A Two-Stage Phase Ib Study to Investigate the Pharmacokinetics, Safety and Tolerability of Subcutaneous Rituximab In Patients with Follicular Lymphoma as Part of Maintenance Treatment

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2858-2858 ◽  
Author(s):  
Antonio Salar ◽  
Reda Bouabdallah ◽  
Christine McIntyre ◽  
Pakeeza Sayyed ◽  
Beate Bittner
Keyword(s):  
Adverse Events ◽  
Follicular Lymphoma ◽  
Patient Experience ◽  
Maintenance Treatment ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Two Stage ◽  
Serious Adverse Events ◽  
Maximum Serum ◽  
Phase Ib

Abstract Abstract 2858 Rituximab-containing regimens have become the standard of care for patients suffering from various CD20-positive B-cell malignancies. Currently, rituximab is administered as an intravenous (IV) infusion over several hours. These long infusion times and the side effects related to the infusion were cited by some patients as uncomfortable consequences of the current therapeutic treatment. Furthermore, the required procedure to establish intravenous access is considered invasive and can be painful, particularly in patients with malignant diseases who are treated repeatedly. Subcutaneous (SC) administration could significantly simplify treatment, shortening administration to less than 10 minutes and improving patient experience. Recombinant human hyaluronidase (rHuPH20) has been developed and approved to improve dispersion and absorption of co-administered drugs. It has been combined with rituximab to allow injection volumes larger than 10 mL to be safely and comfortably administered SC. The aims of this Phase Ib study were to select the dose of a new SC rituximab formulation with rHuPH20 giving comparable exposure to IV rituximab and to assess its safety and tolerability in male and female follicular lymphoma (FL) patients during maintenance treatment. This presentation shows the stage 1 data of a two-stage randomized, open-label, multi-centre adaptive Phase Ib study. 124 patients have been randomized to one of four rituximab maintenance treatment groups: 16 patients IV control, 34 patients SC dose 1 [375 mg/m2], 34 patients SC dose 2 [625 mg/m2] and 40 patients SC dose 3 [800 mg/m2]. Prior to randomization, eligible patients were treated with at least one IV rituximab dose at 375 mg/m2 in the maintenance setting. For patients randomized to one of the SC cohorts, a single IV dose was replaced by an SC dose. Patients received rituximab either on a q2m or q3m regimen, as per local practice. Safety data are available from a total of 119 patients. Rituximab SC was generally well tolerated. No clinically significant observations or treatment-related serious adverse events have been reported. A total of 95 adverse events (AEs) were reported in 46 patients (39%). The most commonly documented AE was “administration-associated reaction” (AAR, including rash, erythema and mild discomfort). These AARs were reversible, predominantly mild in intensity and only 1 event necessitated any treatment (metoclopramide for nausea). Overall, the AE profile is not significantly different to that expected in patients treated with rituximab IV (after AAR, the most frequent events were gastrointestinal disorders and mild infections). Four serious adverse events (SAEs) were reported in 4 separate patients, all reported as unrelated to study medication. There were no AEs leading to death, withdrawal or treatment discontinuation. The total volume administered SC in each patient ranged between 4.4 – 15.0 mL. The average injection duration was 2 mL/min. Rituximab maximum serum concentrations in the SC cohorts occurred between Day 2 and Day 8 (48 h and 168 h). Pharmacokinetic parameters were linear with respect to dose over the range of SC doses administered (375, 625 and 800 mg/m2). Rituximab concentrations on Day 28 (C28) and the extent of serum exposure (AUC0-57) in patients administered 625 mg/m2 rituximab SC were comparable to those in patients administered the standard rituximab IV dose of 375 mg/m2 SC. In conclusion, subcutaneous rituximab can be delivered quickly, comfortably and safely while achieving serum exposure comparable to the approved intravenous formulation in FL patients during maintenance treatment. The patient experience was favourable. These results support further testing of subcutaneous rituximab and a fixed dose of 1400 mg rituximab SC has been selected for formal Ctrough non-inferiority testing in stage 2 of the trial. Disclosures: McIntyre: Hoffmann-La Roche Ltd.: Employment. Sayyed: Hoffmann-La Roche Ltd.: Employment. Bittner: Hoffmann-La Roche Ltd.: Employment.

