Novel organic arsenic molecule darinaparsin: Development of IV and oral forms

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8501-8501 ◽  
Author(s):  
I. Lossos ◽  
M. D. Craig ◽  
M. S. Tallman ◽  
R. V. Boccia ◽  
P. R. Conkling ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Complete Response ◽  
Median Number ◽  
Two Phase ◽  
Phase I Studies ◽  
Advanced Malignancies

8501 Background: Darinaparsin (ZIO-101) is a novel organic arsenical active against diverse cancers in vitro, and in vivo. Darinaparsin i.v. activity in lymphoma is being evaluated in a phase II study. Darinaparsin is orally bioavailable; the oral form is being investigated in two phase I studies in patients with advanced malignancies. Methods: Phase II trial is being conducted in patients diagnosed with advanced lymphomas who had ≥ 1 prior therapy. Patients receive 300 mg/m2/day of darinaparsin i.v. for 5 consecutive days every 28 days. Efficacy and safety are evaluated by standard criteria. Phase I oral dose escalation studies are being conducted in patients with advanced malignancies and explore safety, MTD, DLTs and preliminary efficacy of continuous and intermittent dosing schedules. Starting continuous dose is 100 mg BID for 3 weeks with 1 week rest, starting intermittent dose is 300 mg twice weekly for 3 weeks followed by 1 week rest. Results: The phase II study has accrued 28 lymphoma patients (21 non-Hodgkin's, 7 Hodgkin's); median age at baseline 61 years, ECOG ≤2, median number of prior therapies 3. Seventeen subjects have received at least 2 cycles of darinaparsin and are evaluable for efficacy. Of these, 1 subject (PTCL) has achieved a complete response, 3 - partial responses (2 marginal zone, 1 Hodgkin's), and 4 stable disease (2 PTCL, 1 DLBCL, 1 Hodgkin's). A total of 63 cycles of darinaparsin have been administered to subjects with lymphoma. No Gr. 3 or higher drug-related AEs were reported. Two SAEs were considered possibly drug-related (fall; neutropenic fever). Phase I studies accrued 35 patients; median age at baseline 58 years, ECOG ≤2, median number of prior therapies 3. Predominant tumor types include: colorectal (17), pancreatic (3), NHL (3). Current darinaparsin dose levels: continuous 200 mg BID, 2× weekly 900 mg. Of 18 patients evaluable for efficacy, 10 demonstrate SD ≥ 3 cycles. Oral darinaparsin bioavailability is 58%. Drug-related AEs include nausea/vomiting, fatigue, decreased appetite/anorexia. Conclusions: Darinaparsin is active in heavily pretreated patients with advanced lymphoma and has been very well tolerated. Oral darinaparsin is also well tolerated, and shows early activity. [Table: see text]

Effects of Ofloxacin Administration on the Reliability of Urine Glucose Testing

1996 ◽  
Vol 30 (5) ◽  
pp. 469-472
Author(s):  
Tsong-Mei Tsai ◽  
Brian F Shea ◽  
Paul F Souney ◽  
Fred G Volinsky ◽  
Joseph M Scavone ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Tertiary Care ◽  
Urine Samples ◽  
Care Hospital ◽  
Open Label ◽  
Urine Glucose ◽  
Glucose Testing

OBJECTIVE: TO study the effects of ofloxacin on the reliability of urine glucose testing. DESIGN: Open-label, nonrandomized. SETTING: A university-affiliated tertiary care hospital, ambulatory clinic. PARTICIPANTS: Ten healthy volunteers (8 men and 2 women) aged 22-39 years. MAIN OUTCOME MEASURES: Phase I (in vitro) involved the addition of selected amounts of ofloxacin to a set of standard 50-mL urine samples prepared to simulate glycosuria. Phase II (in vivo) involved the oral administration of ofloxacin 400 mg to 10 subjects. Urine was collected: (1) immediately predose, (2) pooled 0–4 hours postdose, and (3) pooled 4–8 hours postdose. Known glucose concentrations were then added to these samples. Clinitest and Diastix tests were performed on all samples. The accuracy of these tests in determining glucose concentrations was compared among urine samples taken before and after ofloxacin dosing. RESULTS: None of the ofloxacin concentrations in phase I (0,25,50, 100, 200,400, and 800 μg/mL) influenced these testing methods at the urine glucose concentrations of 0.0%, 0.5%, 1%, and 2%. Likewise, the accuracy of these two tests was unaffected by ofloxacin administration in phase II. CONCLUSIONS: In single-dose administration, ofloxacin does not interfere with Clinitest or Diastix for determining urine glucose concentrations. Supported by a grant from the RW Johnson Pharmaceutical Research Institute. Presented in abstract form at the American College of Clinical Pharmacy 1994 Winter Practice and Research Forum, February 6–9, 1994, San Diego. CA.

