bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of tolerability, safety, and pharmacokinetics of INO-1001 plus temozolomide (TMZ) in patients with unresectable stage III/IV melanoma
Authors: Wang C. , Bedikian A. Y. , Kim K. , Papadopoulos N. E. , Hwu W. , Hwu P. 
Published: March 2020

12015 Background: TMZ, an orally bioavailable cytotoxic agent with the same active metabolite as DTIC, is a commonly used for treatment (Rx) of metastatic melanoma (MM). It causes methylation of the O6 position of guanine. Unrepaired O6-methylguanine pairs with thymine rather than guanine and activates DNA mismatch repair. Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear protein that functions as DNA damage sensor. PARP inhibitors increase TMZ cytotoxicity by causing interruption of the repair process of N-methylpurines generated by TMZ. INO-1001 (INO), an ultrapotent PARP inhibitor has been tested in combination of TMZ and found to be safe and well tolerated. Here we report the initial results of Phase Ib clinical trial. Methods: Patients (pts) with unresectable stage III/IV MM with no prior Rx with TMZ or DTIC were treated with INO given IV q 12 hours for 10 doses at the starting dose of 100mg/dose. The doses of INO are planned to escalate from 100 to 200mg/dose and then to the maximum dose of 400 mg/dose in successive groups of 3–6 pts. TMZ is taken po within 2 hours of the second dose of INO at the dose of 200mg/m2/day for 5 days. Blood samples are collected for pharmacokinetics study during cycle 1. The Rx cycles are repeated q 4 weeks and tumor responses are evaluated q 8 weeks. Results: 6 pts with median age 63 (range 55–67) years and median PS Zubrod 1 (range 0–2) have been treated. Initially 3 pts were treated with INO at the dose level of 100mg. One pt with a BSA of 2.76 had grade 4 neutropenia and thrombocytopenia with Rx cycle 1. TMZ dose was not adjusted to her ideal body weight. Subsequently, the dose of TMZ was reduced by 25% and the following 2 cycles were tolerated well. 3 more pts were entered at the dose level 1. To date, a total of 8 cycles of Rx have been completed. All except for the cycle mentioned earlier were tolerated well. 3 pts were evaluated for response, 1 pt had objective tumor regression, 1 had stable disease and 1 had tumor progression. The non-hematologic side effects were mild and are mostly related to TMZ. Conclusions: TMZ-INO combination is fairly well tolerated. A complete report will be presented. No significant financial relationships to disclose.
Final results of a phase I study using oral temozolomide (TMZ) daily for 14 days with weekly paclitaxel in patients (pts) with advanced malignancies
Authors: Figueroa J. A. , Tafur I. , Close D. , Cardona P. , Cruz J. , Quick D. , Shalaby I. , Dinunno L. , Ortiz P. 
Published: March 2020

12020 Background: TMZ is an alkylating agent with activity in a variety of neoplasms. The optimal schedule of administration for TMZ has not been established and only a few studies have studied it in combination with other agents. Repair of TMZ-induced DNA damage is associated with the activity of O-6 alkylguanine-DNA-alkyl transferase (AGT). Preclinical and clinical data indicate that prolonged exposure to TMZ results, not only in enhanced DNA alkylation, but also in depletion of AGT. This serves as the rationale to study TMZ using protracted schedules. Methods: The aim of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of oral TMZ given daily for 14 days with weekly paclitaxel in pts with advanced cancers. Forty-five pts received 136 cycles of TMZ at escalating doses (50, 75, 100, 125 and 150 mg/m2/day × 14 days) plus paclitaxel at 80 mg/m2 on days 1, 8, and 15. Pts were stratified as lightly (LP) or heavily (HP) pretreated and MTD defined as the dose level (DL) at which 1/6 patients developed DLT. Results: Twenty-four LP patients were treated at 5 DLs with all but one evaluable for toxicity. Febrile neutropenia and grade 3 thrombocytopenia were the DLTs. MTD in this group was the 125 mg/m2/day level. Twenty-six HP were treated at 5 DLs and 21 were evaluable for toxicity. Febrile neutropenia and grade 3 thrombocytopenia were the DLTs. MTD for this group was also 125 mg/m2/day. Thirty-eight (84%) pts were evaluable for response after 2 cycles of therapy. Three (8%) pts had a partial response (lung, lymphoma, ependymoma), 20 (53%) remained stable and 15 (39%) developed disease progression. Six (16%) pts remained stable for 6 cycles or more (2 sarcomas, 2 lung, 1 pancreas, 1 glioblastoma). Conclusions: We concluded that combining oral TMZ at a dose of 125 mg/m2/day for 14 days with standard-dose weekly paclitaxel is safe in both HP and LP pts. [Table: see text]
The influence of partial hepatectomy (PH) on pharmacokinetics of docetaxel (D) in sprague-dawley rats (SDR) with experimental mammary neoplasm models (EMNM)
Authors: Demirkan H. B. , Yilmaz O. , Çoker C. , Gümüstekin M. , Batu J. , Bülbül M. , Canda T. , Alakavuklar M. 
