bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas
Authors: Da Fonseca C. O. , Schwartsmann Gilberto 
Published: March 2020

14037 Background: Deregulated p21-Ras function, as a result of mutation, overexpresion or growth factor-induced overactivation, contributes to growth of malignant gliomas. Perillyl alcohol (POH) is a monoterpene with preclinical antitumor activity in several types of tumor in rodent models and is currently under phase I and phase II clinical trials. Its proposed mechanism of action involves inhibition of post- translational isoprenylation of small G proteins, including p21-Ras, thereby blocking signal transduction Methods: The intranasal delivery is a practical and non-invasive approach that allows therapeutic agents, which do not cross the blood brain barrier (BBB) to enter the Central Nervous System (CNS), reducing unwanted systemic side effects. Applying this method we performed a phase I / II study with POH intranasal administration in patients with relapsed malignant gliomas after standard treatment: surgery, radiotherapy and chemotherapy. POH was administrated in concentration 0.3% volume/volume (55mg) 4 times daily. Results: Thirty-seven patients enrolled being 29 with glioblastoma multiform (GBM), 5 with grade III astrocytoma (AA) and 3 with anaplastic oligodendroglioma (AO). The results showed that POH is well tolerated and display at 6 months of treatment partial responses in 1 patient (3,4%) with GBM and 1 patient (33,3%) with AO; stable disease in 13 patients (44,8%) with GBM, 3 patients (60%) with AA and 1 patient (33,3%) with AO; progressive response in 15 patient (51,7%) with GBM, 2 patients (40%) with AA e 1 patient (33,3%) with AO. Conclusions: The POH intranasal delivery in a concentration of 0.3% volume/volume (55 mg) is well tolerated, and may prolong survival in patients with relapsed malignant gliomas patients. No significant financial relationships to disclose.
Proteasome inhibition with bortezomib (BORT) in combination with topotecan : A phase I solid tumor trial
Authors: Chen G. Q. , Vikstrom B. , Beckett L. , Scudder S. , Lara P. N. , Lau D. , Gandara D. , Davies A. 
Published: March 2020

14047 Background: Topoisomerase-I (Topo-I) down-regulation via the ubiquitin/26S proteasome pathway has been associated with drug resistance. We hypothesize that proteasome inhibition by BORT would enhance topotecan sensitivity by preventing down-regulation of topo-I. This phase I trial examined the safety and feasibility of combining weekly BORT with topotecan in patients (pts) with advanced solid tumors. Methods: Pts on 1 of 4 dose levels were treated with topotecan (3–4 mg/m2) IV and BORT (1–1.6 mg/m2) IV on days 1, 8, and 15. BORT was given 3 hours after topotecan based on preclinical studies (Flannery, 2003). Cycles were repeated q28 days. After 6 cycles, pts without progression could remain on BORT alone. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets (plts) (<25K), Gr3 plts (<50K) with bleeding, febrile neutropenia, neutropenia with infection, Gr3 neuropathy, or any=Gr3 non-heme toxicity. Results: 15 pts were accrued. Pt characteristics: Median age 58 years (range 25–73); Male sex:7; Performance status =80%:13. Two DLTs were seen at dose level 4 (Topotecan 4 mg/m2 and BORT 1.6mg/m2): Gr 4 plts (1) and Gr 3 neutropenia with infection (1). Few other toxicities > Gr3 were seen past cycle 1. Of 11 evaluable pts, 1 had a partial response (small cell bladder). 4 had stable disease (lung, brain, adenoid cystic and prostate). Conclusions: Weekly BORT and topotecan is feasible and well tolerated. The recommended phase II dose is topotecan 3mg/m2 and BORT 1.6mg/m2 IV weekly (3 of 4). An expanded cohort at this dose will examine efficacy of this combination in pts with small cell cancers. Correlative studies evaluating serum markers for proteasome inhibition and topo-1 activity are ongoing. No significant financial relationships to disclose.
Different responses of circulating endothelial progenitor cells and VEGF-plasma concentrations to low-dose metronomic and conventional chemotherapy
Authors: Trefzer T. , Stoelting S. , Lemke A. , Kisro J. , Steinke A. , Peters S. O. , Wagner T. 
Published: March 2020

