bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study examining weekly dosing and pharmacokinetics (PK) of a novel spectrum selective kinase inhibitor, XL999, in patients (pts) with advanced solid malignancies (ASM)
Authors: Cooper J. , Mita M. M. , Curtright J. , Ricart A. , Mita A. , Takimoto C. , Tolcher A. , Dowlati A. , Flick S. , Papadopoulos K. P. 
Published: March 2020

13024 Background: XL999 is a small molecule inhibitor of multiple kinases involved in tumor cell growth, angiogenesis, and metastasis, including VEGFR2 (KDR), PDGFRα/β, FGFR1/3, FLT-3, and SRC. A phase I study of XL999 administered as a 4 hr infusion every 2 weeks in pts with ASM showed that the maximum tolerated dose (MTD) was 3.2 mg/kg and the plasma t1/2 was approximately 24 hrs. Three pts dosed at 0.2–1.6 mg/kg (anaplastic thyroid cancer [1], renal cell carcinoma [1], hepatic squamous cell carcinoma [1]) had partial responses and 9 pts had stable disease for 3 to 11 months. Based on these data, a weekly (wkly) dosing schedule with PK monitoring was explored. Methods: XL999 at 3.2 mg/kg was administered to pts as a 4 hr infusion on day (d) 1 and 8 with toxicity assessment. Pts received further doses of XL999 wkly in the absence of unacceptable toxicity, disease progression, or accumulation based on PK results. Results: Overall 15 pts were enrolled and 7 were initially dosed at 3.2 mg/kg. Two of these pts experienced severe drug related toxicities, including 1 pt with G3 fatigue who was able to continue wkly XL999 at 2.4 mg/kg and another pt who was discontinued after developing reversible cardiac dysfunction on d1. The next 8 pts were treated at 2.4 mg/kg and none of these has experienced any G2 or worse drug related adverse events. One asymptomatic pt with non-specific ECG changes after d1 was discontinued from study. Four of 11 evaluable pts had SD. In 7 evaluable pts treated at the 2.4 dose level, the mean Cmax was 519 ng/mL with moderate interpatient variability (coefficient of variation, CV) of 38%. Intrapatient variability in the Cmax values on d1 and d15 was moderate (≤3-fold); however, there was no evidence of drug accumulation on repeat dosing. Conclusions: XL999 administered wkly as a 4 hr infusion at a dose of 2.4 mg/kg appears to be well tolerated with no evidence of drug accumulation. The safety and PK data suggest that 2.4 mg/kg on a wkly schedule is appropriate for phase 2 studies. [Table: see text]
Phase I trial of the oral histone deacetylase inhibitor MS-275 administered with food
Authors: Donovan E. A. , Sparreboom A. , Figg W. , Trepel J. , Maynard K. , Zwiebel J. , Melillo G. , Gutierrez M. , Doroshow J. , Kummar S. 
Published: March 2020

13036 Background: The histone deacetylase (HDAC) inhibitor MS-275, a synthetic benzamide derivative, has demonstrated antitumor activity in vitro & in vivo. After determining maximum tolerable dose (MTD = 2 mg/m2) & dose limiting toxicity (DLT) for MS-275 given to fasting patients (pts) weekly ×4 q6 weeks, we explored toxicity profile, MTD, & pharmacokinetics (PK) of MS-275 when given po on the same schedule with food. Methods: MS-275 at 2, 4, or 6 mg/m2 was administered to pts with advanced malignancy & PS ≤2, LFTs ≤2.5 × normal, adequate hematopoietic & renal function, & normal resting MUGA. PK samples were analyzed by LC-MS. Data for pts in the fed state were compared to data obtained in previous cohorts of pts treated in the fasting state. Protein acetylation assessed by a novel flow cytometric assay & HDAC enzymatic activity were measured in peripheral blood mononuclear cells (PBMC). Results: 16 pts received a median of 2 cycles (1–5) of MS-275 2–6 mg/m2 with food. No DLT occurred on 2 or 6 mg/m2 (n = 3 each), while 1 pt on 4 mg/m2 (n = 10) had a DLT: grade 3 hypophosphatemia. For 2–6 mg/m2 other grade 3 toxicities were neutropenia & lymphopenia. Grade 1–2 toxicities in >1 pt were leucopenia, anemia, thrombocytopenia, fatigue, nausea, vomiting, headache, hypoalbuminemia, hypophosphatemia, hyponatremia, & hypocalcemia. MTD has not been reached; current dose level is 8 mg/m2. Comparing PK for fasting & fed pts on 2–4 mg/m2, there was no difference in Tmax (0.5h); average Cmax & AUC were 35% & 25% lower, respectively, in fed pts; this difference is not statistically significant. Interindividual variability in exposure to MS-275 increased from 52% in fasting pts to 100% in fed pts. PBMC protein acetylation & HDAC inhibition were seen at all dose levels (2–6 mg/m2) in fed pts. Of 9 pts evaluable for response (2–4 mg/m2), 2 of 6 pts on 4 mg/m2 had stable disease. Conclusions: MTD has not yet been established for MS-275 given with food on this schedule but is ≥4 mg/m2 weekly x4 q6 weeks. Interindividual variability in exposure increases with food. Whether intestinal absorption is decreased when MS-275 is given with food requires further evaluation with additional patients. Drug-related protein hyperacetylation & HDAC inhibition were observed. [Table: see text]
Phase I study of the safety and efficacy of atiprimod, a novel azaspirine, for patients with advanced cancer
Authors: Braiteh F. S. , Yao J. , Camacho L. H. , Ng C. , Hong D. S. , Harris P. , Dhillon N. , Kurzrock R. 
Published: March 2020

13050 Background: Atiprimod (N-N-diethl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) is an oral cationic azaspirane that suppresses angiogenesis by inhibiting both bFGF and VEGF induced proliferation and migration. Atiprimod has been shown to down-regulate multiple growth factors involved in tumor progressions and metastases, including IL-6, TNF-α, and VEGF. Methods: This is an ongoing, single-center, open-label, ascending dose (modified Fibonacci) Phase I trial of oral atiprimod in patients with advanced cancers (3+3 design). Atiprimod was given orally for 14 days every 28-day cycle. The primary objectives are to identify the MTD and to evaluate the safety of atiprimod; the secondary objectives include measuring PK and describing efficacy. Data from these patients enrolled are presented here. Results: Fourteen patients have been treated to date with 60 mg tablets (N = 3), 60 mg capsules (N = 3), 90 mg capsules (N = 3) and 120 mg capsules (N = 5). The most common side effects, which occurred in over half the patients, were related to the gastrointestinal system, and include nausea (11), diarrhea (7), vomiting (4) abdominal pain (2) and dyspepsia (2). These events were generally low-grade, occurred primarily during days of active drug administration and tended to resolve during off-drug days. Less common adverse events were sinus headaches, and elevated serum transaminases, alkaline phosphatase and creatinine. One patient who received prolonged therapy (7 months) developed fever and multi-organ failure of unclear etiology. One patient with uterine leiomyosarcoma experienced a DLT (syncope and hypotension) at 120 mg/day, and that dose level is therefore being expanded up to 6 patients. One patient with midgut carcinoid tumor and liver metastasis achieved a partial remission lasting 2+ months (50% decrease in maximum diameter by RECIST). Three patients (carcinoid = 2 and thymoma = 1) had stable disease for four, four and six months, respectively. Conclusions: Preliminary data indicate that atiprimod was reasonably tolerated, with predominantly gastrointestinal side effects. There is early evidence of anti-tumor activity in carcinoid tumors. Dose escalation continues. [Table: see text]
Safety and pharmacokinetics of intravenous VEGF Trap plus FOLFOX4 in a combination phase I clinical trial of patients with advanced solid tumors
Authors: Mulay M. , Limentani S. A. , Carroll M. , Furfine E. S. , Cohen D. P. , Rosen L. S. 