Published: March 2020

12021 Background: Docetaxel (Taxotere-Aventis) is used in the treatment of breast, lung, head and neck, prostate and ovarian cancers. Recently, PH for isolated hepatic metastases of breast cancer has been reported in Japan and France. PH is an experimental model of hepatic insufficiency. Therefore we aimed to study the influence of PH on pharmacokinetics of D in SDR with EMNM. Methods: After the approval of Local Ethical Commitee on Laboratory Animal Researches, 40 female 50-day-old SDR were injected with 50 mg/kg body weight N-nitroso-N-methylurea (NMU) in 09% NaCL solution intraperitoneally. 5 female 50-day-old SDR were only injected with 09% NaCL solution intraperitoneally. After 6-months follow-up period for the formation of EMNM, 8 rats in the Group D+H were hepatectomized partially. Baseline venous blood samples were taken. 24 hours after PH, 6 rats were alive. There were 8 rats in the Group D (without hepatectomy). Before chemotherapy and 1 hour after intravenous infusion of 5 mg/kg body weight D, blood samples were taken for biochemical analyses from both groups. 5., 15., 30. minutes and 1., 2., 4., 5. hours after D infusion, arterial blood samples were taken for pharmacokinetic analyses. Biochemical and Pharmacokinetic tests (BPT) were done by auto-analyzer Hitachi Modular Analytic and HPLC (High Performance Liquid Chromatography) respectively. Area under the concentration-time curve [AUC (0–60)] was determined for each group. Statistical analyses were done by SPSS 11.0 for Windows at the 5% significance level. Results: PH affected liver functions and serum albumin levels negatively (p = 0.028). Although D infusion didn’t affect serum ALT and bilirubine levels, low serum albumin was detected 1 hour after chemotherapy in both groups (p= 0.028 and p= 0.030). AUC(0–60) of plasma D in hepatectomized rats were greater than the other group (p = 0.015). Conclusion: During the treatment of cancer patients in posthepatectomy period with taxanes (D), dose adjustment must be done. In both groups, statistically significant low serum albumin after D infusion may be as a result of decreased intertitial fluid pressure, albumin extravasation and edema formation caused by taxanes. Physiological and preventive studies are needed. No significant financial relationships to disclose.
Implication of clinical and paraclinical covariates in the pharmacokinetics of high dose MTX (HD-MTX) in patients with osteosarcoma
Authors: Dupuis C. , Mercier C. , Salas S. , Yang C. , Deville J. , Balti M. , Ciccolini J. , Iliadis A. , Baciuchka M. , Duffaud F. , Favre R. 
