Pharmacokinetics (PK) of 2 Dosing Regimens of Palifermin in Patients (Pts) with Hematologic Malignancies (HM) Undergoing High-Dose Chemoradiotherapy and Hematopoietic Stem Cell Transplantation (HSCT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5294-5294 ◽  
Author(s):  
Parnian Zia-Amirhosseini ◽  
Margaret Salfi ◽  
Dieter Elhardt ◽  
Jeff Aycock ◽  
Tsui Chern Cheah ◽  
...  
Keyword(s):  
Single Dose ◽  
Phase 1 ◽  
Dose Range ◽  
Volume Of Distribution ◽  
High Dose ◽  
Karnofsky Performance Score ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Dosing Regimens ◽  
Parameter Values

Abstract For pts with HM undergoing HSCT, oral mucositis (OM) is a frequent and debilitating complication that negatively impacts treatment outcomes, patient quality of life, and healthcare resources. Palifermin reduces the incidence and duration of severe OM in the HSCT setting. This phase 1 open-label study assessed the PK of 2 palifermin dosing regimens. Methods: Pts were 18 to 76 years old with HM and a Karnofsky performance score ≥70%. Palifermin was administered intravenously once daily as follows: 60 mcg/kg/day [d] for 3 consecutive days on d -11, -10, and -9 before conditioning (total body irradiation [TBI] + etoposide + cyclophosphamide) and following HSCT on d 0, 1 and 2 (part A) and a single dose of 180 mcg/kg (part B) before conditioning on d -11 and after HSCT on d 0. In part A (6 total doses), PK parameters were assessed after the 1st, 3rd, 4th, and 6th doses. In part B (2 total doses), assessments were made after each dose administration (d -11 and d 0). Results: In part A, 13 pts received palifermin; in part B, 12 pts received the single dose on d -11 and 11 pts received the single dose on d 0. For both dosing regimens, palifermin concentrations declined rapidly (≥98% decrease) in the first 30 minutes postdose, followed by a slight increase in mean concentrations between 1 and 4 hours and then a terminal decay phase. Respective mean (SD) PK parameter values for the 2 dosing regimens are shown in Table 1. In part A, mean AUC0-t values were comparable between doses 1 and 3 (within 15%) and 1 and 4 (within 1%). In part B, mean PK parameter values were similar (within 10% of each other) between doses 1 and 2. The mean AUC after the first 180 mcg/kg dose in part B was approximately 4-fold higher than that after the first 60 mcg/kg dose in part A. Mean half-life values ranged between 3.3 to 5.7 hours in part A and the value was 5.4 hours in part B. Conclusion: The PK data in pts receiving HSCT were consistent with approximately dose-linear PK in the dose range of 60 and 180 mcg/kg, with no observed accumulation, based on AUC, after 3 daily doses of 60 mcg/kg in this pt population in the HSCT setting. Table 1 Dose Number (Dosing Day) n AUC0-t (hr x ng/mL) mean (SD) Clearance (mL/hr/kg) mean (SD) Vss (mL/kg) mean (SD) a Accurate computations of clearance (CL) and volume of distribution at steady state (Vss) were not possible for some concentration-time profiles. Part A - 60 mcg/kg/day x 3 consecutive days 1st dose (day -11) 9–13 34.3 (15.9) 1730a (497) 5320a (2330) 3rd dose(day -9) 13 39.8 (36.4) - - 4th dose(day 0) 11–13 34.8 (22.5) 2030a (862) 3870a (2080) 6th dose(day 2) 13 21.2 (15.1) - - Part B - 180 mcg/kg/day x 1 day 1st dose(day -11) 12 140 (50.9) 1460 (600) 4290 (3270) 2nd dose(day 0) 11 143 (71.8) 1770 (1290) 4270 (4700)

Pharmacokinetics, pharmacodynamics, safety, and tolerability of BION-1301 in adults with relapsed or refractory multiple myeloma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8022-8022
Author(s):  
Jeroen Elassaiss-Schaap ◽  
Peter van Zandvoort ◽  
Jeannette Lo ◽  
Nitya Nair ◽  
Jackie Walling ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase 1 ◽  
Dose Range ◽  
Serum Levels ◽  
Open Label ◽  
Immune Resistance ◽  
Dosing Regimens ◽  
Low Incidence ◽  
Dose Levels

