scholarly journals A phase II, open-label, randomized, multicenter trial of encorafenib + binimetinib evaluating a standard-dose and a high-dose regimen in patients with BRAFV600-mutant melanoma brain metastasis (MBM) (POLARIS)

2019 ◽  
Vol 30 ◽  
pp. v562-v563
Author(s):  
M.A. Davies ◽  
J.S. Weber ◽  
K.T. Flaherty ◽  
G.A. McArthur ◽  
M.B. Reddy ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Phase Ii ◽  
Dose Regimen ◽  
Standard Dose ◽  
Multicenter Trial ◽  
High Dose ◽  
Open Label ◽  
High Dose Regimen ◽  
Melanoma Brain Metastasis

A Randomized Crossover Study of High- and Standard-Dose Recombinant Factor VIIa for Treatment of Hemarthroses in Hemophiliacs with Inhibitors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 323-323
Author(s):  
Elena Santagostino ◽  
Maria E. Mancuso ◽  
Angiola Rocino ◽  
Giacomo Mancuso ◽  
Francesco A. Scaraggi ◽  
...  
Keyword(s):  
Dose Regimen ◽  
Factor Viia ◽  
Standard Dose ◽  
Home Treatment ◽  
Response To Treatment ◽  
High Dose ◽  
Success Rates ◽  
Recurrence Rates ◽  
High Dose Regimen ◽  
Vas Score

Abstract A multicenter randomized crossover trial was designed to compare efficacy, safety, feasibility and cost associated with standard- and high-dosages of rFVIIa for home treatment of hemarthroses in hemophiliacs with inhibitors. Enrolled patients were instructed to treat within 6 hours from the onset of bleeding 4 consecutive haemarthroses of ankles, knees or elbows either with the rFVIIa standard dose of 90 mcg/kg (repeated as necessary every 3 hours) or with a single high dose of 270 mcg/kg. Patients who did not achieve a success within 9 hours continued rFVIIa treatment with repeated standard doses. The response to treatment was assessed for up to 48 hours by patients/caregivers who reported on a visual analogic scale (VAS) graded from 0 to 100 the improvement in symptoms and also rated the response as effective, partially effective or ineffective. Success was defined a treatment rated as effective and VAS score ≥70 and failure a treatment rated as ineffective and VAS score ≤30, responses that did not fulfil these criteria being considered a partial response. Of 20 hemophiliacs with inhibitors enrolled (median age: 27 years), 18 treated 32 hemarthroses assigned to the standard- and 36 to the high-dose regimen during the study period of 18 months. Forty-eight hemarthroses (71%) occurred in target joints. Success rates for standard- and high-dose regimens were similar: 31% and 25% at 9 hours, 53% and 50% at 24 hours, 66% and 64% at 48 hours. Recurrence rates were identical (3%). The median number of rFVIIa boluses needed to achieve a successful course was 3 for the standard-dose and 1 for the high-dose regimen, and the median amount of rFVIIa used per successful course was identical (270 mcg/kg). Our results indicate that the use of a high-dose regimen with rFVIIa for home treatment of hemarthroses is effective, safe, does not imply an increased consumption of rFVIIa and requires the infusion of a smaller number of boluses. Its convenience is particularly relevant in cases with difficult venous access and in hemorrhages into target joints.

Phase I/II study of paclitaxel plus ifosfamide (TI) followed by high-dose paclitaxel, ifosfamide, and carboplatin (TIC) with autologous stem cell transplant (ASCT) for salvage treatment of germ cell tumors (GCT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4534-4534
Author(s):  
Xiaoyu Jia ◽  
Darren Richard Feldman ◽  
Ilya Glezerman ◽  
Lindsay Joy Van Alstine ◽  
Dean F. Bajorin ◽  
...  
Keyword(s):  
Renal Insufficiency ◽  
Phase I ◽  
Phase Ii ◽  
Chronic Renal Insufficiency ◽  
Dose Regimen ◽  
Germ Cell Tumors ◽  
Salvage Treatment ◽  
High Dose ◽  
Cell Transplant ◽  
High Dose Regimen

4534 Background: High-dose chemotherapy (HDCT) can achieve durable remissions in 30-60% of GCT patients (pts) requiring salvage treatment. This Phase I/II study investigated safety and efficacy of a novel high-dose regimen (TI-TIC) in this population. Methods: Pts age ≥18 with GCT and progression after ≥1 cisplatin-based regimen were eligible. TI-TIC consists of 1-2 cycles of conventional-dose paclitaxel plus ifosfamide (TI) q14-21 days followed by 3 cycles of high-dose TIC with ASCT q21-28 days. TI dosing was constant. In Phase I, high-dose TIC was administered in 1 of 5 cohorts (I: 6, 8 or 10g/m2; T: 200 or 250mg/m2; C: AUC=21 or 24) using a standard 3+3 dose escalation design to determine the maximal tolerated dose (MTD). In Phase II, Simon’s 2-stage optimal design was used to estimate the complete response (CR) rate at MTD. Results: Of 26 pts (25 male; median age 31; 21 nonseminoma, 5 seminoma) enrolled, 23 received ≥1 cycle of high-dose TIC. Primary sites included testis (n=15), mediastinum (n=6), other (5). In Phase I, 0/18 pts had dose-limiting toxicity (DLT) during TIC cycle 1, making cohort 5 (T 250mg/m2, I 10g/m2, C AUC=24) the MTD. Toxicities were similar to those reported with TI-CE (Feldman JCO 2010) with little variation across cohorts. However, 2/18 pts in Phase I (1 in cohort 4, 1 in cohort 5) developed grade 3 acute renal insufficiency after cycles 1 and 2 (cycle 3 not given). Both later developed chronic renal insufficiency with 1 pt requiring dialysis 10 months after TI-TIC. A third pt treated in Phase II developed a similar acute and then chronic renal insufficiency pattern with TIC cycles 1 and 2. In Phase II, 7/11 evaluable pts (64%, 90% one-sided CI 40%-100%) achieved a CR, 1 had a partial response with negative markers, and 3 had incomplete responses. Although the CR rate was sufficient to move to the second Simon’s stage, renal toxicity led to premature trial closure. Conclusions: Although there was preliminary evidence of efficacy, high dose TI-TIC was associated with acute and chronic renal insufficiency. TI-CE remains the standard high dose regimen for salvage treatment of GCT at MSKCC. Clinical trial information: NCT00423852.

