bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer
Authors: Sabharwal A. , Corrie P. , Seebaran A. , Anderson D. , Carmichael J. , Mortimer P. , Margison G. P. , Watson A. , Middleton M. R. 
Published: March 2020

2535 Background: The DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) contributes to cellular resistance to irinotecan (IR) and its metabolite SN-38. In human cancer cell lines MGMT expression correlates with SN-38 sensitivity, inactivation of MGMT enhances cell killing and increasing MGMT expression by transfection increases resistance to IR. This study evaluated the safety, tolerability and pharmacokinetics (PK) and pharmacodynamic (PD) effects of lomeguatrib (LM), an MGMT inactivator, in combination with IR. Methods: Patients with stage 4 colorectal cancer, performance status 0–2 and adequate bone marrow and biochemical function took part in the trial, which followed a standard 3 patient cohort dose escalation design. LM was given daily PO for 5 days, with IR by IVI on day 4 of each 21 day cycle. Starting doses were 10 mg/day LM and 350 mg/m2 IR. Tumor response to treatment was measured by RECIST criteria. Blood was taken for PK & PD measurements in cycle 1. Results: 24 patients (14M/10F; median age 62) were enrolled. The first dose level was not tolerated, with 2 of 3 patients experiencing dose limiting haematological toxicity. The IR dose was decreased to 250 mg/m2 for subsequent cohorts, and the LM dose escalated from 10 to 80 mg/day. With LM 80 mg/day a final 6 patient cohort received 300 mg/m2 IR, establishing this as the maximum tolerated dose. Non-hematological toxicity matched that of single agent IR. No partial responses have been seen amongst 22 evaluable patients. 10 patients had prolonged disease stabilisation, completing all 6 treatment cycles, with another 3 patients still on treatment. There was no PK interaction between the drugs. Conclusion: LM and IR is well tolerated, requiring a modest reduction in the single agent dose of IR. Clinical activity, in this pre-treated population, is modest. PD data on MGMT levels and DNA-topoisomerase 1 complex formation in peripheral blood mononuclear cells, measured by bioassay and RIA respectively, will be presented. No significant financial relationships to disclose.
Prediction of response to chemotherapy using sequential F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) in patients with metastatic colorectal cancer
Authors: Kim J. , Choi S. , Yi H. , Lim J. , Lee M. , Hyun I. , Kim C. 
Published: March 2020

2536 Background: Clinical response is determined after 2 or 3 cycles of chemotherapy by changes in tumor size as assessed by conventional imaging procedures such as computed tomography (CT). The aim of this study was to evaluate the use of sequential F-18 FDG PET to predict response to standardized chemotherapy for metastatic colorectal cancer (mCRC). Methods: Clinical response, as assessed by RECIST criteria, served as the reference. Investigators were free to choose chemotherapy regimen. F-18 FDG PET images after every second cycles of chemotherapy were analyzed semiquantitatively for each metastatic lesion using standardized uptake values (SUVs) normalized to patients’ blood glucose levels. PET responses were prospectively assessed as either complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), or progressive metabolic disease (PMD). In addition, sum of SUV of all metastatic lesions (sSUV) and a maximal SUV (mSUV) were recorded each PET-CT scan. Results: Twenty-four patients underwent 73 PET-CT scans since March 2005. The response to chemotherapy included CR in 1 (4.2%), PR in 10 (42%) by RECIST criteria. Median duration of follow- up was 8.3 months (range, 1.7 - 16.2) and median progression free survival (PFS) time was 6.4 months. At the baseline evaluation, PET-CT was the more sensitive test to find metastatic lesion than conventional assessment in 12 (50.0%). Baseline sSUV and mSUV was not significantly different between clinical responders and non-responders. After 2 cycles of chemotherapy, sSUV and mSUV was more decreased in clinical responder with significance (P=.023 and .020, respectively). In the 22 evaluable patients, PET responses were as followed: CMR in 1 (4.5%), PMR in 11 (50.0%), SMD in 7 (31.8%) and PMD in 3 (12.0%). Estimated median PFS was significantly prolonged in metabolic responders: PMR 8.3 months, SMD 4.7 months and PMD 2.3 months (P=.040). Patient with CMR had no evidence of progression for 14.7 month follow-up. Conclusions: In patients with mCRC, sequential FDG-PET predicted PFS and was more accurate than clinical response criteria. FDG- PET appears to be a promising tool for early prediction of response to chemotherapy. No significant financial relationships to disclose.
