The OECD Validation Program of the H295R Steroidogenesis Assay for the Identification of In Vitro Inhibitors and Inducers of Testosterone and Estradiol Production. Phase 2: Inter-Laboratory Pre-Validation Studies (8 pp)

2007 ◽  
Vol 14 (S1) ◽  
pp. 23-30 ◽  
Author(s):  
Markus Hecker ◽  
Henner Hollert ◽  
Ralph Cooper ◽  
Anne-Marie Vinggaard ◽  
Yumi Akahori ◽  
...  
Keyword(s):  
Validation Studies ◽  
Phase 2 ◽  
Production Phase

scholarly journals CTNI-18. FINAL RESULTS OF A PHASE 2 STUDY OF EFFICACY, SAFETY AND INTRATUMORAL PHARMACOKINETICS (PK) OF SELINEXOR MONOTHERAPY IN RECURRENT GLIOBLASTOMA (rGBM)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii46-ii46
Author(s):  
Andrew Lassman ◽  
Patrick Wen ◽  
Martin van den Bent ◽  
Scott Plotkin ◽  
Annemiek Walenkamp ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Median Number ◽  
Recurrent Glioblastoma ◽  
Phase 2 ◽  
Nuclear Retention ◽  
Phase 2 Trial ◽  
Human Gbm

Abstract BACKGROUND Selinexor is an FDA-approved first-in-class, oral selective nuclear export inhibitor which forces nuclear retention of many tumor suppressor proteins. METHODS We conducted a phase 2 trial of selinexor monotherapy for adults with recurrent GBM including a surgical arm to explore intratumoral PK and 3 medical arms to optimize dosing. Prior treatment with radiotherapy and temozolomide was required; prior bevacizumab was exclusionary. The primary endpoint was 6-month progression-free survival (6mPFS) rate. RESULTS Selinexor administered ~2 hours pre-operatively yieleded average intratumoral concentration (136 nM, n=6) comparable to the in vitro IC50 (130 nM) from 7 primary human GBM cell lines. Among all 68 patients accrued to 3 medical arms (~85 mg BIW, n=24; 60 mg BIW, n=14; 80 mg QW, n=30), median age was 56 years (21–78). Median number of prior lines of therapies was 2 (1–7). At 80 mg QW, 28% patients were progression-free at the end of cycle 6; the 6mPFS was 17%; disese control rate by RANO was 37% (1 CR, 2 PRs, 7 SD) among 27 evaluable patients; responses were durable (median 11.1 months), and treatment lasted for 442, 547 and 1282 days in 3 responders, as of data lock, with one responder remaining on treatment off study; median overall survival was 10.2 months with 95% CI (7.0, 15.4). The ~85 mg BIW-schedule was abandoned due to poor tolerability. The related adverse events (all grades) in patients on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (41.7%/64.3%/66.7%), fatigue (70.8%/71.4%/50.0%), neutropenia (29.2%/14.3%/33.3%), decreased appetite (45.8%/71.4%/26.7%), thrombocytopenia (66.7%/28.6%/23.3%) and weight loss (16.7%,/42.9%/6.7%). CONCLUSION Selinexor monotherapy demonstrated encouraging intratumoral penetration and efficacy, with durable disease control in rGBM. Monotherapy dose at 80 mg QW is recommended for further development in rGBM. A phase 1/2 study of combination therapy for newly diagnosed or rGBM has been initiated (NCT04421378).

PSVII-15 Effects of electrolyzed reduced water on intake, digestion and ruminal fermentation parameters in beef cattle

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 446-447
Author(s):  
Natasha L Bell ◽  
Daisy A Gonzalez ◽  
Kendrah DeLeon
Keyword(s):  
Transition Period ◽  
Rumen Fluid ◽  
Phase 1 ◽  
Analysis Data ◽  
Phase 2 ◽  
Ruminal Fermentation ◽  
Fermentation Parameters ◽  
Reduced Water ◽  
Electrolyzed Reduced Water

