Pharmacokinetics, tolerability and cycle control of three transdermal contraceptive delivery systems containing different doses of ethinylestradiol and levonorgestrel

2011 ◽  
Vol 6 (2) ◽  
Author(s):  
Frank Z. Stanczyk ◽  
Arkady Rubin ◽  
Lisa Flood ◽  
Marie Foegh
Keyword(s):  
Randomized Trials ◽  
Low Dose ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Delivery Systems ◽  
Low Doses ◽  
Plasma Drug ◽  
Open Label ◽  
Phase 3 ◽  
Different Doses

AbstractThe only available contraceptive patch, Ortho EvraThree transdermal contraceptive delivery systems (TCDS) containing low doses of ethinylestradiol (EE) and levonorgestrel (LNG) were evaluated in two open-label randomized trials. In a phase 1, two-period, cross-over trial, AG200-12.5 and AG200LE were compared with a 150 μg LNG/30 μg EE oral contraceptive (OC) (LevlenIn Study 1, mean steady-state plasma concentrations (All three patches exhibited excellent safety and wearability profiles while maintaining plasma drug levels required for ovulation suppression and adequate cycle control. A slight increase in the EE dose in AG200-15 still places this TCDS within the range of low-dose OCs, with EE exposure much lower than reported for Ortho Evra. AG200-15 was selected for further testing in phase 3 studies.

scholarly journals Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and Klippel–Trenaunay syndrome (KTS): the TOTEM trial, a phase 1/2 multicenter, open-label, single-arm study

2021 ◽  
Author(s):  
M. Luu ◽  
P. Vabres ◽  
H. Devilliers ◽  
R. Loffroy ◽  
A. Phan ◽  
...  
Keyword(s):  
Low Dose ◽  
Phase 1 ◽  
Pi3k Inhibitor ◽  
Functional Improvement ◽  
Open Label ◽  
Tissue Volume ◽  
Pathogenic Variants ◽  
Patient Reported ◽  
Affected Tissue ◽  
Phosphoinositide 3 Kinase

ABSTRACT Purpose PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients. Methods Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes. Results Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort (n = 6). No significant reduction in affected tissue volume was observed (mean −4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement). Conclusion Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

A randomized, open-label, phase 3 study of low-dose selinexor and lenalidomide (Len) versus len maintenance post autologous stem cell transplant (ASCT) for newly diagnosed multiple myeloma (NDMM): ALLG MM23, Sealand.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS8055-TPS8055
Author(s):  
Hang Quach ◽  
Masa Lasica ◽  
David Routledge ◽  
Anna Kalff ◽  
Andrew Lim ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Nuclear Export ◽  
Low Dose ◽  
Performance Status ◽  
Cell Transplant ◽  
Weekly Schedule ◽  
Open Label ◽  
Phase 3 ◽  
Clinical Trial Registration ◽  
National Cooperative

