bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I trial of fenretinide (4-HPR) intravenous emulsion for hematologic malignancies
Authors: Mohrbacher A. , Gutierrez M. , Murgo A. J. , Kummar S. , Reynolds C. P. , Maurer B. J. , Groshen S. , Vergara L. , Yang A. S. 
Published: March 2020

13007 Background: 4-HPR is a retinoid cytotoxic for cancer cell lines. In clinical trials, oral capsule 4-HPR had limited bioavailability and activity. An intravenous intralipid emulsion formulation of 4-HPR (ILE 4-HPR) was developed to increase bioavailability. The objectives of this phase I trial were to determine a maximally tolerated dose (MTD) of ILE 4-HPR, and to assess toxicities, pharmacokinetics (PK), and preliminary response data. Methods: We used an accelerated titration Simon design 2 dose escalation schema with 100% increase in ILE 4-HPR per dose level tested until moderate toxicity was observed in 2 patients or DLT in one. Ten dose levels were planned with a starting dose of 80 mg/m2/day (continuous i.v. x 5 days q 3 weekly), increasing until Dose level 10 at 1,810 mg/m2. A De-escalation to 1,240 mg/m2/day Dose level 9 was added when DLT was observed in 2 patients at 1,810 mg/m2 dose level 10. Results: To date, 11 patients have been enrolled. At dose level 10 (1,810 mg/m2/day), 2 pts experienced a DLT of grade IV hypertriglyceridemia with grade 2 pancreatitis. A de-escalation to dose level 9 (1,280 mg/m2/day) has enrolled 4 pts, 1 had grade IV hypertriglyceridemia; enrollment is ongoing. We observed a transient response in a patient with NHL at 320 mg/m2 and a continued partial response in one patient with NHL on dose level 10 (1,810 mg/m2). PK showed a linear relationship of dose to plasma level, with steady-state levels of 54 μM (1,280 mg/m2)and 62 μM (1,810 mg/m2). Conclusions: ILE 4-HPR was given via continuous infusion to a dose of 1,810 mg/m2/day x 5 days. 1 patient with NHL had a transient partial response and a second patient with chemotherapy-refractory NHL had a partial response sustained on treatment for > 6 months. The DLT of hypertriglyceridemia is likely related to the intralipids delivered. Enrollment continues at a dose of 1,280 mg/m2/day. ILE 4- HPR can be safely administered and obtained plasma levels 6 to 7 times higher than previously obtained by oral capsule 4-HPR, with clinical activity in hematologic malignancies. No significant financial relationships to disclose.
Pharmacokinetic study of a combination chemo-endocrine treatment of paclitaxel and toremifene
Authors: Saeki T. , Okita A. , Aogi K. , Kakishita T. , Okita R. , Taira N. , Takashima S. , Fujita K. , Nishikawa K. 
Published: March 2020

13017 Background: The mechanism of paclitaxel (PXL) resistance has been investigated. P-glycoprotein (P-gp) on cell membrane could be an important target for improving efficacy of PXL. Toremifene (TOR) may moderate P-gp-related drug resistance in vitro. To determine safety and efficacy of PXL and TOR, we conducted a pharmacokinetic study for a combination chemo-endocrine treatment of PXL plus TOR for metastatic breast cancer. Methods: Patients with metastatic breast cancer, who were previously treated with a standard chemotherapy without PXL, were eligible. Patients received PXL 80 mg/m2(i.v.) weekly on days 1, 8, and 15 in a cycle. Concurrently, toremifene 120mg/body (p.o.) was given dairy from day 1–28 in a cycle. For pharmacokinetic study, single agent of PXL was initially administrated on day 1, 8, and 15. From day 18, TOR 120mg/body was given dairy. On day 22, PXL administration in second cycle was skipped. On day 32, blood samples were collected from the patients received PXL 80 mg/m2 + TOR 120 mg/day/body. Samples were analyzed by HPLC (Unisil Q 5CN). Response was evaluated by WHO criteria and adverse events were evaluated by NCI•CTC Ver.2. Results: Nineteen patients were enrolled. Out of 19, 15 patients had measurable disease, and 1 partial response, 8 stable disease, and 6 progressive disease were observed. The addition of TOR caused in no specific adverse events more than grade 3 and toxic profile in combination was similar that in PXL monotherapy. Pharmacokinetic profile of PXL was similar with/without TOR. In addition, Cmax of TOR was 1.85±0.71 mg/mL. Tmax was 2.9±1.8 hr were observed. AUC0–8 of TOR was not affected in the presence of PXL. AUC0- 8 of TOR-1, metabolite of TOR, also demonstrated the similar pharmacokinetic profile. Pharmacokinetic parameters of PXL did not reveal intra-patient variability in previously treated metastatic breast cancer patients. Conclusions: Pharmacokinetic profile in a combination of PXL and TOR was similar that in PXL monotherapy. The addition of TOR to PXL for previously treated metastatic breast cancer patients might be safety. No significant financial relationships to disclose.
