scholarly journals Effects of sodium zirconium cyclosilicate on sodium and potassium excretion in healthy adults: a Phase 1 study

2020 ◽  
Author(s):  
Mats Någård ◽  
Bhupinder Singh ◽  
David W Boulton
Keyword(s):  
Phase 1 ◽  
Vital Signs ◽  
Systemic Absorption ◽  
Phase 1 Study ◽  
Safety Measures ◽  
Once Daily ◽  
Sodium Zirconium ◽  
High K ◽  
K Concentration ◽  
Sodium Zirconium Cyclosilicate

Abstract Background Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a potassium (K+) binder for treatment of hyperkalemia in adults. SZC binds K+ in exchange for sodium (Na+) or hydrogen (H+) in the gastrointestinal tract, conveying potential for systemic absorption of Na+. Methods This single-center Phase 1 study evaluated the effects of SZC on Na+ and K+ excretion in healthy, normokalemic adults. During an initial run-in period (Days 1–2), participants started a high K+/low Na+ diet. After baseline (Days 3–4), SCZ 5 or 10 g once daily (QD) was administered (Days 5–8). The primary endpoint was mean change in urinary Na+ excretion from baseline (Days 3–4) to the treatment period (Days 7–8). Results Of 32 enrolled participants, 30 entered and completed the study; the first 15 received 5 g and the next 15 received 10 g. Nonsignificant changes from baseline in urinary Na+ excretion were observed with SZC 5 g (mean ± SD −0.93 ± 25.85 mmol/24 h) and 10 g (−5.47 ± 13.90 mmol/24 h). Statistically significant decreases from baseline in urinary K+ excretion (mean ± SD −21.17 ± 21.26 mmol/24 h; P = 0.0017) and serum K+ concentration (−0.25 ± 0.24 mmol/L; P = 0.0014) were observed with the 10-g dose. There were few adverse events and no clinically meaningful changes in vital signs or laboratory safety measures. Conclusions Treatment with SZC 5 or 10 g QD reduced serum K+ concentration and urinary K+ excretion, with no significant effect on urinary Na+ excretion, and was well tolerated.

scholarly journals Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL

Blood ◽  
2019 ◽  
Vol 134 (11) ◽  
pp. 851-859 ◽  
Author(s):  
Constantine S. Tam ◽  
Judith Trotman ◽  
Stephen Opat ◽  
Jan A. Burger ◽  
Gavin Cull ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Phase 1 Study ◽  
End Points ◽  
Once Daily ◽  
Grade 3

Abstract Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

scholarly journals Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia

2019 ◽  
Vol 14 (6) ◽  
pp. 798-809 ◽  
Author(s):  
Bruce S. Spinowitz ◽  
Steven Fishbane ◽  
Pablo E. Pergola ◽  
Simon D. Roger ◽  
Edgar V. Lerma ◽  
...  
Keyword(s):  
Adverse Events ◽  
Confidence Interval ◽  
Serum Potassium ◽  
Maintenance Phase ◽  
Renin Angiotensin Aldosterone System ◽  
Once Daily ◽  
Renin Angiotensin ◽  
Sodium Zirconium ◽  
Sodium Zirconium Cyclosilicate ◽  
Correction Phase

Background and objectivesOral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium via the gastrointestinal tract. Sodium zirconium cyclosilicate–associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial.Design, setting, participants, & measurementsIn the correction phase, adult outpatients with plasma potassium ≥5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24–72 hours until normokalemic (potassium =3.5–5.0 mmol/L). Qualifying participants entered the ≤12-month maintenance phase and received sodium zirconium cyclosilicate 5 g once daily titrated to maintain normokalemia without dietary or medication restrictions. Prespecified primary end points were restoration of normal serum potassium values (3.5–5.0 mmol/L) during the correction phase and maintenance of serum potassium ≤5.1 mmol/L during the maintenance phase. Adverse events were assessed throughout.ResultsOf 751 participants, 746 (99%) achieved normokalemia during the correction phase (mean serum potassium =4.8 mmol/L; 95% confidence interval, 4.7 to 4.8) and entered the maintenance phase; 466 (63%) participants completed the 12-month trial. Participants were predominantly white, men, and age ≥65 years old; 74% had an eGFR<60 ml/min per 1.73 m2, and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3–12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values ≤5.1 and ≤5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor–naïve participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodium zirconium cyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium <3.0 and 3.0–3.4 mmol/L, respectively.ConclusionsAfter achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for ≤12 months.

