive IMC-11F8 intravenously either weekly or every other week for 6 weeks (1 cycle). The initial cohort of patients will receive 100 mg of IMC-11F8. In the absence of a dose-limiting toxicity (DLT), dose escalation will be 200, 400, 600, 800, and 1000 mg in successive cohorts. Prior to the initial cycle, pts receive one IMC-11F8 infusion at their assigned cohort followed by a 2-week pharmacokinetic (PK) period. Pts with stable disease or better after cycle 1 are eligible to receive additional cycles of IMC-11F8. Results: 31 of 40 pts have been enrolled in the 100-, 200-, 400-, 600-, and 800-mg cohorts. Pt characteristics are M/F 20/11, median age 58 years (37 - 76), median ECOG score 1 (0–2). No DLTs have been observed. Only grade 1/2 skin rashes were reported. The most frequent adverse events were nausea, vomiting, fatigue, and headache. No infusion reactions were observed. 2 pts (1 confirmed) have achieved a PR, 1 pt with melanoma in the 200-mg cohort with 39+ weeks of weekly IMC-11F8 treatment and 1 pt with rectal cancer in the 400-mg cohort with 20+ weeks of IMC-11F8 administered every other week. 5 pts in the 200- to 600-mg cohorts have stable disease and have received from 11+ to 35+ weeks of IMC-11F8 treatment. A noncompartmental analysis of 20 pts demonstrated that IMC-11F8 exhibits nonlinear PK. As IMC-11F8 escalated from 100 to 600 mg, T1/2 increased from 67 to 84 hrs, Cmax increased from 30 to 368 μg/mL, AUCinf increased from 1753 to 67295, and CL decreased from 57.0 to 8.9 mL/hr. Conclusions: These interim results indicate that IMC-11F8 is well tolerated in this patient population. Although a maximum tolerated dose has not been established, IMC-11F8 has shown activity at two different dose levels. [Table: see text]
Phase 1 study with BIBW 2992, an irreversible dual tyrosine kinase inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) in a 2 week on 2 week off schedule
Authors: Mom C. H. , Eskens F. A. , Gietema J. A. , Nooter K. , De Jonge M. J. , Amelsberg A. , Huisman H. , Stopfer P. , De Vries E. G. , Verweij J. 
Published: March 2020

3025 Background: BIBW 2992 is a highly selective, potent, irreversible tyrosine inhibitor of EGFR and HER2. A phase 1 study of orally administered BIBW 2992 was performed to determine its safety, PK and PD. Methods: Patients (pts) with advanced solid malignancies received BIBW 2992 once daily (OD) for 2 weeks, in 4 week cycles. Adverse events were evaluated according to CTCv3.0 and tumor response according to RECIST. In cycle 1 and 2, BIBW 2992 plasma PK analysis was performed. Before and after cycle 1, biomarkers involved in EGFR activation were assessed in skin biopsies. Results: 38 pts received 10 mg (n=3), 20 mg (n=3), 30 mg (n=3), 45 mg (n=3), 70 mg (n=18), 100 mg (n=2) and 85 mg (n=6) OD. At 100 mg dose-limiting toxicities (DLTs) consisted of grade 3 skin rash (n=1) and grade 3 diarrhea despite loperamide (n=1). At the dose level of 85 mg, DLTs were seen in 2 pts (diarrhea in both). An additional 12 pts were subsequently enrolled at 70 mg. A total of 3 DLTs was seen in the 18 pts treated at 70 mg (all 3 diarrhea, in one case with additional grade 3 nausea and ALT increase). In other pts, diarrhea was controllable with loperamide, whereas skin events could be ameliorated with minocycline. The dose of 70 mg BIBW 2992 OD was therefore set as the recommended phase 2 dose. Exposure (AUC0-∞ and AUCτ,ss range 82–2080 ng·h/mL) and peak plasma concentrations (Cmax and Cmax,ss range 7–150 ng/mL) increased with increasing doses. High interpatient variability in all PK parameters was found, but was within the range expected for an orally administered drug. The volume of distribution (Vz/F) ranged from 800–2900 L, indicating high tissue distribution. Median tmax values ranged between 1–4 h. The gMean terminal t1/2 ranged between 13–32 h. Accumulation ratio based on AUC was between 2–2.9. Steady state was reached around day 8. After cycle 1, a >20% reduction in Ki-67 (range 20–83%), reflecting inhibition of keratinocyte proliferation, was seen in paired skin biopsies of 31 pts. Ki-67 positive cells (mean ± SD) decreased from 14 ± 4.5% pre-treatment to 7.9 ± 4.5% on day 13 (p<0.0001). SD lasting ≥4 cycles occurred in 8 pts. Conclusions: 70 mg BIBW 2992 OD can be safely administered in a 2 week on, 2 week off schedule. Further evaluation in phase 2 trials in warranted. [Table: see text]
Phase I study of erlotinib (E) for solid tumors in patients with hepatic or renal dysfunction (HD or RD): CALGB 60101
Authors: Miller A. A. , Murry D. J. , Hollis D. R. , Owzar K. , Lewis L. D. , Kindler H. L. , Marshall J. L. , Villalona-Calero M. , Edelman M. J. , Ratain M. J. 