14053 Background: Endothelial progenitor cells (EPCs) may participate in tumor angiogenesis by providing cellular supply. This is a study that compares the effects of two conventional combination chemotherapy schedules to low-dose metronomic trofosfamide (an oral derivate of cyclophosphamide), using the number of circulating EPCs and vascular endothelial growth factor (VEGF) plasma levels in cancer patients. Methods: We measured circulating EPC and VEGF levels in 24 patients that received conventional chemotherapy for either breast cancer in an adjuvant setting or malignant lymphoma, and in 18 patients receiving metronomic chemotherapy with or without celecoxib for advanced cancer. Blood samples were obtained three times: before starting chemotherapy, 10 and 21 days after starting chemotherapy. Peripheral blood EPC levels were determined by fluorescence flow cytometry and defined by CD34- and VEGF-R2-positivity. VEGF plasma concentration was determined by ELISA. Results: The number of circulating EPCs showed a two-fold increase 21 days after conventional chemotherapy but a significant decrease under metronomic chemotherapy. VEGF-plasma-concentrations remained stable in patients under metronomic chemotherapy but significantly increased under conventional chemotherapy.This increase in VEGF plasma levels occurred even in patients that received chemotherapy in an adjuvant setting in supposed absence of tumor. Conclusions: Low-dose metronomic trofosfamide significantly decreased circulating EPCs while conventional chemotherapy increased both the number of circulating EPC and VEGF-concentrations. The increase of VEGF even in an adjuvant setting of chemotherapy without the presence of a tumor may be caused by chemotherapy-induced endothelial cell destruction. Metronomic scheduling of certain cytotoxic drugs may thus prevent tumor progression by inhibiting both tumor cell proliferation and angiogenesis. No significant financial relationships to disclose.
Phase I study of pemetrexed (P) plus gemcitabine (G) in advanced solid tumors (ST)
Authors: Fury M. G. , Larkin J. , Gerst S. R. , Sabbatini P. , Konner J. , Orlando M. , Tai D. F. , Goss T. , Aghajanian C. , Hensley M. L. 
Published: March 2020

14055 Background: P is active in multiple ST types, and preclinical data support P synergy with G. Methods: Eligible advanced ST patients (pts) with no prior P or G, no prior radiotherapy (RT) to ≡ 25% of the marrow, Karnofsky Performance Status ≡ 70%, and adequate organ function enrolled in cohorts (C) of 3, expanding to 6 if dose-limiting toxicity (DLT) occurred. P was given at 300 (C1), 400 (C2), 500 (C3) or 600 (C4) mg/m2 followed by G at 1500 mg/m2 q 14 days (d) without granulocyte-colony stimulating factor. Vitamin B12 and folate supplementation were given. Response was assessed by RECIST Results: 29 pts (median number prior regimens 2, range 1–5; 66% with prior RT) enrolled and are evaluable for safety; 23 are evaluable for response. There were no DLTs in C1. One pt in C2 was replaced after 1 cycle for progression of disease (PD). Among the next 6 pts, 2 had DLTs (1 G3 thrombocytopenia [TP] treatment delay; 1 neutropenic fever [NF]). C2-R (C2, Revised) re-opened after amendment permitting ≡ 2 prior cytotoxic regimens, no history of brain metastases/brain RT. C2-R enrolled 8 pts with 1 DLT (G3 TP with treatment delay) and 2 pts replaced (1 early PD, 1 no documented duration of neutropenia [NP]). C3 had 0/3 pts with DLT. C4 had 2/3 pts with DLTs (1 G4 hyponatremia; 1 herpes zoster-related treatment delay). C3 has been expanded to 5 of 6 planned patients, one with DLT (NF, G4 TP). Toxicities per cycle (n= 189 cycles, 29 patients): include NP-G3 (23%), G4 (14%); TP-G3 (2%); WBC-G3 (30%), G4 (4%); lymphopenia-G3 (11%), Hgb-G3 (4%); G3-NF (1%). 3/23 (13%) had objective partial responses (2 head and neck squamous cell cancer, HNSCC; 1 nasopharyngeal cancer, NPC), 4 stable disease (SD), 16 PD. (1 pt, no measurable disease at baseline; 5 pts, too early for response assesment). Conclusions: G + P is well-tolerated, and yields objective responses in HNSCC and NPC. C3 (P 500 mg/m2 + G 1500 mg/m2 q 14 d) was the phase II recommended dose in another phase I study of this regimen (Melemed ASCO 2005). Our final results will be available for ASCO 2007. No significant financial relationships to disclose.
Phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of oral alvespimycin (A; KOS-1022; 17-DMAG): Two different schedules in patients with advanced malignancies
Authors: Flaherty K. T. , Gore L. , Avadhani A. , Leong S. , Harlacker K. , Zhong Z. , Johnson R. G. , Hannah A. L. , O’Dwyer P. , Eckhardt S. G. 
Published: March 2020

