bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rationally designed treatment for solid tumors with MAPK pathway activation
Authors: Karantza-Wadsworth V. , Stein M. , Tan A. , Mehnert J. , Poplin E. , Lin Y. , White E. , DiPaola R. S. 
Published: August 2020

2532 Background: Preclinical studies shed light to the mechanism conferring paclitaxel resistance in solid tumors with active Ras/Raf/Mitogen-Activated Protein Kinase (MAPK) pathway, and determined a molecular mechanism by which addition of the proteasome inhibitor bortezomib abrogated this resistance, enabling tumor regression in animals in vivo. Methods: A Phase I study was contacted to determine the MTD of paclitaxel and bortezomib combinatorial treatment. Sixteen patients with refractory solid tumors were treated with weekly paclitaxel and bortezomib. Six patients had NSCLC; 4, colon cancer; 2, pancreatic; 2, melanoma; 1, breast; 1, ovarian. Patients with baseline neuropathy greater than or equal to Grade 1 were excluded. The starting dose was 40 mg/m2 for paclitaxel and 0.7 mg/m2 for bortezomib. A modified continual reassessment method (MCRM) was used for dose escalation with 3-patient cohorts treated at each dose level. The Target Toxicity Level (probability of DLT at the MTD) was set at 25%. Maximum dose escalation was no more than 75% of the previous SED level, if no Grade 3 hematologic toxicity or DLT were observed. Otherwise, the maximum dose escalation was no more than 50% of the previous SED level. The process continued until SED changes were no more than 10% for two consecutive cohorts. Results: The MTD for the combinatorial treatment was reached at 60 mg/m2 paclitaxel and 1.0 mg/m2 bortezomib. Of 15 evaluable patients, 1 patient with paclitaxel-resistant NSCLC had PR and 5 patients (2, NSCLC; 1, pancreatic; 1, colon; 1, ovarian) had stable disease. Median TTP was 2.3 months (0.8 to 6 months). Three NSCLC patients achieved TTP longer than 5 months. The combination of paclitaxel and bortezomib was relatively well tolerated. Paclitaxel PK parameters are being determined, and paraffin-embedded tumor specimens are being evaluated for MAPK pathway activation by IHC for phospho-ERK. Results will be correlated with clinical response. Conclusions: The MTD for the proposed combinatorial treatment is 60 mg/m2 for paclitaxel and 1.0 mg/m2 for bortezomib, and is relatively well tolerated. Combination of paclitaxel with bortezomib is effective in taxane-resistant NSCLC, and worthy of further investigation. No significant financial relationships to disclose.
TRAP1, a novel antiapoptotic gene responsible for multidrug resistance in human colorectal carcinoma cells
Authors: Landriscina M. , Costantino E. , Maddalena F. , Piscazzi A. , Fersini A. , Calise S. , Esposito F. 
Published: August 2020

2541 Background: TRAP1 has been recently described as a component of a mitochondrial pathway selectively up- regulated in tumor cells which antagonizes the proapoptotic activity of cyclophilin D and is responsible for maintenance of mitochondria integrity, thus favoring cell survival. Interestingly, novel TRAP1 antagonists cause sudden collapse of mitochondrial function and selective tumor cell death, suggesting that this pathway may represent a novel molecular target to improve anticancer therapy. Furthermore, we recently observed that TRAP1 is significantly up-regulated in osteosarcoma cells adapted to growth in mild oxidizing conditions and this correlates with a phenotype more resistant to H2O2-induced DNA damage and apoptosis. This evidence prompted us to investigate the role of TRAP1 as being responsible for multi-drug resistance in human colorectal cancer. Methods and Results: The evaluation of TRAP1 expression by immunoblot and quantitative RT-PCR analysis in a series of 26 human colorectal carcinomas allowed us to observe up-regulation in 17/26 tumors. Accordingly, TRAP1 protein levels were increased in HT-29 colorectal carcinoma cells resistant to 5-fluorouracil, oxaliplatin and irinotecan. Interestingly, HT-29 colorectal carcinoma and Saos-2 osteosarcoma cells transfected with TRAP1 gene exhibited a phenotype resistant to 5-fluorouracil-, oxaliplatin- and irinotecan-induced apoptosis, evaluated by MTT incorporation analysis and annexin V staining. Consistently, the transfection of a dominant negative N-terminal deletion mutant of TRAP1 as well as the inhibition of TRAP1 activity by the TRAP1 ATPase antagonist, shepherdin, increased the sensitivity to apoptosis induced by 5-fluorouracil, oxaliplatin and irinotecan in wild type HT-29 colorectal carcinoma cells and in HT-29 cells resistant to the single agents. Conclusions: These results suggest that the increased expression of TRAP1 in human colorectal carcinomas could be part of a pro-survival pathway responsible for multidrug resistance. Thus, targeting TRAP1 may represent a novel strategy to improve the efficacy of anticancer agents in colorectal cancer. No significant financial relationships to disclose.
