bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of NK105, a paclitaxel-incorporating micellar nanoparticle, in patients with advanced cancer
Authors: Kato K. , Hamaguchi T. , Yasui H. , Okusaka T. , Ueno H. , Ikeda M. , Shirao K. , Shimada Y. , Nakahama H. , Muro K. , Matsumura Y. 
Published: March 2020

2018 Background: NK105 is a new polymeric micelle carrier system for paclitaxel (PTX). A preclinical study revealed that the plasma AUC and tumor AUC of NK105 were 90-fold higher and 25-fold higher, respectively, than those of free-PTX, i.e., the conventional PTX formulation. NK105 had higher in vivo antitumor activity and lower neurotoxicity than free-PTX. This phase I study was designed to examine the MTD, DLTs, recommended dose (RD) for phase II, and the pharmacokinetics of NK105. Methods: NK105 was administered as a 1-hour intravenous infusion every 3 weeks, without antiallergic premedication. The starting dose was 10 mg PTX equivalent/m2, and the dose was escalated according to the accelerated titration method. Results: To date, 17 patients (pts) have received the following doses: 10 mg/m2 (n=1); 20 mg/m2 (n=1); 40 mg/m2 (n=1); 80 mg/m2 (n=1); 110 mg/m2 (n=3); 150 mg/m2 (n=5); and 180 mg/m2 (n=5). The tumor types treated included pancreatic (n=9), bile duct (n=5), gastric (n=2), and colonic (n=1) cancers. Neutropenia was the most common hematological toxicity. Grade 3 fever developed in 1 pt given 180 mg/m2. No other grade 3 or 4 non-hematological toxicity, including neuropathy, was observed. DLTs occurred in pts given 180 mg/m2 (grade 4 neutropenia lasting for more than 5 days). This dose was designated as the MTD. Allergic reactions developed in only one pt at 180 mg/m2, who was sensitive to other drugs such as antibiotics anti-inflammatory. A partial response was observed in one pt with pancreatic cancer and pts with colonic and gastric cancer had stable disease. The Cmax and AUC of NK105 were dose dependent. The plasma AUC of NK105 at 180 mg/m2 was approximately 30-fold higher than that of the conventional formulation of PTX. Conclusions: Accrual is ongoing at the 150 mg/m2 dose level to determine the RD. DLT was Grade 4 neutropenia. NK105 produces prolonged high levels of PTX in plasma. A 1-hour infusion of NK105 every 3 weeks was feasible, well tolerated, and effective in patients with pancreatic cancer. Even after the long term usage, only grade 1 or 2 neuropathy was observed. NK105 will be evaluated in Phase II studies of patients with advanced pancreatic and gastric cancers. No significant financial relationships to disclose.
Gemcitabine (G) plamsa and intracellular pharmacokinetics in E6201: Greater metabolite levels using fixed dosing rate (FDR) delivery
Authors: Liebes L. , Levy D. E. , Poplin E. , Mendoza S. , Fry D. , Buckley M. , Zoloratov A. , Benson A. , Hochster H. 
Published: March 2020

2024 Background: Gemcitabine (G) is an antimetabolite which requires activation by the rate-limiting enzyme dCK to its active metabolite, dFdCTP. FDR delivery of G at 10 mg/m2/minute may allow greater formation of active metabolite and improved activity. E6201 randomly assigned first line pancreatic cancer patients to three arms: A (G 1000 mg/m2 over 30 minutes), B FDR G (1500 mg/m2 over 150 minutes), and C GemOx (1000 mg/m2 over 100 minutes with oxaliplatin 100 mg/m2). Methods: Investigators from 18 centers contributed 23 sample sets on the first dose of G. Five time points over 4 hrs were sampled (baseline, mid infusion, end infusion, 1–2 post and 4 hrs). Plasma fractionation along with the PBMC purification and subsequent perchloric acid extraction were conducted locally with THU 1 mg (cytidine deaminase inhibitor). Samples were shipped overnight to the central lab where G and its metabolite dFdU were quantified from deproteinized plasma by reverse phase HPLC. dFdCTP was quantified by ion-exchange HPLC in neutralized PBMC extracts after removal of ribonucleotide triphosphates. Data were fit to nonlinear models (WinNonLin, v4.1) and comparisons amongst dosing groups employed the non-parametric, 2-sided Mann-Whitney test. Results: For Arms A, B and C the plasma AUCs were respectively (median ± SD): 4542 ± 2472 (N=9), 8603 ± 2608 (N=8) and 9130 ± 8788 (N=6) ng/ml x hr. The difference between group A and B (p=0.003) and A and C (p=0.05) were statistically different. Intracellular dFdCTP AUCs for groups A, B, and C were: 1862 ± 794 (N=8); 3725 ± 7763 (N=8) and 5024 ± 2113 (N=5) and significantly different for both A vs. B (p=0.05) and borderline significant for A vs C (p=0.065). The latter comparison is limited by a small number of samples. Conclusions: When studied in a multi-centered, randomized cooperative group setting, FDR delivery of G results in higher plasma AUC, and increased intracellular levels of active metabolite dFdCTP. These data support the concept that fixed dose rate delivery of G results in greater intracellular metabolite production at similar and equitoxic doses. Supported by ECOG NYU620HH04–00, NCI CA16087, CA2115, and from Eli Lilly. No significant financial relationships to disclose.
A phase I dose escalation trial of ispinesib (SB-715992) administered days 1–3 of a 21-day cycle in patients with advanced solid tumors
Authors: Heath E. I. , Alousi A. , Eder J. P. , Valdivieso M. , Vasist L. S. , Appleman L. , Bhargava P. , Colevas A. D. , Lorusso P. M. , Shapiro G. 
Published: March 2020