scholarly journals MO214EVALUATION OF THE EFFECT OF A POTASSIUM BINDER ON ARRHYTHMIA-RELATED CARDIOVASCULAR OUTCOMES IN PATIENTS ON CHRONIC HAEMODIALYSIS WITH RECURRENT HYPERKALAEMIA: DESIGN AND RATIONALE FOR THE SODIUM ZIRCONIUM CYCLOSILICATE DIALIZE-OUTCOMES STUDY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Steven Fishbane ◽  
Michel Jadoul ◽  
Laura M Dember ◽  
Csaba Kovesdy ◽  
Ian Sabir ◽  
...  
Keyword(s):  
Ventricular Tachyarrhythmia ◽  
Composite Endpoint ◽  
Primary Objective ◽  
Controlled Study ◽  
Chronic Haemodialysis ◽  
Double Blind ◽  
Once Daily ◽  
Sodium Zirconium ◽  
Outcomes Study ◽  
Sodium Zirconium Cyclosilicate

Abstract Background and Aims Patients with end-stage renal disease (ESRD) on chronic haemodialysis are at an elevated risk of arrhythmias that can increase the risk of sudden cardiac death (SCD) and stroke, along with the need for hospitalisation and interventions. These arrhythmias may be exacerbated by pre-dialysis hyperkalaemia and rapid serum potassium (sK+) shifts that occur during and after haemodialysis sessions. The DIALIZE study (NCT03303521) demonstrated that sodium zirconium cyclosilicate (SZC) was an effective and well-tolerated treatment for pre-dialysis hyperkalaemia, when administered once-daily on non-dialysis days for 8 weeks in patients with ESRD undergoing chronic haemodialysis. The DIALIZE-Outcomes study (EudraCT 2020-005561-14) will evaluate the effect of SZC treatment on arrhythmia-related cardiovascular (CV) outcomes in patients with ESRD on chronic haemodialysis with recurrent hyperkalaemia. Method The DIALIZE-Outcomes study is an international, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, to be conducted at ∼300 study sites across ∼20 countries. Adults (≥18 years of age) with ESRD on haemodialysis three times weekly and with recurrent pre-dialysis sK+ ≥5.5 mmol/L after the long interdialytic interval (LIDI) will be eligible for enrolment. Approximately 2300 patients will be randomised 1:1 to SZC or placebo (Figure), starting at 5 g orally once daily on non-dialysis days (4 days/week) and uptitrated weekly in 5 g increments (maximum 15 g) to achieve pre-dialysis sK+ 4.0–5.0 mmol/L after the LIDI. Dose adjustments after the uptitration phase will be guided by sK+ monitoring, as per clinical practice. The primary objective is to evaluate the efficacy of SZC versus placebo in reducing the incidence of the primary composite endpoint of time to first occurrence of SCD, stroke or hospitalisation/intervention/emergency department visit due to arrhythmias (atrial fibrillation, bradycardia, asystole, ventricular tachyarrhythmia). Secondary endpoints include the efficacy of SZC versus placebo in maintaining normokalaemia (sK+ 4.0–5.5 mmol/L after the LIDI) and preventing severe hyperkalaemia (sK+ ≥6.5 mmol/L after the LIDI) at 1 year (assessed through measurement of sK+ at the 12-month study visit), and time to occurrence of CV outcomes. Safety and tolerability of SZC versus placebo will also be evaluated. The study is event-driven, with patients remaining on study treatment until a pre-specified number of primary endpoint events (770) has occurred. The anticipated average treatment period is ∼25 months. Conclusion The DIALIZE-Outcomes study is the first evaluation of a K+ binder in improving CV outcomes in patients with ESRD on chronic haemodialysis and with recurrent hyperkalaemia. The study findings will provide valuable information that may help to further our understanding of the relationship between hyperkalaemia and CV morbidity and mortality in patients on chronic haemodialysis, and to optimise treatment regimens in this high CV and SCD risk population.