Single nucleotide polymorphisms (SNPs) analysis of CYP2C8, GSTT1, GSTP1, MDR1(A), MDR1(B) and ERCC1 as predictor of survival after weekly paclitaxel for relapsed advanced head & neck cancer patients (AHNCP)
Authors: Grau J. J. , Monzo M. , Vargas M. , Jansa S. , Campayo m. , Alos L. , Domingo-Domenech J. , Verger E. 
Published: March 2020

2540 Background: Gene SNPs correlate with survival in cancer patients (pts) treated with chemotherapy (CHM). CYP2C8 and GSTT1, GTSP1 genes are involved in phase 1 and 2 drug cellular metabolisms respectively; MDR1(A) and MDR1(B) are involved in drug membrane transport and ERCC1 in DNA repair Methods: We evaluated the presence of SNPs of these 6 genes and the survival of AHNCP treated with weekly paclitaxel, 80 mg/m2 iv for 6 weeks. Responding pts continue CHM till progression. All pts were cisplatin resistant and no other local therapies were available. We analysed paraffin-embedded biopsies from 47 consecutive AHNCP for SNPs of the mentioned genes. The status of the alleles wild type (wt) or at least 1 SNP was compared with response rate (RR), time to progression (TTP) and overall survival (OS) Results: Of 47 pts, 43 were male and 4 female. The median of age was 57 yr (46–80). RR was 45% (21/47) and the TTP in responders was 5 months of median. OS for all pts was 5.6 months. Wild type vs at least 1 SNPs frequencies according the genes were: CYP2C8 23/24; GSTT1 45/2; GSTP1 36/11; MDR1(A) 21/28; MDR1(B) 13/34; and ERCC1 27/20. OS was significantly better in pts with 2 or more SNPs accumulated (p=0.0455). No other significant differences were observed in RR, TTP or OS in SNPs vs wild type pts. Conclusions: SNPs of CYP2C8, MDR1(A) and MDR1(B) genes were more frequent than wt in our pts. OS was significantly better in pts with 2 or more SNPs accumulated. Paclitaxel provides high rate of responses of short duration in AHNC pts No significant financial relationships to disclose.
Mechanism-based PKPD model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET- 743) treatment
Authors: Fetterly G. J. , Owen J. S. , Stuyckens K. , Passarell J. A. , Zannikos P. , Matos A. S. , Izquierdo M. A. , Perez-Ruixo J. J. 