14059 Background: A is ∼3–5 fold more potent compared to 17-AAG (the first Hsp90 inhibitor to enter clinical testing), based on in vitro cytotoxicity or the MTD in toxicology studies; it is water-soluble; and oral bioavailability in dogs is estimated at 40%. Toxicity in the dog included kidney, intestinal and liver findings. This study was conducted to determine the toxicity, MTD, recommended phase 2 dose (RP2D), PK and PD of A in pts with solid tumors. Methods: Escalating doses of A were given PO on 2 different schedules: every other day or daily for 4 out of 6 weeks. An initial IV dose was given to calculate absolute bioavailability. PK was evaluated after the IV dose, Day 1 and 21 of oral dosing. PBLs were collected to investigate changes in intracellular signaling proteins by immunoblot (Days 1 and 21 at 1, 3, 24 and 48 hours post-dose). Results: 28 pts were enrolled: 24 on the QOD schedule at doses of 5 (n=4), 10 (n=4), 20 (n=8), 30 (n=5) and 40 mg (n=3); 4 pts received 10mg on the QD schedule. 50% were male, median age/ECOG PS 55 and 0; median prior regimen 3. DLT has not yet been observed. Common drug-related toxicities (n=23): fatigue 43%, nausea 24%, anorexia 19%, proteinuria 19%, and peripheral edema 14%. Of these, fatigue and peripheral edema appear to be possibly dose-related. Drug-related Grade 3–4 toxicity (one patient each) included anemia, neutropenia, peripheral edema, hypokalemia, pain in extremity and hypoxia. For pts with full PK data (n=14), bioavailability equaled 51% and 49% on Day 1 and 21, and was not dose-dependent. Mean Day 21 AUCinf for the 5 to 30 mg/m2 levels equaled 91, 166, 542 and 1889 ng*h/mL. One pt with 3-fold increase in AUCinf comparing Day 1 and 21 dose had been started on dronabinol, a CYP2C9 inhibitor. One pt with fibrosarcoma (4 prior regimens) had necrotic changes in the tumor in the axilla with improved symptoms (active at 5+ months). Additional pts with SD include hemangioendothelioma (7 months), melanoma (6+ months), and renal cell (5 months). Induction in Hsp70 at the 30 mg dose level was seen pre-dose on Day 21 with maximal induction at 24 hours post-dose. Conclusions: Dose escalation continues on both schedules in order to define a RP2D. Toxicity is acceptable. Early signs of activity have been observed. [Table: see text]
Sensitivity of primary hematopoietic tumors and tumor lines to the novel HDAC inhibitor PCI-24781
Authors: Balasubramanian S. , Ramos J. , Sirisawad M. , Buggy J. J. , Miller R. A. , Phan S. 
Published: March 2020

14062 PCI-24781 (formerly CRA-024781) is a novel HDAC inhibitor that is in phase I clinical trials in patients with solid and hematopoietic malignancies. PCI-24781 has favorable pharmacokinetic and pharmacodynamic profiles in animal models and in humans. In the present study we show that PCI-24781 potently induces cell death in a variety of hematopoietic cell lines derived from B-cell, T-cell and myeloid malignancies, and in primary acute leukemic blasts from bone marrow aspirates. In tumor cell lines, growth inhibition and apoptosis were noted at drug concentrations ≡ 0.125 μM and were accompanied by known biochemical markers of HDAC inhibition including histone and tubulin hyperacetylation. To demonstrate the potential clinical utility of PCI-24781 in hematologic tumors, primary leukemia samples were isolated from patients and screened for resistance to PCI-24781-induced growth arrest in vitro. Of these 25 primary samples (10 acute myelogenous leukemia (AML), 6 multiple myeloma (MM) and 9 acute lymphocytic leukemia (ALL)), some of which were derived from patients who had failed standard therapy, none was resistant to PCI-24781 at 0.5 μM and only 4 (1 AML, 2 MM, and 1 ALL) were considered resistant at 50 nM. Gene expression analysis using DNA microarrays on these primary tumor samples revealed alterations of gene expression consistent with HDAC inhibition and defined potential pathways of activity for this compound in these tumors. These results demonstrate that hematopoietic tumors and tumor-derived cell lines are highly sensitive in vitro to the novel HDAC inhibitor PCI-24781. The high sensitivity of primary tumor cells to treatment with PCI-24781 in vitro coupled with the favorable pharmacokinetics of this compound in humans suggests that patients with hematopoietic malignancies would be responsive to treatment with PCI-24781 in clinical trials. No significant financial relationships to disclose.
Early prediction of anti-epidermal growth factor receptor (EGFR) therapy with 18[F]FDG-PET: A preclinical and clinical correlation
Authors: Ma W. , Jimeno A. , Kulesza P. , Chan A. , Zhang X. , Messersmith W. A. , Gillison M. L. , Pomper M. G. , Forastiere A. A. , Hidalgo M. 
Published: March 2020