Abstract The effect of electrolyzed reduced water consumption by cattle is not well defined. The objective of this study was to evaluate the effect of electrolyzed reduced water on intake, in vitro true digestibility (IVTD), ORP and pH in four ruminally cannulated steers (4 Bos taurus; 317 kg BW). Steers were subjected to a two period (14 d), two treatment crossover design. Treatment included: 1) standard water (CON; pH = 7.0 ± 1.0) or 2) electrolyzed reduced water (ERW; pH = 9.0 ± 1.0). The project comprised of two studies where the effects of ERW were observed for steers consuming a roughage diet (phase 1) or concentrate diet (phase 2). During Phase 1, animals were provided bermudagrass hay ad libitum. A 14 d transition period followed phase 1 to allow transition of diets. In phase 2, animals were maintained on a concentrate diet. During each period, d 1–8 served as a treatment adaptation phase, d 9–13 allowed for measures of intake and digestion, and rumen fluid was collected at h 0, 2, 4, 8, and 12 after feeding on d 14 for VFA, pH and ORP analysis. Data were analyzed using the MIXED procedure of SAS 9.4 (SAS Inst. Inc., Cary, NC). Intake, digestion, and ruminal fermentation parameters were not different for CON vs ERW steers (P ≥ 0.06). Analysis of VFA data have not been finalized and will be reported later. Results indicate that ERW has no effect on intake, digestion or ruminal fermentation parameters of steers consuming roughage or concentrate diets.

Proposal for assessment of the antimicrobial efficacy of undiluted medical honey: Using a standardized phase 2/step 2 in vitro stainless steel disc carrier test model

2013 ◽  
Vol 1 ◽  
pp. 20-24
Author(s):  
Anna-Maria Goerdt ◽  
Ojan Assadian ◽  
Behzad Razavi ◽  
Dorothee Igelbrink-Holter ◽  
Arne Simon ◽  
...  
Keyword(s):  
Stainless Steel ◽  
Antimicrobial Efficacy ◽  
Test Model ◽  
Phase 2 ◽  
Stainless Steel Disc ◽  
Steel Disc ◽  
Carrier Test

scholarly journals Microbiological Analysis from a Phase 2 Randomized Study in Adults Evaluating Single Oral Doses of Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused byNeisseria gonorrhoeae

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Nicole E. Scangarella-Oman ◽  
Mohammad Hossain ◽  
Paula B. Dixon ◽  
Karen Ingraham ◽  
Sharon Min ◽  
...  
Keyword(s):  
Randomized Study ◽  
Microbiological Analysis ◽  
Phase 2 ◽  
Therapeutic Success ◽  
Time Curve ◽  
Content Type ◽  
Phase 2 Study ◽  
Critical Residue ◽  
Oral Doses

ABSTRACTWe evaluated microbiological correlates for the successful treatment ofNeisseria gonorrhoeaeisolates from a phase 2 study of gepotidacin, a novel triazaacenaphthylene antibacterial, for therapy of uncomplicated urogenital gonorrhea. Culture, susceptibility testing, genotypic characterization, and frequency of resistance (FoR) were performed for selected isolates. Microbiological success was defined as culture-confirmed eradication ofN. gonorrhoeae. Against 69 baseline urogenital isolates, gepotidacin MICs ranged from ≤0.06 to 1 µg/ml (MIC90= 0.5 µg/ml). For gepotidacin, the ratio of the area under the free-drug concentration-time curve to the MIC (fAUC/MIC) was associated with therapeutic success. Success was 100% (61/61) atfAUC/MICs of ≥48 and decreased to 63% (5/8) forfAUC/MICs of ≤25. All 3 isolates from microbiological failures were ciprofloxacin resistant, had a baseline gepotidacin MIC of 1 µg/ml, and carried a preexisting ParC D86N mutation, a critical residue for gepotidacin binding. In a test-of-cure analysis, the resistance to gepotidacin emerged in 2 isolates (MICs increased ≥32-fold) with additional GyrA A92T mutations, also implicated in gepotidacin binding. Test-of-cure isolates had the same sequence type as the corresponding baseline isolates. For 5 selected baseline isolates, all carrying a ParC D86N mutation, thein vitroFoR to gepotidacin was low (10−9to 10−10); the resistant mutants had the same A92T mutation as the 2 isolates in which resistance emerged. Five participants with isolates harboring the ParC D86N mutation were treatment successes. In summary,fAUC/MICs of ≥48 predicted 100% microbiological success, including 3 isolates with the ParC D86N mutation (fAUC/MICs ≥ 97). Pharmacokinetic/pharmacodynamic determinations may help to evaluate new therapies for gonorrhea; further study of gepotidacin is warranted. (This study has been registered at ClinicalTrials.gov under identifier NCT02294682.)

