bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjustment of creatinine (Cr) to avoid severe thrombocytopenia of carboplatin (C) plus gemcitabine (G) in non-small cell lung cancer (NSCLC)
Authors: Horiike A. , Miyauchi E. , Motokawa I. , Kudo K. , Ohyanagi F. , Mun M. , Sakao Y. , Okumura S. , Nakagawa K. , Horai T. , Nishio M. 
Published: August 2020

2525 Background: Carboplatin plus gemcitabine (CG) is a standard regimen for advanced NSCLC. Although the dose of C is calculated from Cr clearance (CCr) by Calvert‘s formula, severe thrombocytopenia sometimes occurs in the CG regimen. Severe thrombocytopenia might arise from differences in the methods of measuring Cr values. We have used two different techniques, the Jaffé method and the enzymatic method. When the enzymatic method was used, CCr overestimated the glomerular filtration rate and the dose of C calculated by Calvert‘s formula leads to overdosing. The aim of this study was to clarify whether severe thrombocytopenia could be avoided by adjusting the CCr in the CG regimen when Cr is measured by the enzymatic method. Methods: All patients (pts) were treated with CG (C, AUC = 5 on day 1; G, 1,000 mg/m2 on days 1 and 8) every 3 weeks for 4 cycles. Serum Cr values were measured by the enzymatic method and CCr was estimated by the Cockcroft-Gault formula in all patients. In the non-adjusted group, the dose of C was calculated by Calvert‘s formula with no adjustment of CCr. In the adjusted group, the dose of C was calculated by Calvert‘s formula, adjusting Cr as follows: (serum Cr +0.2). We compared the correlations between Cr values and the nadir of thrombocytes, and the frequencies of severe thrombocytopenia in both groups. Results: 32 pts and 28 pts were enrolled in the non-adjusted and the adjusted groups, respectively. Grade 3/4 thrombocytopenia was observed in 19 pts (60%) and these pts had low levels of serum Cr values. On the other hand, significantly fewer cases of grade 3/4 thrombocytopenia were observed in the adjusted group (8 pts; 29%, p < 0.0001). In addition, there was a significant correlation between Cr values and the nadir of thrombocytes in the non-adjusted group (R= 0.442, p= 0.0105), but no significant correlation was observed in the adjusted group (R= -0.196, p= 0.3212). These results suggest that adjustment of CCr can reduce the variable nadir of thrombocytes in the CG regimen when Cr is measured by the enzymatic method. Conclusions: If Cr is measured by the enzymatic method, adjustment of Cr is needed to avoid severe thrombocytopenia in the CG regimen. No significant financial relationships to disclose.
A universal formula based on cystatin C to perform individual dosing of carboplatin in normal weight, underweight, and obese patients
Authors: Chatelut E. , Schmitt A. , Lansiaux A. , Bobin-Dubigeon C. , Etienne-Grimaldi M. , Boisdron-Celle M. , Pinguet F. , Floquet A. , Billaud E. , Le Guellec C. 
Published: August 2020

2527 Background: It has recently been shown that it is possible to improve the prediction of carboplatin clearance by adding plasma cystatin C level (cysC), an endogenous marker of glomerular filtration rate, to the other patient characteristics routinely used for carboplatin individual dosing, namely serum creatinine (Scr), body weight (BW), age, and sex. This multi-center pharmacokinetic study was performed to evaluate prospectively the benefit of using cysC for carboplatin individual dosing. Methods: The 357 patients included in the study were receiving carboplatin as part of established protocols. A population pharmacokinetic analysis was performed using the NONMEM program. Seven covariates were studied: Scr, cysC, age, sex, BW, ideal body weight, and lean body mass. Results: The best covariate equation was: carboplatin clearance (mL/min) = 105. (Scr/75)-0.433. (cysC/1.00)-0.290 . (BW/65)+0.547 . (age/56)-0.351 . 0.855sex, with Scr in μmol/L, cysC in mg/L, BW in kg, age in years, and sex = 0 for male. Using an alternative weight descriptor (ideal body weight or lean body mass) did not improve the prediction. This final covariate model was validated by bootstrap analysis. The bias (mean percentage error) and imprecision (mean absolute percentage error) were +2% and 15% respectively on the total population, and were of a similar magnitude in each of the three subgroups of patients defined according to their body mass index. Conclusions: For the first time, a unique formula is proposed for carboplatin individual dosing to patients which is shown to be equally valid for underweight, normal weight, and obese patients. No significant financial relationships to disclose.