Population pharmacokinetics of docetaxel in elderly patients
Authors: Uriens S. , Rezai K. , Girre V. , Dieras V. , Lokiec F. 
Published: March 2020

13020 Background: Elderly patients (>70 years) may present different pharmacokinetic profile for many drugs , mainly because of altered elimination due to renal function or metabolic decreases. Methods: Docetaxel, 50 to 85 mg/m2, median 70 mg/m2, was infused during 1 hr to 44 patients, aged 70 to 83 years, median 76.5 years. Three blood samples per patient were obtained according to a limited sampling strategy (Baille et al. Clin Cancer Res 1997, vol. 3, 1535–38). Covariates of interest were carefully recorded, age, body weight, body surface area, gender, serum creatinine, orosomucoid, serum albumin. These data were then analysed using NONMEM V to a) obtain individual Bayesian estimates of docetaxel clearance, b) re-analyse the data in order to estimate population parameters for this elderly population, c) show possible covariate effects on the pharmacokinetic parameters. Results: Median docetaxel CL from Bayesian estimation was 29.1 (2.5–97.5% quantiles 12–49) L/h. When the population was re-analysed per se, docetaxel CL was 29.2 (2.5–97.5% quantiles 17–35) L/h. The inter- subject variability for CL was 25% (precision 32%).. No covariate effect was observed on CL. Conclusions: Docetaxel clearance in elderly patients is slightly decreased, 29 L/h versus 36.8 L/h (reported in 547 patients, mean age 56 years, 5–95% quantiles 39–71 years). The inter-subject-variability of CL in elderly patients was decreased to 25% versus 47.5% in the 547 patients population. A pharmacokinetic- pharmacodynamic modelling of neutrophil counts versus time will be performed in these elderly patients in order to point a possible different sensitivity of this population to the myelosuppressive effects of docetaxel. No significant financial relationships to disclose.
Immunological and clinical effects of a multiple peptide vaccine and low-dose cyclophosphamide in prostate carcinoma patients
Authors: Marrari A. , Iero M. , Squarcina P. , Villa S. , Salvioni R. , Parmiani G. , Valdagni R. , Rivoltini L. 