CTNI-21. PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi63-vi64
Author(s):  
Zhong-ping Chen ◽  
Cheng-Cheng Guo ◽  
Yang Qun-ying ◽  
Jia-Wei Li ◽  
Shao-xiong Wu ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Radiation Treatment ◽  
Gene Promoter ◽  
Progression Free Survival ◽  
Common Adverse Event ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 2 Study

Abstract Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT) gene promoter, which confers a limited clinical response to standard-of-care treatment with temozolomide (TMZ), resulting in shorter median survival when compared to patients with a methylated MGMT promoter. VAL-083 is a novel bi-functional DNA targeting agent that induces interstrand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated TMZ resistance in vitro and in vivo. A Phase 2 study has been conducted to evaluate efficacy and safety of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. The study was conducted in 2 stages: Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). At the end of this stage, 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 in combination with RT. All patients have been enrolled, with a total of 29 patients in the study, and 25 patients receiving 30 mg/m2/day VAL-083. All 29 patients have completed treatment and patients are in the follow-up phase of the study. Consistent with our prior experience, myelosuppression was the most common adverse event. As of March 2021, 22/29 (75.9%) subjects had disease progression. The median progression free survival for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Sixteen (16/29; 55.2%) patients had died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. Further safety and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.

scholarly journals Phase 2, Randomized, Double-Blind Study of the Efficacy and Safety of Two Dose Regimens of Eravacycline versus Ertapenem for Adult Community-Acquired Complicated Intra-Abdominal Infections

2013 ◽  
Vol 58 (4) ◽  
pp. 1847-1854 ◽  
Author(s):  
Joseph S. Solomkin ◽  
Mayakonda Krishnamurthy Ramesh ◽  
Gintaras Cesnauskas ◽  
Nikolajs Novikovs ◽  
Penka Stefanova ◽  
...  
Keyword(s):  
Clinical Success ◽  
Clinical Success Rate ◽  
Blind Study ◽  
Double Blind Study ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Gram Negative ◽  
Abdominal Infections

ABSTRACTEravacycline is a novel fluorocycline, highly active against Gram-positive and Gram-negative pathogensin vitro, including those with tetracycline and multidrug resistance. This phase 2, randomized, double-blind study was conducted to evaluate the efficacy and safety of two dose regimens of eravacycline compared with ertapenem in adult hospitalized patients with complicated intra-abdominal infections (cIAIs). Patients with confirmed cIAI requiring surgical or percutaneous intervention and antibacterial therapy were randomized (2:2:1) to receive eravacycline at 1.5 mg/kg of body weight every 24 h (q24h), eravacycline at 1.0 mg/kg every 12 h (q12h), or ertapenem at 1 g (q24h) for a minimum of 4 days and a maximum of 14 days. The primary efficacy endpoint was the clinical response in microbiologically evaluable (ME) patients at the test-of-cure (TOC) visit 10 to 14 days after the last dose of study drug therapy. Overall, 53 patients received eravacycline at 1.5 mg/kg q24h, 56 received eravacycline at 1.0 mg/kg q12h, and 30 received ertapenem. For the ME population, the clinical success rate at the TOC visit was 92.9% (39/42) in the group receiving eravacycline at 1.5 mg/kg q24h, 100% (41/41) in the group receiving eravacycline at 1.0 mg/kg q12h, and 92.3% (24/26) in the ertapenem group. The incidences of treatment-emergent adverse events were 35.8%, 28.6%, and 26.7%, respectively. Incidence rates of nausea and vomiting were low in both eravacycline groups. Both dose regimens of eravacycline were as efficacious as the comparator, ertapenem, in patients with cIAI and were well tolerated. These results support the continued development of eravacycline for the treatment of serious infections, including those caused by drug-resistant Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01265784.)

An ultrastructural analysis of cyst wall development in the metacestode ofHymenolepis diminuta(Cestoda)

Parasitology ◽  
1984 ◽  
Vol 89 (3) ◽  
pp. 537-566 ◽  
Author(s):  
K. Sylvia Richards ◽  
C. Arme
Keyword(s):  
Cyst Wall ◽  
Phase 1 ◽  
Basal Membrane ◽  
Hymenolepis Diminuta ◽  
Phase 2 ◽  
Phase 3 ◽  
Muscle System ◽  
Initial Development ◽  
Final Maturation