Evaluation of renal function and carboplatin clearance in Japanese cancer patients
Authors: Shimokata T. , Yasuda Y. , Hamada A. , Kawada K. , Hasagawa Y. , Ando Y. 
Published: August 2020

2556 Background: There is a close relationship between carboplatin clearance and glomerular filtration rate (GFR). Calvert developed the following formula for the dosing of carboplatin: dose (mg) = target area under the concentration versus time curve (AUC, mg ml-1 min) × [GFR (ml min-1) + 25]. However, this formula has not been evaluated in Japanese population. In this study, we prospectively evaluated renal function and carboplatin clearance in Japanese cancer patients. Methods: GFR was measured by inulin clearance before chemotherapy. The dose of carboplatin was determined by Calvert's formula using adjusted 24-h creatinine clearance (Ccr) by adding 0.2 (mg dl-1) to serum creatinine. A pharmacokinetic study was performed during the first cycle of the chemotherapy. Blood samples were obtained at 10 points within 24 hours. The observed AUC of carboplatin and the observed carboplatin clearance were calculated. Results: Inulin clearance was estimated in 28 cancer patients. Estimation of renal function with adjusted 24-h Ccr and estimated GFR equation (eGFR) were unbiased [mean prediction error (MPE) = -2.3%, 5.2% respectively] and acceptably precise [root mean squared error (RMSE) = 23.7%, 25.7% respectively], whereas non-adjusted Ccr and the Cockcroft-Gault equation overestimated GFR (MPE = 24.2%, 12.5% and RMSE = 37.2%, 32.7% respectively). Observed carboplatin clearance was proportional to GFR in range of renal function in this study (r = 0.903) and we verified the linearity. Non-renal clearance of carboplatin in Japanese cancer patients was 5.6 (ml min-1). Conclusions: 24-h Ccr adjusted by adding 0.2 (mg dl-1) to serum creatinine and eGFR were useful in assessing renal function for carboplatin dosing. It was suggested that non-renal clearance of carboplatin in Japanese cancer patients was less than 25 (ml min-1). No significant financial relationships to disclose.
A phase I study of enzastaurin (Enz) combined with pemetrexed (Pem) in advanced non-small cell lung cancer (NSCLC)
Authors: Takahashi T. , Yamamoto N. , Murakami H. , Ohe Y. , Kunitoh H. , Nokihara H. , Koshiji M. , Tamura T. 
