A Phase I Study To Investigate the Pharmacokinetics (PK) and Pharmacodynamics (PD) of an Oral Platelet Growth Factor (SB-559448) in Healthy Subjects.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1072-1072 ◽  
Author(s):  
Sheng-Fang Su ◽  
Bin Peng ◽  
Daphne Williams ◽  
Jung Wook Park ◽  
Malcolm L. Handel ◽  
...  
Keyword(s):  
Platelet Count ◽  
Adverse Events ◽  
Phase I ◽  
Healthy Subjects ◽  
Phase I Study ◽  
Pharmacokinetic Profile ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Once Daily ◽  
Orally Bioavailable

Abstract Introduction: SB-559448, is an orally bioavailable, non peptide, small molecule thrombopoietin receptor agonist that induces proliferation and differentiation of megakaryocytes and progenitor cells, ultimately increasing the production of platelets. Method: In a randomized, single blind, placebo-controlled, parallel group, phase I study in healthy subjects, SB-559448 was administered as oral capsules once daily for 1 day and, after a 7-day washout, for 10 days at doses of 160 to 640 mg. In this dose escalation study, subjects were randomized into 4 groups of 9 subjects to receive either active or placebo medication in a ratio of 6:3. Serial blood samples were collected to determine SB-559448 concentrations and estimate PK parameters following single- and repeat-dosing. PD assessments were performed every 4 to 5 days up to 31 days following initiation of repeat dosing. Results: The preliminary results showed that SB-559448 was well tolerated in the study, there were no serious adverse events, no significant changes in laboratory or cardiovascular safety parameters and there was no observed relationship between the incidence or severity of adverse events and dose. Most adverse events were mild in intensity and self-limiting. SB-559448 was also shown to be orally bioavailable in humans with a pharmacokinetic profile suitable for a once daily oral dosing. When administered at oral doses of 160 mg and above for 10 days, a dose dependent increase in the platelet count was observed with maximum platelet count observed on days 14 to 15 following initiation of repeat dosing. Conclusion: The results suggest that SB-559448 is an orally administered agent that increased platelet counts in healthy subjects. Additional studies will be needed to evaluate its effects in individuals with thrombocytopenia.

scholarly journals Phase I Study Evaluating the Safety and Pharmacokinetics of MDX-1303, a Fully Human Monoclonal Antibody against Bacillus anthracis Protective Antigen, in Healthy Volunteers

2011 ◽  
Vol 18 (12) ◽  
pp. 2136-2142 ◽  
Author(s):  
Valerie Riddle ◽  
Phillip Leese ◽  
Diann Blanset ◽  
Melany Adamcio ◽  
Matthew Meldorf ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Adverse Events ◽  
Phase I ◽  
Bacillus Anthracis ◽  
Phase I Study ◽  
Protective Antigen ◽  
Human Monoclonal Antibody ◽  
Systemic Exposure ◽  
Healthy Human ◽  
Serious Adverse Events

ABSTRACTMDX-1303 (Valortim) is a fully human monoclonal antibody (hMAb) with a high affinity forBacillus anthracisprotective antigen (PA). MDX-1303 binds to PA and interferes with the activity of the anthrax toxin; it was selected based on its superior functional activity in the toxin neutralization activity (TNA) assay. MDX-1303 has demonstrated efficacy in the postexposure and therapeutic settings in New Zealand White rabbits, cynomolgus monkeys, and African green monkeys. This phase I study sought to characterize the safety, tolerability, immunogenicity, and pharmacokinetics (PK)/pharmacodynamics (PD) of MDX-1303 in healthy human subjects. Cohorts of 3 to 10 subjects were administered MDX-1303 as either a single intravenous (i.v.) dose at dose levels of 0.3, 1, 3, 10, and 20 mg/kg of body weight or as a single intramuscular (i.m.) dose at 100 mg. Forty-six subjects were enrolled, and 16 (35%) of these subjects experienced one or more grade 1 adverse events considered to be related to treatment with MDX-1303. There were no grade 2 to 4 adverse events or serious adverse events (SAEs) considered to be related to treatment. The mean half-life of MDX-1303 ranged from 22 to 33 days across the i.v. administration cohorts and was approximately 32 days following i.m. administration. Systemic exposure following 100-mg i.m. administration was within the range of exposure following 1-mg/kg i.v. administration with a relative bioavailability of approximately 65%. MDX-1303 was generally well tolerated, and no anti-MDX-1303 antibodies were detected following a single dose.