Comparison of Subcutaneous Versus Intravenous Administration of Rituximab As Maintenance Treatment for Follicular Lymphoma: Results From a Two-Stage, Phase IB Study

2014 ◽  
Vol 32 (17) ◽  
pp. 1782-1791 ◽  
Author(s):  
Antonio Salar ◽  
Irit Avivi ◽  
Beate Bittner ◽  
Reda Bouabdallah ◽  
Mike Brewster ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Geometric Mean ◽  
Dose Finding ◽  
Fixed Dose ◽  
Two Stage ◽  
Phase Ib ◽  
Additional Group ◽  
Serum Trough ◽  
Equivalent Efficacy ◽  
Stage 1

Purpose This two-stage phase IB study investigated the pharmacokinetics and safety of subcutaneous (SC) versus intravenous (IV) administration of rituximab as maintenance therapy in follicular lymphoma. Patients and Methods In stage 1 (dose finding), 124 patients who responded to rituximab induction were randomly assigned to SC rituximab (375 mg/m2, 625 mg/m2, or an additional group at 800 mg/m2) or IV rituximab (375 mg/m2). The objective was to determine an SC dose that would yield a rituximab serum trough concentration (Ctrough) in the same range as that of IV rituximab. In stage 2, 154 additional patients were randomly assigned (1:1) to SC rituximab (1,400 mg) or IV rituximab (375 mg/m2) given at 2- or 3-month intervals. The objective was to demonstrate noninferior rituximab Ctrough of SC rituximab relative to IV rituximab 375 mg/m2. Results Stage 1 data predicted that a fixed dose of 1,400 mg SC rituximab would result in a serum Ctrough in the range of that of IV rituximab. Noninferiority (ie, meeting the prespecified 90% CI lower limit of 0.8) was then confirmed in stage 2, with geometric mean Ctrough SC:Ctrough IV ratios for the 2- and 3-month regimens of 1.24 (90% CI, 1.02 to 1.51) and 1.12 (90% CI, 0.86 to 1.45), respectively. Overall safety profiles were similar between formulations (in stage 2, 79% of patients experienced one or more adverse events in each group). Local administration-related reactions (mainly mild to moderate) occurred more frequently after SC administration. Conclusion The fixed dose of 1,400 mg SC rituximab predicted by using stage 1 results was confirmed to have noninferior Ctrough levels relative to IV rituximab 375 mg/m2 dosing during maintenance, with a comparable safety profile. Additional investigation will be required to determine whether the SC route of administration for rituximab provides equivalent efficacy compared with that of IV administration.

scholarly journals Comparison of Safety and Tolerability of Deutetrabenazine During Titration and Maintenance in Patients with Tardive Dyskinesia

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 164-180
Author(s):  
Amanda Wilhelm ◽  
Karen E. Anderson ◽  
Hubert H. Fernandez ◽  
Hadas Barkay ◽  
Nayla Chaijale ◽  
...  
Keyword(s):  
Suicidal Ideation ◽  
Adverse Events ◽  
Tardive Dyskinesia ◽  
Dry Mouth ◽  
Fixed Dose ◽  
Open Label ◽  
Serious Adverse Events ◽  
Open Label Extension ◽  
Pharmaceutical Industries ◽  
Flexible Dose

