bluuebunny/crossref_metadata_2025_split huggingface dataset:
A genomic strategy to combinatorial therapeutics in solid tumors
Authors: Potti A. , Dressman H. K. , Bild A. , Riedel R. , Kelley M. , Ginsburg G. , Lancaster J. , Nevins J. , Febbo P. 
Published: March 2020

2031 Background: For most advanced solid tumors, the response rate to cytotoxic drugs is generally low, highlighting the importance of identifying those patients most likely to respond, either to single agents or combinations of cytotoxic or targeted therapies. Methods: We have made use of in vitro drug response data generated on the NCI-60 panel of cancer cell lines, coupled with Affymetrix U133 2.0 plus gene expression data, to develop genomic predictors of chemotherapy sensitivity. These models were then validated in independent cancer cell lines as well as response data from patient treatment studies. Results: Predictive models making use of gene expression data were developed for docetaxel, adriamycin, 5-flourouracil, cyclophosphamide, paclitaxel, and topotecan. These models were shown to accurately predict sensitivity to the drugs in an independent set (n = 30) of cancer cell lines. Importantly, three of the predictors (docetaxel, topotecan, paclitaxel) also accurately (> 80%) predicted response in patient studies. When evaluated in a large collection of human cancers (n = 381), these gene expression signatures of drug response identified patterns of predicted sensitivity suggesting potential opportunities for novel combinations. We also combined the predictions of chemotherapy sensitivity with predictions of pathway deregulation (Bild A, Nature 2005), to develop further opportunities for combination therapy. For instance, this analysis revealed a significant relationship between PI3 kinase pathway deregulation and docetaxel resistance (p = 0.001), and a correlation between docetaxel sensitivity and the activation of the Rb/E2F pathway (p = 0.009). Furthermore, cell lines showing an increased probability of PI3 kinase and Rb/E2F activation were also more likely to respond to a PI3 kinase (LY-294002) inhibitor (p = 0.01) or R-Roscovitine (p = 0.03), a cell cycle inhibitor, respectively. Conclusions: The development and validation of chemotherapeutic response predictors, together with oncogenic pathway signatures that can guide the use of targeted agents, provides an opportunity to develop effective combinatorial therapeutic strategies geared to the individual patient. No significant financial relationships to disclose.
A phase I repeated dose escalation study of the Polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumours
Authors: Hofheinz R. , Hochhaus A. , Al-Batran S. , Nanci A. , Reichardt V. , Trommeshauser D. , Hoffmann M. , Steegmaier M. , Munzert G. , Jäger E. 
Published: March 2020

2038 Background: BI 2536 is a novel highly potent and selective inhibitor of the serine-threonine kinase polo-like kinase 1 (Plk1), which is a key regulator of cell cycle progression. Objectives of this trial were the assessment of the maximum tolerated dose (MTD), overall safety, pharmacokinetics and efficacy of BI 2536 given intravenously. Methods: Sequential cohorts of 3 to 6 patients (pts) with pretreated advanced or metastatic solid tumours received intravenous infusions of BI 2536 on days 1 and 8 of a 3-week treatment course following a toxicity guided dose escalation design. Further treatment courses were administered to pts in the absence of disease progression and if toxicity after a 3-week treatment course had resolved. Results: A total of 42 pts was treated at doses of 25 mg (n=3), 50 mg (n=3), 100 mg (n=22), 125 mg (n=5), 150 mg (n=6) and 200 mg (n=3). Reversible CTCAE grade ≥ 3 neutropenia in 14/42 pts represented the main drug related toxicity with an incidence of 3/5 in the 125 mg cohort, 4/6 in the 150 mg and 2/2 in the 200 mg dose cohorts. Dose limiting toxicity (DLT) was defined as drug related toxicity prohibiting administration of the day 8 dose of BI 2536 (hematologic: CTCAE ≥ 3 grade, non-hematologic toxicity: CTCAE ≥ 2). No DLT other than d8 neutropenia was observed. The MTD was defined at 100 mg for the given day 1 and 8 schedule. Further related adverse events (AE’s) were of mild to moderate intensity (CTCAE grade ≤ 2). There were no related AEs resulting in study discontinuation. Preliminary PK analysis showed dose proportionality of Cmax and AUC0-∞ with a high clearance (∼ 1500 mL/min) and a high volume of distribution (∼ 2000 L). No accumulation from d1 to d8 occurred. Patients were treated for up to 8 courses without evidence of accumulating toxicity. No objective responses were observed according to RECIST criteria in this heavily pretreated patient population. Conclusions: In summary BI 2536 is a Plk1 inhibitor with a favorable PK and safety profile at the tested dose and schedule. Neutropenia as a mechanism-related toxicity indicates target inhibition in vivo. [Table: see text]
Population pharmacokinetic of total cisplatinum: Application to adaptative dosing with feed back in testicular cancer patient
Authors: Salas S. , Mercier C. , Ciccolini J. , Pourroy B. , Dupuis C. , Deville J. , Baciuchka-Palmaro M. , Durand A. , Duffaud F. , Tranchand B. , Favre R. 
Published: March 2020