An Oral, Non-Petide, Small Molecule Thrombopoietin Receptor Agonist Increases Platelet Counts in Healthy Subjects.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2916-2916 ◽  
Author(s):  
Julian Jenkins ◽  
Richard Nicholl ◽  
Daphne Williams ◽  
Charlotte Baidoo ◽  
Jennifer Phillips ◽  
...  
Keyword(s):  
Platelet Count ◽  
Adverse Events ◽  
Small Molecule ◽  
Receptor Agonist ◽  
Once Daily ◽  
Thrombopoietin Receptor ◽  
Thrombopoietin Receptor Agonist ◽  
Orally Bioavailable ◽  
Dose Dependent Increase ◽  
Dose Dependent

Abstract SB497115, is an orally bioavailable, small molecule thrombopoietin receptor agonist that induces differentiation and proliferation of megakaryocytes. In a randomized, single blind, placebo-controlled, parallel group, phase I study conducted in the UK in 72 healthy male subjects, SB497115 was administered as oral capsules once daily for 1 day and, after a 1 week washout, for 10 days at doses of 5 to 75 mg. Subjects were randomized into six groups of 12 subjects to receive either active or placebo medication in a ratio of 9:3. The study was conducted according to Good Clinical Practice and all subjects gave their written informed consent to participate in the study. SB497115 was well tolerated in the study, there were no serious adverse events, no significant changes in laboratory or cardiovascular safety parameters and there was no observed relationship between the incidence or severity of adverse events and dose. Most adverse events were mild in intensity and self-limiting. SB497115 was shown to be orally bioavailable in humans with a linear pharmacokinetic profile suitable for a once daily oral medication. When administered at oral doses of 30mg and above for 10 days a dose dependent increase in the platelet count was observed, maximum platelet count was observed on days 14 to 16 following initiation of dosing. The dose dependent increase in platelet count is shown in the table below. On the basis of these safety, pharmacokinetic and pharmacodynamic data the oral thrombopoietin receptor agonist, SB497115, will be studied in phase II trials involving thrombocytopenic patients. Preliminary Data: Mean Platelet Count (platelets/uL) Oral Dose Baseline (Day 1) Maximum (Day 14 or 16) Change from Baseline Placebo 234000 255000 21000 5 mg 217000 249000 32000 10 mg 251000 291000 40000 20 mg 236000 279000 43000 30 mg 249000 323000 74000 50 mg 254000 356000 102000 75 mg 239000 357000 118000

The safety profile of eltrombopag, a novel oral platelet growth factor, in thrombocytopenic patients and healthy subjects

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 18596-18596 ◽  
Author(s):  
D. Provan ◽  
M. Saleh ◽  
S. Goodison ◽  
R. Rafi ◽  
N. Stone ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Phase Ii ◽  
Platelet Function ◽  
Healthy Subjects ◽  
Clinical Laboratory ◽  
Serious Adverse Events ◽  
Parallel Group ◽  
Apparent Relationship ◽  
Tolerability Data