SUMMARYA series of development stages (I–XI) have been devised to describe the development of the cyst wall of the metacestode ofHymenolepis diminuta. The cyst wall possesses tegumentary, muscular, fibrous and inner cyst tissues, the developmental rates and differentiation patterns of which are not identical. The tegumentary tissue differentiates posteriorly. Its microvillus-bearing distal cytoplasm remains simple until scolex retraction, after which rapid increase in depth followed by vacuolation occurs and basal membrane infoldings surround Phase 3 fibrogenesis fibrils. Senescence, which also affects the tegumentary cytons, then ensues. The muscle system development is posteriad and maturation, completed before scolex retraction, is followed by myocyton senescence. Posteriorly differentiated fibroblasts commence Phase 1 fibrogenesis after scolex retraction and the primary fibrous zone is fully established within approximately 6 days. Phase 2 and 3 fibrogenesis develop centrifugally, the fibrils of Phase 2 surrounding the tegumentary cytons and myocytons prior to their senescence, and those of Phase 3 lying more peripherally. The inner cyst tissue, established posteriorly, differentiates anteriorly, centripetally and early, the penultimate stage commencing just before scolex retraction, about 6 days after which the final maturation junctional complexes start development. Neitherin vitroexcystment nor infectivity of the definitive host can be satisfactorily achieved before the initial development of the primary fibrous zone. This may play a skeletal role during excystment, and is shown to be unaffected by the digestive enzymes which cause loss of cytoplasmic integrity in the outer regions of the cyst.

Phase 2 Study of Oblimersen Sodium (G3139; Bcl-2 Antisense; Genasense®) Plus Gemtuzumab Ozogamcin (Mylotarg®) in Elderly Patients with Relapsed Acute Myeloid Leukemia (AML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 865-865 ◽  
Author(s):  
Joseph O. Moore ◽  
Karen Seiter ◽  
Jonathan E. Kolitz ◽  
Wendy Stock ◽  
Richard Yu ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Response Rate ◽  
Apoptotic Cell ◽  
Gemtuzumab Ozogamicin ◽  
Phase 2 ◽  
Serious Adverse Events ◽  
Normal Platelet ◽  
Phase 2 Study ◽  
Eligibility Requirements

Abstract Patients with relapsed AML over the age of 60 have a poor prognosis. Gemtuzumab ozogamicin (GO) has been approved for older pts in first relapse, although many pts who attain complete remission (CR) do not fully recover normal platelet count (so-called CRp). In vitro studies have shown that oblimersen down-regulates Bcl-2 in AML cells and enhances apoptotic cell death induced by GO. We conducted a Phase 2 study to evaluate the safety and efficacy of GO combined with oblimersen for older pts with AML. Eligibility requirements included: age ≥ 60 yrs; AML in 1st relapse; ≥ 3 mos 1st CR duration; ≥ 25% CD33-positive AML cells. Pts received oblimersen at a dose of 7 mg/kg/d for 7 days by CIV beginning on days 1 and 15; GO was given at a dose of 9 mg/m2 IV over 2 hrs on days 4 and 18. A total of 48 pts were enrolled (ITT population), all of whom received at least 1 dose of oblimersen; 9 pts failed to receive the required 2 doses of GO (per-protocol population, n=39). The median age was 67 (range, 59 to 88 yrs). Duration of 1st CR: < 6 mos: 7 pts; (15%); 6 to 12 mos: 29 pts (60%); > 12 mos: 12 pts (25%). No. of prior regimens: 1 (17 pts, 35%); 2 or 3 (26 pts, 54%); ≥ 4 (5 pts, 10%). Among treated pts, 79% completed 21 days of protocol therapy. Overall, 12 pts achieved a major response, either CR (n=5) or CRp (n=7), for an ITT response rate of 25% and a per-protocol response rate of 31%. The median time to remission was 52 days. Ten of the 12 responders survived > 6 mos, whereas only 6 non-responders survived ≥ 6 mos. Serious adverse events for the oblimersen/GO combination were qualitatively similar to those reported for GO alone and included among other reactions: Grade 3-4 febrile neutropenia (42%) or thrombocytopenia 33%; nausea; fever; rigors, and dyspnea. Treatment-emergent adverse reactions led to discontinuation of protocol therapy in 10 pts (21%). The most common serious adverse event was febrile neutropenia (25%). One pt (2.1%) died during treatment (sepsis) and 16 pts (33%) died within 30 days of last study medication (infection, bleeding, respiratory failure, progressive AML, and other disease-related complications). No episodes of VOD were observed. Oblimersen can be safely combined with GO; however, pts enrolled in this study appear to have had more unfavorable characteristics at entry compared with prior studies using GO alone in pts with relapsed AML. Therefore, assessment of an incremental benefit from the addition of oblimersen will require a randomized trial.