Published: March 2020

2545 Background: Reversible transient elevations in transaminases have been observed after trabectedin (T) administration, despite no alteration in plasma PK. A PKPD model was developed to evaluate the time course of ALT elevation, tolerance development, and covariate effects following different dosing schedules in cancer subjects. Methods: T was administered to 711 subjects as monotherapy (dose range: 0.024 - 1.8 mg/m2) as 1-, 3-, or 24-hr infusions every 21 days; 1- or 3-hr infusions on days 1, 8, and 15 every 28 days; or 1-hr infusions daily for 5 consecutive days every 21 days. Population PKPD modeling was performed with covariate evaluation [dexamethasone use (469/711 pt), ECOG PS scores (89.7% pts = 1), and BW (36–122 kg)] on PD parameters, followed by model validation. Simulations assessed the influence of dosing regimen and selected covariates on the time course of ALT and the effectiveness of the dose reduction strategy. Results: A precursor-dependent PKPD model described the temporal relationship between ALT elevation and T concentrations, where the transfer process of ALT from hepatocytes to plasma is stimulated by trabectedin plasma concentration. Overall, 66% of subjects had transaminitis. Mean predicted (%SEM) baseline ALT (ALTo) and T1/2 in plasma were 33 (5.5) U/L and 1.4 days, respectively. The magnitude of the T stimulation on the ALT transfer rate from hepatocytes to plasma was 11.2% per 100 pg/mL of trabectedin plasma concentration. Dexamethasone decreased the rate of T-induced ALT release from hepatocyte by 63% (p<0.001). Model validation results showed good concordance with the observed incidence of grade 3/4 toxicity. Simulations showed that severity of ALT elevation was dose- and schedule-dependent. The dose reduction strategy decreased the incidence of grade =3 toxicity by 13% and 39% following 2 and 4 cycles of therapy, respectively. Conclusions: A PKPD model quantifying the hepatoprotective effect of dexamethasone on transient and reversible transaminitis after T treatment has been developed. The model predicts that co-administration of dexamethasone and the suggested dose reduction strategy will enhance the safe use of T in the clinic. No significant financial relationships to disclose.
Ratiometric dosing of irinotecan (IRI) and floxuridine (FLOX) in a phase I trial: A new approach for enhancing the activity of combination chemotherapy
Authors: Batist G. , Miller W. , Mayer L. , Janoff A. , Swenson C. , Louie A. , Chi K. , Chia S. , Gelmon K. 
Published: March 2020

2549 Background: Like many pairs of chemotherapy agents, the combination of IRI and FLOX displays ratio-dependent activity in vitro. CPX-1, a liposome formulation of IRI:FLOX, was developed to maintain a synergistic 1:1 molar ratio in vivo, was highly active in preclinical models, and was evaluated in a phase 1 trial (CLTR0104–101). Methods: Doses were escalated from 30U/m2 (1U= 1 mg IRI + 0.36 mg FLOX) to 270 U/m2 given on day 1 and 15 of each 28 day cycle. Adult patients (pts) with advanced solid tumors, ECOG PS<2, adequate bone marrow, liver, and renal function were eligible; 4 pts per cohort. After defining the MTD, additional pts with CRC were enrolled (extension phase). IRI completed greater than 12 months prior to this trial was allowed in the absence of resistance to IRI. PK was done on day 1 and 15 of the 1st cycle. Results: Safety: The dose escalation phase enrolled 24 pts in 6 cohorts and added 2 pts in the 5th cohort (210U/m2; the MTD) after noting dose limiting diarrhea (3 pts) and neutropenia (1 pt) including one death from dehydration and renal failure due to prolonged diarrhea (gr3) & vomiting (gr2) at 270U/m2. An additional 7 pts with CRC received 210U/m2 in the extension phase. Grade 3/4 adverse events included diarrhea, nausea, vomiting, neutropenia and thrombocytopenia with most occurring at 270U/m2. No new toxicities were observed for this combination. Response: 30/33 pts were evaluable with 2 confirmed PRs (NSCLC and CRC), 21 SD and 7 PD. Median PFS was 5.4 mos. (0.3–11.8 mos.) in 15 pts w/CRC. PK: All pts maintained synergistic plasma IRI:FLOX ratios for 24h. IRI and FLOX AUCs (0-inf) were greater for CPX-1 than expected for conventional drugs. AUCs for SN-38 and 5FU at 210U/m2 were 0.8 ± 0.1 and 10 ± 8.7 μg-hr/mL, respectively, indicating bioavailability for both drugs. Conclusion: CPX-1 was well tolerated in the outpatient setting and evidence of anti-tumor activity was obtained. This is the first clinical evaluation of ratiometric dosing in which a synergistic drug ratio, pre-selected in vitro based on optimal anti-tumor activity, was maintained systemically to enhance therapeutic benefit. [Table: see text]
Phase I study to determine the safety and pharmacokinetics of 4-hour intravenous infusion of TAS-106 on a once per week for 3 consecutive weeks every 28-day schedule in patients with solid tumors
Authors: Chadha R. , Mita A. , Iwasaki M. , Lassere Y. M. , Bogaard K. R. , Waldrum S. A. , Abbruzzese J. L. , Thomas M. B. 