Effects of novel heparin-derived compounds on tumor uptake of chemotherapeutics and chemoresponse
Authors: Phillips P. , Yalcin M. , Cui H. , Abdel-Nabi H. H. , Sajjad M. , Bernacki R. , Mousa S. 
Published: August 2020

2537 Thrombotic complications are the second most common cause of mortality in cancer patients and fibrin deposition in the tumor microenvironment might play a key role in tumor progression and inference with tumor chemotherapeutic uptake. Treatments that target these processes may result in improved uptake of chemotherapeutic agents and subsequent inhibition of tumor growth and metastasis. Tissue Factor (TF) is frequently associated with aggressive behavior and poor outcome in tumors. We have previously demonstrated potent anti-tumor efficacy for various mechanisms that interfere with TF/VIIa. The purpose of this study was to investigate the effects of low molecular weight heparins (LMWH) and sulfated non-anticoagulant LMWH (S-NACH) on tumor chemotherapeutic uptake. Studies: (1) Nude mice xenograft A549 human lung carcinoma: LMWH or S-NACH at 10 mg/kg S.C. daily effectively limited tumor growth. (2) LCC6 human lung tumor xenograft model: Paclitaxel alone or in combination with Tinzaparin or S-NACH on tumor re-growth after discontinuation of treatment: Paclitaxel + S-NACH treatment showed significant (P<0.01) tumor growth suppression and improved survival when compared to Paclitaxel. (3) Biodistribution studies: animals were injected with LMWH S.C. daily for 5 days (10 mg/kg) then injected i.v. with [124-I]-Paclitaxel. LMWH increased [124-I]-Paclitaxel uptake into LCC6 tumors with tumor: muscle ratios several fold greater than that of [124-I]-Paclitaxel alone at 24 hrs post injection. This is a highly significant result in the light of the fact that the FDA criterion for a clinically meaningful effect is a 15% increase in uptake. (4) HPLC studies of tumor uptake of Doxorubicin (DOX in mice treated with 10 mg/kg of LMWH or S-NACH for 10 days followed by Doxorubicin (2.5 mg/kg). Both LMWH and S-NACH significantly (P<0.01) increased the uptake of chemotherapeutic agent DOX in MCF7 DOX resistant tumors by 1.5–2 folds but not in heart or lung tissues, confirming the findings obtained with another agent [124-I]-Paclitaxel. Conclusions: LMWH or S-NACH increased chemotherapeutics uptake and hence chemoresponse. Protocols utilizing adjuvant or neo-adjuvant therapy with LMWH or S-NACH could lead to increase tumor chemo responsiveness and overcoming tumor chemo resistance. No significant financial relationships to disclose.
Population pharmacokinetics of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced solid tumors
Authors: Wu H. , Ramanathan R. K. , Srychor S. , Zamboni B. A. , Ramalingam S. , Edwards R. P. , Friedland D. M. , Stoller R. G. , Belani C. P. , Zamboni W. C. 