14064 Background: Predictive biomarkers for response to anti-EGFR therapy are of significant clinical importance. We hypothesized that early changes in 18[F]FDG tumor uptake predict response to anti-EGFR therapy. We investigated this in a mice model and correlated these findings with human patients undergoing anti-EGFR therapy. Methods: Mice bearing two head and neck squamous cell cancer (HnNSCC) xenografts (Hep2, Cal27) received vehicle or erlotinib for 3 weeks. 18[F]FDG uptake were imaged with small animal micro- PET at baseline and after 1 week of therapy, and reported in SUVmax. For clinical correlation, human patients with HnNSCC receiving erlotinib were identified from an ongoing clinical trial. 18[F]FDG-PET images were obtained at baseline and after 2 weeks of erlotinib monotherapy. Tumor specimens were obtained by fine-needle aspiration biopsy at the same time as PET. A panel of pharmacodynamic markers (including Ki-67 and pMAPK) were assessed . Results: Hep2 was resistant to erlotinib therapy (Tumor/Control [T/C]: 0.8) while Cal27 was sensitive (T/C: 0.2). SUVmax in the resistant Hep2 xenografts was not significantly different from the control (86% ± 70% of control) while SUVmax in the treated sensitive Cal27 xenografts showed a significant decrease than control (-2% ± 7%). Ki-67 in the treated Hep2 was not significantly different from control while that in Cal27 was <50% of control. For clinical correlation, ki-67 score was higher after 2 weeks in the patient resistant to erlotinib monotherapy by 18[F]FDG-PET (SUVmax increased by 14%, ± 11%) and was lower in the patient who was 18[F]FDG-PET sensitive (SUVmax decreased by 56%, ± 13%). pMAPK decreased in all cases and had a poor correlation with efficacy. Conclusions: Early dynamic changes in 18[F]FDG tumor uptake is predictive of response to anti-EGFR therapy and correlates with changes in ki-67 expression, both in a preclinical and a clinical scenario. No significant financial relationships to disclose.
Technical criteria of “clinical readiness” to qualify validated pharmacodynamic (PD) assays for clinical trial use
Authors: Parchment R. E. , Kinders R. J. , Hollingshead M. , Dancey J. E. , Tomaszewski J. E. , Doroshow J. H. 
Published: March 2020

14068 Background: Pharmacodynamics may inform drug development decisions by providing evidence of drug action on molecular target and additional data supporting dose/schedule. While a bad decision when selecting the most appropriate PD assay to use is not fatal to completing Phase 1–2 trials, assays that cannot produce meaningful scientific results create an ethical dilemma if patients are being subjected to invasive procedures, and weaken decision making. In some exploratory IND trials, the primary endpoint is demonstrating a PD effect of investigational drug on molecular target, so selection of a PD assay becomes a critical decision. Methods: SAIC-Frederick’s applied research program developed, validated and implemented a PD assay to quantify drug-induced PARP inhibition as the primary endpoint of a Phase 0 trial of ABT-888 at the NIH Clinical Center (see Kinders et al, Kummar et al). This project has been analyzed to identify technical requirements critical for establishing the clinical readiness of a PD assay. Results: Many more technical requirements arose than were originally expected, but the requirements fell into three conceptual categories: assay validation, clinical feasibility and therapeutic relevance. Assay validation requires formal assessment of analytical performance on a set of standards and specimens relevant to the trial, including storage stability of the analyte. Clinical feasibility requires the PD assay to yield analytically valid results in preclinical models when using clinically relevant tissue acquisition, handling procedures and biopsy scheduling, including significant drug effect in needle biopsies when confounded by stress, previous biopsy, biopsy method, and co-medications. Therapeutic relevance requires a relationship between dose/exposure, target modulation quantified with the PD assay, and a disease outcome of interest. Conclusions: “Clinical readiness” sets a very high standard for accepting PD assays into clinical trials, and a highly integrated team is required to meet it. However, the use of such rigorous assay development criteria holds much promise for the clinical development of molecularly targeted agents. Funded by NCI Contract N01-CO-12400. No significant financial relationships to disclose.
Activity of the aurora kinase inhibitor MK-0457 (VX-680) in combination with taxotere
Authors: Hoover R. R. , Harding M. W. 
Published: March 2020