TPS8055 Background: Len maintenance post ASCT is standard of care for patients (pts) with NDMM. Deep responses (CR or better) post ASCT correlates with better progression free survival (PFS). In a meta-analysis of len maintenance post ASCT (McCarthy PL et al. J Clin Oncol. 2017), only 10.7% of pts achieve CR post ASCT, and 72% of pts who discontinued len maintenance did so because of progressive disease (PD). Selinexor is a selective inhibitor of nuclear export that blocks exportin 1, thus retaining tumour suppressor proteins within the nucleus while blocking proto-oncoprotein translation. It is approved in combination with bortezomib and dexamethasone (dex) for pts with MM who have had at least 1 prior line of treatment, or with dex for pts with penta-refractory MM by the FDA. The oral bioavailability and weekly schedule of selinexor makes it suitable in combination with len for maintenance therapy. Given the encouraging activity (ORR 92%) and tolerability of selinexor, len and dex from the phase 1b/2 STOMP study, we hypothesise that combination low-dose selinexor and len (XR) will be well tolerated and effective, increasing CR and MRD negativity rate post ASCT, thus prolonging PFS compared to len. Methods: ALLG MM23 SeaLAND, is an ongoing randomised, multi-centre, phase 3 trial. Eligible pts ( > 17 years of age) have measurable disease, have undergone 3-6 cycles (C) of induction containing a proteasome inhibitor (PI) and/or immunomodulatory drug and recovered post melphalan-conditioned ASCT with adequate haematopoiesis, renal and liver function, and with ECOG performance status. Registration occurs prior to ASCT with screening between 75 to 115 days post ASCT. The study includes a lead-in safety phase of 20 patients with XR: Len 10mg daily days 1 to 21 and Selinexor 40mg weekly in a 28-day cycle. If well tolerated, Selinexor escalates to 60mg po weekly from C2 and Len to 15mg po daily from C4. Two safety reviews will occur after the 10th and 20th patients completes C2, respectively. Upon meeting safety criteria, a sample size of 290 pts will be randomised 1:1 to XR or lenalidomide (R). Therapy will continue until PD. The primary endpoint is PFS at 3 years post randomisation. Secondary endpoints include ORR and MRD-negativity rate (International Myeloma Working Group Response Criteria), PFS on next treatment line (PFS2), OS, safety and tolerability, quality of life, and cost effectiveness. Main analysis occurs after 232 patients complete 3-years of follow-up. Exploratory objective is to correlate immunological and molecular profiles to treatment response and resistance. ALLG MM23 SeaLAND is a multisite bi-national investigator-initiated trial lead by Australia and New Zealand’s national cooperative group, the Australasian Leukaemia & Lymphoma Group. Clinical trial registration: ACTRN12620000291987p. Clinical trial information: 12620000291987.

scholarly journals 066 Avxs-101 gene-replacement therapy (GRT) for spinal muscular atrophy type 1 (SMA1): pivotal phase 3 study (STR1VE) update

2019 ◽  
Vol 90 (e7) ◽  
pp. A22.1-A22 ◽  
Author(s):  
John W Day ◽  
Claudia A Chiriboga ◽  
Thomas O Crawford ◽  
Basil T Darras ◽  
Richard S Finkel ◽  
...  
Keyword(s):  
Preliminary Data ◽  
Muscular Atrophy ◽  
Phase 1 ◽  
Neuromuscular Disorders ◽  
Ventilatory Support ◽  
Genetic Diagnosis ◽  
Survival Motor Neuron ◽  
Open Label ◽  
Phase 3 ◽  
Pivotal Phase

IntroductionSMA1 is a neurodegenerative disease caused by bi-allelic survival motor neuron 1 gene (SMN1) deletion/mutation. In the phase 1 study, SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of symptomatic SMA1 patients. We report preliminary data of STR1VE, a pivotal study (NCT03306277) evaluating efficacy and safety of a one-time intravenous AVXS-101 infusion.MethodsSTR1VE is a phase 3, multicenter, open-label, single-arm study in SMA1 patients aged <6 months (bi-allelic SMN1 loss, 2xSMN2). Primary outcomes: independent sitting for ≥30 seconds (18 months) and survival (14 months). Secondary outcomes: ability to thrive and ventilatory support (18 months). Exploratory outcomes: Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and Bayley Scales of Infant and Toddler Development scores.ResultsEnrollment is complete with 22 patients dosed. Mean age at symptom onset, genetic diagnosis, and enrollment was 1.9 (0–4.0), 2.1 (0.5–4.0), and 3.7 (0.5–5.9) months. At baseline, no patient required ventilatory/nutritional support, and all exclusively fed by mouth. Mean baseline CHOP-INTEND score was 32.6 (17.0–52.0), which increased 6.9 (-4.0–16.0, n=20), 10.4 (2.0–18.0, n=12), and 11.6 (-3.0–23.0, n=9) points at 1, 2, and 3 months. Updates will be provided at the congress.ConclusionsPreliminary data from STR1VE show rapid motor function improvements in SMA1 patients, paralleling phase 1 findings.