AbstractBackgroundDeutetrabenazine is approved to treat tardive dyskinesia (TD) in adults and is titrated weekly by 6 mg/day, from 12 to 48 mg/day, based on dyskinesia control and tolerability. This analysis compared the safety of deutetrabenazine during titration versus maintenance.MethodsSafety was assessed during titration versus maintenance using integrated data from two 12-week placebo-controlled studies (ARM-TD and AIM-TD) and the open-label extension study. Rates were compared for overall and serious adverse events (AEs), AEs leading to discontinuation, treatment-related AEs, common AEs (≥4%), and specific AEs (parkinsonism, suicidal ideation, akathisia, restlessness).ResultsIn titration versus maintenance, AE rates with placebo (n=130) were: overall, 43.1% vs 25.4%; serious, 4.6% vs 2.3%; leading to discontinuation, 3.1% vs 0; treatment-related, 26.9% vs 10.0%. For placebo, common AEs during titration were somnolence, headache, nausea, fatigue, and dry mouth; none occurred during maintenance. In titration versus maintenance, AE rates in fixed-dose deutetrabenazine 12–36 mg (n=216) were: overall, 33.3–38.9% vs 22.2–29.2%; serious, 2.8–6.9% vs 0–1.4%; leading to discontinuation, 2.8–5.6% vs 0; treatment-related, 8.3–16.7% vs 8.3–13.9%. For fixed-dose deutetrabenazine, common AEs during titration were headache, diarrhea, nasopharyngitis, depression, hypertension, and dry mouth; headache was the only common AE during maintenance. In titration versus maintenance, AE rates with flexible-dose deutetrabenazine (n=168) were: overall, 49.4% vs 32.7%; serious, 3.6% vs 2.4%; leading to discontinuation, 2.4% vs 0.6%. For flexible-dose deutetrabenazine, the only common AE during titration was somnolence; none occurred during maintenance. Rates of parkinsonism, suicidal ideation, akathisia, and restlessness were low and comparable in titration and maintenance.ConclusionsDeutetrabenazine was well-tolerated, with AE rates similar to placebo during both phases; AE rates were higher during titration and decreased during maintenance.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel

Repurposing Domperidone in Secondary Progressive MS

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011863
Author(s):  
Marcus W. Koch ◽  
Kayla Sage ◽  
Sharanjit Kaur ◽  
Janet Kim ◽  
Graziela Cerchiaro ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive Multiple Sclerosis ◽  
Phase 2 ◽  
Disability Progression ◽  
Two Stage ◽  
Serious Adverse Events ◽  
Secondary Progressive ◽  
Link Type

ObjectiveTo assess whether treatment with the generic drug domperidone can reduce the progression of disability in secondary progressive multiple sclerosis (SPMS), we conducted a phase 2 futility trial following the Simon two-stage design.MethodsWe enrolled patients in an open-label, Simon two-stage, single-center, phase 2, single-arm futility trial at the Calgary MS Clinic if they met the following criteria: age 18–60 years, SPMS, screening EDSS score of 4.0–6.5 and screening T25FW of 9 seconds or more. Patients received domperidone 10 mg QID for one year. The primary outcome was worsening of disability, defined as worsening of the T25FW performance by 20% or more at 12 months compared to at baseline. This trial is registered with ClinicalTrials.gov, number NCT02308137.ResultsBetween February 13, 2015 and January 3, 2020, 110 patients were screened, 81 received treatment, 64 completed follow-up, of whom 62 were analysed. The study did not meet its primary endpoint: 22 of 62 (35%) patients experienced significant worsening of disability, which is close to the expected proportion of 40%, and above the pre-defined futility threshold. Patients with higher prolactin levels during the study had a significantly lower risk of disability progression, which may warrant further investigation. Domperidone treatment was reasonably well tolerated, but adverse events occurred in 84% and serious adverse events in 15% of patients.ConclusionsDomperidone treatment could not reject futility in reducing disability progression in SPMS. The Simon two-stage trial model may be a useful model for phase 2 studies in progressive MS.Classification of evidenceThis study provides Class III evidence that in individuals with secondary progressive multiple sclerosis participating in a futility trial, domperidone treatment could not reject futility in reducing disability progression at 12 months.