14069 Background: MK-0457 (VX-680) is a reversible kinase inhibitor that targets Aurora A, B and C (Ki’s of 0.7, 18 and 4.6 nM, respectively). Clinical trials are on-going in patients with solid tumors and hematologic malignancies. This study evaluated the in vitro combination of MK-0457 and Taxotere (TXT) to determine if inhibition of Aurora kinases, which are critical for cytokinesis and spindle assembly may synergize with a microtubule targeted agent. Methods: A panel of cancer cell lines (that were either wild-type, mutant, or null for p53) and a matched pair of A549 cell lines either expressing p53 shRNA or vector control (A549p53- and A549p53+) were evaluated for sensitivity to MK-0457 and/or TXT. Viability was measured by Cell Titer Glo (Promega). Cell cycle profiles were determined by FACS analysis, and colony formation (CFU) assays were performed in soft agar and on plastic. Combination effects were evaluated by the Bliss Independence method. Results: Single agent IC50’s ranged from 50 nM to > 5 μM for MK-0457 and 0.4 to 10 nM for TXT. FACS analysis of DNA content showed MK-0457 induced G2/M arrest and polyploidy, characteristic of Aurora kinase inhibition. The effects of MK-0457 and TXT combination ranged from antagonism to synergy and were concentration, cell context, and regimen dependent. In 3–4 day viability assays simultaneous combination of MK-0457 + TXT did not show synergy, however sequential exposure showed synergy at low concentrations of both agents. In contrast to the short-term viability assays, simultaneous exposure to MK-0457 + TXT in long term survival assays (i.e. CFU on plastic or soft agar) resulted in enhanced cell death compared to the single agents. Conclusions: The synergy observed for MK-0457 + TXT, especially in long term survival assays, supported the evaluation of this combination in xenograft models (described in B. Furey et al., ASCO 2006). No significant financial relationships to disclose.
A phase I dose finding study of E7080 in patients (pts) with advanced malignancies
Authors: Glen H. , Boss D. , Evans T. R. , Roelvink M. , Saro J. M. , Bezodis P. , Copalu W. , Das A. , Crosswell G. , Schellens J. H. 
Published: March 2020

14073 Background: E7080 is a potent inhibitor of the split-kinase family of transmembrane growth factor receptors including Flt-1 and KDR. In addition, E7080 also potently inhibits FGFR1 and PDGFRβ tyrosine kinase activities. In an in vitro angiogenic model, E7080 inhibited VEGF-driven umbilical vein endothelial cell (HUVEC) proliferation and tube formation. Using H460 and Colo205 mouse xenograft models, E7080 significantly inhibited tumor growth at doses from 1 to 100 mg/kg. Methods: A Phase I and pharmacologic study was conducted to determine the Maximum Tolerated Dose (MTD) and Dose Limiting Toxicity (DLT) of E7080 in pts with advanced malignancies. Eligible pts with adequate hematologic, renal and hepatic function, and with tumors refractory to standard therapies, were treated with E7080 administered orally on a once daily continuous dose schedule in cycles of 4 weeks. Dose escalation was performed according to an accelerated design of 100% dose increases in subsequent cohorts until the first patient experienced ≥ CTC grade 2 toxicity. Results: As of November 17th, 2006, 37 pts with documented progressive disease (PD) have been treated at the following dose levels: 0.2 mg/d, 0.4 mg/d, 0.8 mg/d, 1.6 mg/d, 3.2 mg/d, 6.4 mg/d, 12.5 mg/d and 16 mg/d. Median number of cycles was 1 (0–11). Median age = 60 years (25–84), 20 pts were male, 17 were female. 37 pts were evaluable for toxicity. 1 patient experienced grade 3 hypertension (DLT) in the 16 mg/d cohort, other related toxicities ≥ grade 2 include hemorrhage and thrombosis (n=1), tachycardia (n=1), febrile neutropenia (n=1), proteinuria (n=1), thrombocytopenia (n=1) and hypertension (n=1). MTD has not been reached and this study is continuing to recruit. 24 pts were evaluable for efficacy, 3 are too early to evaluate. 1 patient had a partial response (high grade sarcoma) after 2 cycles, and 15 pts experienced stable disease from 2+ to 11 months, and 11 pts continue on therapy. Pharmacokinetic (PK) studies: preliminary data suggest that the PK is linear over the range 0.2 mg/d to 12.5 mg/d. Conclusions: E7080 is safe and well tolerated at doses acheived so far and has shown promising first signs of anti-cancer activity associated with potent activity in pre-clinical models. Clinical and PK data from subsequent doses and follow- up will be presented. No significant financial relationships to disclose.