8022 Background: APRIL (“a proliferation-inducing ligand”) levels are elevated in the serum of patients diagnosed with multiple myeloma (MM) and is correlated to promotion of malignancy, chemo- and immune-resistance. BION-1301 (BION) is a recombinant, humanized monoclonal antibody against APRIL. We report on the initial pharmacokinetic/ pharmacodynamic (PK-PD) profile, safety, and tolerability of BION in adults with relapsed or refractory MM. Methods: Adults with MM and disease progression after ≥3 systemic therapies were recruited for the study. BION was administered every 14 days through intravenous infusion. This ongoing Phase 1/2, open-label, multicenter study is evaluating 6 cohorts with increasing BION dose levels of 50, 150, 450, 1350, and 2700 mg administered Q2W intravenously (cohort 6 - 1350 mg dose given QW and Q2W). Serum was analyzed for BION, anti-drug antibodies (ADA), and free APRIL (fAPRIL) at baseline and upon treatment, and evaluated by PK-PD modeling. Results: As of 7Dec2018 reporting through the first 4 cohorts, 15 patients were enrolled in the study (N = 3-4 per cohort). BION has been well-tolerated to date. While exposure increased dose-proportionally from 50 to 1350 mg, half-life and clearance did not significantly differ between 50 and 1350 mg. APRIL serum levels decreased with increasing BION doses. To date no DLT was observed. Non-neutralizing ADA were detected in 1 of the 15 patients. BION transiently reduced fAPRIL levels starting at a dose of 50 mg. A prolonged reduction was seen at higher doses, and at 450 mg, reduction was maintained in 2 patients on treatment for 6 cycles (5.5 months). The area under the normalized fAPRIL curve (Days 1-15) decreased 5-fold from 50 to 1350 mg. Data fit well in an exploratory PK-PD model, with kinetic binding of BION and fAPRIL according to in vitro parameters, and peripheral compartments for both entities. While at 450 mg, 95% target engagement (TG) was achieved around peak exposure levels, at 1350 mg this 95% TG was maintained throughout the dosing interval of 3 doses. Conclusions: BION dose-dependently inhibits serum levels of fAPRIL between 50 to 1350 mg dose levels. Exposure was approximately dose-linear over the dose range evaluated, with a low incidence of ADA. Promising TG was obtained at prolonged dosing of 450 mg Q2W. A favorable safety profile supports continued dose escalation and more frequent dosing regimens based on PK-PD modeling. The study is ongoing with subjects exposed to higher and/or more frequent doses anticipated to result in accelerated and sustained APRIL TG. Clinical trial information: NCT03340883.

166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2684-2691 ◽  
Author(s):  
Sergio Giralt ◽  
William Bensinger ◽  
Mark Goodman ◽  
Donald Podoloff ◽  
Janet Eary ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Phase 1 ◽  
High Dose ◽  
Two Phase ◽  
Hematopoietic Stem

Abstract Holmium-166 1, 4, 7, 10-tetraazcyclododecane-1, 4, 7, 10-tetramethylenephosphonate (166Ho-DOTMP) is a radiotherapeutic that localizes specifically to the skeleton and can deliver high-dose radiation to the bone and bone marrow. In patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation two phase 1/2 dose-escalation studies of high-dose 166Ho-DOTMP plus melphalan were conducted. Patients received a 30 mCi (1.110 Gbq) tracer dose of 166Ho-DOTMP to assess skeletal uptake and to calculate a patient-specific therapeutic dose to deliver a nominal radiation dose of 20, 30, or 40 Gy to the bone marrow. A total of 83 patients received a therapeutic dose of 166Ho-DOTMP followed by autologous hematopoietic stem cell transplantation 6 to 10 days later. Of the patients, 81 had rapid and sustained hematologic recovery, and 2 died from infection before day 60. No grades 3 to 4 nonhematologic toxicities were reported within the first 60 days. There were 27 patients who experienced grades 2 to 3 hemorrhagic cystitis, only 1 of whom had received continuous bladder irrigation. There were 7 patients who experienced complications considered to be caused by severe thrombotic microangiopathy (TMA). No cases of severe TMA were reported in patients receiving in 166Ho-DOMTP doses lower than 30 Gy. Approximately 30% of patients experienced grades 2 to 4 renal toxicity, usually at doses targeting more than 40 Gy to the bone marrow. Complete remission was achieved in 29 (35%) of evaluable patients. With a minimum follow-up of 23 months, the median survival had not been reached and the median event-free survival was 22 months. 166Ho-DOTMP is a promising therapy for patients with multiple myeloma and merits further evaluation. (Blood. 2003;102:2684-2691)

scholarly journals Pharmacokinetics and Safety of Intravenous Ceftolozane-Tazobactam in Healthy Adult Subjects following Single and Multiple Ascending Doses