Published: March 2020

12022 Background: Methotrexate (MTX) is a mainstay in the treatment of ostosarcoma. MTX is characterized by a narrow therapeutic window, combined with high intra- and inter-patient variabilities. In our institute, safe administration of high dose MTX is ensured by using bayesian, adaptive dosing with feedback strategy. In patients with osteosarcoma, up to 20g/patient MTX is administred following an 8h infusion. From the 6th hour, the dose is tailored according to individual pharmacokinetics parameters, determined in real-time from two early sampling times (T3.5, T4.5) and a reference population. This method enables accurate adjustment of most patients around a target Cend of 10−3 M/L. Still, 15–20% of the patients show reduced MTX elimination rate, thus leading to an overlasting hospitalization time with folate rescue required to prevent severe toxicities. In this work, we studied the relevance of clinical or pareaclinical covariates likely to be associated with the MTX clearance so as to identify patients at risk of impaired elimination with subsequent increase in iatrogeny. Methods: This retrospective study was performed on 49 patients treated with HD-MTX. Population PK parameters were computed using Apis and NonMem routines. The second objective was to predict for how long MTX plasma concentration would remain above 0.2 μM/L, the threshold associated with toxicity, upper which folinic acid is required. Finally, simplified sampling strategy for folate rescue protocol was developed. Results: two covariates (creatinemia and ALAT) have been identified as being correlated with MTX clearance. Besides, simulation of the 0.2μM/L threshold reaching showed that it was possible to predict accurately the time most patients can leave the hospital safely. This, would have led to reduce the hospitalization stay by at least one day in 25% of the patients, thus optimizing their life quality while being cost-effective. Conclusions: in this study, we showed that high dose MTX can be administred safely using an adaptive dosing with drug monitoring strategy. Besides, modelling of MTX PK parameters leads to an accurate estimation of the elimination pattern of this drug, thus enabling a planification of the time patients leave the hospital. No significant financial relationships to disclose.
Phase II study of docetaxel (T), carboplatin (C), and gemcitabine (G), in advanced tumors of unknown primary site
Authors: Mel Sr. J. R. , Provencio M. , Balañá C. , López-Vega J. M. , Casado A. , Segura A. , Cervera J. M. , Martí J. L. , Munárriz J. , Arranz F. 
Published: March 2020

12028 Background: Treatment of tumors of unknown primary site is still a challenge nowadays. D, C and G have shown high activity in solid tumors. We designed this study to evaluate activity and toxicity profile of a combination of these three drugs, according a protocol previously tested in lung cancer (Pectasides D, et al. J Clin Oncol 1999). Methods: Patients with histological diagnosis of solid tumor of unknown primary site, age ≥ 18 years old, ECOG PS ≤ 2 and adequate bone marrow, renal, hepatic and cardiac functions, were included. Treatment consisted in (d1): C AUC = 5 and G 800 mg/m2 IV; and d8): D 75 mg/m2 and G 800 mg/m2 IV, with G-CSF support. Courses were repeated every 28d for a maximum of 8 cycles, unless progression, unacceptable toxicity or consent withdrawal, whichever comes first. Results: Sixty-three patients have been included: median age was 66 years old (28–90), 89.6% of patients had ECOG PS 0–1. Tumor histology included adenocarcinoma (65.1%), undifferentiated (17.5%) and carcinoma (7.9%) or large-cell carcinoma (1.6%). Main metastatic sites were lung (49%), liver (44%), lymph nodes (41%) and bone (25%). Previous treatments included surgery (20.6%), chemotherapy (1.6%) and radiotherapy (12.7%). Treatment: 296 cycles (median 6, range 1–11) were administered. Median relative dose intensity was 96% for D, C and G. Efficacy: 8 patients achieved CR and 15 PR, resulting in an overall response rate of 36.5% (95% CI: 24.6–48.4%). Main grade III/IV toxicity per patient were asthenia (19%), diarrhea (18%), mucositis (11%), vomiting (10%), nausea (6%), thrombocytopenia (38%), neutropenia (24%), leucopenia (19%) and anemia (13%). Febrile neutropenia was observed in 2 patients (3%). Fourteen patients (22.2%) experienced severe toxicity: 9 of them were dropped out and 5 were toxic deaths (2 sepses, 2 pancytopenia and 1 pulmonary thromboembolism). Median time to treatment failure was 6.0 months (95% CI: 4.8–7.1), median TTP was 10.8 months (95% CI: 8.6–13.0) and median OS was 11.8 months (95% CI: 9.4–12.3), with a median follow up of 10.8 months. Conclusions: Despite the combination of D, C and G shows high activity in tumors of unknown primary site, its toxic death rate is > 5%. Thus, our group is working no longer with such a triplet combination. No significant financial relationships to disclose.