Published: August 2020

2572 Background: Enz is an oral serine-threonine kinase inhibitor that is designed to suppress tumor growth through PKC and PI-3 kinase/AKT. Pre-clinical data shows Enz's synergistic activity with Pem in many cancer cell lines including NSCLC. This phase 1 study is to evaluate the safety, pharmacokinetics (PK), and clinical activity of two schedules of Enz combined with Pem in patients (pts) with previously treated advanced NSCLC. Methods: An oral daily dose of 500 mg Enz was given once daily (QD) in cohort 1 or twice daily (BID) in cohort 2 in combination with 500 mg/m2 Pem on day 1 in repeated 21-day cycles. Cycle 1 started with a 7-day Enz lead-in treatment that preceded Pem administration: a loading dose of 1125 mg on day 1 followed by 500 mg total daily dose on days 2–7. Blood samples for PK evaluation were collected on day 2 of cycle 1 (following loading dose) and day 1 of cycle 2 (steady- state). Samples were analyzed for Enz, Pem, and its active metabolites. Results: 12 pts (8 males, 4 females; ECOG PS 0–1) with median age of 62 (49 - 74) were enrolled into this study and completed safety evaluation for cycle 1: 8 pts with adenocarcinoma, 3 pts with squamous cell carcinoma, and one with other. All pts had received prior platinum-based chemotherapy. Total analyte concentrations (sum of Enz and its metabolites) reached steady-state by day 8 of dosing. Total analyte mean steady-state average concentrations (%CV) following QD and BID dosing were 2850 nmol/L (53.5%) and 3420 nmol/L (39.5%), respectively. Exposures following loading dose were within the range of concentrations seen at steady-state. Enz dosing regimen (QD or BID) did not alter Pem PK. One dose-limiting toxicity (Grade 3 QTc prolongation) occurred 1 day after the Enz loading dose in cohort 1. Grade 3/4 toxicities occurring in 6 pts included leukocytopenia, neutropenia (3 pts each), increased ALT, and increased AST (2 pts each). To date, 1 pt achieved PR and 6 pts achieved SD. 5 pts received more than 10 cycles of treatment without disease progression; 4 of these pts are still on therapy. Conclusions: Both schedules of Enz in combination with Pem are well tolerated and clinically active in pts with advanced NSCLC. [Table: see text]
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of the selective aurora A kinase (AAK) inhibitor MLN8054 in patients (pts) with advanced solid tumors
Authors: Macarulla T. , Rodríguez-Braun E. , Tabernero J. , Roselló S. , Baselga J. , Lee Y. , Manfredi M. , Liu H. , Fingert H. , Cervantes A. 
Published: August 2020

2578 Background: MLN8054, a first-generation, selective AAK inhibitor, induces chromosome alignment and segregation defects during mitosis, leading to cell death (Hoar et al, MolCellBio 2007;27:4513). This phase I trial examined the safety, PK, and PD of MLN8054 administered orally to adult pts with advanced solid tumors. Methods: Pts received increasing oral doses of MLN8054 until dose-limiting toxicity (DLT) in the first cycle was seen in ≥2 of 3–6 pts in a cohort. Two cohorts received 10 and 20 mg once daily (QD) on d1–5 and d8–12 of 28d cycles. Benzodiazepine-like adverse effects (somnolence) associated with chemical structure and presumably unrelated to AAK inhibition were observed with QD dosing in another Phase 1 study (Dees et al, EJC Suppl 2008;6[12]:91), so subsequent cohorts in this trial were treated with 25, 35, 45, 55, 60, 70, and 80 mg/d in four divided doses (QID) on d1–14, with the largest dose at night. To manage somnolence, methylphenidate 5–15 mg was permitted with daytime doses in the 45–80 mg cohorts. Results: 43 pts received MLN8054 (median 1 cycle [range 1–10]). Dose escalation stopped at 80 mg/d due to DLTs including G3 somnolence (n=1) and G3 transaminitis (n=1). G2 oral mucositis (n=1), which may signal target-related toxicity, was observed first at 80 mg/d, a dose considered to be above the MTD. In PK analyses, MLN8054 was absorbed rapidly (Tmax = 1–2h) and terminal half-life was 30–40h, presenting a linear exposure-dose profile. In PD analyses, MLN8054 at higher doses increased mitotic count in skin and tumor biopsies and reduced chromosome alignment and spindle bipolarity in the mitotic cells in tumor biopsies, outcomes consistent with AAK inhibition. Stable disease (range 4–9 cycles) was observed in 3 pts (colorectal, non-small cell lung, and melanoma). Conclusions: MLN8054 was absorbed rapidly with a long half-life; PD findings supported MLN8054 inhibition of AAK at higher doses. Dosing for 14d of a 28-d cycle was feasible, but off-target DLTs limited dose escalation before mechanism-based toxicity was seen. MLN8237, a second-generation AAK inhibitor designed with greater mechanistic potency and to minimize benzodiazepine effects, is now in clinical trials. [Table: see text]
A phase I pharmacokinetic study of a liposomal formulation of paclitaxel administered weekly to Asian patients with solid malignancies
Authors: Lim W. T. , Leong S. S. , Toh C. K. , Ang C. S. , Wong N. S. , Tan E. H. , Chowbay B. 