A phase Ib study of telatinib (BAY 57–9352), a VEGFR-2 inhibitor, in combination with docetaxel in patients with advanced solid tumours

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14035-14035
Author(s):  
H. M. Shaw ◽  
L. R. Molife ◽  
J. Spicer ◽  
V. Karavasilis ◽  
C. Marriott ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Partial Response ◽  
Adverse Events ◽  
Tyrosine Kinases ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Toxic Dose ◽  
Phase Ib ◽  
Ecog Ps ◽  
Relevant Interaction

14035 Background: Telatinib (BAY 57–9352) inhibits VEGFR-2 and VEGFR-3 tyrosine kinases, and PDGFR-β and c-Kit. Preclinical data suggests that targeting VEGFR signaling increases antitumor activity. Methods: This trial investigated the safety, pharmacokinetics (PK), and tumor efficacy of telatinib combined with docetaxel (D). D was administered at a fixed dose of 75mg/m2 on day 1 of 21-day cycles. Telatinib was administered orally, twice daily (bid) from day 3 of Cycle 1 and onwards, thereafter continuously. Dosing of telatinib commenced at 600mg bid (cohort 1, n=6) and increased to 900mg bid (cohort 2, n=7). PK in Cycle 1 were determined on day 1 (D) and day 21 (telatinib). In Cycle 2 comparative PK profiles for both telatinib and D were sampled on days 1–3. Results: Thirteen patients (pts) with advanced solid tumors were enrolled (9M/4F; median age: 56 [range: 34–69]; ECOG PS 0/1: 3/10). A total of 69 cycles have been completed (range,1–10). Treatment-emergent adverse events of CTCAE =3 (NCI-CTC v3.0) were neutropenia (n=11, 79%), fever (n=2, 15%), and fatigue (n=2, 11%). Adverse events of CTC =3 occuring in two pts was febrile neutropenia. Others occurring in only one patient were; hypertension, ALT increase, dehydration, and reversible symptomatic pneumonitis. Study treatment-related adverse events leading to a dose reduction or interruption were neutropenia (n=5, 38%), hypertension (n=1), ALT increase (n=1), and fatigue (n=1). Two pts with prostate ca and 1 with cervical ca had a confirmed partial response. Five pts (1 NSCLC, 1 esophageal ca, 1 renal cell ca and 2 prostate ca) had stable disease for =4 cycles. Mean AUC of D increased by 48% in cohort 1, but only by 16% in cohort 2. Thus, PK data to date do not indicate a clear clinically relevant interaction between telatinib and D. Conclusions: The combination of telatinib and D was tolerated without reaching the toxic dose at telatinib 900mg bid and D 75mg/m2. This combination has demonstrated promising antitumor activity. An extension of the cohort at 900mg bid with 75mg/m2 D is being evaluated to gain further safety and PK data. No significant financial relationships to disclose.

scholarly journals A Phase Ib Study of Obinutuzumab Combined with Lenalidomide for Relapsed/Refractory Follicular B-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4458-4458 ◽  
Author(s):  
Franck Morschhauser ◽  
Gilles Salles ◽  
Steven Le Gouill ◽  
Herve Tilly ◽  
Catherine Thieblemont ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Fixed Dose ◽  
Unique Type ◽  
Phase Ib ◽  
Advisory Boards ◽  
Grade 3