2026 Background: Ispinesib, a novel cytotoxic agent inhibiting the kinesin spindle protein (KSP) has demonstrated significant antitumor activity in multiple murine tumor models. The primary objectives of the study were to assess the safety and tolerability of SB-715992, to determine the dose limiting toxicity (DLT), and the maximum tolerated dose (MTD). Methods: Ispinesib was administered days 1–3 intravenously over 1 hour every 21 days, starting at a dose of 1 mg/m2/day. Traditional 3-patient cohort trial design was utilized with dose levels of 2, 4, 6, 8 mg/m2/day. Results: Twenty-seven patients (24 Caucasians, 3 African-Americans, 16 males, 11 females) with various tumor types were enrolled; colorectal (7), renal (5), bladder (2), lung (2), pharynx (2), pancreas (2), others (7). Grade 3/4 toxicities were noted starting at the 4 mg/m2 dose level with two patients developing grade 4 neutropenia; one for < 5 days, one for > 5 days (with grade 3 leukopenia). At the 6 mg/m2 dose level, grade 3 neutropenia and leukopenia were reported. At the 8 mg/m2 dose level, 3 of 3 patients had grade 4 neutropenia and leukopenia. The 6 mg/m2 dose level was declared the MTD. Toxicities seen in the additional 6 patients included grade 1 fatigue (1/6), grade 1 infusion- related flushing (1/6), grade 3 febrile neutropenia (1/6), and grade 4 neutropenia and leukopenia (1/6). The MTD cohort has been expanded to 10 evaluable patients for confirmation of tolerability and pharmacodynamic endpoints including phosphohistone 3 (PH3), cyclin E, and TUNEL assay on serial tumor biopsies. Preliminary pharmacokinetic data appear linear, but not dose proportional. As predicted, between days 1 and 3, accumulation ranged from 40 to 106%. Exposures appear comparable between cycles 1 and 2. Stable disease in 2 patients with renal cell carcinoma (4 and 5 cycles) and minor response in one patient with bladder cancer were seen. Conclusions: Treatment with ispinesib at the MTD of 6 mg/m2/day x 3 days in patients with advanced solid tumors was well tolerated with consistent dose limiting toxicity of myelosuppression. No significant financial relationships to disclose.
An open-label phase I dose escalation study of KRN951, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 1 in a 4 week on, 2 week off schedule in patients with advanced solid tumors
Authors: Eskens F. A. , Planting A. , Van Doorn L. , Isoe T. , Hayashi K. , Hussain S. , Ekman L. , Burger H. , Verweij J. 
Published: March 2020