2012 ◽  
Vol 56 (6) ◽  
pp. 3086-3091 ◽  
Author(s):  
Benjamin Miller ◽  
Ellie Hershberger ◽  
David Benziger ◽  
MyMy Trinh ◽  
Ian Friedland
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Healthy Adult ◽  
Volume Of Distribution ◽  
Dose Administration ◽  
Mean Values ◽  
Multiple Doses ◽  
Dosing Regimens ◽  
Dose Levels ◽  
Dose Limiting Toxicity

ABSTRACTThe pharmacokinetics and safety of ceftolozane, a novel cephalosporin, and tazobactam, a β-lactamase inhibitor, alone and in combination as a 2:1 ratio in single doses of up to 2,000 and 1,000 mg of ceftolozane and tazobactam, respectively, and multiple doses of up to 3,000 and 1,500 mg of ceftolozane and tazobactam, respectively, per day were evaluated in healthy adult subjects. In part 1, groups of six subjects each received single ascending doses of ceftolozane, tazobactam, and ceftolozane-tazobactam in a within-cohort crossover design. In part 2, groups of 5 or 10 subjects each received multiple doses of ceftolozane, tazobactam, or ceftolozane-tazobactam for 10 days. After a single dose of ceftolozane alone, the ranges of mean values for half-life (2.48 to 2.64 h), the total clearance (4.35 to 6.01 liters/h), and the volume of distribution at steady state (11.0 to 14.1 liters) were consistent across dose levels and similar to those observed when ceftolozane was coadministered with tazobactam. Mean values after multiple doses for ceftolozane alone and ceftolozane-tazobactam were similar to those seen following a single dose. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Ceftolozane-tazobactam was well tolerated and systemic adverse events were uncommon. Mild infusion-related adverse events were the most commonly observed following multiple-dose administration. Adverse events were not dose related, and no dose-limiting toxicity was identified.

scholarly journals An open label, adaptive, phase 1 trial of high‐dose oral nitazoxanide in healthy volunteers: an antiviral candidate for SARS‐CoV‐2

2021 ◽  
Author(s):  
Lauren E Walker ◽  
Richard FitzGerald ◽  
Geoffrey Saunders ◽  
Rebecca Lyon ◽  
Michael Fisher ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Phase 1 ◽  
High Dose ◽  
Open Label ◽  
Phase 1 Trial ◽  
Dose Oral

High Dose Plerixafor Is Safe and Mobilizes Higher Numbers of CD34+ Cells Compared with Standard Dose Plerixafor

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 585-585
Author(s):  
Jeremy M Pantin ◽  
Xin Tian ◽  
Matthew M. Hsieh ◽  
Lisa Cook ◽  
Theresa Donohue ◽  
...  
Keyword(s):  
Stem Cell ◽  
Single Dose ◽  
Adverse Events ◽  
Dose Level ◽  
Peripheral Blood ◽  
Standard Dose ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Cell Numbers ◽  
Cd34 Cells