Immunological effects after an adoptive cellular immunotherapy with reactivated autologous memory T-Cells from bone marrow
Authors: Schuetz F. , Rom J. , Ehlert K. , Schirrmacher V. , Schneeweiss A. , Sohn C. , Beckhove P. 
Published: March 2020

12502 Tumor-reactive CD4 and CD8 memory T cells (MTC) can be found in bone marrow (BM) of the majority of primary and metastatic breast cancer patients. In xenotransplant mouse models these cells, upon specific re-activation ex vivo, mediated efficient rejection of autologous breast tumors suggesting that the polyclonal natural MTC repertoire possesses therapeutic potential. In order to clinically exploit these anti-tumor capacities we treated 11 advanced metastasized breast cancer patients with autologous, tumor-reactive, reactivated MTC of BM in a phase-1 trial. Activation of T cells was done by MCF-7 lysate pulsed dendritic cells (DC). After reactivation both, T cells and pulsed DC were injected once intravenously. Peripheral blood was drawn on day 0, 1, 7, 14, 28. BM-re-aspiration was done on day 28 and 84. While TAA-reactive memory T cells were absent in the peripheral blood (PB) before therapy, 5 from 11 patients (=responders) showed TAA-specific PB T cell reactivity 7 days after therapeutic cell application suggesting a massive proliferation and mobilization into the blood of TAA-reactive T cells in these patients. A comparison of responders to adoptive cellular immunotherapy with non-responders revealed differences in the numbers of therapeutic cells that could be generated ex vivo and in the decreased frequency of tumor-reactive MTC in responders’ BM on days 28 and 84 which could be expained by a mobilization due to in situ activation by co-transferred DCs or due to local or systemic cytokine signals by transferred, activated T lymphocytes. Such effect might have contributed to the high numbers of circulating TAA-reactive T cells observed 7 days after the transfer. Furthermore we observed different concentrations of IL-4, IL-10, TNF-α, and INF-γ in PB and BM between the two groups leading to the hypothesis of a polarization in T cell responses (T1 type in responders vs T2 type in non-responders). No significant financial relationships to disclose.
Tandem HD-chemotherapy and myeloablative radioimmunotherapy with 131I-anti-CD20 rituximab in relapsed and refractory B-cell lymphoma: Results of a phase II study of the German RAIT Study Group
Authors: Hohloch K. , Wulf G. , Jung W. , Stitz E. , Meller J. , Glass B. , Truemper L. , Griesinger F. 
Published: March 2020

13007 Background: Radioimmunotherapy has been shown to be effective in CD20 + B-cell lymphomas. Both non-myeloablative as well as myeloablative regimens have been employed for low grade and high grade lymphomas with impressive response rates and remission durations. Recently, the Press group and our group published data on myeloablative 131-I-anti-CD20 RAIT with high response rates and favourable long term survival especially in follicular lymphomas and transformed FL. Therefore, a phase II study is currently being done within the German Radioimmunotherapy Group, interim analysis data are presented. Methods: Patients were to receive R-Dexa-BEAM, followed by BEAM and HD-RAIT 2–6 months after BEAM. 131-I-Rituximab was administered with a maximum kidney and lung dose of 25 Gy. Sample size was calculated to be 16 to evaluate toxicity and feasibility of the tandem approach as primary endpoint. Results: 16 pts with relapsed (14) or primary refractory (2) B-cell lymphomas (FLI,II: 4pts; DLBCL: 4pts (all early relapses); transformed FL: 6 pts; MCL:1 pt, marginal zone lymphoma: 1 pt) were treated with 1 (15 pts) or 2 cycles (1 pt) of R-Dexa-BEAM. 13/16 pts achieving PR (5) or CRu (8) were treated with BEAM, 2 pts with PD and 1 with subdural hematoma were drop outs. After BEAM, 9/13 pts were in CR, 3/13 PR, 1/13 PD. Of 12 responding pts, 6 received HD-RAIT (1 pancytopenia, 1 hepatic, 2 pulmonary toxicity, 3 too early). After HD RAIT, 5/6 pts were in CR, 1 in PR. 4/6 pts (3 CR, 1 PR) are alive for 22–31 months, 2 pts died in CR, 1 of interstitial lung disease 2 months after HD-RAIT, 1 pt of pneumonia 8 months after HD-RAIT. Conclusions: Myeloablative RAIT is a feasible and effective treatment modality for relapsed poor prognosis CD20+ B-NHL not having severe toxicity due to the salvage regimen and HD-chemotherapy. HD RAIT offers the potential for long term relapse free survival. Final analysis of toxicity and outcome of this phase II study will be presented at the meeting. No significant financial relationships to disclose.