Abstract BACKGROUND: Lenalidomide exerts anti-proliferative activity on lymphoma cells, enhances T- and NK-cell function, and improves ADCC. The combination of lenalidomide and rituximab (R2) has been shown to be synergistic in pre-clinical models and in patients with relapsed and first-line follicular lymphoma (FL). Obinutuzumab, a unique type II glycoengineered monoclonal anti-CD20 antibody with increased ADCC and increased direct cell death induction compared to rituximab, has shown promising efficacy in NHL. Combining obinutuzumab with lenalidomide might be even more efficient than R2 combination. In 2012, we started a phase Ib/II study to assess the safety and efficacy of this combination (ClinicalTrials.gov: NCT01582776, GALEN) for relapsed/refractory lymphoma patients. Here, we report the phase Ib part whose primary objective was to determine the maximum tolerated dose (MTD) of lenalidomide in combination with a fixed dose of obinutuzumab. METHODS: To identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1-21 of a 28-day cycle for the first cycle and on days 2-22 of a 28-day cycle from cycles 2 to 6. Intravenous infusions of obinutuzumab at a flat dose of 1000mg were given on Days 8, 15, and 22 of the first cycle and at D1 of cycles 2 to 6 (total of 8 infusions). Steroid premedication was mandatory before first obinutuzumab infusion. All subjects were required to take daily aspirin (100 mg) for deep vein thrombosis (DVT) prophylaxis during study period. Subjects who were unable to tolerate aspirin and subjects with prior history of DVT or at high risk received low molecular weight heparin therapy or warfarin (coumadin) treatment. Dose was escalated in a 3+3 design based on dose limiting toxicity (DLT) assessment during cycle 1 RESULTS: 20 patients with FL ([10 mg: 7; 15 mg: 3; 20 mg: 6, 25 mg: 4] QD) were enrolled between Oct 2012 and Feb 2014 at 7 centers, 10 men/10 women, median age 64 (range, 39–80) years, 15 with Ann Arbor stage IV, median number of prior systemic therapies 2 (range, 1–5) and 8 were rituximab refractory. One patient was withdrawn before receiving any treatment due to neutropenia occurring at baseline screening. Median number of cycles was 6 (range, 1–6). We observed 163 AEs (87 grade 1; 53 grade 2; 21 grade 3; one grade 4 and one grade 5). The most common AEs (All grades, ≥20% patients) were neutropenia (10/19; 53%), constipation (10/19; 53%) asthenia (7/19; 37%), upper respiratory tract infection (7/19; 37%), rash/cutaneous eruption (5/19; 26%), cough (5/19; 26%), diarrhea (4/19 ; 26%) and fever (4/19, 21%). Grade (G) 3/4 AEs occurring in ≥2 patients only consisted in neutropenia (8/19; 42%). Infusion related reactions occurred in 3 patients and did not exceed grade 2. Four DLTs have occurred in 2 patients: one unexplained death (G5) at 10 mg in the setting of G3 worsening pleural effusion; another patient treated at 20 mg had G3 pulmonary infection with G3 hypokalemia, both deemed unrelated to study treatment. The MTD was not reached. Among 19 evaluable patients, 13 (68%) had an overall response according to Cheson 1999 criteria: 7 achieved CR, 3 CRu and 3 PR. CONCLUSION: Oral lenalidomide plus obinutuzumab is well tolerated and effective in patients with relapsed or refractory FL. Recommended dose of lenalidomide was established at 20mg based on the increased incidence of grade 3/4 neutropenia between cycle 2 and 6 at 25mg. The Phase II partis currently assessing theefficacy of lenalidomide (at 20 mg) in combination with obinutuzumab in 2 separate populations of patients: relapsed/refractory follicular lymphoma in one cohort and relapsed/refractory aggressive lymphoma (diffuse large B-cell lymphoma and mantle cell lymphoma) in another cohort. Disclosures Morschhauser: Celgene: advisory boards, advisory boards Other, Honoraria; Genentech/roche: Honoraria, travel grants Other. Off Label Use: obinutuzumab and lenlidomide in relapsed follicular lymphoma. Salles:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: advisory boards, advisory boards Other, Honoraria, Research Funding. Le Gouill:Roche: Consultancy. Tilly:Roche/Genetech: advisory boards, advisory boards Other, Honoraria; Celgene: advisory boards Other, Honoraria. Cartron:roche: Consultancy, Honoraria; celgene: Honoraria.

scholarly journals A Single- and Multiple-Dose Study to Characterize the Pharmacokinetics, Safety, and Tolerability of Imipenem and Relebactam in Healthy Chinese Participants