2043 Background: Cisplatinum (CDDP) is major drug used in germ cell testicular cancer. Pharmacokinetics (PK)/pharmacodynamics relationships have been described after measurement of free CDDP in plasma, and subsequently, CDDP administration is standardized using body surface area (BSA) for only dose tailoring. Methods: Based on a rapid assay of total CDDP in plasma we have developed an alternative 120-hours continuous infusion schedule, coupled to a Bayesian adaptive dosing strategy. We present a retrospective evaluation of this schedule in 19 patients (66 courses) treated for testicular germ cell tumors. A NONMEM analysis was then performed to identify the covariates associated with total CDDP clearance. We compared doses effectively given to our patients with the ones calculated with BSA. Results: Plasma samples were analyzed to allow real-time Bayesian estimation of individual PK parameters with subsequent daily dose adjustment in order to reach a target Cend of 1.95 mg/l of total platinum. No statistical difference was observed between experimental and target values, and Cend adjustment was achieved with an overall 6.6% precision, a performance to be compared with the 54% inter-patient variability observed in drug clearance. Course number (CNB) was the only covariate to be correlated with total CDDP clearance. A weaker correlation was found with BSA, and only when considering first courses. Moreover, doses of CDDP administered were significantly higher than the ones classically normalized with BSA, thus leading to an overall greater exposure in our patients. Only few severe toxicities were reported, and all of the patients presented in this study were still alive and disease-free after a follow up of up to 15 years. Conclusions: Our alternative schedule is a convenient and safe strategy to ensure administration of optimal dose-intensity of CDDP, with limited side-effects in patients with testicular cancer. We demonstrate a linear correlation between course number and decrease of CDDP clearance (25%). This, highlights the critical importance of total drug accumulation on CDDP PK when several infusions are to be administered in a row, and therefore the need for developing dynamic dose individualization strategies that includes CNB. No significant financial relationships to disclose.
A phase I dose-escalation and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced cancer
Authors: Leong S. , Camidge R. , Eckhardt G. , Basche M. , Musib L. , Darstein C. , Thornton D. , Britten C. 
Published: March 2020

2048 Background: Enzastaurin (ENZ), an oral inhibitor of protein kinase C (PKC), affects signal transduction associated with angiogenesis, proliferation, and survival. The combination of ENZ and capecitabine (CAPE) has the potential for additive or synergistic anticancer effects without excessive toxicity. Methods: Patients (pts) with advanced, refractory, solid tumors received lead-in treatment with ENZ for 7–14 days (cycle 1), to achieve steady-state exposures. In subsequent 21-day cycles, ENZ was given once daily, orally, on days 1–21 and CAPE twice daily (bid), orally, on days 1–14 in 3 dose levels (L): L 1 = ENZ 350 mg + CAPE 750 mg/m2; L 2 = ENZ 350 mg + CAPE 1000 mg/m2; L 3 = ENZ 525 mg (some pts received 500 mg tablets) + CAPE 1000 mg/m2. PK for ENZ was assessed on day 1–3 and 7 in cycle 1 and day 8 in cycle 2 and for CAPE on day 1, 8 in cycle 2. Therapy continued until disease progression or unacceptable toxicity occurred. Results: 27 pts (13 males; 14 females, ECOG ≤1) with a median age of 58 yrs (range: 38–74 yrs), received a median number of 3 cycles (range: 2–14 cycles). High interpatient PK variability was noted for total ENZ analytes. Ratio of geometric mean AUC (90% CI) of ENZ with CAPE versus ENZ alone at 500/525 mg was 0.65 (0.38–1.11, n=6) and of Cmax was 0.66 (0.42–1.10, n=4). PK parameters of CAPE in the presence of ENZ were similar to those previously reported for CAPE alone. No grade (Gr) 4 toxicities occurred. Gr 3 toxicities were anemia (1 pt), headache (1 pt), intestinal perforation (1 pt with gastric carcinoma), fatigue (1 pt), hand-foot syndrome (2 pts), and cardiac ischemia (1 pt). PBMCs demonstrated PKC inhibition following exposure to ENZ. Plasma VEGF and bFGF levels did not reflect any significant changes. No objective tumor responses were seen. Five pts had stable disease (lung, breast, pancreas, head/neck, and hemangiopericytoma) for ≥ 6 months (range: 6–9.7 months). Conclusions: The recommended phase II dose is ENZ 500 mg, qd and Cape 1000 mg/m2 bid, days 1–14 every 21 days. This regimen was well tolerated, and exposures of ENZ and CAPE did not appear to be significantly altered when given in combination. [Table: see text]
Dose dependent inhibition of uridine phosphorylase (UP) by eniluracil (EU): Was the clinical inferiority of the EU/5-fluorouracil (5-FU) phase III trials due to an unrecognized inhibition of 5-FU anabolism?
Authors: Fourie J. , Guarcello V. , Diasio R. B. 
Published: March 2020