Published: March 2020

13502 Background: Despite effective therapeutic strategies for the treatment of prostate cancer (PC), patients still recur and progress in a significant percentage. Here we describe the preliminary clinical and immunological data of a peptide-based strategy of vaccination in biochemical relapsed PC patients. Methods: We planned to enroll 30 HLA-A*0201 patients with biochemical failure after surgery, radiation or androgen deprivation therapy (ADT), according to the ASTRO criteria. On entering the study, patients discontinue ADT. No selections were made based on PSA levels at diagnosis, Gleason pattern score or other pathological features. Vaccination includes three peptides derived from proteins highly expressed in PC, PSMA (PSMA-P14–12 and PSMA-P2711–719) and Survivin (SVV96- 104/97M). Peptides, emulsified in Montanide ISA 51, are administered subcutaneously (8 injections) at two-weeks intervals. Vaccine is preceded by systemic administration of low dose cyclophosphamide (300 mg/m2/four weeks), aimed at selectively down- modulating regulatory T cells (Treg). Immunological monitoring includes evaluation of peptide and tumor-specific CD8+T cells in peripheral blood (IFN?-Elispot and HLA/multimer staining) and analysis of the frequency and suppressive activity of CD4+CD25+Foxp3+Treg. Results: So far, ten patients have been enrolled. Treatment is well tolerated, with mild cutaneous toxicity due to Montanide injection. A significant increase in the frequency of antigen-specific CD8+ T cells was observed in 8/10 patients. Treg, only marginally expanded in these patients, do not seem to decrease by cyclophosphamide treatment, although studies on the potential modulation of their suppressive activity are in progress. After a follow-up of 6–12 months, PSA stabilization was observed in 7 patients, 2 of which entered the trial after maximal androgen blockade discontinuation. Interestingly, PSA stabilization appears to directly correlate with the induction of antigen-specific T cell responses. Conclusions: Our vaccination strategy proved to be safe, non toxic and well tolerated. Initial monitoring data show an expansion of antigen specific T cells, with an apparent correlation between immunological and biochemical responses. No significant financial relationships to disclose.
Dynamic contrast-enhanced CT (DCE-CT) as an early biomarker of response in metastatic renal cell carcinoma (mRCC) under anti-angiogenic treatment
Authors: Fournier L. , Thiam R. , Cuenod C. , Medioni J. , Trinquart L. , Balvay D. , Banu E. , Balcaceres J. , Frija G. , Oudard S. 
Published: March 2020

14003 Background: Evaluation of treatment response for cancer relies on application of criteria based on size such RECIST. However, changes in size are often delayed and small. An accurate and early evaluation of tumor vascular characteristics would allow selection of patients (pts) who would most likely benefit of these therapies and early detection of treatment response to tailor therapy on an individual basis. Changes in tumor vascular parameters were quantified using dynamic contrast-enhanced computed tomography (DCE-CT) as a biomarker for tumor angiogenesis. Methods: A total of 44 mRCC pts were enrolled in an imaging study corollary of two phase III trials evaluating efficacy of anti-angiogenic drugs: sorafenib (N=9) vs. placebo (N=13), or sunitinib (N=17) vs. interferon (N=5). Perfusion CT acquisitions after injection of 80 ml of iodinated contrast agent were performed on a single “functional metastatic target” before treatment and every 6 weeks for follow-up. Microvascular parameters of the functional target were calculated using a dedicated software based on compartmental models: tumor blood flow (TBF) (ml/min/100g), tumor blood volume (TBV) (%), vascular permeability (VP) (ml/min/100g) and mean transit time (MTT) (s). These parameters were correlated to the best treatment response as evaluated by the size variation of the RECIST targets. Results: Among the 26 treated pts, there was a statistically significant drop in TBF and TBV as early as the first cycle of treatment (respectively -50%, p=0.03 and -51%, p<0.01) compared to pre-treatment, showing the biological effect of the drug on tumor vascularity. There was a significantly higher drop in TBF and TBV in pts who would be later classified as responders (N=16) vs. non-responders (N=10) after the first cycle of treatment (-66% vs. -6%, p=0.02; -60% vs. -26.5%, p=0.04). The changes in MTT and VP were not correlated to the best response. Conclusions: The functional imaging biomarkers TBF and TBV quantified by DCE-CT detect the biological effect of anti-angiogenic drugs on tumor vessels. TBF appears as very early predictor of mRCC response to anti-angiogenic drugs supporting the hypothesis that DCE-CT may constitute a surrogate biomarker of angiogenesis inhibition. No significant financial relationships to disclose.