Published: March 2020

13061 Background: VEGF Trap is a potent angiogenesis inhibitor comprising portions of human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (KDR) extracellular domains fused to the Fc portion of human IgG. VEGF Trap binds VEGF and neutralizes all VEGF-A isoforms plus placental growth factor. FOLFOX4 is an approved chemotherapy regimen for the treatment of colorectal cancer. This study was designed to evaluate the safety and pharmacokinetics (PK) of VEGF Trap plus FOLFOX4 administered intravenously. Methods: Successive cohorts of 3–6 patients (pts) with advanced solid tumors received intravenous VEGF Trap plus FOLFOX4 every 2 weeks. Study endpoints included safety, PK, and immunogenicity. Antitumor activity was assessed by CT scan. Results: Six pts (3 male/3 female), median age 55 (25–74), ECOG PS 0/1/2: 2/4/0, with a variety of advanced solid tumors, including 2 gastric and 2 neuroendocrine tumors, have received a total of 19 cycles of VEGF Trap plus FOLFOX4 across 2 VEGF Trap dose levels (2.0 mg/kg, 4.0 mg/kg) to date. Three of these 6 pts had grade 3 AEs (hypertension [n=2], neutropenia [n=2]), which were manageable and reversible. However, no dose-limiting toxicities or grade 4 AEs have been encountered so far. Preliminary mean free VEGF Trap clearance was 17.1 mL/kg/day. No pts have developed anti-VEGF Trap antibodies. Conclusions: VEGF Trap may be safely combined with FOLFOX4 at the dose levels studied. Preliminary free VEGF Trap clearance did not differ significantly from that seen with single-agent exposure; chemotherapy PK analysis is pending. The maximum tolerated dose has not yet been reached, and dose escalation continues. Updated safety, pharmacokinetic, and preliminary efficacy results from this ongoing study will be presented. [Table: see text]
ABT-869, a novel multi-target receptor tyrosine kinase inhibitor (RTKI), combined with chemotherapy is synergistic in the therapy of acute myeloid leukemia cells with FLT3-ITD mutation (FLT3-AML)
Authors: Zhou J. , Pan M. , Loh S. , Xie Z. , Lim Y. , Lilly M. , Glaser K. , Albert D. , Davidsen S. , Chen C. S. 
Published: March 2020

13064 Background: Internal tandem duplications (ITDs) of fms-like tyrosine kinase 3 (FLT3) receptor are identified in 20–25% of adult AML patients associated with poor prognosis. ABT-869 is active in FLT3-AML and is currently under clinical investigaton. We hypothesize that the combination of ABT-869 with chemotherapy can improve the therapeutic index in FLT3-AML. Methods: Using Calcusyn software, the additive, synergistic or antagonistic effect of ABT-869 with concurrent or sequential cytosine arabinoside (Ara-C) or doxorubicin (Dox) was measured in MV4–11 and MOLM-14 cells. The synergistic combination sequence was further tested in a MV4–11 xenograft model in four groups (10 mice/group) including control, Ara-C, ABT-869, and combination (Ara-C first for 4 days, then daily ABT-869). Cell cycle analysis and apoptosis and signal pathway assays were performed in vitro and in vivo. Results: ABT-869 induced dose- and time-dependent apoptosis on FLT3-AML cells resulting in down regulation of p-FLT3, p-STAT5, Bcl-XL and up regulation of p53 and BID. ABT-869 caused G1-phase arrest and the removal of cells in the S- and G2/M-phase mediated by reduction of cyclins D and E. We observed significant synergistic effect with Ara-C or Dox first, followed by ABT-869, as well as in concurrent treatment with ABT-869 and Dox. Simultaneous treatment with ABT-869 and Ara-C only achieved additive effect. Conversely, we found an antagonistic effect in the sequence of pretreatment of ABT-869 followed by chemotherapy. In a MV4–11 xenograft model, all mice succumbed to leukemia in the control and Ara-C groups (median survival = 53 and 55.5 days respectively). Combination therapy gave a faster reduction of tumor volume compared to ABT-869 treatment alone (p=0.03) without recurrence of leukemia in either group by day 67. In vivo immunohistochemistry (IHC) analysis revealed ABT-869 potently inhibited VEGF and phosphor-ERK. Conclusions: ABT-869 can be given after Ara-C or Dox to act synergistically. Our study suggests that combinations of RTKIs with chemotherapy should be carefully tested prior to clinical protocol development. A clinical trial of such combination therapy in FLT3-AML is warranted. No significant financial relationships to disclose.