Published: August 2020

2581 Background: Genexol-PM is a sterile, lyophilized polymeric micellar formulation of paclitaxel which is devoid of Cremophor EL and hence is more tolerable and less toxic. This phase 1 study sought to determine the maximum tolerated dose and the pharmacokinetic profile of Genexol-PM in Asian cancer patients with solid malignancies. Methods: Patients (N=35) refractory to previous chemotherapy were enrolled in a phase 1, open-label, dose-escalating study to assess safety, tolerability ad pharmacokinetics of Genexol-PM administered as a 1h infusion on a weekly basis for 3 weeks followed by a resting week. The starting dose was 80mg/m2. Cohorts of 1–6 patients were treated at 100, 120, 140, 160, 180 and the maximum administered dose was 200 mg/m2. Results: The median age was 56 years (range: 39 - 67 years) and two thirds of the enrolled patients were male (67%). Twenty-three patients (96%) had received prior chemotherapy, including eleven patients (46%) who had previously received taxane-based chemotherapy. The majority of patients had lung, nasopharyngeal and breast cancers. DLT was reached at 200 mg/m2. The MTD was 180 mg/m2. Grade 3 granulocytopenia was common in patients receiving Genexol-PM at doses of 120 mg/m2 or higher in the first cycle. The most common grade 3 non-haematologic adverse events in cycle 1 were fatigue, myalgia and neuropathy and occurred mainly at dose level 7 (200 mg/m2) in 4%, 4% and 8% of the patients. Five (21%) patients had partial response, 9 (38%) had stable disease and seven (29%) patients had disease progression. The pharmacokinetics of Genexol-PM displayed dose-proportionality, with both Cmax and AUC0-∞ values increasing by approximately 4- and 3-fold as the dose of Genexol-PM was increased from 80mg/m2 to 200mg/m2 with no significant change in clearance. The median total-body clearance of Genexol-PM for all patients was 43.9 L/hr. Conclusions: The weekly regimen of Genexol-PM was found to be well-tolerated and responses were observed in patients with refractory tumours, including patients who had failed taxane-based chemotherapy previously. No significant financial relationships to disclose.
Comparison of the immunogenicity of Montanide ISA 51 adjuvant and cytokine-matured dendritic cells in a randomized controlled clinical trial of melanoma vaccines
Authors: O'Neill D. W. , Adams S. , Goldberg J. D. , Escalon J. B. , Rolnitzky L. M. , Cruz C. M. , Angiulli A. , Old L. , Pavlick A. C. , Bhardwaj N. 
Published: August 2020

3002 Background: Dendritic cell (DC) vaccines have been widely used in clinical trials to treat cancer. However, no study has compared the immunogenicity of the most commonly used DC type (cytokine-matured, monocyte-derived DCs) to more traditional vaccine adjuvants. We performed a randomized controlled trial comparing the immunogenicity of cytokine-matured DCs loaded with 6 HLA-A2-restricted peptide antigens and a foreign protein, KLH, to a vaccine containing the same antigens emulsified in the mineral oil adjuvant Montanide ISA 51 VG. Methods: 51 HLA-A2+ patients with resected stage IIb-IIIc melanoma were randomized to receive DCs (25 patients) or Montanide (26 patients). DCs were differentiated from autologous blood monocytes with IL-4 and GM-CSF, then matured with IL- 1β, IL-6, TNFα and PGE2. 18 million DCs were given i.d. every 4 weeks x 4, and immune responses analyzed (MHC multimers, T cell proliferation, cytokine secretion, antibodies). A 3-fold increase over baseline was considered a response. Results: Both vaccines were well tolerated. Immunogenicity was significantly greater with Montanide, as demonstrated by response rates to Flu, Melan-A and NY-ESO-1 peptides by IFNγ ELISPOT. Similar results were obtained by MHC multimer staining, with higher response rates seen using pre-sensitized assays. T cell proliferation to KLH was seen in both arms (90% DC, 100% Montanide), but the magnitude of response was significantly higher for Montanide (36-fold vs. 14-fold increase over baseline, p=0.002, Wilcoxon). KLH-specific CD4+ T cells that produced IFNγ, TNFα and IL-2 were seen only with Montanide, and all Montanide patients, but only 5% of DC patients, developed antibodies to KLH (p<0.001, Fisher's). Conclusions: A water-in-oil vaccine adjuvant, Montanide ISA 51, was significantly more immunogenic than DCs. Future studies of new DC vaccines should compare DCs to standard adjuvants to determine if their added difficulty and expense are truly warranted. [Table: see text] [Table: see text]
Phase I study of intranodal direct injection of adenovirus encoding recombinant CD40-ligand (Ad-ISF35) in patients with chronic lymphocytic leukemia
Authors: Castro J. E. , Sandoval-Sus J. D. , Melo-Cardenas J. , Darrah D. , Urquiza M. , Pakbaz R. S. , Prussak C. E. , Kipps T. J. 