Published: March 2020

3026 Background: We sought to determine a tolerable dose and characterize the pharmacokinetics (PK) of E in patients with HD or RD. Methods: Patients with biopsy-proven solid tumors that commonly express EGFR, refractory to or without available standard therapy, performance status 0–2, and without biliary or renal obstruction were assigned to one of 3 cohorts (C): C1, AST ≥ 3 × ULN but no RD; C2, direct bilirubin 1–7 mg/dl but no RD; C3, creatinine 1.6–5.0 mg/dl but no HD. After slow accrual of 3 patients, an amended C1 for albumin < 2.5 g/dl accrued 3 additional patients. E was administered po daily in groups of at least 3 evaluable patients in escalating doses of 50, 75, 100, 150 mg starting with 50 mg in HD and 75 mg in RD. Patients had to take E for at least 4 weeks to be considered evaluable for toxicity unless dose-limiting toxicity (DLT) occurred sooner. DLT was defined as: grade 4 neutrophils or platelets; bilirubin ≥ 1.5 × baseline in C1/2 and ≥ 2.5 × ULN in C3; creatinine ≥ 2 × ULN in C1/2 and ≥ 2.5 × baseline in C3; grade ≥ 3 nausea,vomiting,diarrhea despite optimal supportive care; or any other grade ≥ 3 non-hematologic toxicity. Blood samples were obtained before and 1, 2, 3, 4, 6, 24 hrs after the first dose. Plasma E concentrations were measured by HPLC. A 2-compartment PK model was used to estimate total clearance of E. Results: Between 12/01 and 5/05, 55 patients were accrued but 1 never started therapy: male/female, 34/20; white/black, 46/8; median age 56 (range, 39–78); PS 0/1/2, 12/25/17. The distribution of treated/evaluable patients was: 6/5 in C1, 30/16 (attrition due to progressive disease) in C2, and 18/18 in C3. DLT consisted of both total and direct bilirubin ≥ 1.5 × baseline in 3 patients: C1, 1 of 5 at 50 mg; C2, 2 of 6 at 100 mg. In C2, 1 of 7 patients had grade 4 diarrhea/dehydration and grade 3 hypotension at 75 mg. No DLT was encountered in C3 with 12 patients at 150 mg. Clearance (mean ± SD) was cohort-dependent: 1.51 ± 0.64 (C1), 2.36 ± 1.17 (C2), 4.34 ± 2.53 (C3) l/hr; 2-sided exact Kruskal-Wallis p < 0.0006. Conclusions: Patients with RD tolerate 150 mg and appear to have normal clearance of E. Patients with HD should be treated at a reduced dose (i.e. 75 mg) consistent with their reduced clearance. [Table: see text]
Phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with selected chemotherapy regimens in patients with advanced solid tumors
Authors: Lorusso P. M. , Heath E. , Valdivieso M. , Pilat M. , Wozniak A. , Gadgeel S. , Shields A. , Puchalski T. , Ewesuedo R. 