Perifosine (P) can be combined with docetaxel (T) without dose reduction of either drug
Authors: Cervera A. , Bernhardt B. , Nemunaitis J. J. , Ebrahimi B. , Birch R. , Richards D. A. , Smith G. B. , Allerton J. P. , Henderson I. C. 
Published: March 2020

13066 Background: Perifosine is an alkylphospholipid that modulates several signal transduction pathways, including Akt, which is often activated in taxane resistant tumors and is thought to be one mediator of such resistance. The combination of T, 75 mg/m2 every 3 weeks, and prednisone (Pr), 5 mg bid has become standard therapy for patients (pts) with metastatic prostate cancer. The addition of P might decrease resistance to T in these patients who often have activated Akt because of PTEN mutations. This phase I trial is the first attempt to combine these agents. Methods: Between 12/04 and 9/05, 39 pts were enrolled. P was given either daily as a 50 mg tablet 1, 2 or 3 times per day on days 1–14 or weekly in doses of 300 mg every 4 - 6 hours 3, 4 or 5 times on days 1–2, 8–9 and 15–16 of each 21 day cycle. T, 75 mg/m2, was given on day 8 of a 21 day cycle with or without Pr. Results: Disease sites: prostate 11, NSCLC 9, ovary 4, head/neck 3, pancreas 3, breast 2 & other 7. Median age was 63 (range 37–80); 24 patients were male and median ECOG performance status was 1 (range 0–2). 34 pts had received prior chemotherapy including 24 previously given a taxane. Three patients were entered at each dose level for each schedule and the cohort expanded to 6 patients if 2 or more patients experienced a grade 3/4 non-hematologic toxicity (DLT) during the first cycle of therapy. A dose level was toxic if 4 or more patients experienced a DLT during cycle 1. The grade 3/4 toxicities for each perifosine dosing schedule are given in the table . Glucose values for the grade 3 toxicities were between 253 and 306. This was seen only in the Pr pts & has not been observed in other P trials. P dose reductions were required in 4% of cycles for daily P, 5% for daily P+Pr and 37% for weekly P. Conclusions: Daily doses up to 150 mg could be administered either with or without Pr but the maximum tolerated dose for the weekly regimen was 1200 mg It is concluded that daily P ± Pr is well tolerated with T 75 mg/m2 q 3 weeks and that daily doses are preferred for phase II studies to further define activity of the combination. [Table: see text] [Table: see text]
Pharmacogenetic influence of OATP1B1 variants *1b and *15 on irinotecan disposition in Asian and Caucasian cancer patients
Authors: Chowbay B. , Sparreboom A. , R Jada S. , Xiaoqiang X. , H Li H. , H Mathijssen R. , H van Schaik R. , Verweij J. , Goh B. C. , Lim R. , H Tan E. 
Published: March 2020

13069 Background: The objective of this study was to evaluate the impact of OATP1B1 (SLCO1B1; OATP-C) functional variants on the disposition of irinotecan in Asian and Caucasian cancer patients. Methods: Irinotecan pharmacokinetic parameters and OATP1B1*1a, *1b, *5 and *15 genotyping data were obtained from Asian (N=71) and Caucasian (N=30) cancer patients receiving the drug as a 90-minute i.v. infusion. Genotypic-phenotypic correlations were assessed in cancer patients from each ethnic group. Results: The *1a/*1a genotype and the *15/*15 diplotype were absent in Caucasian cancer patients but present in Asians (*1a/*1a, N=6; *15/*15, N=1). Statistically insignificant differences were observed between patients carrying *1a/*1b and *1b/*1b genotypes and also between *1b/*15, *15/*15 and *15/*15 diplotypes. Compared to wild-type patients (N=6), total irinotecan clearance normalized by BSA was 2- and 3-fold lower in Asian patients carrying at least one *1b (*1a/*1b + *1b/*1b; N=54; P=0.055) and one *15 (*1b/*15 + *5/*15 + *15/*15; N=11; P=0.001) allele, respectively. Significant differences were also present between Asian patients carrying the *15 diplotype and wild-type patients with regard to exposure levels (Cmax/dose/BSA) to irinotecan (P=0.007), SN-38 (P=0.009) and SN-38G (P=0.004) as well as REC (P=0.005) and REG (0.001). The REG was 5-fold (P=0.022) and 27-fold (P=0.001) lower in Asian cancer patients carrying at least one *1b allele and at least one *15 haplotype, respectively, when compared with wild-type patients. No significant differences in pharmacokinetic parameters were found when comparing Caucasian cancer patients carrying at least one *1b allele and those carrying at least one *15 allele (P>0.05). Conclusions: The genotype and diplotype frequencies of the studied OATP1B1 variants were ethnically dependent, and OATP1B1 genotype status accounts, at least in part, for the observed differences in irinotecan disposition in Asian cancer patients. The lack of significant influence of OATP1B1 variants on irinotecan disposition in Caucasian cancer patients is not clear but may have resulted from the small patient population. No significant financial relationships to disclose.