P0220EFFECTIVENESS OF SODIUM ZIRCONIUM CYCLOSILICATE (SZC) IN HAEMODIALYSIS PATIENTS WITH SEVERE HYPERKALAEMIA IN THE DIALIZE STUDY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Martin Ford ◽  
Steven Fishbane ◽  
Bruce Spinowitz ◽  
Anjay Rastogi ◽  
Nicolas Guzman ◽  
...  
Keyword(s):  
Rescue Therapy ◽  
Adverse Outcomes ◽  
Dose Titration ◽  
Once Daily ◽  
Sodium Zirconium ◽  
Titration Phase ◽  
Evaluation Phase ◽  
Starting Dose ◽  
Post Hoc ◽  
Sodium Zirconium Cyclosilicate

Abstract Background and Aims Patients with severe hyperkalaemia require urgent intervention to avoid serious adverse outcomes and mortality. The phase 3b DIALIZE study (NCT03303521) showed that sodium zirconium cyclosilicate (SZC) reduces predialysis serum potassium (sK+) after the long interdialytic interval and is well tolerated in haemodialysis patients with hyperkalaemia. This post-hoc analysis of the DIALIZE data assessed the efficacy of SZC in patients with severe hyperkalaemia (defined as sK+ ≥6.0 mmol/L) at baseline. Method The DIALIZE study randomised 196 patients 1:1 to placebo (n=99) or SZC (n=97). The study consisted of an 8-week treatment period, comprising a 4-week SZC dose titration phase followed by a 4-week evaluation phase. The starting dose of SZC was 5 g orally once daily on non-dialysis days (4 days/week) for the 4-week dose titration phase (titrated in 5 g increments to a maximum of 15 g on non-dialysis days) to achieve predialysis sK+ 4.0–5.0 mmol/L. Patients maintained a stable dose of SZC for the 4-week evaluation phase (SZC 5, 10 or 15 g). Here, treatment response was defined as achievement of predialysis sK+ of 4.0–5.5 mmol/L during ≥3 of 4 haemodialysis treatments after the long interdialytic interval during the 4-week evaluation phase and not requiring potassium-lowering rescue therapy. Rates of response were compared between those patients with and without baseline severe hyperkalaemia (sK+ ≥6 mmol/L and &lt;6 mmol/L, respectively). The sK+ measurement on Visit 1 (Day –7) was used as the baseline value. Results At baseline, 88 patients had sK+ ≥6 mmol/L (SZC n=46, placebo n=42) and 106 patients had sK+ &lt;6 mmol/L (SZC n=49, placebo n=57); data were missing for two SZC patients. The overall proportion of treatment responders (irrespective of treatment and dose) in patients with baseline sK+ ≥6 mmol/L and &lt;6 mmol/L was 44.3% and 43.4%, respectively. The proportion of treatment responders was greater with SZC compared with placebo in patients with baseline sK+ ≥6 mmol/L and sK+ &lt;6 mmol/L (Figure). For patients receiving SZC, the proportion of treatment responders was consistent in those with baseline sK+ ≥6 mmol/L (67.4%) compared with those with baseline sK+ &lt;6 mmol/L (71.4%; Figure). Conclusion Our results suggest that SZC is effective in haemodialysis patients with severe hyperkalaemia.

scholarly journals The pharmacokinetics of pamiparib in the presence of a strong CYP3A inhibitor (itraconazole) and strong CYP3A inducer (rifampin) in patients with solid tumors: an open-label, parallel-group phase 1 study

2021 ◽  
Author(s):  
Song Mu ◽  
Chester Lin ◽  
Anna Skrzypczyk-Ostaszewicz ◽  
Iurie Bulat ◽  
Marina Maglakelidze ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Open Label ◽  
Phase 1 Study ◽  
Time Curve ◽  
Clinical Safety ◽  
Once Daily ◽  
Cns Penetration ◽  
Dose Modifications ◽  
Cyp3a Inhibitor