Combination of Oxaliplatin Plus Irinotecan in Patients With Gastrointestinal Tumors: Results of Two Independent Phase I Studies With Pharmacokinetics

1999 ◽  
Vol 17 (6) ◽  
pp. 1751-1751 ◽  
Author(s):  
Ernesto Wasserman ◽  
Caroline Cuvier ◽  
François Lokiec ◽  
François Goldwasser ◽  
Salima Kalla ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Two Phase ◽  
Phase I Studies ◽  
Phase Ii Studies ◽  
Minute Period ◽  
Grade 3 ◽  
Febrile Episodes

PURPOSE: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. PATIENTS AND METHODS: Patients with a performance status (PS) of ≤2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m2 for oxaliplatin and 150 to 250 mg/m2 for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m2 plus irinotecan 200 mg/m2 in one study and oxaliplatin 110 mg/m2 plus irinotecan 250 mg/m2 in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2. At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION: This combination is feasible, with activity in 5-FU–resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.

Gas Chromatographic Determination of Poly chlorinated Biphenyls (as Aroclor 1254) in Serum: Collaborative Study

1989 ◽  
Vol 72 (4) ◽  
pp. 649-659
Author(s):  
Virlyn W Burse ◽  
Margaret P Korver ◽  
Larry L Needham ◽  
Chester R Lapeza ◽  
Elizabeth L Chester R ◽  
...  
Keyword(s):  
Phase I ◽  
Silica Gel ◽  
Phase Ii ◽  
Collaborative Study ◽  
Chlorinated Hydrocarbons ◽  
Aroclor 1254 ◽  
Relative Standard

Abstract A gas chromatographic-electron capture detection method for determining the concentration of polychlorinated biphenyls (PCBs) as Aroclor 1254 (AR 1254) in serum was evaluated through a 2-phase collaborative study. In Phase I, each collaborator's lot of Woelm silica gel (70-150 mesh) was evaluated for elution and recovery of AR 1254, which had been added in vitro at 25 ng/mL to a serum extract. In Phase II, each collaborator analyzed a series of bovine serum samples that contained the following: (1) in vitro-spiked AR 1254; (2) in vivo AR 1254 and 8 in vitro-spiked chlorinated hydrocarbons; (3) in vivo AR 1254 only; (4) 8 in vitro-spiked chlorinated hydrocarbons only; and (5) neither AR 1254 nor chlorinated hydrocarbons above the detection limit of the method. In Phase I, the average recovery of AR 1254 from silica gel for the 6 collaborators was 87.9 ± 15.44% (mean ± 1 SD; N = 18; range = 52.3-105.8%). In Phase II, the analysis of in vitro spikes of AR 1254 in serum at 8.58,16.8, 41.8, and 84.3 ppb gave mean (X) interlaboratory recoveries of 89.0, 83.3, 79.4, and 76.9%, respectively, with within-laboratory (repeatability) relative standard deviations (RSDr) of 18.8, 20.5, 10.2, and 14.1%, respectively, and among-laboratory (reproducibility) relative standard deviations (RSDR) of 21.5, 21.1, 14.6, and 20.8%, respectively. The determination of in vivo AR 1254 in samples containing approximately 10, 25, 50, and 100 ng/mL of AR 1254 resulted in interlaboratory means of 10,22,39, and 79 ng/mL, respectively, with RSDr = 6.7,9.7,6.4, and 5.8%, respectively, and RSDR = 20.6,16.0, 10.9, and 10.3%, respectively. The precision of the method for incurred AR 1254 showed a maximum RSDr of less than 10% and a maximum RSDR of less than 21% for a concentration range of 10-100 ng/mL. The accuracy of the method as demonstrated by the mean recovery of in vitro-spiked AR 1254 over a concentration range of 8.58-84.3 ng/mL was 82.2%. The method has been approved interim official first action.