Erlotinib-associated rash correlates with plasma levels at steady state
Authors: Strother R. M. , Jones D. R. , Skaar T. , Huh W. S. , Porter J. , Foster A. , Sweeney C. 
Published: March 2020

13008 Background: Erlotinib is a small molecule epidermal growth factor receptor tyrosine kinase inhibitor that is approved for non-small cell lung cancer as a single agent and for pancreatic cancer in combination with gemcitabine. Significant inter-individual variation in drug exposure may explain differential patient outcomes. Genetic polymorphisms of metabolizing enzymes of erlotinib may explain this variability in exposure. Biotransformation assays have implicated cytochrome 3A4/5 (CYP3A4/5) as the predominant metabolizing enzyme. Methods: Patients were enrolled onto a phase-1 dose-escalation study of weekly docetaxel with fixed oral daily dosing (150 mg) of erlotinib. Pharmacodynamic data regarding grade of rash per CTCAE v. 2 were recorded on all 23 patients. Samples for erlotinib pharmacokinetics were obtained after 28 days of continuous daily dosing. Pharmacokinetic (PK) data was attained in 21 patients using LC/MS/MS and analyzed using noncompartmental analysis. Genomic DNA was available for analysis in all 23 patients. Analysis for single nucleotide polymorphisms CYP3A5*3 and CYP2D6*4 were performed by real-time polymerase chain reaction and confirmed by restriction fragment length polymorphism analysis when needed. Results: Average age of patients was 56 (34–76). Nine patients had grade 0–1 rash and 12 had grade 2 rash. As summarized in the table below, the AUC for patients exhibiting grade 2 rash was approximately twice that of patients with grade 0–1 rash. No significant association was found between PK parameters and either CYP3A5 or CYP2D6 polymorphisms. Conclusions: In patients treated with erlotinib the pharmacodynamic endpoint of rash, which has been previously linked with improved patient outcomes, is significantly correlated to the degree of exposure to the drug at steady state. Preliminary data in this small study analyzing pharmacogenetics of erlotinib found no significant correlation between CYP3A5*3 and CYP2D6*4 polymorphic status in either PK or pharmacodynamic measures. [Table: see text] [Table: see text]
First-in-human phase-I pharmacokinetic trial of NS-9, a liposomal poly(I):poly(C), in patients with liver metastases from various primary cancers
Authors: Perez R. P. , Lewis L. D. , Cohen G. I. , Hwang J. , Malik S. , Marshall J. L. , Baker J. , Phan A. T. , Yao J. C. , Ajani J. A. 