18596 Background: Eltrombopag (SB-497115) is an oral, non-peptide, small molecule, thrombopoietin receptor agonist being tested as a potential treatment for thrombocytopenia. Eltrombopag has been shown to increase platelet counts in both healthy subjects and thrombocytopenic patients. Methods: Safety and tolerability data for eltrombopag (3–75 mg for up to 6 weeks) is presented from randomized, placebo-controlled, parallel group clinical trials involving 115 healthy subjects and 104 immune thrombocytopenic purpura (ITP) patients. Safety and tolerability endpoints involved assessment of adverse events (AE) and clinical laboratory parameters, including ECGs and platelet function. Results: In 3 Phase I trials, 98 healthy males received active eltrombopag QD for up to 10 days at 3–75 mg. In the Phase II dose ranging study, 78 chronic ITP patients (28 male/50 female) received active eltrombopag QD for 6 weeks at doses of 30–75 mg. There was no apparent relationship between active and control arms, the dose of eltrombopag and the incidence or severity of AEs, changes in laboratory values, platelet function or cardiac parameters in any of the studies. There were no serious adverse events (SAEs) reported by subjects in the 3 Phase I studies. 5 SAEs were reported in 1 patient in the ITP study that were considered by the investigator as possibly associated with administration of 50 mg eltrombopag. No SAEs were related to 30 mg or 75 mg eltrombopag, and 2 SAEs in 2 patients were related to placebo. Conclusions: There was no apparent relationship between eltrombopag dose and safety endpoints in these studies. These encouraging safety and tolerability data support the further testing of eltrombopag in phase II and III studies involving patients with ITP and chronic liver disease, and cancer patients receiving thrombocytopenic chemotherapy. [Table: see text]

scholarly journals The safety, tolerability and pharmacokinetics of niraparib in Japanese patients with solid tumours: results of a phase I dose-escalation study

2021 ◽  
Author(s):  
Kan Yonemori ◽  
Toshio Shimizu ◽  
Shunsuke Kondo ◽  
Satoru Iwasa ◽  
Takafumi Koyama ◽  
...  
Keyword(s):  
Platelet Count ◽  
Adverse Events ◽  
Phase I ◽  
Dose Escalation ◽  
Locally Advanced ◽  
Tumour Response ◽  
Japanese Patients ◽  
Solid Tumours ◽  
Dose Escalation Study ◽  
Number Of Patients

Abstract Background Niraparib is the only poly (adenosine diphosphate-ribose)-polymerase (PARP) inhibitor available as oral monotherapy for maintenance, regardless of BRCA mutational status. Methods This phase I, open-label, non-randomized, dose-escalation study was conducted in Japan using a 3 + 3 design. Adults (≥20 years) with metastatic or locally advanced solid tumours were enrolled. Niraparib 200 mg (cohort 1) or 300 mg (cohort 2) was administered once daily in 21-day cycles (no drug holiday between cycles) until progressive disease (PD) or unacceptable toxicity. The primary objective was to evaluate the safety and tolerability of niraparib in Japanese patients with advanced solid tumours. The number of patients with dose-limiting toxicities in cycle 1 and number with treatment-emergent adverse events were primary endpoints. Secondary endpoints were pharmacokinetics and tumour response. Results There were three patients in cohort 1 and six patients in cohort 2. Only one patient, in cohort 2, developed a dose-limiting toxicity (grade 4 platelet count decreased). All patients in both cohorts developed treatment-emergent adverse events. The most common treatment-related treatment-emergent adverse events were decreased appetite (n = 2) in cohort 1, and platelet count decreased as well as aspartate aminotransferase increased (both n = 5) in cohort 2. Mean Cmax and AUC0–24 of niraparib increased dose-proportionally after multiple doses (accumulation ratio of between 1.64 and 3.65); median tmax was 3–4 h. Two patients, both in cohort 2, had a partial response to treatment. Conclusions Niraparib (200 or 300 mg/day) was tolerable and had a favourable pharmacokinetic profile in Japanese patients with advanced solid tumours.

scholarly journals Phase I study of napabucasin in combination with FOLFIRI + bevacizumab in Japanese patients with metastatic colorectal cancer