2020 ◽  
Author(s):  
Xiaohong Wang ◽  
Na Liu ◽  
Yudong Wei ◽  
Shuang Zhang ◽  
Haiyan Li ◽  
...  
Keyword(s):  
Adverse Events ◽  
Geometric Mean ◽  
Safety Data ◽  
Chinese Patients ◽  
Pharmacokinetic Parameters ◽  
Dependent Manner ◽  
Serious Adverse Events ◽  
Time Curve ◽  
Multiple Doses ◽  
Healthy Chinese

Relebactam/imipenem/cilastatin is approved in the US to treat complicated urinary tract and intra-abdominal infections in patients that have limited or no alternative treatment options and HABP/VABP. Initial pharmacokinetic, safety, and tolerability studies of relebactam with and without imipenem/cilastatin included mostly Caucasian participants. This study evaluated pharmacokinetics, safety, and tolerability of relebactam/imipenem/cilastatin in 12 healthy Chinese participants after three single doses of increasing concentration (relebactam 125, 250, or 500 mg/cilastatin 250, 500, or 1000 mg/imipenem 250, 500, or 1000 mg) and after multiple doses every 6 h of a single concentration (relebactam 250 mg/cilastatin 500 mg/imipenem 500 mg) for 14 days. After single doses, area under the concentration–time curve (AUC) extrapolated to infinity (relebactam, 15.0–70.7 h*mg/liter; imipenem, 24.1–109.8 h*mg/liter; cilastatin, 18.4–95.3 h*mg/liter) and AUC from 0–6 h (relebactam, 14.2–66.3 h*mg/liter; imipenem, 23.4–107.3 h*mg/liter; cilastatin, 18.3–94.4 h*mg/liter) increased in a dose-dependent manner; clearance (relebactam, 6.9–8.3 liters/h; imipenem, 8.6–10.4 liters/h; cilastatin, 10.5–13.6 liters/h) and half-life (relebactam, 1.4–1.6 h; imipenem, 1.0–1.2 h; cilastatin, 0.7–1.0 h) were consistent between doses. Pharmacokinetic parameters after multiple doses were similar to parameters after a single dose (geometric mean ratios of 0.8–1.0 for all three agents). Relebactam/imipenem/cilastatin was well tolerated; mild adverse events occurred during single dosing, and one participant experienced serious adverse events after multiple doses. Pharmacokinetics and safety data are comparable with data from participants of other ethnicities, supporting the use of relebactam/imipenem/cilastatin at the approved dose and schedule in Chinese patients.

scholarly journals Phase Ib Trial To Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Nadine G. Rouphael ◽  
Selwyn J. Hurwitz ◽  
Mari Hart ◽  
Allison Beck ◽  
Evan J. Anderson ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Laboratory ◽  
Subcutaneous Tissue ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Plasma Exposure ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Time Curve

ABSTRACT Filociclovir (MBX-400, cyclopropavir) is an antiviral agent with activity against cytomegalovirus (CMV). A phase 1, double-blind, randomized, placebo-controlled (3:1 ratio), single-center, multiple-ascending-dose trial was conducted to assess the safety, tolerability, and pharmacokinetics of filociclovir. Filociclovir (n = 18) or placebo (n = 6) was administered as a daily oral dose (100 mg, 350 mg, or 750 mg) for 7 days to normal healthy adults (ages, 25 to 65 years) who were monitored for 22 days. Safety assessments included clinical, laboratory, and electrocardiogram monitoring. Plasma and urine samplings were used to determine pharmacokinetic parameters. All study product-related adverse events were mild, most commonly gastrointestinal (17%), nervous system (11%), and skin and subcutaneous tissue (11%) disorders. One subject had reversible grade 3 elevation in serum creatinine and bilirubin, which was associated with an ∼1-log increase in plasma filociclovir exposure compared to levels for other subjects in the same (750-mg) cohort. No other serious adverse events were observed. Plasma exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) on days 1 and 7 were similar, suggesting negligible dose accumulation. There was a sublinear increase in plasma exposure with dose, which plateaued at the daily dose of 350 mg. The amount of filociclovir recovered in the urine remained proportional to plasma exposure (AUC). Doses as low as 100 mg achieved plasma concentrations sufficient to inhibit CMV in vitro. (This study has been registered at ClinicalTrials.gov under identifier NCT02454699.)