Published: August 2020

2545 Background: CKD-602, a semi-synthetic analogue of campothecin, is a potent topoisomerase I inhibitor. S-CKD602, a PEGylated long-circulating liposomal formulation of CKD-602, was developed to achieve a longer intra-tumoral exposure of CKD602 and a higher therapeutic index. Age and body composition were reported to affect the pharmacokinetics (PK) of S- CKD602 (Zamboni, ASCO'07). A population PK model for encapsulated and released CKD-602 following administration of S- CKD602 was developed to assess factors that may influence S-CKD602 PK. Methods: Plasma samples from 45 patients (pts) with solid tumors were collected in a phase I study. S-CKD602 was administered as a 1 h IV infusion with doses ranging from 0.1 to 2.5 mg/m2. Plasma concentrations of encapsulated (n=292) and released (n=268) CKD-602 were measured by LC-MS/MS, and population PK modeling was performed using NONMEM. Results: Pts were classified as linear and nonlinear pts according to the clearance (CL) of encapsulated CKD-602 using a classic two stage PK modeling approach. Mean ± SD ratio of total body weight to ideal body weight of pts with linear and nonlinear CL of encapsulated CKD-602 was 1.13 ± 0.16 and 1.53 ± 0.29, respectively (P = 0.003). PK of encapsulated CKD-602 was described by 1-compartment model with nonlinear CL (Michaelis-Menten kinetics). PK of released CKD-602 was described by a 2- compartment model with linear CL for all pts. The presence of primary or metastatic tumor(s) located in the liver decreased the inter- individual variability (IIV) in the CL of encapsulated CKD-602 by 13%. Typical values of Vmax of encapsulated CKD-602 in pts with and without hepatic tumor(s) were 156 and 103 μg/h, respectively (P < 0.001). The inclusion of age decreased IIV in the release of CKD-602 from S-CKD602 by 22%. Typical values of release of CKD-602 from S-CKD602 in pts < 60 years old (yo) and pts ≥ 60 yo were 0.21 and 0.10 L/h, respectively (P < 0.001). Conclusions: These data suggest that older patients (pts ≥ 60 yo) have a reduced release of CKD-602 from S-CKD602. In addition, pts with tumors in the liver may have an increased clearance of S-CKD602. These observations have potential implications in the optimal dosing of liposomal agents. [Table: see text]
Phase I and pharmacokinetic (PK) study of IHL-305 (pegylated liposomal irinotecan) in patients with advanced solid tumors
Authors: Jones S. F. , Zamboni W. C. , Burris H. A. , Chan E. , Infante J. R. , Keedy V. , Bendell J. C. , Lee W. , Ikeda S. , Rothenberg M. 
Published: August 2020

2547 Background: Irinotecan (CPT-11) is a prodrug of SN-38 that has antitumor activity in a wide range of solid tumors. IHL- 305 is a PEGylated-liposomal formulation of irinotecan designed to increase the therapeutic index by prolonging the duration of exposure in both plasma and tumors. IHL-305 demonstrates superior anti-tumor activity in preclinical models. Methods: Eligible patients (pts) had advanced solid tumors, ECOG ≤2, adequate organ function and no prior exposure to CPT-11. In a standard 3+3 escalation, IHL-305 was infused over 60 minutes q 28 days. UGT1A1*28 genotyping was performed with the homozygous (*28/*28) variants treated at 50% of current dose (subsequent escalation allowed). The area under the plasma concentration- time curve (AUC) of sum total (encapsulated + released) CPT-11, released CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was calculated. The % CPT-11 released was calculated as the ratio of released CPT-11 AUC to sum total CPT-11 AUC x 100. The primary objectives were to determine the dose limiting toxicities (DLTs), phase II recommended dose (P2RD), and clinical pharmacology of IHL- 305. Results: 42 pts treated; homozygous wild-type (wt/wt; n=23), heterozygous (wt/*28; n=13) and homozygous variants (*28/*28; n= 6). 10 dose levels explored; 7, 14, 28, 37, 50, 67, 88, 120, 160 and 210 mg/m2. DLTs included: 1 Gr 3 acute nausea/vomiting at 67 mg/ m2 (subsequent pts received premedication), 1 Gr 3 delayed-onset diarrhea at 160 mg/m2, and 1 Gr 3 delayed nausea/vomiting and one Gr 3 febrile neutropenia at 210mg/m2. Pts received repeated courses of IHL-305 with no delays for myelosuppression or diarrhea. 7 pts had stable disease ≥ 6 cycles. The mean ± SD PK parameters are summarized in the table below. Conclusions: The MTD and P2RD of IHL-305 is 160 mg/m2 IV q 28 days. IHL-305 shows a high and prolonged exposure of sum total and released CPT-11 and SN-38. [Table: see text] [Table: see text]
A phase I study of daily oral TRC102 (methoxyamine) to enhance the therapeutic effects of pemetrexed in patients with advanced refractory cancer
Authors: Anthony S. P. , Rosen L. S. , Weiss G. J. , Gordon M. S. , Adams B. J. , Gerson S. L. , Alvarez D. , Theuer C. P. , Leigh B. R. 