Published: March 2020

2556 Background: Most solid tumors are slow growing so the S-phase-specific anti-tumor drugs have limited efficacy. The antitumor nucleoside 3’-C-ethynylcytidine (ECyd, TAS-106) inhibits RNA synthesis by blocking RNA polymerases. In vitro, TAS-106 has demonstrated cytotoxicity 300 times greater than that of 5-FU against human lung, colorectal, gastric, pancreas and breast cancer cells. This trial was based on a previous clinical trial, in which study drug was administered as a bolus injection wkly for 3 consecutive weeks every 28- days and TAS-106 caused reversible dose-limiting peripheral neuropathy, and the safety dose was 1.32 mg/m2/dose. Methods: Objectives of this study were to determine the recommended phase II dose (RP2D) and the dose-limiting toxicity of TAS-106 administered by 4-hour IV infusion wkly for 3 consecutive weeks every 28-days; to investigate the clinical pharmacokinetics and pharmacodynamics of TAS-106, and document any antitumor activity observed. Results: A total of 18 patients (pts) were treated in the study; 16 pts were evaluable. The med age was 59; 11 female. A total of 44 courses of therapy were initiated by pts during the study; 39 courses (88.6%) were completed. Six pts had best tumor responses of stable disease (SD) and 9 pts had best tumor responses of progressive disease (PD); no pts had a complete or partial response. The mean duration of SD was 103.7 days. Median time to treatment failure was 57.0 days. At the RP2D (2.04 mg/m2/dose), 2 of 8 pts had best tumor response of SD with a mean duration of 132.0 days and three of the 8 pts had PD. For 12 pts (66.7%), adverse events (AEs) were considered to be related to TAS-106; the most commonly reported drug-related AEs were tremor (8 pts, 44.4%), neuropathy (4 pts, 22.2%), and peripheral neuropathy and fatigue (3 pts, 16.7% each) . No Grade 4 drug-related AEs were reported. Plasma concentrations increased with increasing dose, and at 2.04 mg/m2, the Cmax was 47.6±1.3 ng/mL. Conclusions: The safety profile of TAS-106 administered via wkly 4-hour IV infusion appears to be similar to the toxicity profile of TAS-106 when administered as a wkly bolus. In wkly 4-hour IV infusion, peripheral neuropathy was acceptable at the RP2D. No significant financial relationships to disclose.
Effects of reduced glutathione (GSH) on oxaliplatin pharmacokinetics (OXA pk) and on Pt-DNA adducts formation in advanced colorectal cancer patients treated by FOLFOX4 regimen
Authors: Zanon C. , Airoldi M. , Passera R. , Cattel L. , Milla P. , Jaehde U. , Drescher A. , Branciforte L. , Gozzelino I. , Pedani F. 