Correlative study of EGFR mutations or protein expressions of EGFR, phosphorylated EGFR, HER2, phosphorylated HER2 and IGFR-1 with gefitinib sensitivity in patients with non-small cell lung cancer: Results of West Japan Thoracic Oncology Group trial (WJTO)
Authors: Hirashima T. , Nakagawa K. , Kashii T. , Kubo A. , Sasaki J. , Tanaka K. , Sato S. , Kurata T. , Tamura K. , Fukuoka M. 
Published: March 2020

14008 Background: Both epidermal growth factor receptor (EGFR) mutation and gene copy number of HER2, a member of EGFR family, are associated with gefitinib sensitivity. We carried out a correlative study to determine the relationships between EGFR mutations, EGFR or HER2 protein expressions, their activation status (pEGFR, pHER2) or insulin-like growth factor receptor 1 (IGFR-1) protein expressions and clinical outcomes after gefitinib treatment in advanced NSCLC. Method: Tumors from patients (pts) were evaluated for EGFR mutations by DNA sequence, and for protein expressions of EGFR, pEGFR, HER2, pHER2 and IGFR-1 by immuno-histochemistry. Time to progression (TTP) was calculated by the Kaplan-Meier method; groups were compared using the log-rank test. Risk factors associated with TTP were evaluated with Cox proportional hazard regression modeling. Correlation between EGFR mutation and response was evaluated by Fisher’s direct method. Relationship between each protein expression and response was tested by two-sided. Primary endpoint was to detect biomarkers to predict gefitinib sensitivity. Results: From Dec. 2003 to Dec. 2005, 103 consecutive pts were enrolled onto the study, and received gefitinib until disease progression. Median age was 68 years, female (58%), adenocarcinoma (83%), never smoker (55%) and no previous chemotherapy (49%). 98 pts were evaluable for efficacies, toxicities and gene analyses. Forty-one pts (42%) had EGFR mutations; 14 pts had deletional mutation in exon 19, 27 pts had missense mutation (L858R) in exon 21. EGFR mutations were significantly related to response (62 vs. 26%; P = 0.001), disease control rate (92 vs. 65%; P = 0.003) and TTP (median, 10.1 vs. 5.1months; hazard ratio = 0.64; P = 0.048). Both pEGFR (0, +1 vs. =+2; P = 0.002,) and pHER2 (0 vs. =+1; P = 0.001) expressions are significantly associated with incidence of EGFR mutation. Conclusions: EGFR mutation was a significant predictive biomarker of response to gefitinib. Phosphorylated EGFR protein expression is a potent replaceable biomarker for EGFR mutation. No significant financial relationships to disclose.
Synergistic apoptosis and antitumor activity induced by ST1926, an atypical retinoic acid derivative
Authors: Zanna C. , Pisano C. , Vesci L. , Pace S. , Lucreziotti M. R. , Merlini L. , Zunino F. , McCanna S. , Penco S. , Carminati P. 
Published: March 2020

14029 Background: ST1926 is a novel adamantyl retinoid active against a wide panel of human tumor cell lines, including p53-defective cells. Moreover, its cytotoxic activity is not affected by Pgp overexpression or resistance to cisplatin. The drug induces an early G1/S cell cycle arrest associated with a modulation of genes involved in apoptosis and DNA damage. Although the ST1926 molecular targets are still not fully elucidated, some in vitro studies suggest that this drug induces activation of both intrinsic and extrinsic apoptotic pathways. Methods: ST1926 antiproliferative activity was evaluated in vivo by oral route using fractionated daily schedules in CD1 nude mice against different human tumor xenografts, including NSCLC, ovarian carcinoma, H&N, neuroblastoma and melanoma, as well as hematological malignancies. Pharmacokinetic and toxicological studies were conducted in rodents and dogs after single and repeated (5 days and 4 weeks) oral administration. Results: As monotherapy, ST1926, showing a favorable tolerability profile, was effective in inhibiting tumor growth in several tumor models. In particular, ST1926 showed significant tumor inhibition on doxorubicin- and platinum-resistant ovarian carcinomas at 30 mg/kg po given according to different schedules. The most prominent tumor growth inhibitory effects were noted in combination regimens with cisplatin and carboplatin in both sensitive and resistant ovarian carcinoma. The plasma t1/2 was about two hours in all animal species tested. The hemolymphopoietic system and GI tract were identified as the main target organs of toxicity. Toxicology findings indicated the starting dose in humans at 30 mg daily for five consecutive days. Conclusions: ST1926 is a new antitumor proapototic agent acting through particular molecular mechanisms. ST1926 is active by oral administration on both solid tumors, especially ovarian carcinoma, and acute myeloid leukemia. A Phase I clinical program to evaluate safety and tolerability of ST1926 as monotherapy and in combination with platinum compounds is ongoing in women with advanced ovarian cancer. [Table: see text]
A phase Ib study of telatinib (BAY 57–9352), a VEGFR-2 inhibitor, in combination with docetaxel in patients with advanced solid tumours
Authors: Shaw H. M. , Molife L. R. , Spicer J. , Karavasilis V. , Marriott C. , Ong T. J. , Tate L. , Brendel E. , Christensen O. , de Bono J. S. 