Pilot study of fixed-dose bevacizumab (200 mg) for solid malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14600-e14600
Author(s):  
S. K. Reddy ◽  
M. Curti ◽  
M. Janis ◽  
R. Minow
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Optimal Dose ◽  
Median Number ◽  
Fixed Dose ◽  
Phase I Studies ◽  
Phase Ii Studies ◽  
Prospective Phase ◽  
Grade 3 ◽  
Grade Iii

e14600 Background: We report our initial experience with fixed dose bevacizumab at 200mg (approximately 3mg/kg). Phase I studies suggested that an optimal dose for phase II studies with bevacizumab is 3mg/kg and that circulating VEGF was undetectable at 0.3mg/kg. (Gordon et al. JCO 2001) We proposed a fixed-dose regimen of bevacizumab which we hypothesized would yield equivalent response rates with reduced toxicities and cost versus higher-dose regimens. Patients with advanced malignancies for whom bevacizumab would be indicated were analyzed. Methods: 15 patients were treated with 200mg bevacizumab in combination with antineoplastic therapy. 6 patients had NSCLCa, 8 patients had Colorectal cancer, and 1 patient had BRCA. Results: 15 patients are evaulable for response and have completed a total of 234 doses of bevacizumab (median number of doses =13) with no grade III/IV toxicity, or bevacizumab associated toxicities seen. No grade III or greater hypertension was observed. Proteinuria was not formally assessed, but no grade 3 or greater proteinuria was reported. All patients are evaluable for response with overall response rate of 33% (5/15). With a median follow-up (from the start of bevacizumab) of 452 days (222–1,699 days), median survival has not been reached with only 2 deaths. Conclusions: Fixed dose bevacizumab appears to be effective, less toxic, significantly less expensive and supported by biologic rationale and prior phase I studies and warrants further investigation. Additional patients will be accrued in a prospective phase II trial. [Table: see text]

scholarly journals Urinary Excretion Kinetics of 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) and Its Phase I and Phase II Metabolites in Humans following Controlled MDMA Administration

2011 ◽  
Vol 57 (12) ◽  
pp. 1748-1756 ◽  
Author(s):  
Andrea E Schwaninger ◽  
Markus R Meyer ◽  
Allan J Barnes ◽  
Erin A Kolbrich-Spargo ◽  
David A Gorelick ◽  
...  
Keyword(s):  
Urinary Excretion ◽  
Phase I ◽  
Phase Ii ◽  
Urine Analysis ◽  
Liver Microsomes ◽  
Forensic Toxicology ◽  
Urinary Metabolites ◽  
Phase Ii Metabolites

BACKGROUND 3,4-Methylendioxymethamphetamine (MDMA) is excreted in human urine as unchanged drug and phase I and II metabolites. Previous urinary excretion studies after controlled oral MDMA administration have been performed only after conjugate cleavage. Therefore, we investigated intact MDMA glucuronide and sulfate metabolite excretion. METHODS We used LC–high-resolution MS and GC-MS to reanalyze blind urine samples from 10 participants receiving 1.0 or 1.6 mg/kg MDMA orally. We determined median Cmax, tmax, first and last detection times, and total urinary recovery; calculated ratios of sulfates and glucuronides; and performed in vitro–in vivo correlations. RESULTS Phase II metabolites of 3,4-dihydroxymethamphetamine (DHMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-dihydroxyamphetamine (DHA), and 4-hydroxy-3-methoxyamphetamine were identified, although only DHMA sulfates, HMMA sulfate, and HMMA glucuronide had substantial abundance. Good correlation was observed for HMMA measured after acid hydrolysis and the sum of unconjugated HMMA, HMMA glucuronide, and HMMA sulfate (R2 = 0.87). More than 90% of total DHMA and HMMA were excreted as conjugates. The analyte with the longest detection time was HMMA sulfate. Median HMMA sulfate/glucuronide and DHMA 3-sulfate/4-sulfate ratios for the first 24 h were 2.0 and 5.3, respectively, in accordance with previous in vitro calculations from human liver microsomes and cytosol experiments. CONCLUSIONS Human MDMA urinary metabolites are primarily sulfates and glucuronides, with sulfates present in higher concentrations than glucuronides. This new knowledge may lead to improvements in urine MDMA and metabolite analysis in clinical and forensic toxicology, particularly for the performance of direct urine analysis.

scholarly journals Phase I studies of peptide vaccine cocktails derived from GPC3, WDRPUH and NEIL3 for advanced hepatocellular carcinoma