Published: August 2020

3003 Background: Transduction of chronic lymphocytic leukemia (CLL) cells with replication-defective adenovirus (Ad) encoding a genetically engineered, membrane-stablized CD154 (ISF35) converts transduced, and “bystander” non-transduced, CLL cells into proficient antigen presenting cells that can induce immunity against autologous leukemia cells. Preclinical studies demonstrated that direct injection of Ad-ISF35 into lymphoma nodules can induce potent anti-lymphoma immune responses in test animals, capable of eradicating lethal tumors at distal sites and protect against recurrent disease upon subsequent re-challenge with syngeneic tumor. Methods: We conducted a phase I study on 15 patients to evaluate the safety of intranodal direct injection (IDI) of Ad-ISF35. Pts, ages 45–71 yrs, with rapidly progressive disease (median CLL doubling time of 3.7 months) each received a single ultrasound guided IDI of 1 to 30 x 1010 Ad-ISF35 viral particles in 4 different dose cohorts. Results: IDI of Ad-ISF35 was well-tolerated and effective in inducing systemic responses. Some pts had grade ≤ 2 injection-site erythema, pain and/or swelling, or flu-like symptoms. Some pts in the highest-dose cohorts had transient, asymptomatic grade 3/4 hypophosphatemia. No long-term (≥ 6 wk) adverse effects were observed. Although there was no evidence for dissemination of Ad-ISF35 beyond the injected lymph node, IDI of Ad-ISF35 induced blood CLL cells to express death receptors, pro-apoptotic proteins, and immune co-stimulatory molecules similar to those induced on “bystander” CLL cells co-cultured with Ad-ISF35 transduced cells in vitro. Importantly, IDI of Ad-ISF35 resulted in significant reductions in blood leukemia cell counts and a median reduction of 53.2% (range 25–75.4%) in the size of lymph nodes and/or spleen, which was durable (≥ 4 months) in 9 pts. Despite aggressive disease prior to treatment, the median treatment-free survival was 5.3 months and 3 pts have yet to require additional treatment after 1-year follow-up. Conclusions: Single IDI of Ad-ISF35 was safe and effective in inducing systemic biologic and clinical responses in pts with CLL. IDI of Ad-ISF35 might be effective in the treatment of CLL and related lymphomas. [Table: see text]
Survival update from a multicenter, randomized, phase III trial of vitespen versus observation as adjuvant therapy for renal cell carcinoma in patients at high risk of recurrence
Authors: Wood C. G. , Srivastava P. , Lacombe L. , Gorelov A. I. , Gorelov S. , Mulders P. , Zielinski H. , Teofilovici F. , Isakov L. , Escudier B. 