Published: March 2020

14035 Background: Telatinib (BAY 57–9352) inhibits VEGFR-2 and VEGFR-3 tyrosine kinases, and PDGFR-β and c-Kit. Preclinical data suggests that targeting VEGFR signaling increases antitumor activity. Methods: This trial investigated the safety, pharmacokinetics (PK), and tumor efficacy of telatinib combined with docetaxel (D). D was administered at a fixed dose of 75mg/m2 on day 1 of 21-day cycles. Telatinib was administered orally, twice daily (bid) from day 3 of Cycle 1 and onwards, thereafter continuously. Dosing of telatinib commenced at 600mg bid (cohort 1, n=6) and increased to 900mg bid (cohort 2, n=7). PK in Cycle 1 were determined on day 1 (D) and day 21 (telatinib). In Cycle 2 comparative PK profiles for both telatinib and D were sampled on days 1–3. Results: Thirteen patients (pts) with advanced solid tumors were enrolled (9M/4F; median age: 56 [range: 34–69]; ECOG PS 0/1: 3/10). A total of 69 cycles have been completed (range,1–10). Treatment-emergent adverse events of CTCAE =3 (NCI-CTC v3.0) were neutropenia (n=11, 79%), fever (n=2, 15%), and fatigue (n=2, 11%). Adverse events of CTC =3 occuring in two pts was febrile neutropenia. Others occurring in only one patient were; hypertension, ALT increase, dehydration, and reversible symptomatic pneumonitis. Study treatment-related adverse events leading to a dose reduction or interruption were neutropenia (n=5, 38%), hypertension (n=1), ALT increase (n=1), and fatigue (n=1). Two pts with prostate ca and 1 with cervical ca had a confirmed partial response. Five pts (1 NSCLC, 1 esophageal ca, 1 renal cell ca and 2 prostate ca) had stable disease for =4 cycles. Mean AUC of D increased by 48% in cohort 1, but only by 16% in cohort 2. Thus, PK data to date do not indicate a clear clinically relevant interaction between telatinib and D. Conclusions: The combination of telatinib and D was tolerated without reaching the toxic dose at telatinib 900mg bid and D 75mg/m2. This combination has demonstrated promising antitumor activity. An extension of the cohort at 900mg bid with 75mg/m2 D is being evaluated to gain further safety and PK data. No significant financial relationships to disclose.
Nuclear factor kB (NF-kB) may predict efficacy of cetuximab therapy in EGFR-positive colorectal cancer
Authors: Scartozzi M. , Bearzi I. , Pierantoni C. , Mandolesi A. , Loupakis F. , Catalano V. , Berardi R. , Silva R. , Falcone A. , Cascinu S. 