Published: March 2020

3034 Background: AZD2171 is an oral, potent, selective inhibitor of vascular endothelial growth factor receptor (VEGFR). Trials have demonstrated that inhibition of the VEGF pathway, in combination with certain chemotherapy, provides benefit to patients with a broad range of solid tumors. Methods: This Phase I trial was conducted in heavily pretreated solid tumor patients. In a single protocol, escalating doses of AZD2171 were evaluated (20, 30 and 45 mg) in combination with four separate chemotherapy regimens: mFOLFOX6 (oxaliplatin 85 mg/m2; 5-FU 400 mg/m2; leucovorin 400 mg/m2 q2 weeks; Arm 1); irinotecan 300 mg/m2 q3 week (Arm 2); docetaxel 75 mg/m2 (Arm 3) and pemetrexed 500 mg/m2 (Arm 4). The primary objective was to evaluate safety and tolerability of the combinations and secondary objective to evaluate pharmacokinetic (PK) interaction and clinical efficacy. Maximum tolerated dose (MTD) toxicity was defined through two cycles. Results: 46 patients have been enrolled: 28/35 evaluable for efficacy/toxicity. The MTD has been reached in two arms: Arm 2 - 20 mg AZD2171 and Arm 4 - 30 mg AZD2171. Arm 3 enrollment continues at 45 mg AZD2171. Two dose-limiting toxicities (DLTs) were observed in eight patients at 30 mg AZD2171 in Arm 1. Enrollment of an additional cohort of less heavily pre-treated patients is ongoing to determine the tolerability of 30 mg AZD2171 with FOLFOX. DLTs have included grade 3 fatigue in Arms 1, 2 & 4; grade 3 diarrhea in Arm 1; grade 3 hand-foot syndrome & grade 4 neutropenic fever in Arm 2; and grade 3 hypertension in Arm 4. AZD2171 did not appear to have a major effect on the PK profile of any chemotherapy regimen tested. Steady-state values are comparable with AZD2171 monotherapy. There have been 13 responses (minor response, n=5; partial response, n=6; complete response, n=2; stable disease ≥ 4 cycles, n=6) in heavily pretreated patients, some having demonstrated resistance to identical chemotherapies. Duration of response has been impressive (4-22+ cycles). Conclusions: AZD2171 combinations have been well tolerated with expected toxicities and encouraging responses. [Table: see text]
A phase I study of a novel spectrum selective kinase inhibitor (SSKI), XL880, administered orally in patients (pts) with advanced solid tumors (STs)
Authors: Eder J. P. , Appleman L. , Heath E. , Malburg L. , Zhu A. , Pilat M. J. , Shapiro G. , Lorusso P. 
Published: March 2020

3041 Background: XL880 is a sub-nM inhibitor of the hepatocyte growth factor receptor (Met) and vascular endothelial growth factor (VEGF) family receptor tyrosine kinase (RTK). PDGFRβ, KIT, FLT3, and Tie-2 are also inhibited at low nM concentrations in vitro. XL880 is the 1st orally bioavailable small molecule Met inhibitor to enter the clinic. Methods: Pts with advanced STs were enrolled in successive cohorts to receive XL880 orally as a single dose on Day (D) 1 with pharmacokinetic (PK) sampling, followed by 5 consecutive daily doses (DD) starting on D 4 with additional PK sampling. Pts then continued to receive XL880 for 5 consecutive days, repeated every 14 days. Results: Nineteen pts have been treated across 5 dose levels: 0.1, 0.2, 0.4, 0.8, and 1.6 mg/kg. No dose-limiting toxicities have been observed. Two pts have demonstrated grade 2 hypertension, at 0.8 and 1.6 mg/kg respectively. PK analysis indicated that systemic drug exposure (AUC) and peak plasma levels (Cmax) increased approximately dose-proportionally (r2 values = .89 and .87 respectively) with increasing XL880 dose (0.1–1.6 mg/kg). Following 5 consecutive DD, AUC values were 175–304% higher and Cmax values were 30–203% higher than following a single XL880 dose, suggesting possible drug accumulation with repeat dosing. Terminal half-life values were ∼60 hours (hrs) following 5 consecutive DD (D 8 range: 40–66 hrs), were more variable following a single dose (D 1 range: 26–87 hrs), and appeared to be unaffected by dose. A pt with papillary renal cell carcinoma has a partial response (DD = 0.2 mg/kg) and pts with carcinoid and melanoma have had minor responses. Conclusions: XL880 is a RTK inhibitor with a novel spectrum of activity that targets both tumor cells and tumor-associated vasculature. XL880 is well tolerated up to the 1.6 mg/kg dose, with continued dose escalation ongoing. XL880 demonstrates biologic activity through hypertension and antitumor activity. [Table: see text]
A phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of CHIR-258, a novel oral multiple receptor tyrosine kinase (RTK) inhibitor
Authors: Sarker D. , Evans J. , Hardie M. , Molife R. , Marriott C. , Morrison R. , Garzon F. , Heise C. , Michelson G. , De-Bono J. 