A Phase 1, Open-Label Assessment of a Dengue Virus-1 Live Virus Human Challenge Strain

2020 ◽  
Author(s):  
Timothy P Endy ◽  
Dongliang Wang ◽  
Mark E Polhemus ◽  
Richard G Jarman ◽  
Louis E Jasper ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Phase 1 ◽  
Human Infection ◽  
Open Label ◽  
Serious Adverse Events ◽  
Live Virus ◽  
Challenge Virus ◽  
Infection Models ◽  
And Performance

Abstract Background Dengue human infection models (DHIM) have been used as a safe means to test the viability of prophylaxis and therapeutics. Methods A phase 1 study of 12 healthy adult volunteers using a challenge virus, DENV-1-LVHC strain 45AZ5, was performed. A dose escalating design was used to determine the safety and performance profile of the challenge virus. Subjects were evaluated extensively until 28 days and then out to 6 months. Results Twelve subjects received the challenge virus: 6 with 0.5 mL of 6.5 × 103 plaque-forming units (PFU)/mL (low-dose group) and 6 with 0.5 mL of 6.5 × 104 PFU/mL (mid-dose group). All except 1 in the low-dose group developed detectable viremia. For all subjects the mean incubation period was 5.9 days (range 5–9 days) and mean time of viremia was 6.8 days (range 3–9 days). Mean peak for all subjects was 1.6 × 107 genome equivalents (GE)/mL (range 4.6 × 103 to 5 × 107 GE/mL). There were no serious adverse events or long-term safety signals noted. Conclusions We conclude that DENV-1-LVHC was well-tolerated, resulted in an uncomplicated dengue illness, and may be a suitable DHIM for therapeutic and prophylactic product testing. Clinical Trials Registration NCT02372175.

ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4017-4017 ◽  
Author(s):  
Vincenzo Mazzaferro ◽  
Bassel F. El-Rayes ◽  
Christian Cotsoglou ◽  
William Proctor Harris ◽  
Nevena Damjanov ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Phase 1 ◽  
Treatment Options ◽  
Plasma Concentrations ◽  
Moderate Intensity ◽  
White Female ◽  
Open Label ◽  
Genetic Aberrations ◽  
Tumor Reduction ◽  
Ecog Ps

4017 Background: FGFR genetic aberrations have been implicated in the development and progression of a number of solid tumor types, including iCCA. Pts with unresectable advanced iCCA who relapse after first-line chemotherapy have limited treatment options with poor prognosis. Recently, FGFR2 fusions, observed in up to 20% of pts, have been recognized as a potential therapeutic target. ARQ 087 is a multi-kinase inhibitor with a potent pan-FGFR activity. Methods: 119 cancer pts were enrolled in the phase 1/2, open-label study of ARQ 087. Study design and results of the phase 1were reported previously. Assessments included response by RECIST v1.1 every 8 wks, safety (physical examination, vital signs, ECOG PS, laboratory tests), plasma concentrations of phosphate and FGF19, 21 and 23 (potential biomarkers). Results: As of 1Feb17, 35 iCCA pts with FGFR2 genetic aberrations were treated with ARQ 087 300 (n = 33) or 400 mg (n = 2) daily. FGFR2 status was identified by FISH or NGS, 29/35 pts were FGFR2 fusion positive (FISH n = 15/18; NGS n = 14/17). Pts were all white, female (60%) with ECOG PS 0 (69%) and median age 58 yrs (31-82). Median number of prior systemic therapies was 1(0-6). Drug-related AEs (all grades) were reported in 89% of pts; the most common (≥10%) included nausea (37%), dry mouth (29%), asthenia (26%), fatigue, vomiting (23%, each), abnormal LFTs, dysgeusia (20%, each), alopecia, diarrhea, vision blurred (14%, each), and conjunctivitis (11%). Grade 3/4 AEs occurring in ≥2 pts were asthenia and abnormal LFTs (6%, each). AEs were mostly (71%) of mild to moderate intensity, manageable and reversible. Median time on treatment was 183 days (95%CI: 166-289). 19 pts were on treatment for > 16 wks, nine are ongoing. 30 pts had at least one post-treatment radiographic assessment: 6 (20%) had PR (32-47% tumor reduction, all FGFR2 fusion positive), 17 SD (7 had tumor reduction between 10 to 25%), and 7 had PD. One pt died prior to scheduled assessment and assessment in 4 pts is pending. Conclusions: ARQ 087 demonstrated encouraging antitumor activity and manageable safety profile. Updated data, including safety, efficacy and biomarkers will be presented. Clinical trial information: NCT01752920.

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