The combination of arsenic trioxide and rapamycin has potent inhibitory effects on acute myeloid leukemia (AML) cells
Authors: Altman J. K. , Yoon P. J. , Sassano A. , Smith J. , Mears H. , Tallman M. S. , Platanias L. C. 
Published: March 2020

13101 Background: Arsenic trioxide (As2O3) exhibits potent growth inhibitory and pro-apoptotic effects against a variety of neoplastic cells, but the precise mechanisms by which it mediates such effects are not known. The mammalian target of rapamycin (mTOR) is a key cellular regulator of multiple signaling events that control initiation of mRNA translation in leukemia cells. We examined the effects of As2O3 on the activation of mTOR-dependent pathways that regulate initiation of mRNA translation in acute myeloid leukemia (AML) cells. We also determined the effects of the combination of As2O3 with the mTOR inhibitor rapamycin on the growth of AML cell lines. Methods: The human leukemia cell lines, KG-1, U937, and MM6, were incubated and cultured with increasing concentrations of As2O3, in the presence or absence of the mTOR inhibitor rapamycin. Cell lysates were immunoprecipitated with an anti-p70 S6 kinase antibody, and immune-complex kinase assays to detect p70 S6 kinase activity were performed. In addition, cell proliferation assays were carried out in cells treated with or without rapamycin (10 or 20 nM) and increasing concentrations of AS2O3 (0 to 5 uM). Results: As2O3-treatment of U937 cells resulted in strong induction of p70 S6 kinase activity, which was inhibited by concomitant treatment of cells with rapamycin. In cell proliferation assays, we found that rapamycin alone significantly inhibited the growth of U937, KG-1, and MM6 cells. The addition of As2O3 further enhanced the inhibitory effects of rapamycin, in a dose-dependent manner, indicating that the combination of these agents is more potent in inhibiting the growth of AML cell lines than each agent alone. Conclusions: During treatment of AML cell lines with As2O3, the p70 S6 kinase pathway is activated, apparently in a negative feedback regulatory manner. Pharmacological inhibition of mTOR with rapamycin has potent antileukemic properties, which are further enhanced by As2O3. Therefore, the use of As2O3 and rapamycin in combination may be a promising strategy for the treatment of AML. No significant financial relationships to disclose.
Azurin, highly potent and selective anticancer agent for breast cancer
Authors: Yamada T. , Mehta R. , Majumdar D. , Chakrabarty A. M. , Das Gupta T. K. 