2021 ◽  
Author(s):  
Hiroya Taniguchi ◽  
Toshiki Masuishi ◽  
Akihito Kawazoe ◽  
Kei Muro ◽  
Shigenori Kadowaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Phase I Study ◽  
Tumour Response ◽  
Stage Iv ◽  
Japanese Patients ◽  
Pharmacokinetic Profile ◽  
Serious Adverse Events ◽  
Unacceptable Toxicity

Abstract Background Napabucasin is an oral NAD(P)H:quinone oxidoreductase 1 bioactivatable agent that generates reactive oxygen species, is hypothesised to affect multiple oncogenic cellular pathways, including STAT-3, and is expected to result in cancer cell death. This phase I study investigated the safety, tolerability, and pharmacokinetics of napabucasin co-administered with fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) chemotherapy plus bevacizumab in Japanese patients with metastatic colorectal cancer (CRC). Methods Patients with histologically confirmed unresectable stage IV CRC received oral napabucasin 240 mg twice daily (BID). Intravenous FOLFIRI and bevacizumab therapy was initiated on day 3 at approved doses. Unacceptable toxicity was evaluated over the first 30 days of treatment, after which treatment continued in 14-day cycles until toxicity or disease progression. Endpoints included safety, pharmacokinetics, and tumour response based on RECIST v1.1. Results Four patients received treatment; three were evaluable during the unacceptable toxicity period. All four patients experienced diarrhoea and decreased appetite (considered napabucasin-related in four and two patients, respectively), and three patients experienced neutrophil count decreased. No unacceptable toxicity was reported during the 30-day evaluation period. No grade 4 events, deaths, or serious adverse events were reported. The addition of FOLFIRI and bevacizumab to napabucasin did not significantly change the pharmacokinetic profile of napabucasin; however, results were variable among patients. The best overall response was stable disease in two patients (50.0%). Conclusions Napabucasin 240 mg BID in combination with FOLFIRI and bevacizumab was tolerated, with a manageable safety profile in Japanese patients with metastatic CRC.

Abstract 427: An Oral, Rising, Multiple-dose Tolerance, Pharmacokinetic, and Pharmacodynamic Study of Gemcabene in Healthy Volunteers

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Margaret McShane ◽  
Louis Radulovic ◽  
Charles L Bisgaier
Keyword(s):  
Plasma Concentration ◽  
Adverse Events ◽  
Total Cholesterol ◽  
Healthy Subjects ◽  
Multiple Dose ◽  
Maximum Plasma ◽  
Serious Adverse Events ◽  
Apo B ◽  
Once Daily ◽  
Pharmacodynamic Study

Background: Gemcabene is a novel lipid-regulating compound being developed as an adjunct to diet and statin therapy for the treatment of dyslipidemia. Gemcabene was administered in a randomized, double-blind, rising, multiple-dose safety, tolerance, pharmacokinetic, and pharmacodynamic study in healthy subjects. Methods: Fifty healthy subjects (34 men and 16 women), with a mean age of 39.7 years and mean baseline LDL-C of 116.7 mg/dL were randomized (6:1) to either gemcabene 50, 150, 300, 450, 600/750, or 900 mg or placebo once daily for 29 days in six rising-dose cohorts. Results: Forty-seven subjects completed the study. Gemcabene significantly lowered total cholesterol by 18-21%, low-density lipoprotein-cholesterol (LDL-C) by 26-32%, and apolipoprotein B (apoB) by 8-21% from both baseline and placebo at the 450, 750/600, and 900 mg doses ( Table below ). Gemcabene was rapidly absorbed with dose proportional increases in maximum plasma concentration (Cmax) and area under plasma concentration time curve from 0 to 24 hours (AUC (0-24) ) values. Elimination half-life values were independent of dose and averaged 32-41 hours. Multiple doses of gemcabene up to 900 mg for 29 days were generally well-tolerated. There were no treatment-related serious adverse events. Adverse events reported were generally mild to moderate in intensity. Conclusion: Gemcabene exposure increased proportional with dose, was well tolerated, and was observed to significantly lower total cholesterol, LDL-C, and apo B at once daily doses of 450 to 900 mg. Gemcabene is being developed as an oral, lipid-altering agent to be used as an adjunctive therapy for the treatment of dyslipidemia, including the rare indication of HoFH. Clinical Implications: Gemcabene is being developed as a potential treatment for dyslipidemia.