2034 Background: KRN951 inhibits VEGF induced phosphorylation of VEGF receptors (VEGFR)2 and 1 (IC50 of 0.16 and 0.21 nM) and phosphorylation of c-Kit and Platelet Derived Growth Factor Receptor (PDGFR), (IC50 of 1.63 and 1.72 nM). Methods: The principal objectives of this study were (1) to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of KRN951 administered once daily (OD) for 28 days followed by 14 days off treatment, (2) to characterize safety and tolerability, (3) to characterize single and multiple dose pharmacokinetics, (4) to explore inhibitory effects on tumor blood flow, and (5) to look for evidence of antitumor activity. Results: 10 male and 5 female patients, median age 57 yrs (28–72) have been enrolled at dose levels of 1 mg (n=6), 2 mg (n=8), and 1.5 mg (n=1). The total number of courses given is 63 (1–15 per patient) At 2 mg DLT consisting of grade 3 asymptomatic proteinuria, grade 3 ataxia and grade 4 intracranial hemorrhage was seen in three patients. In the next-lower dose level of 1 mg one DLT (grade 3 fatigue) was seen. An intermediate dose of 1.5 mg is currently studied. Hypertension occurred in 14/15 patients but could be medically controlled. Pharmacokinetic analysis revealed dose dependent drug exposure and peak plasma concentrations. Plasma levels of sVEGFR2 decreased following exposure to KRN951. Exploratory analysis by means of Dynamic Contrast Enhanced MRI analysis indicated a decrease in tumorperfusion in selected patients. One confirmed partial response lasting more than 80 weeks in a patient with renal cell carcinoma was seen, and stable disease lasting more than 2 courses of treatment was seen in 6 patients. Conclusion: Once daily KRN951 can be administered safely when given for 28 days followed by 14 days off treatment. The recommended phase II dosing is currently being defined. No significant financial relationships to disclose.
Paclitaxel and pegylated liposomal doxorubicin in recurrent head/neck cancer: An unexpected administration interval-dependent pharmacokinetic interaction
Authors: Airoldi M. , Cattel L. , Passera R. , Milla P. , Delprino L. , Boselli C. , Buffa C. , Pedani F. 
Published: March 2020

2042 Background: Combination of paclitaxel (PTX) with pegylated liposomal doxorubicin (PLD) is an interesting opportunity for recurrent head/neck cancer treatment. Their pharmacokinetic (PK) behavior could be dependent not only on PTX excipient (polyethoxylated castor oil) interference, but also on different iv administration interval between the two drugs. The study endpoint was to evaluate any possible administration interval-dependent PK interaction, when PLD infusion start is delayed from 0 to 24 h after PTX infusion end. Methods: 24 patients affected by recurrent cisplatin pre-treated squamous cellhead/neck cancer were enrolled, receiving PTX 80 mg/m2 q 1w and PLD 12.5 mg/m2 q 2w for 6w/2w rest. Administration interval was 0 h at d1 (PTX-PLD 0) and 24 h at d15 (PTX-PLD 24). Blood sampling was performed at d1–15, PTX and PLD blood levels were analyzed by high performance liquid chromatography techniques, while PK parameters by non-compartmental analysis. Results: PTX PK parameters had large statistically significant differences (median/IQR, PTX-PLD 0 vs. PTX-PLD 24, Mann-Whitney test): Cmax 261/219–531 vs. 407/250–1473 ng/ml p=0.142, AUC 869/688–1331 vs. 3361/969–7853 ng*h/ml p=0.013, Kel 0.39/0.26–0.57 vs. 0.11/0.02–0.26 h⁁−1 p=0.001, Cl 153/89–198 vs. 41/17–138 l/h p=0.013. Similarly, PLD Cmax and AUC were higher in PTX-PLD 24 (Cmax 5.1/3.3–8.1 vs. 6.8/5.3–7.8 mg/l p=0.043, AUC 341/104–1472 vs. 603/106–1006 mg*h/l p=1.000). The overall response rate was 37.5%, including 1 CR (4%); median response duration was 5.5 months (range, 2–16), median overall survival 10 months (range, 2–25+). Conclusions: This exploratory study, having a favourable palliative role in heavily pre-treated patients, showed that PTX PK profile is unexpectedly affected by a different administration interval. In PTX-PLD 0, PTX AUC is fourfold reduced, with a similar increase in Cl, totally due to Kel alteration: therefore, patients could be underexposed to PTX. PLD PK behavior confirmed previous studies results, in which PTX modified PLD disposition, prolonging the duration of its elimination phase and increasing total body exposure to PLD. No significant financial relationships to disclose.
Pharmacokinetic interaction and safety of enzastaurin and pemetrexed in patients with advanced or metastatic cancer
Authors: Hanauske A. , Weigang Koehler K. , Yilmaz E. , Graefe T. , Kuenen B. , Thornton D. , Lahn M. , Darstein C. , Musib L. , Guiseppe G. 
Published: March 2020