Published: March 2020

13106 Background: The use of live or attenuated pathogenic bacteria in the treatment of cancer dates back to the late nineteen hundreds when William B. Coley first reported that inducing Streptococcal infection resulted in tumor regression. However, the hazards of using live bacteria are obvious. Similarly, the results of using attenuated bacteria have been spotty and enthusiasm for it has waxed and waned. Recently, we have shown that redox protein azurin (14 kDa) secreted by an opportunistic pathogen, Pseudomonas aeruginosa, is not only cytotoxic to cancer cells in vitro but also produces tumor regression in athymic mice without producing any toxicity (PNAS, 99, 14098–14103, 2002; Science’s STKE, 158, tw416, 2002). Methods: In this study, we show the effect of 1mg/kg of azurin injected i.p. starting 72 hours after inoculation of 5x107 MCF-7 breast cancer cells in estradiol pretreated nude mice for 28 days (n = 20, control = 10, azurin-treated = 10). Results: Univariate analysis of the data showed the difference in tumor growth rates between control animals and azurin-treated animals was significant. For instance, 22 days after the start of treatment, the mean tumor volume in azurin-treated animals was only 22% of the mean tumor volume in the control mice (i.e., 0.0267 cm3 + 0.124 cm3 respectively, P = 0.0179 Kruskal-Wallis test). At the end of the experiment on the 29th day there was a reduction in the tumor volume by 85% in the treated group. We used a multivariate model, where the tumor growth over time was taken to be exponential with coefficients that were subject specific mixed effect (For control, tumor volumes = exp (−4.23 + 0.06 time) while for the treated group it was tumor volume = exp (−4.23 + 0.03 time)). The difference is statistically significant (P = 0.0456). Taken together, this in vivo data shows azurin exerts an inhibitory effect in the growth and progression of MCF-7 tumor xenotransplants. During the 28 days of treatment, treated animals did not show any sign of toxicity. Conclusions: Bacterial redox protein azurin can be explored as a novel therapeutic agent for treatment of breast cancer. Recently, we have prepared a truncated version of azurin which has 28 amino acids. It appers that this chemically synthesized peptide (2.8 kDa) has similar properties as azurin. No significant financial relationships to disclose.
A phase 1 study of daily oral perifosine (P) with weekly paclitaxel (T)
Authors: Ebrahimi B. , Nemunaitis J. J. , Shiffman R. , Birch R. , Diaz-Lacayo M. , Berdeaux D. H. , Rettenmaier M. A. , Goggins T. F. , Henderson I. C. 
Published: March 2020

13117 Background: P is an oral signal transduction modulator with limited toxicity. P combined with 3-weekly T led to no toxicity beyond that expected with each drug alone. Weekly T is more effective than 3-weekly T in some settings (Seidman, ASCO 2004:512), so this study evaluated whether weekly T altered the tolerance to P. Methods: Twelve patients (pts) were enrolled. T was given at 80 mg/m2 on days 1, 8 and 15 of a 28 day cycle. P, 50 mg, was given 1, 2 or 3 times a day on days 1–21 of each cycle. Results: Tumor types were lung 2, breast 4, endometrium 3 and other 3. Median age was 55 (range 41–82). All pts had received prior chemotherapy (median 2.5, range 1–3 regimens) and 6 a prior taxane. Three pts were entered at each dose and the cohort expanded to 6 pts if 2 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose was toxic if 4 or more pts experienced a DLT during cycle 1. Since toxicity was not dose limiting in any cohort, the 150 dose was expanded to 6 pts. There were no grade 3/4 hematologic toxicities. The grade 3/4 non-hematologic toxicities at least possibly related to perifosine are given in the table below: The high glucose values were 276 and 277. A total of 38 cycles and a median of 2.5 cycles per pt (range 1–10+) were delivered. Full dose T was given in 85% of cycles (50 mg–100%, 100 mg–85%, 150 mg–86%). Dose reductions of T in 3 pts were related to neuropathy, suspected bronchitis and fatigue. One pt treated at 100 mg requested T be stopped after 6 cycles due to neurotoxicity and has received 6 additional cycles of perifosine alone. Perifosine dose reductions were required in 13% of cycles (50 mg - 0%, 100 mg - 21%, 150 mg - 9%). One pt each was reduced due to constipation, nausea and diarrhea. Five of 7 evaluable pts had stable disease (breast 2, cervix, endometrium, thyroid) for at least 3 months. Four remain stable at 3+ to 10+ months. Conclusions: The single agent doses of P (150 mg daily) & T (80 mg/m2 weekly) were given without increasing the toxicities expected from using each drug alone. Phase II studies are warranted to define the activity of the combination. [Table: see text] [Table: see text]