Published: August 2020

2552 Background: TRC102 (methoxyamine) is a small molecule inhibitor of base-excision repair (BER) that enhances the cytotoxicity of alkylator and antimetabolite chemotherapy and reverses chemotherapy resistance. TRC102 inhibits BER by stabilizing abasic sites produced by glycosylase removal of damaged DNA bases. Methods: A phase 1 trial evaluated the safety, PK, and PD of oral TRC102 combined with intravenous pemetrexed in patients with advanced refractory cancer. Patients were required to have ECOG PS ≤ 1 and adequate organ function. TRC102 was escalated in cohorts of 3–6 patients in combination with standard dose pemetrexed. All patients received TRC102 alone on Days 1–4 of a 2 week cycle followed by the combination of pemetrexed and TRC102 every 3 weeks thereafter. Results: Eight patients were treated with a total of 22 cycles of TRC102 at 15 mg/m2 (n=3) and 30 mg/m2 (n=5). No adverse events were attributed to TRC102 alone, and grade 3–4 neutropenia without fever, grade 3 thrombocytopenia, and grade 1–2 fatigue and asthenia were considered possibly related to the combination of TRC102 and pemetrexed. One patient at 30 mg/kg TRC102 experienced grade 3 anemia during Cycle 2 that was considered a dose-limiting toxicity. He recovered after 2 units PRBCs and a 50% dose-reduction of TRC102, and remained on study through Cycle 5. Clinical PK analyses indicate that TRC102 plasma concentrations required for in vivo activity are achievable with daily oral administration (Cmax = 49–62 ng/mL, half-life = 29–40 hr), and PD studies confirm that TRC102 stabilizes pemetrexed-induced abasic sites in these patients. Conclusions: Daily oral TRC102 is tolerated at doses that potentiate the clinical activity of pemetrexed in patients with advanced refractory cancer. Phase 2 studies are planned in multiple indications. [Table: see text]
Analysis of a phase I pharmacokinetic (PK)/food effect study of AT-101 in patients with advanced solid tumors
Authors: Pitot H. C. , Mould D. , Maleski J. , Leopold L. 
Published: August 2020

2557 Background: AT-101 is an oral, pan-Bcl-2 inhibitor (Bcl-2, Bcl-XL, Bcl-W, Mcl-1). Overexpression of Bcl-2 family proteins is common in human cancers. AT-101 activity as a single agent as well as in combination with docetaxel has been reported. The ongoing Phase 1 study of AT-101 as a single agent was expanded to include a cohort of patients to determine the PK of AT-101 in fed and fasted states. Methods: Twelve patients (pts) were enrolled and randomized into cohorts of six pts each. Cohort A received AT-101 (80 mg) orally on day 1 on an empty stomach (fasted) and again on day 8 with a high fat high calorie breakfast (fed), per FDA guidelines. Cohort B received AT-101 on day 1 fed and on day 8 fasted. Preliminary plasma concentration time data for AT-101 from 10 patients administered 80 mg orally were evaluated using noncompartmental analysis. Log transformed peak concentration (Cmax) and exposure (AUC) were compared the between fed and fasted groups with the fasted group as the reference treatment. Results: Preliminary PK results from the first 10 pts are shown in the Table. For AUC and Cmax, the effect of food resulted in an approximately 42% and 5% increase, respectively. However the confidence intervals were not wholly outside the 80–125% intervals. Conclusions: These data indicate that food may increase AT-101 exposure in terms of AUC and Cmax. Updated results from all 12 pts will be presented at the meeting. Based on our preliminary results, it is recommended that AT-101 be taken at least an hour (or more) before or after food. [Table: see text] [Table: see text]
Phase I evaluation of SF1126, a vascular targeted PI3K inhibitor, administered twice weekly IV in patients with refractory solid tumors
Authors: Chiorean E. G. , Mahadevan D. , Harris W. B. , Von Hoff D. D. , Younger A. E. , Rensvold D. M. , Shelton C. F. , Hennessy B. T. , Garlich J. R. , Ramanathan R. K. 