Published: August 2020

3009 Background: Vitespen (formerly HSPPC-96) is a novel, autologous, heat shock protein (gp96)-peptide complex vaccine. The survival registry is investigating long-term efficacy of vitespen in renal cell carcinoma (RCC) patients at high risk for recurrence postnephrectomy. Methods: Eligible patients were enrolled and active in Antigenics’ C-100–12 phase III protocol, with a last survival status of alive at study end. Patients randomized in C-100–12 (1:1, vitespen vs. observation) had AJCC stage I (T1b), II (≥5 cm; Fuhrman grade 3/4), stage III, or stage IV (M0) RCC, ≥25% clear cells, ECOG performance score 0/1 and ≥7 g viable tumor tissue for vaccine production. The registry's primary objective is to assess OS. Registry patients are contacted every 6 (no recurrence) or 3 (upon recurrence) m, for a total of 3 y from final C-100–12 data cutoff. Results: Upon C-100–12 termination, 513 of 728 patients were eligible for follow-up. Currently, 306/513 (60%) patients are in the registry database; 207 patients are being contacted. The cohort of 306 patients is well balanced by C-100–12 randomization arm: (59.8% vitespen, 59.5% observation). Formal statistical analyses are in process. Descriptively, updated OS data show a favorable trend in the vitespen arm vs. observation in all analysis sets, especially among patients with earlier-stage disease (stage I/II high grade; n = 118) or at intermediate risk for recurrence (stage I/II high grade, III T1, T2, T3a, low grade; n = 184 ), with 13/125 (10.4%) vs. 21/115 (18.3%), and 18/184 (9.8%) vs. 33/178 (18.5%) deaths reported in the vitespen and observation arms, respectively. Conclusions: The registry provides an opportunity to confirm whether the emerging survival advantage demonstrated at the data cutoff for the C-100–12 trial improves with prolonged follow-up. Formal statistical analyses are ongoing; data available to date show continuing signals of clinical benefit associated with vitespen treatment in patients with better prognostic factors. [Table: see text]
A phase I study of the anti-natural killer inhibitory receptor (KIR) monoclonal antibody (1–7F9, IPH2101) in elderly patients with acute myeloid leukemia (AML)
Authors: Vey N. , Bourhis J. , Dombret H. , Bordessoule D. , Prebet T. , Charbonnier A. , Squiban P. , Damholt B. , Blaise D. , Olive D. 
Published: August 2020

3015 Background: The outcome of the majority of patients with AML remains poor, especially in the oldest patients. Allogeneic SCT is a curative approach for AML. In some models, it has been shown that KIR mismatch is important for the anti-leukemic effect of the graft, most probably through unleashed NK cells towards AML blasts, as suggested by enhanced in vitro NK lytic activity of KIR-HLA mismatched donor NK against recipient blasts. To mimic this effect with a pharmaceutical agent, a fully human IgG4 anti-KIR mAb specific for KIR2DL1/2/3 (HLA-C specific KIRs) was generated. We present the results of the first-in-human phase I trial of this agent in patients with AML in complete remission (CR). Methods: Patients aged 60–80 years with non promyelocytic AML in first CR following induction and 1–6 cycles of consolidation chemotherapy, normal renal, and hepatic functions, KIR-expression on patient NK-cells and who signed informed consent were eligible.Dose escalation (0.0003, 0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg) was studied using a 3+3 scheme. Pharmacokinetic (PK) and circulating cytokines (MIP1β, TNF) were measured by ELISA. KIR occupancy and activation markers (CD69) were monitored by flow cytometry. Results: To date, inclusion has been completed until 1mg/kg cohort. Data of the first 15 patients (end of 0.3 mg/kg cohort) are available. No dose limiting toxicity has been observed. Side effects that could be related to drug administration were mild and transient. The first dose level resulted in a transient KIR occupancy ranging from 20 to 50%. PK values were then in line with modelling data, resulting at 0.3 mg/kg in a Cmax= 6350 ± 504 ng/mL, >80% KIR saturation for one week, and desaturation in the following week. As expected for an IgG4, NK cell numbers were unaffected by the treatment. Upregulation of CD69 on NK cells and concomitant increases in TNF and MIP1b circulating cytokines were observed in some patients at the highest doses (0.075, 0.1, 0.3 mg/kg) but a dose dependency has not been reached yet. Conclusions: Anti-KIR treatment is safe and well tolerated to date. At the 0.3mg/kg dose, MTD has not been reached, but a one week receptor blockade and signs of NK activation were observed. [Table: see text]