Immunotherapy ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 371-385
Author(s):  
Masafumi Ikeda ◽  
Takuji Okusaka ◽  
Izumi Ohno ◽  
Shuichi Mitsunaga ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase I ◽  
Peptide Vaccine ◽  
Complete Response ◽  
Advanced Hepatocellular Carcinoma ◽  
Two Phase ◽  
Good Tolerability ◽  
Clinical Trial Registration ◽  
Phase I Studies ◽  
Advanced Hcc

Aim: Two peptide cocktail vaccines using glypican-3, WD-repeat-containing protein up-regulated in hepatocellular carcinoma (HCC) and nei endonuclease VIII-like three epitopes were evaluated in advanced HCC in two Phase I studies. Patients & methods: Study 1 evaluated dose-limiting toxicities (DLTs) of peptides 1–3 (HLA-A24-restricted) and study 2 evaluated DLTs of peptides 1–6 (HLA-A24 or A02-restricted). Results: Overall, 18 and 14 patients were enrolled in studies 1 and 2, respectively. No DLTs were observed up to 7.1 mg of the vaccine cocktail. No complete response/partial response was observed. Stable disease was reported in nine and five patients with a disease control rate of 52.9% and 35.7% in studies 1 and 2, respectively. Conclusion: Both vaccines showed good tolerability and potential usefulness against HCC. Clinical trial registration: JapicCTI-121933 ; JapicCTI-142477

Phase II study of gefitinib in metastatic or locoregionally recurrent nasopharyngeal carcinoma (NPC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15509-15509
Author(s):  
A. T. Chan ◽  
B. Ma ◽  
E. P. Hui ◽  
A. King ◽  
M. Kam ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Growth Factor Receptor ◽  
Median Number ◽  
Molecule Inhibitor ◽  
Disease Stabilization ◽  
Recurrent Nasopharyngeal Carcinoma ◽  
Epidermal Growth ◽  
Grade 3

15509 Background: Our preclinical work has shown that epidermal growth factor receptor (EGFR) is expressed in ∼ 80% of undifferentiated NPC & gefitinib is a small molecule inhibitor against EGFR with anti-proliferative activity in NPC in vitro. Methods: We report the preliminary result of a phase II study of gefitinib in patients (pts) who progressed after 1–2 lines of chemotherapy (at least 1 line had to contain platinum) for metastatic or locoregionally recurrent NPC. Fourteen Chinese pts were accrued, of whom the median age was 48 years (range 34–64 years), 12 were males, 9 had metastatic & 5 had locoregionally recurrent NPC. All received gefitinib at 500mg/day orally, every 28 days with radiological assessment performed every 2 cycles for a maximum of 8 cycles. Ten pts had 1 line & 5 pts had 2 lines of prior chemotherapy. Results: The median number of administered cycles was 2 (range 1–8). Of the 14 pts evaluable for toxicity, the most commonly reported were acneiform rash (86%, grade 1–2, n = 10; grade 3, n = 4), dry skin (86%, grade 1–2), diarrhea (71%, grade 1–2), fatigue (64%, grade 1–2), anorexia (64%, grade 1–2) & nausea (20%, grade 2). Other grade 3–4 toxicities included fever (n = 2, skin cellulitis, infective pneumonia), hyponatremia (n = 2), near-syncope (n = 2), anemia (n = 1). Dose reduction to 250mg/day was required in 4 pts who encountered grade 3 skin rash. Of the 11 pts evaluable for response, 2 had stable disease (SD) for ≥ 6 months (m) (mean 6.8 m) 9 progressed and no partial responders. Five pts have died mostly of progressive disease & there were no treatment-related deaths. Conclusions: Gefitinib is well tolerated in pts with advanced NPC with some pts experiencing disease stabilization for over 6 months & study accrual is ongoing. No significant financial relationships to disclose.