Abstract Purpose Pamiparib is an investigational, selective, oral poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor that has demonstrated PARP–DNA complex trapping and CNS penetration in preclinical models, as well as preliminary anti-tumor activity in early-phase clinical studies. We investigated whether the single-dose pharmacokinetic (PK) profile of pamiparib is altered by coadministration of a strong CYP3A inducer (rifampin) or a strong CYP3A inhibitor (itraconazole) in patients with solid tumors. Methods In this open-label, phase 1 study, adults with advanced solid tumors received either oral pamiparib 60 mg (days 1 and 10) and once-daily oral rifampin 600 mg (days 3–11) or oral pamiparib 20 mg (days 1 and 7) and once-daily oral itraconazole 200 mg (days 3–8). Primary endpoints included pamiparib maximum observed concentration (Cmax), and area under the plasma concentration–time curve from zero to last quantifiable concentration (AUC0–tlast) and infinity (AUC0–inf). Secondary endpoints included safety and tolerability. Results Rifampin coadministration did not affect pamiparib Cmax (geometric least-squares [GLS] mean ratio 0.94; 90% confidence interval 0.83–1.06), but reduced its AUC0–tlast (0.62 [0.54–0.70]) and AUC0–inf (0.57 [0.48–0.69]). Itraconazole coadministration did not affect pamiparib Cmax (1.05 [0.95–1.15]), AUC0–tlast (0.99 [0.91–1.09]), or AUC0–inf (0.99 [0.90–1.09]). There were no serious treatment-related adverse events. Conclusions Pamiparib plasma exposure was reduced 38–43% with rifampin coadministration but was unaffected by itraconazole coadministration. Pamiparib dose modifications are not considered necessary when coadministered with CYP3A inhibitors. Clinical safety and efficacy data will be used with these results to recommend dose modifications when pamiparib is coadministered with CYP3A inducers.

Bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor: Preliminary results from a phase 1 study in patients with advanced malignant solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3552-3552 ◽  
Author(s):  
W. A. Messersmith ◽  
S. Krishnamurthi ◽  
B. A. Hewes ◽  
C. M. Zacharchuk ◽  
R. Abbas ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Solid Tumors ◽  
Stable Disease ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Human Tumor ◽  
Dependent Manner ◽  
Phase 1 Study ◽  
Once Daily ◽  
Grade 3

3552 Background: Bosutinib (SKI-606) is a potent, low molecular weight, orally active, competitive inhibitor of both Src and Abl tyrosine kinases. Elevations of Src kinase activity occur in a variety of human tumor types and are correlated with aggressiveness. We conducted a phase 1 study in patients (pts) with advanced solid tumors to assess tolerability, safety, pharmacokinetics (PK), and preliminary antitumor activity of bosutinib. Methods: Patients in cohorts of 3–6 received 50, 100, 200, 300, 400, 500 or 600 mg bosutinib orally on study day 1 and then once daily beginning on day 3. Timed blood samples were collected on days 1–3, 15 and 16 for PK analysis. Tumor assessments (modified RECIST criteria) were made at baseline and the end of every third cycle (21 days/cycle). Collection of tissue samples for analysis of Src biomarkers was optional. Results: Preliminary data are presented for 51 pts (median 57 years, 57% women). Three pts who received 600 mg bosutinib/day had drug-related dose-limiting toxicity of grade 3 diarrhea (2 pts) and grade 3 rash (1 pt). Gastrointestinal (GI) toxicity was reported among 6 pts in the 500-mg maximum tolerated dose (MTD) lead-in cohort so that 400 mg was selected as the MTD. Drug-related adverse events (AEs), any grade, occurring in =25% of pts were nausea (67%), diarrhea (55%), anorexia (45%), vomiting (43%), asthenia (41%). The only grade 3 drug-related AE occurring in =5% of pts was diarrhea (14%). After oral administration, bosutinib exposure increased in a dose-dependent manner. Multiple-dose exposure was nearly 2- to 3-fold higher than single-dose exposure. Mean elimination half-life was approximately 17 to 21 hours, supporting a once-daily dosing regimen. Six pts had stable disease >15 weeks (2 pts each with breast, colorectal cancer, non-small cell lung cancer [NSCLC]) and 1 pt had stable disease >52 weeks (pancreatic cancer). Conclusions: Bosutinib was generally well tolerated with predominantly gastrointestinal AEs. Accrual and evaluation of an expanded cohort restricted to patients with colorectal, pancreatic, and NSCLC tumors is ongoing. The patient with pancreatic cancer has had stable disease >52 weeks. No significant financial relationships to disclose.

scholarly journals Efficacy and Safety of Sodium Zirconium Cyclosilicate for Treatment of Hyperkalemia: An 11-Month Open-Label Extension of HARMONIZE