Published: March 2020

2559 Background: Neurotoxicity is a common OXA toxicity in FOLFOX4 regimen for patients with advanced colorectal cancer. Recently, Cascinu et al. (JCO 2002; 20: 3478–3483) provided evidence that GSH reduces the OXA-induced neurotoxicity, but GSH influence on the formation of Pt-DNA adducts still remains unknown. This study evaluated the effect of GSH addition on OXA pk and on Pt-DNA adducts formation Table of Contents Methods: 28 patients were given twelve FOLFOX4 courses and randomized to receive either GSH 1,500 mg/m2 or normal saline solution (placebo) before OXA iv infusion. OXA pk and Pt-DNA adducts formation were evaluated at courses 5, 9 and 12. Total and ultrafiltered platinum were analyzed by atomic adsorption, Pt-DNA adducts in leukocytes (as model for tumour tissue) by adsorptive stripping voltammetry. Pk analysis were done by non-compartmental analysis, statistical analysis by non-parametric Mann-Whitney test. Results: Median total and ultrafiltered platinum median Cmax and AUCtot values were comparable to previously reported ones, being higher in the placebo arm, due to a moderate reduction of platinum clearance. The formation of Pt-DNA adducts was more pronounced in GSH arm (median value 20.3 Pt atoms/106 nucleotides vs. 5.7 Pt atoms/106 nucleotides), even not statistically significant. Conclusions: The addition of GSH to FOLFOX4 regimen is able to reduce the OXA-induced neurotoxicity, without affecting either the OXA pk behaviour or the formation of Pt-DNA adducts, without modifying FOLFOX4 clinical efficacy. [Table: see text] No significant financial relationships to disclose.
The complete phase Ib clinical trial: A method to accelerate new agent development
Authors: Von Hoff D. D. , Nieves J. A. , Vocila L. K. , Weitman S. D. , Cvitkovic E. 
Published: March 2020

2562 Background: The usual clinical development plan for a new agent (NA) includes a phase I monotherapy trial. However, because many new agents are eventually developed as part of a combination, additional phase I trials assessing the new agent in combination with a standard agent are usually performed (usually as individual phase Ib studies). Our hypothesis was that within a single protocol, several combination phase I trials could be conducted simultaneously. Methods: The design of the protocol is (assuming the new agent is synergistic with an anthracycline, a tubulin interactive agent, an antimetabolite, an angiogenesis inhibitor or an antibody to EGFR): patients with advanced cancer are treated with the combination deemed most likely to be of help-with a choice of a) anthracycline + NA; b) tubulin interactive + NA; c) antimetabolite + NA; d) angiogenesis inhibitor + NA; e) antibody to EGFR + NA. The standard agent is started at full dose with 3 patients placed at 1/3 full dose of NA, 3 patients at 2/3 dose of NA, and 3–6 patients at full dose of the NA in the combination. Results: Our experience with the complete phase Ib trial has found several advantages over conducting separate phase I trials. The advantages include: (a) a very rapid follow-up on preclinical data in one study; (b) a saving of time and expense in the start up; (c) accrual is rapid because many patients in a practice are likely to be eligible (e.g. the standard agent is the standard of care); (d) patients are often less pretreated; (e) the trial generates information for more informed selection of follow-up randomized phase II or III trials. Conclusions: Utilizing a Complete phase Ib trial design is feasible. Our initial experience has suggested that this approach is safe and highly efficient with several potential advantages over multiple sequential combination phase Ib studies. No significant financial relationships to disclose.
Age-related effects on the pharmacodynamic (PD) relationship between STEALTH liposomal CKD-602 (S-CKD602) and monocytes in patients with refractory solid tumors
Authors: Maruca L. J. , Ramanathan R. K. , Strychor S. , Zamboni B. A. , Ramalingam S. , Edwards R. P. , Kim J. K. , Bang Y. J. , Lee H. P. , Zamboni W. C. 