2058 Background: Eniluracil (EU) is an irreversible inactivator of dihydropyrimidine dehydrogenase (DPD). EU inhibits DPD dependent 5-fluorouracil (5-FU) catabolism, allowing for oral 5-FU administration with essentially complete bioavailability. Although earlier murine studies suggested an increased antitumor effect when EU was administered before 5-FU, clinical studies used co-administered EU and 5-FU (ratio: 10 EU:1 5-FU) (b.i.d.). These phase III trials demonstrated inferiority compared to a regimen of 5-FU/leukovorin, leading to discontinuation of EU development. We hypothesize that the clinical failure of this EU/5-FU schedule may have resulted from competitive inhibition of 5-FU anabolic (ANA) activation by EU. In this study we examined whether EU could competitively inhibit uridine phosphorylase (UP) or orotate phosphoribosyl transferase (OPRT), the primary ANA enzymes of 5-FU. Methods: The cytoplasmic fraction of human embryonic kidney cells (HEK-293) was used as the source of UP and OPRT. Reverse phase HPLC with radioactivity detection was used to quantify [2-14C]-uracil formation from [2-14C]-uridine (UP activity) and to quantify [6-14C]-FUMP formation from [6-14C]-5-FU (OPRT activity). For UP activity, reaction mixtures consisted of increasing concentrations of EU in phosphate buffer containing 150 μM [2-14C]-uridine. For OPRT activity, reaction mixtures consisted of increasing concentrations of EU in phosphate buffer containing 5 μM [6-14C]-FU and 100 μM benzylacyclouridine (UP inhibitor). Reactions were initiated with addition of UP/OPRT enzyme source and allowed to proceed for 30 min at 37°C. Results: EU displayed dose-dependent competitive inhibition of UP activity (IC50 = 0.375 mM). In particular, the EU/5-FU ratio of 2.5:1 produced approximately 50% inhibition of UP activity. In contrast, EU did not inhibit OPRT activity. Conclusions: This study demonstrates that EU competitively inhibits UP, an important enzyme in 5-FU ANA activation, and suggests that changing the dose ratio and/or increasing the interval between EU and 5-FU administration may be useful in optimizing 5-FU antitumor efficacy. [Table: see text]
Pharmacological inhibition and silencing of classical IKK-NF-κB pathway by siRNA sensitizes cancer cells to doxorubicin
Authors: Tapia M. , Bosch M. , Rolfe M. , Ross J. S. , Gascón P. , Perona R. , Rovira A. , Albanell J. 
Published: March 2020