2019 ◽  
Vol 50 (6) ◽  
pp. 473-480 ◽  
Author(s):  
Simon D. Roger ◽  
Bruce S. Spinowitz ◽  
Edgar V. Lerma ◽  
Bhupinder Singh ◽  
David K. Packham ◽  
...  
Keyword(s):  
Point Of Care ◽  
Efficacy And Safety ◽  
Open Label ◽  
Once Daily ◽  
End Point ◽  
Sodium Zirconium ◽  
Open Label Extension ◽  
Median Daily Dose ◽  
Sodium Zirconium Cyclosilicate ◽  
Secondary Results

Background: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for treatment of hyperkalemia. An open-label extension (OLE) of the ­HARMONIZE study evaluated efficacy and safety of SZC for ≤11 months. Methods: Patients from HARMONIZE with point-of-care device i-STAT K+ 3.5–6.2 mmol/L received once-daily SZC 5–10 g for ≤337 days. End points included achievement of mean serum K+ ≤5.1 mmol/L (primary) or ≤5.5 mmol/L (secondary). Results: Of 123 patients who entered the extension (mean serum K+ 4.8 mmol/L), 79 (64.2%) completed the study. The median daily dose of SZC was 10 g (range 2.5–15 g). The primary end point was achieved by 88.3% of patients, and 100% achieved the secondary end point. SZC was well tolerated with no new safety concerns. Conclusion: In the HARMONIZE OLE, most patients maintained mean serum K+ within the normokalemic range for ≤11 months during ongoing SZC treatment.

scholarly journals Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study

Blood ◽  
2020 ◽  
Author(s):  
Eytan M. Stein ◽  
Courtney D. DiNardo ◽  
Amir T. Fathi ◽  
Alice S. Mims ◽  
Keith W Pratz ◽  
...  
Keyword(s):  
Residual Disease ◽  
Phase 1 ◽  
Multiparameter Flow Cytometry ◽  
Intensive Chemotherapy ◽  
Newly Diagnosed ◽  
Concurrent Administration ◽  
Phase 1 Study ◽  
Platelet Recovery ◽  
Once Daily ◽  
Qt Interval Prolongation

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted, oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.

scholarly journals An open-label, exploratory documentation of proving-symptoms of CVN01 (Coronavirus nosode from the clinical sample) in healthy volunteers

2021 ◽  
Vol 20 (2-3) ◽  
pp. 44-50
Author(s):  
Rajesh Shah ◽  
Gitanjali Talele
Keyword(s):  
Healthy Volunteers ◽  
Clinical Sample ◽  
Phase 1 ◽  
Vital Signs ◽  
Liver Function Tests ◽  
Open Label ◽  
Phase 1 Study ◽  
Study Materials ◽  
Prophylactic Use ◽  
Fatal Adverse Events

INTRODUCTION Homeopathic Pathogenetic Trials (Proving) are human studies to examine the pathogenetic effects of investigational drugs in high dilution on healthy volunteers. As a part of the new coronavirus nosode development process for prophylactic use, the phase 1 study was conducted. The documentation of proving symptoms for a fast-track nosode development for a pandemic condition was the objectives of this study. MATERIALS AND METHODS An open-label trial to evaluate the safety and proving symptoms of Coronavirus nosode given orally to 10 volunteers (18-65 years age and of both the genders). Volunteers were administered 6 doses of nosode as 6 pills twice daily for 3 consecutive days. Pre and post examinations (physical), vital signs, and laboratory investigations, were done at day 0, 17, 34. Symptoms experienced by the volunteers were recorded. RESULTS Symptoms reported by volunteers were analyzed. The symptoms reported were mild to severe but reversible and matching with the symptoms produced by the viral infection. There were no serious/fatal adverse events during the study. The basic biochemistry and Liver Function tests were not affected by the Nosode. CONCLUSION New nosode developed during a pandemic condition produced certain symptoms in the homeopathic pathogenetic trial as a part of the Phase 1 study.