Cisplatin Dose Intensity in Non-Small Cell Lung Cancer: Phase II Results of a Day 1 and Day 8 High-Dose Regimen

1989 ◽  
Vol 81 (10) ◽  
pp. 790-794 ◽  
Author(s):  
D. R. Gandara ◽  
H. Wold ◽  
E. A. Perez ◽  
A. B. Deisseroth ◽  
J. Doroshow ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Dose Regimen ◽  
Dose Intensity ◽  
Small Cell ◽  
High Dose ◽  
Small Cell Lung ◽  
High Dose Regimen

Efficacy and Safety of Tigecycline for Patients with Hospital-Acquired Pneumonia

Chemotherapy ◽  
2016 ◽  
Vol 61 (6) ◽  
pp. 323-330 ◽  
Author(s):  
Li Xu ◽  
Ya-Li Wang ◽  
Shuai Du ◽  
Lin Chen ◽  
Li-Hui Long ◽  
...  
Keyword(s):  
Dose Regimen ◽  
Clinical Cure ◽  
Standard Dose ◽  
Meta Analysis ◽  
High Dose ◽  
Efficacy And Safety ◽  
High Dose Regimen ◽  
Significant Difference ◽  
Hospital Acquired Pneumonia ◽  
Hospital Acquired

Background: Tigecycline is an antibiotic agent with a broad spectrum, which has an antibacterial effect against many multidrug-resistant organisms. However, its clinical efficacy in the treatment of hospital-acquired pneumonia (HAP) is disputed. Materials and Methods: In this report, a systematic review and meta-analysis were conducted to evaluate the efficacy and safety of tigecycline for the treatment of HAP. The primary outcome was the rate of clinical cure, and the secondary outcomes were mortality and adverse events (AEs). Results: Four trials involving 1,234 patients were included. The standard-dose tigecycline and comparator groups did not differ significantly in their rates of clinical cure. However, high-dose tigecycline was more effective than standard-dose tigecycline or the comparators for the treatment of HAP. There was no significant difference in mortality between the standard-dose or high-dose regimen and the comparators. Although the safety profile of standard-dose tigecycline was similar to the comparators, the high-dose regimen exhibited more AEs compared with the other groups. Conclusion: High-dose tigecycline is efficient for the treatment of HAP but is associated with more AEs.

scholarly journals High-dose oral and intravenous rifampicin for the treatment of tuberculous meningitis in predominantly HIV-positive Ugandan adults: a phase II open-label randomised controlled trial

2021 ◽  
Author(s):  
Fiona V Cresswell ◽  
David B Meya ◽  
Enock Kagimu ◽  
Daniel Grint ◽  
Lindsey te Brake ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Geometric Mean ◽  
Standard Of Care ◽  
Hiv Positive ◽  
High Dose ◽  
Open Label ◽  
Dose Oral ◽  
Csf Levels

Abstract Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in HIV co-infection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods In this phase II open-label trial, Ugandan adults with suspected TBM were randomised to standard-of-care control (PO-10, rifampicin 10mg/kg/day), intravenous rifampicin (IV-20, 20mg/kg/day), or high-dose oral rifampicin (PO-35, 35mg/kg/day). We performed PK sampling on day 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration and grade 3-5 adverse events. Results We enrolled 61 adults, 92% were HIV-positive, median CD4 count was 50cells/µL (IQR 46–56). On day 2, geometric mean plasma AUC0-24hr was 42.9h.mg/L with standard-of-care 10mg/kg dosing, 249h.mg/L for IV-20 and 327h.mg/L for PO-35 (P<0.001). In CSF, standard-of-care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27mg/L, compared with 1.74mg/L (95%CI 1.2–2.5) for IV-20 and 2.17mg/L (1.6–2.9) for PO-35 regimens (p<0.001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (p=0.34) Conclusion Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe, and respectively resulted in exposures ~6- and ~8-fold higher than standard-of-care, and CSF levels above the MIC

scholarly journals Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
S. Dian ◽  
V. Yunivita ◽  
A. R. Ganiem ◽  
T. Pramaesya ◽  
L. Chaidir ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Standard Dose ◽  
Geometric Mean ◽  
Phase Iii ◽  
High Dose ◽  
Treatment Area ◽  
Double Blind ◽  
Time Curve

ABSTRACT High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC0–24], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.)

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