A Phase Ib Dose-Finding Study of Oral Panobinostat In Combination with Cytarabine (ara-C) and Mitoxantrone as Salvage Therapy for Refractory or Relapsed Acute Myeloid Leukemia (AML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3310-3310
Author(s):  
Jürgen Krauter ◽  
Richard F. Schlenk ◽  
Markus Schaich ◽  
Didier Bouscary ◽  
Hervé Dombret ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Fixed Dose ◽  
Phase Ib ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Abstract 3310 Background: Panobinostat (PAN) is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of a series of proteins such as HSP90, p53, α-tubulin and HIF-1α which are involved in cell cycle regulation, gene transcription, angiogenesis, and tumor cell survival. Preclinical studies demonstrated that PAN potentiates the activity of cytarabine (ara-C) and fludarabine and has synergistic activity in combination with doxorubicin in AML cell lines and patient (pt) blast cells. Clinical activity of single-agent PAN has been demonstrated in a phase I trial, including complete responses in pts with AML. Acute myeloid leukemia (AML) is associated with a poor prognosis, particularly in pts with relapsed or refractory disease. The addition of PAN to a chemotherapeutic regimen that is active in pts with AML who have relapsed or are refractory to prior induction therapy has the potential to improve therapeutic outcomes in this setting. Methods: This phase Ib, multicenter, open-label study is comprised of 3 parts: 1) dose-escalation to determine the maximum tolerated dose (MTD) of PAN in combination with ara-C and mitoxantrone, 2) dose-expansion to assess safety and preliminary activity at the MTD, and 3) optional dose extension to assess safety of single-agent PAN (60 mg thrice weekly) in pts who responded but are not eligible for other therapies. The primary objective is to determine the MTD of PAN in combination with a fixed dose of ara-C and mitoxantrone. The primary endpoint is incidence of dose-limiting toxicities (DLTs) within the first treatment cycle. Secondary and exploratory objectives include assessment of the safety profile of PAN and evaluation of anti-leukemic activity. Adult pts with AML (WHO criteria) who are relapsed or refractory to 1 prior treatment regimen with an ECOG PS ≤2 were eligible for enrollment on the study. PAN was orally administered (20 mg starting dose) thrice weekly on Days (D) 1, 3, 5, 8, 10, and 12, in combination with iv ara-C (1 g/m2) D1–6, and iv mitoxantrone (5 mg/m2) D1–5 of a 28-D cycle (C). Pts can receive a maximum of 3 cycles of combination therapy. Pts who are eligible for the optional dose extension part received single-agent PAN (60 mg thrice weekly). Results: As of July 29, 2010, 23 pts have been enrolled, 5 in cohort 1 (20 mg PAN), 8 in cohort 2 (30 mg PAN), and 10 in cohort 3 (40 mg PAN). Safety and efficacy analyses are based on 18 pts. The median age of the pts was 53.5 years (range 19–72). Prior to treatment, all had received ara-C. One DLT has been observed (sepsis and tachyarrhythmia) in the 40 mg cohort. Adverse events were observed with 16 pts (89%): hematologic adverse events (AEs) were observed in 12 pts (67%): including thrombocytopenia, febrile neutropenia, anemia, leukopenia and neutropenia. Non-hematologic AEs included: general disorders and administration site conditions (16 [89%]), gastrointestinal and metabolism/nutrition disorders (15 [83%] each), infections (12 [67%]), respiratory/thoracic disorders (11 [61%]), vascular and skin/subcutaneous tissue disorders (10 [56%] each) and cardiac disorders (8 [44%]). Most frequent Grade 3/4 adverse events (AEs) observed in all cohorts to date were hematologic, including febrile neutropenia and thrombocytopenia (8 [44%] each), leukopenia (5 [28%]), anemia and neutropenia (4 [22%] each). Grade 3/4 AEs suspected to be study treatment related were mostly related to thrombocytopenia (6 [33%]) and neutropenia (4 [22%]). Serious AEs were observed in all cohorts, with most related to infectious complications (8 [44%]), febrile neutropenia (6 [33%]) pneumonia and fungal pneumonia (2 [11%]). QTcF prolongation of ≥480 ms (but < 500 ms) was observed in 2 pts (11%), but no pt demonstrated QTcF prolongation of > 500 ms. Encouraging clinical efficacy was observed, especially with higher doses of PAN, with 8 responders (partial response [PR] or better) (44%): 3 complete remissions (CR), 2 complete remissions with incomplete blood count recovery (CRi) and 3 partial responses (PR). Conclusions: The MTD of PAN in combination with ara-C and mitoxantrone has not been reached, and the study is ongoing. The current data show that the addition of PAN to ara-C and mitoxantrone is safe with no unexpected toxicities and showing promising activity in refractory or relapsed AML pts. Updated data, including safety and preliminary efficacy data will be presented at the meeting. Disclosures: Krauter: Novartis: Research Funding. Off Label Use: Panobinostat is an investigational agent currently being evaluated for the treatment of hematologic and solid malignancies. Schlenk:Novartis: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Amgen: Research Funding; Cephalon: Research Funding. Winiger:Novartis Pharma AG: Employment. Squier:Novartis: Employment. Bengoudifa:Novartis Pharma AG: Employment. Ottmann:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Pharmacokinetic similarity demonstrated after crushing of the elbasvir/grazoprevir fixed-dose combination tablet for HCV infection