2047 Background: Enzastaurin, an orally administered potent PKC inhibitor, is an anti-angiogenic agent that also suppresses PI3K/AKT to inhibit tumor cell proliferation and induce tumor cell death. Preclinical data suggest that the combination of enzastaurin and pemetrexed (Alimta) produced additive or synergistic antitumor activity in tumor specimens. This phase 1b study evaluated the safety, pharmacokinetic (PK) interaction, and antitumor activity of enzastaurin when combined with pemetrexed. Methods: Patients (pts) with advanced or metastatic cancer and an ECOG status of 0–2 received an intravenous dose of 500 mg/m2 pemetrexed on day 1 and an oral dose of 500 mg enzastaurin once daily, (after day 4 in cycle 1) in repeat 21-day cycles for up to 6 cycles. In cycle 1, a loading dose of 1200 mg enzastaurin (400 mg/3×/day) was given on day 4. Pts were also given oral folic acid daily and vitamin B12 every 9 weeks for the duration of pemetrexed therapy, and 5–7 days before cycle 1. Results: Blood samples for PK analysis of enzastaurin (n = 21) were collected on day 21 of cycle 1 and day 1 of cycle 2, and for analysis of pemetrexed (n = 22) on day 1 of cycle 1 and cycle 2. Steady-state concentration [geometric mean (%CV)] of total analytes (enzastaurin and its metabolites) was 1270 nM (126%) when administered alone and 1130 nM (100%) when administered with pemetrexed. Thus, no significant differences in exposures were observed when combined with pemetrexed. Clearance of pemetrexed was the same when dosed either with enzastaurin (2.48 L/h/m2) or as a single agent (2.62 L/h/m2). Safety data from the first 2 cycles are consistent with the known toxicity profile of pemetrexed. No grade 3 or 4 toxicity was reported following the loading dose of 1200 mg enzastaurin. Conclusions: Preliminary data suggest that there is no significant PK interaction between enzastaurin and pemetrexed, and that the combination is well tolerated. The current study is ongoing and subsequent analyses will document tumor responses and safety for longer-term treatment of enzastaurin combined with pemetrexed. This first PK study of enzastaurin and pemetrexed will help determine if enzastaurin has an additive clinical benefit to pemetrexed treatment and support future studies in NSCLC and mesothelioma. [Table: see text]
Bexarotene prevents and reverses gemcitabine resistance in non-small-cell lung cancer cells by affecting gene amplification
Authors: Hermann T. W. , Yen W. , Tooker P. , Ng S. , Negro-Vilar A. , Lamph W. W. 
Published: March 2020

2057 Background: Bexarotene (BEX) is a retinoid X receptor selective drug approved for treatment of CTCL and has activity in various cancers. Here we evaluate its effect on acquired drug resistance towards gemcitabine (GEM) in Calu3 NSCLC models. Methods: Parental or GEM-resistant Calu3 NSCLC cells were treated with BEX and GEM as single agents or in combination. Over the treatment course the cells were evaluated for molecular changes (RNA expression and DNA amplification), which were associated with resistance status. Results: Calu3 cells treated with repeated cycles of GEM alone gradually developed resistance to this drug. However, inclusion of BEX prevented the development of resistance and cells remained chemosensitive. Microarray analysis showed a strong increase of rrm1 (ribonucleotide reductase M1) expression in the resistant cells (Calu3-GemR), a gene known to be involved in GEM resistance. In addition, the expression of genes surrounding the chromosomal location of rrm1 was increased suggesting that resistance was due to gene amplification at the 11p15 locus. This was confirmed by analysis of genomic DNA, indicating a 20-fold increase of rrm1 gene copy number. To evaluate BEX’s activity on pre-existing GEM-resistance, Calu3-GemR cells were treated with ten 10-day cycles of vehicle, GEM, BEX, or GEM plus BEX. After 4 treatment cycles the cultures treated with the combination regimen showed a loss in cell numbers, which continued until the end of the 10th cycle. This indicated a re-sensitization of the Calu3-GemR cells to treatment. The cultures treated with the single drug regimens expanded as the vehicle controls. However, analysis of RNA and DNA samples collected over the treatment course revealed that rrm1 gene amplification was gradually reduced even in the cultures treated with BEX alone, reaching parental levels at the end of the study. As expected from these data, the BEX-treated Calu3-GemR cells were again sensitive to GEM. Conclusions: The data indicate that bexarotene can re-sensitize GEM-resistant tumor cells by reversing gene amplification. This suggests that bexarotene may have general clinical utility in cancers where drug-resistance by gene amplification is a major obstacle to successful therapy. [Table: see text]
Optimal circadian time of vinorelbine (V) combined with chronomodulated 5-FU in pretreated metastatic breast cancer patients. EORTC 05971 randomized multicenter study
Authors: Coudert B. , Focan C. , Genet D. , Giacchetti S. , Lentz M. , Marreaud S. , Baron B. , Gorlia T. , Lévi F. 
Published: March 2020