Published: March 2020

14036 Background: NF-kB is part of the aberrant activation of the EGFR-downstream signalling pathway in colorectal tumours, which is described to be inhibited by anti-EGFR therapies. Methods: We retrospectively analysed nuclear immunoreactivity for NF-kB with the aim to determine a correlation between NF-kB expression and outcome in terms of response rate and time to progression in EGFR-positive advanced colorectal cancer patients receiving cetuximab and irinotecan. Results: To date 67 patients (40 males and 27 females, median age 62, range 38–78) were analysed. Cetuximab and irinotecan were administered as a second-line in 18 cases (27%) and after = 3 lines of chemotherapy in the remaining 49 patients (63%). Among the 56 patients evaluable for response we observed a partial (PR) or a complete response (CR) in 10 and 1 cases respectively for an overall response rate of 20%. Twenty-seven patients (48%) obtained progressive disease, median time to progression (TTP) was 3,6 months, median overall survival was 16 months. NF-kB was positive in 46 cases (69%). All main clinical characteristics resulted well balanced between NF-kB positive and NF-kB negative patients. Response rate was 6% (2 PR) vs 43% (8 PR and 1 CR) (p= 0.001) in NF-kB positive and NF-kB negative tumours respectively whereas progressive disease was observed in 19 (54%) vs 8 (23%) cases in NF-kB positive and NF-kB negative cases respectively. Median TTP in NF- kB positive patients was 2.9 months versus 6.8 months in the remaining NF-kB negative patients (p= 0.01). Conclusions: Both the difference in median TTP and in response rate seem to confirm that NF-kB may play a crucial role in predicting the efficacy of cetuximab therapy in advanced colorectal tumours. The analysis is ongoing and updated results on an expanded number of cases will be presented. No significant financial relationships to disclose.
A phase I study with exploratory pharmacodynamic endpoints of XL647, a novel spectrum selective kinase inhibitor, administered orally daily to patients (pts) with advanced solid malignancies
Authors: Wakelee H. A. , Molina J. R. , Fehling J. M. , Lensing J. L. , Sikic B. I. 
Published: March 2020

14044 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumorigenesis, angiogenesis, and metastasis, including EGFR/ErbB1, ErbB2/HER2, VEGFR2/KDR, and EphB4. In a previous Phase I study, the MTD was 350 mg when XL647 was dosed orally for 5 consecutive days every 14 days. Of 41 pts treated, one pt with NSCLC achieved a PR and 14 pts had prolonged stable disease (3.5–14+ months). The purpose of the present study is to determine the MTD of XL647 administered orally on a continuous daily schedule. Methods: Pts are enrolled in successive cohorts to receive XL647 daily for repeated 28 day cycles. PK sampling is performed to determine Cmax, and AUC at each dose level. Plasma samples are analyzed by ELISA for mechanism-of-action related molecules. Eyebrow hair bulbs are being evaluated by IHC to monitor effects of XL647 on signal transduction pathways downstream of EGFR. Tumor response is assessed every 8 weeks by RECIST. Pts remain on study until PD or unacceptable AEs. Results: Twelve pts have been enrolled. The starting dose was 75 mg (n=3) and has been escalated to150 mg (n=3), 200 mg (n=3) and 300 mg (n=3). To date, dose escalation continues as no DLTs have occurred and the MTD has not been determined. Ten pts remain on study, including 4 with stable disease for at least 3 months. In cohort 2, eyebrow samples from 3 pts were analyzed. XL647 caused a significant reduction in the phosphorylation of the EGFR downstream signaling kinases AKT (up to 73%) and ERK (up to 78%) in 2/3 and 3/3 pts, respectively. Preliminary analysis of potential plasma protein biomarkers from pts in cohorts 1 and 2 showed a trend towards upregulation of PlGF plasma levels in 4/6 pts during XL647 treatment. Conclusions: XL647 is well-tolerated when administered daily at doses tested to date. Dose escalation will continue until the MTD is defined. Analysis of eyebrow samples demonstrated its feasibility as a potential surrogate epidermal tissue for assessing inhibition of EGFR downstream targets by XL647. Updated safety, PK and pharmacodynamic results will be presented. [Table: see text]