scholarly journals A Phase 1 Study of Milademetan in Combination with Quizartinib in Patients with Newly Diagnosed (ND) or Relapsed/Refractory (R/R) FLT3-ITD Acute Myeloid Leukemia (AML)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1389-1389 ◽  
Author(s):  
Naval G. Daver ◽  
Weiguo Zhang ◽  
Richard Graydon ◽  
Vikas K Dawra ◽  
Jingdong Xie ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Wild Type ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Once Daily ◽  
Flt3 Inhibitor ◽  
Equity Ownership ◽  
Mdm2 Inhibitor

Background: FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations occur in ≈ 25% of patients with AML and are associated with poor prognosis. Quizartinib is a once-daily, oral, highly potent and selective FLT3 inhibitor. In the phase 3 QuANTUM-R trial (NCT02039726; Cortes et al. Lancet Oncol 2019), quizartinib prolonged overall survival compared with salvage chemotherapy in patients with R/R FLT3-ITD AML. Murine double minute 2 (MDM2), an E3 ubiquitin ligase, negatively regulates the p53 tumor suppressor and has been shown to be upregulated in patients with AML; TP53 mutations in AML are infrequent except within complex karyotypes. Milademetan, a novel and specific MDM2 inhibitor, showed activity in an ongoing phase 1 trial in patients with AML or myelodysplastic syndromes (MDS) [DiNardo et al. ASH 2016, abstract 593]. Preclinical studies have shown that quizartinib plus milademetan may act synergistically to target FLT3-ITD and restore p53 activity in FLT3-ITD/TP53 wild-type AML [Andreeff et al. ASH 2018, abstract 2720]. Targeting MDM2 may restore p53 activity in cell signaling pathways altered by FLT3-ITD in patients with wild-type TP53 AML. Methods: This open-label, 2-part, phase 1 study (NCT03552029) evaluates quizartinib in combination with milademetan in patients with FLT3-ITD AML. Key inclusion criteria comprise a diagnosis of FLT3-ITD AML (de novo or secondary to MDS) and adequate renal, hepatic, and clotting functions. Key exclusion criteria include acute promyelocytic leukemia, prior treatment with a MDM2 inhibitor, QTcF interval &gt; 450 ms, significant cardiovascular disease, and unresolved toxicities from prior therapies. Dose-escalation (part 1) comprises patients with R/R AML. In part 1, quizartinib will be administered once daily in 28-day cycles, at 3 proposed levels (30, 40, and 60 mg) with appropriate dose modifications based on QTcF monitoring and concomitant use of strong CYP3A inhibitors. Milademetan will be administered on days 1-14 of each 28-day cycle, at 3 proposed levels (90, 120, and 160 mg). Dose escalation will be guided by modified continual reassessment with overdose control. The primary objectives of part 1 are to evaluate the safety and tolerability, optimum dosing schedule, maximum tolerated dose (MTD), and recommended dosing for the expansion (RDE) cohort. Dose expansion (part 2) comprises a cohort of patients with R/R FLT3-ITD AML who have not received &gt; 1 salvage therapy and not received &gt; 1 prior FLT3 inhibitor, and a second cohort including ND patients with FLT3-ITD AML who are unfit for intensive chemotherapy. Patients in part 2 will be treated with quizartinib plus milademetan at the RDE doses identified in part 1. The objectives of part 2 are to confirm the safety and tolerability of quizartinib plus milademetan at RDE and identify the recommended phase 2 dose. Pharmacokinetics and preliminary assessment of efficacy are also being evaluated as secondary outcomes. Pharmacodynamic and biomarker assessments such as leukemic stem cell numbers, STAT5 downstream signaling, minimal residual disease measured by flow cytometry, and gene mutations will be evaluated as exploratory endpoints. Approximately 24 to 36 dose-limiting toxicity-evaluable patients are needed in part 1 to determine the MTDs and the RDE; approximately 40 patients per cohort will be treated at the RDE in part 2. This study is currently recruiting at multiple sites in the United States for part 1; recruitment for part 2 may be expanded to additional sites worldwide as necessary. Disclosures Daver: Jazz: Consultancy; Glycomimetics: Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Servier: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy; Abbvie: Consultancy, Research Funding; Agios: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Otsuka: Consultancy; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Consultancy; Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding. Graydon:Daiichi Sankyo, Inc.: Employment. Dawra:Daiichi Sankyo, Inc.: Employment; Pfizer Inc: Employment. Xie:Daiichi Sankyo, Inc.: Employment. Kumar:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Andreeff:Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees.

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