Abstract Abstract 585 Introduction Plerixafor is a bicyclam compound that inhibits the binding of stromal cell derived factor-1 (SDF-1) to its cognate receptor CXCR4. This results in therapid release of CD34+ cells into circulation, which can then be collected by apheresis. Plerixafor is FDA approved at the 240 μg/kg dose to be used in conjunction with G-CSF to mobilize autografts for transplantation. Allogeneic grafts can also be mobilized using single agent plerixafor without G-CSF, and following transplantation, result in sustained donor derived hematopoiesis. However, when the 240 μg/kg dose is used, 1/3 of donors fail to mobilize minimally acceptable doses of CD34+ cells. Recently, we demonstrated the safety of administration of a single dose of 480 μg/kg of subcutaneous (sc) plerixafor in humans. We subsequently conducted a randomized cross-over trial comparing CD34+ mobilization in healthy subjects mobilized with a single dose of sc plerixafor given at either a high dose (480 μg/kg) or a conventional dose (240 μg/kg). Methods Twenty normal healthy volunteers were randomized and received either a 240 or 480 μg/kg dose of sc plerixafor followed by at least a 2 week wash out period then were administered the other dose of plerixafor. Circulating numbers of leukocytes and CD34+ cells/μlwere measured at multiple time points for 24 hours following each plerixafor injection and the CD34+ AUC over 24 hours was calculated for each subject at each dose level. Peripheral blood colony forming unit (CFU) assays were performed at baseline and 6 hours after plerixafor dosing. Adverse events were graded using CTCAE version 3.A sample size of 20 subjects was determined to have over 90% power to detect an absolute CD34+ count difference of 10/μl using this crossover design and a two-sidedpaired t-test at the 0.05 level. Results Twenty-three subjects were enrolled and 20 completed administration of both doses. Peak circulating CD34+ cell numbers (median 31.5 vs 25, p=0.0009), circulating CD34+ cell numbers at 24hrs (median 15.5 vs 9, p<0.0001), and the CD34+ AUC over 24 hours (median 543 vs 411, p<0.0001) were all significantly higher following the administration of the 480 μg/kg plerixafor dose compared to the 240 μg/kg dose. The time to peak CD34+ was also slightly longer after the 480 μg/kg dose (median 10 vs 8 hrs, p=0.011). These differences were not related to the order of administration of the 2 different plerixafor doses. Although GM-CFUs from the peripheral blood at 6hrs following plerixafor were significantly higher compared to baseline levels at both plerixafordoses, there was no dose-effect relationship observed between drug dose and fold increase in GM-CFUs. The incidence and severity of AE's did not differ between lower and higher doses of plerixafor and no grade 3 or greater adverse events occurred at either dose level. Conclusion These preliminary data suggest high dose plerixafor can be administered safely and may mobilize more CD34+ cells than standard dose plerixafor. Furthermore, these data suggest mobilization following a single dose of plerixafor and a single apheresis procedure would result in graft collections containing higher CD34+ cell numbers when allogeneic stem cell donors are mobilized with high-dose plerixafor compared to standard-dose. Disclosures: Off Label Use: Plerixafor, a hematopoietic stem cell mobilizer, is indicated in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM).

Phase 1 study to evaluate safety and efficacy of ipilimumab + nivolumab + external beam radiotherapy in patients with metastatic melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS9591-TPS9591
Author(s):  
Michael Andrew Postow ◽  
Susan Jane Knox ◽  
Danielle McCabe ◽  
Mary J. Macri ◽  
Paul Schwarzenberger ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Metastatic Melanoma ◽  
Phase 1 ◽  
External Beam Radiotherapy ◽  
Objective Response ◽  
Palliative Therapy ◽  
Dose Fractionation ◽  
High Dose ◽  
Melanoma Metastasis ◽  
Open Label

TPS9591 Background: Immunotherapy (IMT) with checkpoint blocking antibodies has led to progress in metastatic melanoma with 3 FDA-approved drugs, including the combination of ipilimumab (IPI), a CTLA-4 antibody, and nivolumab (NIVO), a PD-1 antibody. Although radiotherapy (RT) is primarily used as local palliative therapy in metastatic melanoma, it also possibly affects systemic antitumor immunity. Preclinical data suggest RT alters the tumor microenvironment and renders tumor cells more susceptible to immunologically-mediated disease regression. These preclinical immunologic effects of RT have been shown to vary by RT dose and fractionation. We are now conducting the first clinical trial in patients to evaluate the triple combination of IPI + NIVO + RT using 2 different dose/fractionation schemes of RT. Methods: This ongoing Phase 1, open-label, multicenter study (NCT02659540) evaluates safety, efficacy, and immunologic effects of IPI + NIVO + RT in 18 patients with unresectable stage IV melanoma. Patients must have 1 melanoma metastasis that can be safely irradiated for palliative purposes and at least 1 measurable lesion that will not be irradiated. Patients receive concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks (Q3W) x 4, followed by NIVO monotherapy (240 mg Q2W), with RT initiated between the first and second doses of IPI + NIVO. In Cohort A, the irradiated metastasis receives a conventionally fractionated low dose of 30 Gy in 10 fractions of 3 Gy each over 2 weeks. If ≤7 of 9 patients (78%) in Cohort A have Grade 3/4 drug- or radiation-related adverse events, safety is deemed acceptable and Cohort B enrollment opens. In Cohort B, the irradiated metastasis receives a hypofractionated high dose of 27 Gy in 3 fractions of 9 Gy each over 2 weeks. The primary endpoint is safety. Secondary endpoints are objective response rate and disease control rate by RECIST and immune-related RECIST measured at Weeks 12 and 18, duration of response, progression-free survival, and overall survival. Exploratory endpoints include correlative studies of immunological effects. Enrollment opened on 05 Aug 2016. As of 31 Dec 2016, 4 patients are enrolled in Cohort A; enrollment is ongoing. Clinical trial information: NCT02659540.