2020 ◽  
Vol 75 (9) ◽  
pp. 2661-2665
Author(s):  
Daniëlle W M Pijnenburg ◽  
Minou van Seyen ◽  
Evertine J Abbink ◽  
Angela Colbers ◽  
Joost P H Drenth ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Swallowing Disorders ◽  
Similarity Criteria ◽  
Fixed Dose Combination ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Serious Adverse Events ◽  
Combination Tablet ◽  
Significant Difference ◽  
Dose Combination

Abstract Background Finding a suitable treatment for HCV patients with swallowing disorders is still a major challenge. In practice, direct-acting antivirals are crushed without knowledge of adequate absorption. Crushing can alter drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Currently, there is no information about crushing of the fixed-dose combination tablet of elbasvir/grazoprevir; therefore, crushing of this tablet is not recommended. Objectives To investigate the influence of crushing on the pharmacokinetics of the elbasvir/grazoprevir fixed-dose combination tablet. Methods We conducted an open-label, two-period, randomized, cross-over, Phase I, single-dose trial in 11 healthy adult volunteers. Subjects randomly received whole-tablet elbasvir/grazoprevir or crushed and suspended elbasvir/grazoprevir in a fasted state. Pharmacokinetic similarity criteria (90% CIs lie within 70%–143% acceptance range) were used for AUC0–∞ and AUC0–72. Results Mean plasma concentration–time curves of elbasvir and grazoprevir showed similar pharmacokinetic profiles. The primary pharmacokinetic parameters AUC0–∞ and AUC0–72 of elbasvir and grazoprevir after intake of a crushed tablet were on average 12%–16% higher compared with the whole tablet, but 90% CIs were all within the predefined boundaries of pharmacokinetic similarity. Crushing leads to a higher Cmax of grazoprevir (42%); no significant difference was found between treatments with regard to the Cmax of elbasvir. No serious adverse events were reported during the trial. Conclusions Pharmacokinetic similarity could be demonstrated for a crushed and suspended tablet compared with a whole tablet, without impacting drug safety or efficacy. Crushed and suspended administration of elbasvir/grazoprevir can be used in patients with swallowing disorders.

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