2059 Background: The IKK/NF-κB pathway (IKK1, IKK2 and NEMO; p65, p50, p52, c-Rel, RelB) is involved in chemoresistance. NF-κB is activable by either a classical or an alternative Ipathway. Here we studied whether NF-κB inhibitors sensitized cells to doxorubicin (dox), and assessed the role of individual IKK or NF-κB subunits by RNA interference [ small interfering RNA (siRNA)] on doxorubicin sensitization. Methods: We used BT474 and MDA-MB453 cells (breast) and HeLa cells (cervix). NF-κB inhibitors were bortezomib (Velcade, a proteasome inhibitor, which inhibits NF-κB by promoting accumulation of the inhibitory Iκ B-α) and a NEMO-Binding-Peptide (NBP, which prevents IKK proteins from complexing). NF-κB DNA binding activity was measured by EMSA. Western blot was used to assess nuclear translocation of individual NF-κB subunits (Iκ B-α, p65, c-Rel, RelB, p50 and p52). BT474 and MDA-MB453 cells were cultured with dox with/without NF-κB inhibitors and viability was assayed by MTT. siRNA was used to transiently down-regulate subunits that act preferentially on the classical NF-κ B (p65, p52, c-Rel, or NEMO) or on the alternative pathway (RelB) in HeLa cells. Chemosensitivity of transfected and control cells to dox was measured by MTT. Results: Dox increased NF-κB activity in BT474 and HeLa cells, as assayed by EMSA and/or by showing Iκ B-α degradation and phosphorylation of p65. Pretreatment of BT474 cells with bortezomib followed by dox resulted in a 30% reduction in cell viability compared to dox alone. Moreover, a 40% higher dox sensitivity was observed when cells were pretreated with a NEMO-Binding-Peptide. Similar data were obtained in MDA-MB453 cells. Transient down-regulation of key members of the classical IKK- NF-κB pathway (p65, p52, c-Rel and NEMO) by siRNA in HeLa cells lead to a 30% increase in dox cytotoxicity. In contrast, silencing of RelB, a key subunit of the alternative pathway, had no effect on dox cytotoxicity under our assay conditions. Conclusions: NF-κB inhibition sensitized cells to dox, implying directly p65, p52, c-Rel and NEMO subunits in chemoresistance, but not RelB. These findings suggest that selective inhibition of the classical IKK-NF-κB pathway is sufficient to improve dox antitumor effects. [Table: see text]
A three schedule phase I trial of CP-4055, weekly and q2 weeks in patients with advanced or metastatic solid tumors
Authors: Delaunoit T. , Raymond E. , Awada A. , Savinelli F. , Culine S. , Rasch W. , Yovine A. , Houédé N. 
Published: March 2020

2067 Background: CP-4055 (ELACYT, ara-C 5’-elaidic acid ester) is a novel cytotoxic agent with broad preclinical antitumor activity in solid tumors. CP-4055 is based on Lipid Vector Technology and has a different cellular uptake compared to ara-C. An initial phase I trial of a day 1–5 q4 weeks (w) schedule (sch) determined a recommended dose of 200 mg/m2/day and showed clinical activity (Aamdal et al, AACR 2005). We report a multiple sch, parallel, dose intensity-guided dose escalation phase I trial, with pharmacokinetic (PK) assessment, intended to determine Maximum Tolerated Dose (MTD). Methods: Patients (pts) with refractory solid tumors received i.v. CP-4055 over 2 hours according to 3 sch: days 1, 8 q3w (Sch 1); days 1, 15 q4w (Sch 2); days 1, 8, 15 q4w (Sch 3). Dose escalation: dose level (DL) 1: 80 mg/m2/w, DL2: 160; DL3: 240; DL4: 320; DL5: 400; DL6: 440; DL7: 520, with standard definitions of dose limiting toxicity (DLT). Results: Since June 2004, 45 pts have been treated in 4 European centers; 3 are still ongoing, 37 discontinued for progressive disease, 3 for refusal, 2 for AE (1 treatment-related grade [gr] 3 paresthesia), trial is ongoing. Demographics: male/female: 27/18; median age 54 (range 35–79); ECOG PS 0/1/2: 19/24/2. Main tumor types: colorectal 6, breast 5, head & neck 5; median 3 lines prior chemotherapy (range 0–5). Exposure: 128 cycles administered, including 5 pts with ≥ 6 cycles. MTD: No DLT has been observed and dose escalation is ongoing. Safety (NCI-CTCAE v3): 45 pts assessable. Principal toxicities by pt (gr 1–2/3): anemia 34/1; nausea and vomiting 29/3; asthenia 24/1; neutropenia 12/2; headache 8/0; thrombocytopenia 3/0. No clear association with sch or DL was observed for this mild/moderate toxicity. There were no dose reductions. PK: ara-U/ara-C AUC ratio exceeds by 3-fold the standard ara-U/ara-C AUC ratio. Efficacy: 41 pts were assessable, 10 pts had stable disease (lasting > 6 months in 4 pts: 2 NSCLC, 1 colorectal, 1 kidney). Conclusions: CP-4055 shows preliminary evidence of activity and is well tolerated up to a dose of 440 mg/m2/w. PK results indicate that a majority of ara-U in plasma originates from intracellular deamination of ara-C from CP-4055, confirming intracellular retention of CP-4055. Accrual is ongoing at the DI of 520 mg/m2/w. [Table: see text]
Phase I study of vorinostat, a histone deacetylase (HDAC) inhibitor, in combination with carboplatin (Cb) and paclitaxel (P) for patients with advanced solid malignancies (NCI #6922)
Authors: Ramalingam S. , Parise R. A. , Egorin M. J. , Argiris A. , Stoller R. , Beattie L. , Aparicio A. , Newman E. M. , Zwiebel J. , Belani C. P. 
Published: March 2020