Published: August 2020

2558 Background: SF1126 is composed of the pan PI3K inhibitor LY294002 conjugated to an RGD targeting peptide. It is designed to increased solubility and binding to integrins expressed on tumor vasculature. This targeted prodrug enhances tumor delivery of the active inhibitor, improving antitumor efficacy and tolerability in xenograft models. LY294002 inhibits other kinases including mTOR, DNA-PK, PIM1, PLK1, and CK2, and induces oxidative stress in cancer cells independent of its PI3K inhibition. Methods: Pts with advanced solid tumors are enrolled in sequential cohorts in standard 3+3 design. SF1126 is administered days 1, 4 weekly by 90 minute IV infusion in cycles of 4 weeks. Pharmacodynamic (PD) evaluations of PI3K pathways are being measured in PBMC, skin/hair and tumor samples as well as by 18FDG PET scans. Primary objectives are safety, establish MTD and recommended phase 2 dose. Results: 28 pts have been treated with SF1126126 across 7 dose levels of 90, 140, 180, 240, 320, 430, and 630 mg/m2. One dose limiting toxicity (DLT) was seen at the 180 mg/m2 dose, consisting of transient G3 diarrhea. No other grade 3/4 drug related toxicities have been reported. No consistent effects on blood glucose levels noted. Eleven pts showed stable disease for ≥ 8 wks, including durations of 20 wks for one GIST, 1 endometrial, and 1 prostate; 15 wks for 1 pancreatic; 11 wks for 2 GIST, 2 ovarian, and 1 CRC pt. PK: SF1126 is rapidly cleared after infusion termination. PK of active hydrolysis product (LY294002) shows t1/2 ∼1.6–2 hrs; dose proportional Cmax, achieving ∼ 21uM at 630 mg/m2; and AUC(0-t) nearly dose proportional. Mean AUC values at doses ≥ 140 mg/m2 exceed those found effective in mouse xenograft studies. PD: Compared to baseline biopsy, we observed significant inhibition of pS6 by IHC in a tumor biopsy 20 hours after the 8th dose in a pancreatic cancer pt at 240 mg/m2. Conclusions: SF1126 is well tolerated at doses up to 630 mg/m2 given twice weekly. MTD has not been reached; dose escalation continues. Clinical activity includes disease stabilization in multiple pts with refractory tumors. There is early evidence of target pathway inhibition. [Table: see text]
Phase I dose escalation study of continuous oral dosing of OSI-906, an insulin like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor, in patients with advanced solid tumors
Authors: Lindsay C. R. , Chan E. , Evans T. R. , Campbell S. , Bell P. , Stephens A. W. , Franke A. , Poondru S. , Rothenberg M. L. , Puzanov I. 