Phase I Study of a Liposomal Carrier (CPX-351) Containing a Synergistic, Fixed Molar Ratio of Cytarabine (Ara-C) and Daunorubicin (DNR) in Advanced Leukemias

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2984-2984 ◽  
Author(s):  
Eric J. Feldman ◽  
Jeffrey Lancet ◽  
Jonathan E. Kolitz ◽  
Ellen Ritchie ◽  
Alan F. List ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Molar Ratio ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Refractory Aml

Abstract Background: CPX-351 is a liposomal formulation of Ara-C and DNR which fixes the synergistic 5:1 molar ratio found to enhance efficacy in both in vitro and in vivo preclinical leukemia models. CPX-351 overcomes the pharmacokinetic (PK) differences of each drug, enabling the maintenance of the 5:1 molar ratio for extended periods of time after IV administration and the delivery of this ratio to bone marrow. Preclinical data from in vitro models show that CPX-351 is actively internalized by leukemic cells within vacuoles and subsequently releases DNR intracellularly. A Phase I study was performed with CPX-351 in patients with acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS). Objectives: to determine safety, tolerability, and pharmacokinetics of a 90 min IV infusion of CPX-351 given on days 1, 3, 5 to patients with advanced leukemia and MDS, and to seek preliminary evidence of antitumor activity. Methods: Patients with relapsed/refractory AML/ALL and MDS were eligible. A second induction course was permitted if the day 14 bone marrow showed evidence of antileukemic effect and persistent leukemia. Dosing started at 3 units/m2 (1 u = 1 mg Ara-C and 0.44 mg DNR) using single patient cohorts and dose doublings. Three patient cohorts and 33% dose increments began after evidence of antileukemic activity and continued until limiting toxicities (DLTs) completed dose escalation. PK samples were collected after each dose. Results: Forty-seven subjects received 69 courses of CPX-351: Male/Female = 31/16, median age = 62 years (range 23–81); 44 patients had AML and 3 patients had ALL; median number of prior regimens = 2 (1–7). Thirty-seven patients entered the escalation phase of the study and ten subjects, most in first relapse, were treated after completion of dose escalation to confirm safety. At 24 u/m2 antileukemic effects were observed leading to increased cohort size to 3 and decreased escalation rate to 33%. The MTD and recommended Phase 2 dose was 101 u (101 mg Ara-C + 44 mg DNR)/m2 after observing 3 DLTs (decreased LVEF, hypertensive crisis, prolonged aplasia) at 134 u/m2. Adverse events data are available for 36 of 37 patients from the escalation phase of the study. Nonhematologic grade 3–5 toxicities occurring in more than one patient included: infections (58%), dyspnea (11%), fever (11%), hypophosphatemia (8%), hypokalemia (6%), renal failure (6%), skin rash (6%), headache (6%) hyperglycemia (6%) hypoxia (6%) and respiratory failure (6%). Mucositis of any grade was observed in 42% of patients with 3% having grade 3 mucositis. Diarrhea of grade 1 and 2 severity occurred in 39% of patients. Interim analysis of PK data demonstrates maintenance of the 5:1 molar ratio and detectable encapsulated drug persisting up to 24 hours. The average half-lives were 35 hr for total Ara-C and 23 hr for DNR, significantly longer than reported for the conventional drugs. Overall, 11 patients achieved CR/CRp. Among the 19 patients treated at the MTD, 5 of the 13 patients evaluable for response achieved CR. Six patients were treated above the MTD (134 u/m2) and 2 achieved CR. Median time to CR was 43 days. Conclusions: The recommended phase 2 dose is 101 u/m2. CPX-351 was well tolerated, with no unexpected toxicities noted up to the MTD. GI toxicities and mucositis were transient and nearly always of mild to moderate severity. Reduced LV function was observed in two patients both with substantial prior anthracycline exposure. CRs were observed in heavily pre-treated patients with relapsed/refractory AML. Future plans include a randomized Phase 2 study comparing CPX-351 versus Cytarabine + Daunorubicin (“7 + 3”) in older (&gt;60 yo) subjects with previously untreated AML, and a phase 2 study in patients with AML in 1st relapse.

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