2066 Background: Chronotherapy is an aim to increase efficacy/toxicity ratio. Objectives: to define the dosing least toxic time (DLTT) of V (30 mg/m2/d at D1 and D6), combined with chrono 5-FU (10 pm-10 am) (850 mg/m2 D2-D5) over 3 courses q3w. Methods: A logistic regression model (LRM) estimated the DLTT assuming a sinusoidal distribution over time (i.e. over the 8 different arms) of the toxicity rate observed in each arm. The associated 90% confidence limits (CL) has been obtained by bootstrap method. Results: 90 patients were recruited. Toxicity in 46 pts led to the V dosage reduction to 25 mg/m2/d. 40 and 43 pts were assigned the V30 and the V25 regimen. 12% pts went off for toxicity, 5% for PD, 1% for refusal, 1% for unrelated death. 224 cycles were analyzed . V and 5FU relative dose intensities were 79.4% and 78.2% in the V30 while 88.1% and 87.4% in the V25 pts. Over the 3 cycles, toxicity by cycle was: Grade (G) 3 and G4 leucopenia in 47% and 29%, G3 and G4 neutropenia in 12% and 77%. G3 febrile neutropenia in 34%. G2 thrombopenia and anemia in 4% each. Other G3 and G 4 toxicity were stomatitis (12%), alopecia (7%), and less than 5%: cardiovascular, lethargy, diarrhea, constipation, other gastrointestinal, infection, sensory, pulmonary. LRM could not demonstrate a DLTT for the neutropenia G3–4 incidence, the primary endpoint. However, based on the stratified by dose analysis, a 90% CI of less than 6 hours width was observed: - around 17H17 [14H04–20H03] for the incidence of leucopenia G3–4. - around 8H16 [06H04–10H39] for tolerability (dose reduction, dose delay or treatment interruption for toxicity reason). This suggests that treatment tolerability was influenced by other factors beside leucopenia nadir. No other 90% CI of less than 6 hours width could be observed for other toxicity endpoints. Conclusions: Using a novel time finding study design with ad hoc statistics, this first randomized multicenter study has determined a DLTT for Vinorelbine in 90 women with MBC. Additional studies are ongoing to further assess the relevance of this trial design method that could prove useful for improving the safety of anticancer drugs during their clinical development. Support Pierre Fabre Oncology, Ligue Bourguignonne contre le Cancer No significant financial relationships to disclose.
A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a continuous schedule in patients with advanced solid tumours
Authors: Agus D. B. , Terlizzi E. , Stopfer P. , Amelsberg A. , Gordon M. S. 
Published: March 2020

2074 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of both EGFR and HER2 receptor tyrosine kinases with IC50 values of 0.5 and 14 nM, respectively. Methods: BIBW 2992 was administered orally as a continuous once daily dose starting at 10 mg daily and doubled in successive cohorts until observation of drug-related adverse events (AE) ≥ CTC grade 2. Thereafter, escalation steps of no more than 50% were allowed. All pts underwent pharmacokinetic sampling. The enrolled patient population included a variety of advanced solid malignancies, historically known to express EGFR and/or HER2. After reaching DLT, the MTD dose group was expanded to a total of 18 treated at that dose level. Results: To date in this continuing study, twenty-two patients have been included (13 M/ 9 F). Median age: 61.5 (range: 34–80). Administered doses (patients) were 10 (5), 20 (3), 40 (11), and 60 (3) mg in a once daily schedule. Ten pts who completed the initial 28 treatment days were eligible to continue treatment beyond the first treatment cycle. Duration of treatment is up to 7 cycles so far in this ongoing study. A total of three dose-limiting toxicities (DLT) were observed. DLT events were diarrhea (CTC grade 3) and patients recovered fully upon cessation of the drug. The 60 mg dose level was considered dose-limiting with the occurrence of two DLT. The dose level below (40 mg) was expanded to a total of 18 patients. A pharmacokinetic interim analysis (9 pts) showed, in general, increasing exposure to BIBW 2992 with increasing doses at steady state. A high inter-patient variability in all PK parameters was detected. Conclusions: BIBW 2992, in an oral once daily administration of 40mg, is well tolerated with an acceptable toxicity profile. The further evaluation of BIBW 2992 in Phase II clinical trials is warranted. [Table: see text]