Published: March 2020

2576 Background: STEALTH liposomal CKD-602 (S-CKD602), a camptothecin analogue, is eliminated by the reticuloendothelial system (RES), which consists of cells including monocytes. CKD-602 released from S-CKD602 is eliminated by the kidney. Therefore, we evaluated the PD relationship between monocyte and absolute neutrophil counts (ANC; as a control) in blood and S-CKD602 and non-liposomal CKD-602 (NL-CKD602) in patients (pts) with refractory solid tumors. We also evaluated the effect of age on these relationships. Methods: In a phase I study, S-CKD602 was administered IV x 1 q 3 wk at 0.1 to 2.5 mg/m2. In phase I and II studies, NL-CKD602 was administered IV qdx5d q 3 wk at 0.5 to 0.9 mg/m2/d and 0.5 mg/m2/d, respectively. The % decreases in ANC and monocytes at nadir were calculated. For S-CKD602, pharmacokinetic studies of encapsulated (E), released (R), and sum total (ST=E+R) CKD-602 in plasma and ST in urine were performed and measured by LC-MS/MS. Area under the plasma concentration versus time curve (AUC) was calculated. Results: For S-CKD602 in all pts (n = 27), the % decrease in ANC and monocytes were 42 ± 30 % and 58 ± 34 %, respectively (P = 0.003). For S-CKD602 in pts < 60 years old (yo) (n = 12), the % decrease in ANC and monocytes were 43 ± 31% and 58 ± 26 %, respectively (P = 0.001). For S-CKD602 in pts = 60 yo (n = 15), the % decrease in ANC and monocytes were 41 ± 31% and 45 ± 36 %, respectively (P = 0.50). For NL-CKD602 (n = 42), % decrease in ANC and monocytes were similar (P > 0.05). For S-CKD602, the relationship between % decrease in monocytes and released CKD-602 AUC in plasma in pts < 60 yo (R2 = 0.54) and = 60 yo (R2 = 0.49) was similar. For S-CKD602, the relationship between the % decrease in monocytes and the amount of CKD-602 recovered in the urine was stronger in pts < 60 yo (R2 = 0.82) compared with = 60 yo (R2 = 0.30). Conclusions: Monocytes are more sensitive to S-CKD602 compared with neutrophils and the increased sensitivity is related to the liposomal formulation and not CKD-602. These results suggest that monocytes engulf S-CKD602 which causes the release of CKD-602 from the liposome and toxicity to the monocytes, and that the effects are more prominent in pts < 60 yo. [Table: see text]
A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/interferon-α2a vs placebo/interferon- α2a as first-line therapy in metastatic renal cell carcinoma
Authors: Escudier B. , Koralewski P. , Pluzanska A. , Ravaud A. , Bracarda S. , Szczylik C. , Chevreau C. , Filipek M. , Melichar B. , Moore N. 
Published: March 2020

3 Background: Bevacizumab (BEV) is a monoclonal antibody that inhibits tumor angiogenesis by targeting VEGF. In relapsed RCC, BEV improved time to progression compared with placebo (2.5 vs. 4.8 months). A phase III trial was conducted to evaluate the efficacy and safety of BEV in combination with interferon (IFN)-a2a as first-line treatment in metastatic (m) RCC. The final analysis of progression-free survival (PFS) and interim analysis of overall survival (OS) are presented. Methods: Nephrectomized patients with clear cell mRCC, KPS of =70%, no CNS metastases and adequate organ function received IFN- a2a (x3/week at a recommended dose of 9 MIU for up to 1 year) plus BEV (10mg/kg q2w) or placebo until disease progression. Tumor assessments were performed every 8 weeks until week 32 and 12 weekly thereafter. Patients were stratified according to country and Motzer score. Results: Between June 2004 and October 2006, 649 patients were randomized (641 treated) at 101 centers in 18 countries. The treatment arms were well balanced for prognostic factors. At the data cutoff, 505 progression events had occurred, 111 patients remained on treatment, 287 had discontinued (discontinuations due to AEs were 12% with IFN vs. 28% with IFN-a2a/BEV), and 251 died. BEV-related side effects were generally mild and consistent with previous observations. The addition of BEV to IFN-a2a significantly increased PFS (10.2 vs. 5.4 mo) (HR=0.63; p<0.0001) and objective tumor response rate (30.6% vs. 12.4%; p<0.0001). A trend toward improved OS was observed with the addition of BEV to IFN-a2a (p=0.0670). Conclusions: BEV improves PFS when combined with IFN-a2a in mRCC. No unexpected safety events were observed. [Table: see text] [Table: see text]