Published: August 2020

2559 Background: OSI-906 is a potent small molecule inhibitor of IGF-1R, a receptor tyrosine kinase activated by insulin like growth factor, which is overexpressed in numerous malignancies and implicated in resistance to chemotherapy. Methods: Patients with advanced cancer entered escalating dose cohorts of OSI-906. Study objectives included assessment of: safety; determination of MTD; pharmacokinetics (PK), pharmacodynamics (PD) including IGF-1R levels in peripheral blood cells; and tumor response (RECIST). Results: To date, 32 pts have been treated (22M/10F, median age 62y) at 10, 20, 40, 75, 150, and 300 mg QD and at 20, 40 mg and 75 mg BID. Median number of weeks on trial was 6 (range 0–44). No DLTs have been observed. Hyperglycemia (5/20 pts) related to OSI-906 was transient and mild (grade 1 only). In addition to hyperglycemia, grade 1–2 nausea and vomiting (5/20 pts) were the most frequent related adverse events (AEs). There was grade 3 elevated lipase in 1 pt. At doses of 10–150 mg, OSI-906 exhibited linear PK, median terminal t1/2 ranged from 2.18–4.30 hr, AUC0-inf from 284–10200 ng.hr/mL, and Cmax 76.6–1440 ng/mL. There was no relationship between glucose or insulin levels and OSI-906 plasma concentrations. Stable disease > 12 weeks was seen in 7/20 pts (range 12–34 weeks), including 1 pt each with thymic (27 w), adrenocortical (28w), and colorectal (34w) cancer. PD data on IGF-1R phosphorylation will be presented. Conclusions: Plasma concentrations of OSI-906 achieved in this trial exceed concentrations required for antitumor efficacy in preclinical models. PD target modulation and preliminary anti-tumor activity have been observed. It is interesting to note that clinically meaningful hyperglycemia has yet to occur. Minimal toxicity was observed and further dose escalation is in progress. [Table: see text]
Pharmacodynamic effects of MLN4924, a novel NAE inhibitor, on blood and skin
Authors: Kauh J. S. , Cohen R. , Clarke J. W. , Harvey R. , Mulligan G. , Venkatakrishnan K. , Berger A. , Smith P. G. , Petruzelli L. , Sarantopoulos J. 
Published: August 2020

2562 Background: MLN4924 is a first-in-class, small molecule inhibitor of NEDD8 Activating Enzyme (NAE) with potent antitumor activity in animal models. Inhibition of NAE by MLN4924 leads to decreased neddylation and inhibition of cullin-RING ubiquitin ligase (CRL) activity. CRLs are enzyme complexes that control the ubiquitination and degradation of proteins with important roles in cell cycle and survival. Potent antitumor activity in animal models correlates with accumulation of substrates of the CRLs associated with DNA replication (e.g.Cdt-1), stress response (e.g.Nrf-2), and signal transduction (e.g. pIκB). Methods: A primary objective of this phase I trial in patients (pts) with advanced non-hematologic malignancies was to evaluate the pharmacodynamic (PD) effects of MLN4924 as measured by accumulation of pIκB in peripheral blood mononuclear cells (PBMCs) and Cdt-1 and Nrf-2 in skin. Pts were treated with a daily infusion of MLN4924 for 5 days of a 21-day cycle. PBMCs were isolated for analysis of pIκB levels at screening, baseline, and at selected time points following its administration. Skin biopsies for assay of Cdt-1 and Nrf-2 were performed at baseline and following the second dose of MLN4924. Results: 10 pts have been treated at 3 dose levels. Treatment emergent adverse events include elevations in transaminases, bilirubin and alkaline phosphatase. PK analysis indicated approximately dose-proportional increases in MLN4924 exposure with an estimated half life of 5 to 15 hours and no readily apparent drug accumulation. Analysis of pIκB levels in PBMCs demonstrated accumulation from baseline levels following administration of MLN4924. Cdt-1 and Nrf-2 levels in skin rose above baseline following the second dose of MLN4924. Conclusions: Treatment of pts with MLN4924 results in accumulation of substrates associated with inhibition of NAE in both peripheral blood and skin. Inhibition occurs at exposure levels that are comparable to those resulting in pharmacodynamic activity and in vivo tumor activity in xenograft models. Evidence of PD modulation of NAE activity through the accumulation of CRL substrates has been established in this early analysis, and dose escalation is ongoing to establish the MTD of this agent. [Table: see text]