Published: March 2020

13016 Background: NS-9 is a complex of poly-inosinate [poly(I)] and poly-cytidylate [poly(C)] in a cationic liposome and is active in vitro and in vivo. Objectives: to determine the tolerability, safety, and maximal tolerated dose (MTD), and pharmacokinetics of NS-9 by 1 hr IV infusion, given daily x5 q 28 days. Methods: A phase I dose escalation study was undertaken in patients with liver metastases from solid tumors. Eligible patients were adults with ECOG PS 0–1 and no recent chemotherapy (≥ 4 wks prior). Dose cohorts studied were 0.1, 0.15, 0.2, 0.3 and 0.4mg/m2. Results: 18 patients were enrolled (13M:5F) median age 58 (range 21 to 77 yrs). Tumor types included neuroendocrine (8), and ocular melanoma (1), gastric (1), GE junction (1), esophageal (2), and colorectal (5) carcinomas. Two of three patients treated at the first dose level (0.4 mg/m2) had grade 3/4 reversible lipase elevation with or without acute pancreatitis, a dose limiting toxicity (DLT). De-escalation to doses ranging from 0.1 to 0.2 mg/m2/day was with no DLT. At 0.3 mg/m2 two of three patients treated had a DLT (neutropenia and thrombocytopenia). The MTD was determined at 0.2 mg/m2. Common toxicities included pyrexia, chills, nausea, fatigue, abdominal pain, myalgia, anorexia, sweating, neutropenia, thrombocytopenia, and elevated glucose, amylase, and LFTs. Pharmacokinetics showed rapid elimination (T1/2 ranged from 2.4 to 5.0 hours) without accumulation after multiple doses. 1 patient (esophageal Ca) had a PR in the target lesions in the liver. Conclusions: The MTD is 0.2 mg/m2/day with a hint of antitumor activity. NS-9 should be pursued in phase-II studies. No significant financial relationships to disclose.
A phase I-II and pharmacodynamic (PD) study of the combination of the proteasome inhibitor bortezomib (B) and paclitaxel (P) in patients with taxane-sensitive solid tumors
Authors: Gallerani E. , Cresta S. , Tosi D. , Sessa C. , Capri G. , Catapano C. V. , Bertoni F. , Marsoni S. , Tursi J. , Gianni L. 
Published: March 2020

13029 Background: Proteasome inhibition blocks the chemotherapy-induced activation of NF-кB increasing chemosensitivity to anticancer agents due to increased apoptosis. NF-кB is frequently aberrantly activated in primary human carcinomas and over-expressed in aggressive breast cancer lines1 supporting the rationale for combining B with P. We designed a phase I-II and PD trial to determine the recommended dose (RD) of the B&P combination, to screen for antitumor activity in patients with potentially taxane-sensitive tumors, to search for drug-induced changes and to identify potential surrogate markers of drug activity and toxicity in peripheral blood mononuclear cells (PBMC). Methods: Eligibility included ECOG performance status < 2, neurotoxicity < 2 and adequate organ functions. Treatment was given Q21 days: B on days 1,4, 8 and 11 and P on days 1 and 8. PBMC for gene expression profiling have been collected on day 1 and 4 before and after therapy. RECIST for response was applied. Results: Twenty-nine patients (20 female, median age 60 yrs) were accrued and 25 are evaluable (breast cancer: 13, ovarian cancer: 7, prostate cancer 1, other 4) ; 16 pts were treated in 4 escalation levels and the RD defined respectively at 1.3 mg/m2/dose & 100 mg/m2/dose for B&P. Neurotoxicity was the main toxicity (G1 36%, G2 20% and 1 case G3) requiring treatment discontinuation in 2 pts at cy 6 & 7. Other toxicities (all grades) were nausea and vomiting (68%), diarrhea (56%, G3 12%), alopecia (52%), asthenia (36%, G2 4%), and myalgia (32%, G2 8%). Antitumor activity consisted of 3 PR in pts with ovarian cancer lasting respectively 14, 8+ and 16 wks; 2 PRs in pts with breast cancer (12+ wks,14+ wks) and 1 PR in a pt with prostate cancer. Conclusions: Thus far the regimen has acceptable toxicity with evidence of antitumor activity. The trial will continue until accrual of four additional patients as planned. Footnotes 1 Adams J Current Opin Oncol 2002, 14:628–634. [Table: see text]