Phase II study of weekly docetaxel plus cisplatin as first-line therapy in advanced or metastatic non-small cell lung cancer (CHN TAX-206)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18173-18173
Author(s):  
D. Chu ◽  
J. Li ◽  
X. Zhang ◽  
J. Liu ◽  
Z. Chen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Complete Response ◽  
Median Number ◽  
Common Adverse Event ◽  
Stage Iiib ◽  
Hematologic Toxicity ◽  
First Line ◽  
Weekly Administration ◽  
Weekly Docetaxel

18173 Background: There has been increasing interest in the use of weekly administration of docetaxel as a way of reducing its hemotologic toxicity. Weekly docetaxel plus cisplatin has also shown promising efficacy and well tolerability for first-line treatment of advanced or metastatic NSCLC in our previous phase I study (2002 ASCO, abstract No 2744). We conducted this phase II trial to further evaluate this regimen’s efficacy and toxicity. Methods: Patients with histologically confirmed stage IIIB or IV NSCLC were treated with docetaxel (35 mg/m2, 30 min. iv. infusion) on days 1, 8, 15 and cisplatin (75 mg/m2, 30 min. iv. infusion) on day 1 repeated every 4 weeks for up to 6 cycles. Pts received oral dexamethasone 7.5 mg twice daily from the day before chemotherapy and consecutive two days thereafter. The primary endpoint of this phase II study is efficacy of the regimen. Results: A total of 83 patients were enrolled from July 2002 to June 2004, 75 patients were evaluable for response and 83 for safety. Median age was 55 years (range 29–70 years); and 69.9% were male; adenocarcinoma/squamous cell carcinoma/others (65/12/6); stage IIIB /IV( 47/36); ECOG PS 0/1(52/31). Median number of chemotherapy cycles was 3(1–5). One CR (complete response) and 22 PR (partial response) were achieved with an ORR of 30.7% in the evaluable patients. The 1-year survival was 48.6% with a median survival of 10.7 months (range: 3–34 months). Neutropenia was the most common adverse event, though most were mild; Grade III/IV toxicities per patient were: Neutropenia (15.6%), asthenia (11%), skin/nail toxicity (10.8%) and vomiting (9.6%). Febrile neutropenia was not observed. Conclusions: In the present study, the combination of weekly administration docetaxel combining with cisplatin appears well tolerated with very low frequency of severe hematologic toxicity and similarly efficacious as 3-weekly docetaxel in NSCLC pts. No significant financial relationships to disclose.

ME-143, a novel inhibitor of tumor-specific NADH oxidase (tNOX): Results from a first-in-human phase I study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3067-3067
Author(s):  
Carla Kurkjian ◽  
Shubham Pant ◽  
Howard A. Burris ◽  
Johanna C. Bendell ◽  
Suzanne Fields Jones ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Nadh Oxidase ◽  
Testicular Atrophy ◽  
Pharmacokinetic Analysis ◽  
In Vivo Models ◽  
Human Dose

3067 Background: ME-143, a second generation isoflavone-derived compound, specifically binds tNOX, shifting the ceramide-S1P equilibrium and resulting in prompt apoptosis via pleotrophic caspase activation. A first generation compound, phenoxodiol (PXD), showed promising phase II activity with cisplatin in ovarian cancer. ME-143 is broadly active against human cancers in both in vitro and in vivo models, with IC50’s 1-2 logs lower than PXD. Toxicology studies up to 140mg/kg (human dose equivalent ~23mg/kg) showed no STD level. The only significant findings were dose dependent hypospermia and testicular atrophy in rats. We report clinical and PK results from the first-in-human phase I study. Methods: A 3+3 dose escalation design was used with 4 dose cohorts: 2.5, 5, 10, and 20mg/kg IV over 30 minutes weekly times 3, followed by a 1 week break, and then continuous weekly dosing in patients with advanced solid tumors. Dense PK sampling was performed at 0, 5, 10, 20, 30, 60, 90, 120, 180, 240, 300, 360 minutes, and 24 hours post-infusion day 1 and 15 of the first treatment cycle. Results: To date, 9 patients have been enrolled, 3 in each of the first 3 cohorts. Median time on treatment is 56 days (range 6 to 62). Five patients have discontinued protocol therapy, all due to PD. No DLT’s have been observed. Related AE’s include grade 1: myalgia (1), anorexia (1), fatigue (2), headache (1), diarrhea (1), vomiting (1) and grade 2: fatigue (1). Preliminary PK analyses in the first 2 cohorts is shown in table below. Conclusions: ME-143 appears to be well tolerated when administered IV. Preliminary PK data suggest that drug levels achieve target concentration extrapolated from pre-clinical studies (AUC0-t ~10mg*hr/mL) and exceed levels obtained with IV PXD in the phase II study (AUC0-t ~2mg*hr/mL) . Updated clinical data from all planned dose cohorts, including the final pharmacokinetic analysis and planned phase II dose, will be presented. [Table: see text]

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