Bosutinib in combination with pemetrexed in patients with selected metastatic solid tumors: A phase I study (NCT03023319).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3022-3022
Author(s):  
Nagla Fawzy Abdel Karim ◽  
Mahran Shoukier ◽  
Ihab Eldessouki ◽  
Ahmed Khaled ◽  
John Morris
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Weekly Schedule ◽  
Dose Escalation Study ◽  
Grade 3

3022 Background: Activation of the Src kinase pathway has been observed in about 50% of cancers of the colon, liver, lung, breast and pancreas. Ceppi, et al, explored that Src inhibitors might be synergistic in combination with pemetrexed. Bosutinib is an approved oral ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an inhibitory effect on Src kinases. Methods: In this phase 1, dose-escalation study, we enrolled 10 patients with advanced metastatic solid tumors who progressed on standard of care chemotherapy, 9 of whom were evaluable, to receive bosutinib and pemetrexed. Bosutinib was administered once daily in a 3 + 3 dose-escalation study design where the first cohort started at an oral dose of 200 mg daily with I.V. pemetrexed 500 mg/m2 on a three weekly schedule. The primary objective was to determine the dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of bosutinib with pemetrexed, and the type and frequency of adverse events. Secondary objective(s) were to estimate tumor response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: All patients had progressed on prior chemotherapy and included 9 patients with adenocarcinoma of the lung, and 1 patient with metastatic adenocarcinoma of the appendix. Two patients (22%) had prior pemetrexed exposure. Median age was 62 years (range, 58-44). The median number of bosutinib and pemetrexed cycles received was 2 (range, 1-4). Nine patients were evaluable. The MTD of bosutinib was 300 mg daily in this combination as 2 out of the 3 patients who received 400 mg experienced elevated liver transaminases (>CTCAE Grade 3) and one patient experienced grade 3 fatigue. Two patients (22%) had a partial response, and 6 patients (67%) had stable disease, including 2 patients with prior pemetrexed exposure, and 1 patient had disease progression. The two responders and the subject with the longest stable disease duration demonstrated Src overexpression on immunohistochemical staining of their tumor. Two patients died of sepsis; both had stable disease. Median PFS was 4.1 months (range, 1.2-11.6), and the median OS was 11.9 months (range, 4-36.7). Adverse events included pneumonia/sepsis, diarrhea, fatigue, rash, weakness, transaminitis, hypertension, and thrombocytopenia. Conclusions: The MTD of oral bosutinib was 300 mg daily in combination with pemetrexed 500 mg/m2 every 3 weeks. Despite the limitations of this phase I study there appears potential efficacy of this combination in pretreated patients. We are currently enrolling patients in the expansion cohort. Clinical trial information: NCT03023319.

scholarly journals A phase I study of a dual PI3-Kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

2020 ◽  
Author(s):  
Fabian Lang ◽  
Lydia Wunderle ◽  
Susanne Badura ◽  
Eberhard Schleyer ◽  
Monika Brüggemann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Leukemia ◽  
Phase I ◽  
Mtor Inhibitor ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Prolonged Treatment ◽  
Small Subset ◽  
Serious Adverse Events ◽  
Efficient Treatment

Abstract Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single centre open lable study was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia.Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300-400 mg BID (cohort -1/1)) to assess safety, tolerability, preliminary efficacy and pharmakokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3+3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. Results Twenty-four patients with ALL (n=11) or AML (n=12) or CML-BP (n=1) were enrolled. All patients had failed one (n=5) or more lines of therapy (n=5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML. Trial registration ClinicalTrials.gov, identifier NCT01756118. registered 19th Decembre 2012, https://clinicaltrials.gov/ct2/show/NCT01756118

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