Phase 1 study of elotuzumab in combination with autologous stem cell transplantation and lenalidomide maintenance for multiple myeloma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8021-8021
Author(s):  
Keren Osman ◽  
Hearn J. Cho ◽  
Ajai Chari ◽  
Samir S. Parekh
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Treatment Plan ◽  
Phase 1 ◽  
Consolidation Therapy ◽  
Open Label ◽  
Peripheral Blood Mononuclear ◽  
Hematopoietic Stem

8021 Background: Elotuzumab is a humanized monoclonal antibody directed against SLAMF7 that is approved for use in relapsed multiple myeloma. We initiated a single-center, open label, phase 1 trial based on the hypothesis that the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) reconstitution to standard-of-care autologous hematopoietic stem cell transplantation (auto-SCT) and lenalidomide maintenance for consolidation therapy in myeloma patients will be safe and feasible. Methods: This is a Phase 1b, open-label, trial investigating elotuzumab and autologous PBMC reconstitution with auto-SCT consolidation therapy and lenalidomide maintenance. The primary objective of this study is to assess the safety and tolerability of elotuzumab and autologous PBMC reconstitution in the setting of auto-SCT and lenalidomide maintenance. The secondary objectives are to assess myeloma disease status and progression-free survival (PFS) after one year of treatment. Subjects must be eligible for auto-SCT, and meet inclusion/exclusion criteria. Fifteen subjects participated in this study. The treatment plan is: In addition to PBSC harvest, subjects undergo steady-state leukopheresis for PBMC collection. Subjects receive standard melphalan (day -1) and autologous stem cell rescue (day 0). Autologous PBMC are reinfused on day +3 and cycle 1 of elotuzumab 20 mg/kg IV is given on day +4. Subjects receive elotuzumab every 28 days up to cycle 12. Lenalidomide maintenance at 10 mg orally daily begins with cycle 4 of elotuzumab. The evaluable population constitutes all subjects who received at least four of the first five planned doses of elotuzumab. Results: 15 subjects have been enrolled in the study. All of these subjects are included in the safety population, having received at least 1 dose of elotuzumab. Nine of 15 subjects have completed 4 of the first 5 planned elotuzumab infusions.. The majority of adverse events, including infusion reactions attributable to elotuzumab, have been grade 2 or lower. There were no delays in hematopoietic reconstitution. No AEs were attributed to PBMC reconstitution. Conclusions: The combination of elotuzumab and PBMC reconstitution with standard auto-SCT and lenalidomide maintenance for consolidation therapy appears to be safe and feasible. The trial is ongoing and has completed accrual. The clinical results will be updated for presentation.

scholarly journals Treatment withα-Lipoic Acid over 16 Weeks in Type 2 Diabetic Patients with Symptomatic Polyneuropathy Who Responded to Initial 4-Week High-Dose Loading

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Hector Garcia-Alcala ◽  
Celia Isabel Santos Vichido ◽  
Silverio Islas Macedo ◽  
Christelle Nathalie Genestier-Tamborero ◽  
Marissa Minutti-Palacios ◽  
...  
Keyword(s):  
Lipoic Acid ◽  
Phase 1 ◽  
Treated Group ◽  
Diabetic Patients ◽  
High Dose ◽  
Phase 2 ◽  
Open Label ◽  
Type 2 Diabetic Patients ◽  
Type 2 Diabetic

Effective treatment of diabetic sensorimotor polyneuropathy remains a challenge. To assess the efficacy and safety ofα-lipoic acid (ALA) over 20 weeks, we conducted a multicenter randomized withdrawal open-label study, in which 45 patients with type 2 diabetes and symptomatic polyneuropathy were initially treated with ALA (600 mg tid) for 4 weeks (phase 1). Subsequently, responders were randomized to receive ALA (600 mg qd;n=16) or to ALA withdrawal (n=17) for 16 weeks (phase 2). During phase 1, the Total Symptom Score (TSS) decreased from 8.9 ± 1.8 points to 3.46 ± 2.0 points. During phase 2, TSS improved from 3.7 ± 1.9 points to 2.5 ± 2.5 points in the ALA treated group (p<0.05) and remained unchanged in the ALA withdrawal group. The use of analgesic rescue medication was higher in the ALA withdrawal group than ALA treated group (p<0.05). In conclusion, in type 2 diabetic patients with symptomatic polyneuropathy who responded to initial 4-week high-dose (600 mg tid) administration of ALA, subsequent treatment with ALA (600 mg qd) over 16 weeks improved neuropathic symptoms, whereas ALA withdrawal was associated with a higher use of rescue analgesic drugs. This trial is registered with ClinicalTrials.gov Identifier:NCT02439879.

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