Published: March 2020

3043 Background: CHIR-258 is a potent small molecule inhibitor of VEGF, FGF, PDGF and c-KIT RTKs with IC50≤10nM that demonstrates activity in a variety of angiogenesis, tumour and metastasis models. Methods: Patients (pts) with histologically confirmed advanced solid tumors, ECOG PS 0–2 were treated in cohorts of 3–6 with CHIR-258. Treatment was as single daily doses on a repeated 7 days (d) on/7d off schedule (25–100mg), with a subsequent protocol amendment to continuous (cont) daily dosing. The objectives were to determine maximum tolerated dose (MTD) and dose limiting toxicity (DLT), evaluate PK and PD endpoints - ERK phosphorylation in PBL - and describe anti-tumour activity. Results: 35pts (median age 56.5 yrs; 15F/20M) were treated in 4 intermittent dosing cohorts (25, 50, 75, 100 mg/d) and 3 continuous dosing cohorts (100,125, 175 mg/d). The most common drug related adverse events were (grade [gr], number of pts): nausea (gr 1–3, 12); fatigue (gr 1–2, 9); headache (gr 1–3, 8); vomiting (gr 1–2, 7); anorexia (gr 1–2, 7); diarrhoea (gr 1–2, 6); dysgeusia (gr1–2, 6); anaemia (gr 2–3, 4); hypertension (gr 1–3, 3) and reversible asymptomatic drop in left ventricular ejection fraction (gr 2, 2). DLTs were gr 3 hypertension (HTN) in 1 pt with pre-existing HTN (100mg, cont); asymptomatic uncomplicated grade 2 elevation in cardiac troponin I (125mg); gr 3 anorexia/fatigue and gr 3 rise in alkaline phosphatase (both at 175mg). 3 pts have had prolonged stable disease (all 4m+; parotid, renal and imatinib-refractory GIST). The plasma PKs of CHIR-258 were linear over the dose range of 25–175 mg with respect to Cmax and AUC. On d1, the mean Cmax was 13.5(5.3) ng/mL to 109 (26) ng/mL, the mean AUC (0–24) was 224(97.4)ng*h/mL to 1740(466)ng*h/mL, and the t½ was 17h. Trough CHIR-258 concentrations at doses >50 mg/d were above the concentrations known to inhibit target receptor activation in vitro. Data on evaluable samples demonstrate up to 90% inhibition of basal ERK phosphorylation. Conclusions: CHIR-258 was safely administered at continuous daily doses up to 175mg/d. Modulation of p-ERK was demonstrated. Treatment is associated with disease stabilization. [Table: see text]
Imaging with FLT-PET demonstrates that PF-477736, an inhibitor of CHK1 kinase, overcomes a cell cycle checkpoint induced by gemcitabine in PC-3 xenografts
Authors: McArthur G. A. , Raleigh J. , Blasina A. , Cullinane C. , Dorow D. , Conus N. , Hicks R. J. , Kornmann J. , Chen E. , McCarthy T. J. , Anderes K. 
Published: March 2020

3045 Background: The development of strategies to monitor the molecular and cellular response to novel agents that target the cell cycle is vital to provide proof of mechanism and biological activity of these compounds. The protein kinase CHK1 is activated following DNA damage in the S and G2-phases of the cell cycle and mediates cell cycle arrest. In vitro studies demonstrate that inhibition of CHK1 can overcome cell cycle arrest induced by DNA damage and enhance cytotoxic activity of DNA damaging agents. In vivo studies show that combining DNA damaging agents with a CHK1 inhibitor potentiates antitumor activity. We hypothesize that functional imaging with 18F-fluorine-L-thymidine (FLT), a PET-tracer where tumor uptake is maximal in the S and G2 phases of the cell cycle can be used to non-invasively monitor the induction and therapeutic inhibition of a cell cycle checkpoint in vivo. Methods: Nude mice harbouring PC-3 xenografts were treated with vehicle controls, gemcitabine, the CHK1-inhibitor PF-477736 or gemcitabine + PF-477736. FLT-PET scans were performed and tumors harvested for ex-vivo biomarkers to assess S-phase, M-phase and DNA-repair. Results: Gemcitabine induced a 8.3 ±0.8 fold increase in tumoral uptake of FLT at 21 hours that correlated with a 3.3 ±0.2-fold increase in thymidine kinase activity and S-phase arrest as demonstrated by BrdU incorporation and elevated expression of cyclin-A. Treatment with PF-477736 at 17 hours after gemcitabine abrogated the early FLT-flare at 21 hours by 82% (p<0.001). This was associated with both an increased fraction of cells in mitosis and G1-phase of the cell cycle as determined by phos-histone H3 and flow cytometry. Furthermore, the combination of gemcitabine and PF-477736 enhanced DNA damage as measured by phos-gamma-H2AX and significantly delayed tumor growth when compared to tumors treated with gemcitabine alone. Conclusion: These data clearly indicate that the CHK1-inhibitor PF-477736 can overcome the cell cycle checkpoint induced by gemcitabine and increase associated DNA damage in tumors in-vivo. The PET studies indicate that functional imaging with FLT-PET is a promising strategy to monitor responses to therapeutic agents that target cell cycle checkpoints. [Table: see text]