2077 Background: Vorinostat (SAHA) induces differentiation & growth arrest in a variety of human carcinoma cell lines by inhibiting HDAC. It also enhances the efficacy of chemotherapy. We are conducting a phase I study to evaluate the combination of vorinostat, Cb & P for patients with advanced solid malignancies. Methods: Patients with advanced solid malignancies who were candidates for combination therapy with Cb & P were eligible. Vorinostat was given orally on d 1–14 of each 21-d-cycle, except in cycle 1 when begun on d -4 to facilitate PK studies. Cb & P were given on d 1 of each cycle. Plasma concentrations of vorinostat, & its 2 major metabolites were quantitated with a novel LC-MS/MS assay. Results: Dose level 4 has been determined as the recommended phase II dose (RP2D) for the combination, since the RP2D of single agent vorinostat is 400 mg on this schedule. Observed toxicities included nausea, vomiting, neutropenia & thrombocytopenia, none of which were dose-limiting. Of 9 patients evaluable for response, 4 had PR (1 head & neck cancer, 3 non-small cell lung cancer), & 2 had stable disease. Vorinostat was rapidly absorbed & AUC increased with dose. Vorinostat PK parameters included Tmax 0.5–2 h, t1/2 1.6 ± 0.5 h, & CL/F 5.8 ± 1.7 l/min. Cb & P did not alter vorinostat PK. 4-Anilino-4-oxobutanoic acid was the major, & long-lived, vorinostat metabolite, with Cmax 1.5–7 fold > vorinostat Cmax & t ½ ∼6h. Vorinostat glucuronide Cmax was 1–5 fold > vorinostat Cmax & glucuronide t ½ ∼2h. The RP2D cohort is being expanded to 12 patients to obtain additional clinical & PK data. Conclusions: Vorinostat can be safely administered in combination with Cb & P at their recommended doses. Vorinostat PK are not altered by Cb & P. Promising anti-cancer activity has been noted in patients with advanced NSCLC. Support: U01CA099168–01, U01CA62505, NIH/NCCR/GCRC grant 5M01RR 00056. [Table: see text] No significant financial relationships to disclose.
Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody
Authors: Vonderheide R. H. , Flaherty K. T. , Khalil M. , Stumacher M. S. , Bajor D. L. , Gallagher M. , Sullivan P. , Mahaney J. J. , O’Dwyer P. J. , Huhn R. D. , Antonia S. J. 
Published: March 2020

2507 Background: The cell-surface molecule CD40 plays a critical role in activating antigen presenting cells (APC) and mediates upregulation of costimulatory and MHC molecules, cytokine release, and enhancement of tumor immunity. CD40 is also expressed by 30%-70% of solid tumors, and engagement of CD40 on tumor cells results in apoptosis. CP-870,893 - a fully human and selective CD40 agonist monoclonal antibody - activates human APC in vitro and inhibits growth of human tumors in immune-deficient and immune-reconstituted SCID-beige mice. Methods: A phase 1, dose-escalation study of CP-870,893 was designed to characterize the safety and maximum tolerated dose (MTD) of single doses of CP-870,893 in patients (pts) with advanced solid tumors. CP-870,893 was administered i.v. on day 1 and pts were followed for 43 days. Results: Twenty-nine pts received CP-870,893 in doses ranging from 0.01 to 0.3 mg/kg. Dose limiting toxicity was observed in 2 of 7 pts at the 0.3 mg/kg dose level (venous thromboembolism and grade 3 headache). The MTD was defined as 0.2 mg/kg. The most common adverse event was dose-related cytokine release syndrome (grade 1 to 2). Abnormal lab findings included dose-related and transient elevations in liver transaminases (grade 1 to 2; one pt with grade 3). Modest elevations in serum D-dimer were observed in pts treated at the highest dose levels. Four pts with melanoma (14% of all pts and 27% of pts with melanoma) had objective partial responses (PR) at day 43 evaluation (one PR sustained at 7+ months and 3 unsustained on follow-up scans). Each pt with a PR received 0.2 or 0.3 mg/kg of antibody. To assess pharmacodynamic actions of CP-870,893, flow cytometry was performed on peripheral blood B cells, which uniformly express CD40. CP-870,893 infusion resulted in depletion of peripheral CD19+ B cells (>80% depletion at the highest dose levels). Among B cells remaining in blood, we found a marked, dose-related upregulation of costimulatory and MHC molecules after treatment. Conclusions: Clinical and laboratory findings demonstrate biological activity of CP-870,893. Antitumor activity was observed in 4 pts with melanoma. Further studies of repeated doses of CP-870,893, and CP-870,893 in combination with other antineoplastic agents, are warranted. [Table: see text]