Pharmacokinetics, pharmacodynamics, and tolerability of BCD-017, a novel pegylated filgrastim: Results of open-label controlled phase I study with dose escalation in healthy volunteers.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9060-9060
Author(s):  
Kirill D. Nikitin ◽  
Sergei B. Fitilev ◽  
Tatiana V. Chernovskaya ◽  
Elena G. Rudenko ◽  
Alexander V. Vozzhaev ◽  
...  
Keyword(s):  
Phase I ◽  
Healthy Volunteers ◽  
Phase I Study ◽  
Phase Ii Study ◽  
Open Label ◽  
Post Dose ◽  
Median Increase ◽  
Open Label Phase ◽  
To Receive ◽  
Median Maximum

9060 Background: Pegfilgrastim (conjugate of filgrastim and 20 kDa PEG) is approved for treatment of chemotherapy-associated neutropenia. BCD-017 is a covalent conjugate of filgrastim with 30 kDa PEG. Increased molecular weight of PEG molecule may provide additional benefits compared to pegfilgrastim. We have conducted this open-label phase I study to assess the PK, PD and tolerability of BCD-017. Methods: 24 healthy male volunteers signed the informed consent and were sequentially assigned to receive 1, 3 or 9 mg of BCD-017 or 5 mcg/kg/day of filgrastim for 7 days, 6 volunteers per group. Outcome measures included absolute neutrophil count (ANC) and СD34+ cell count, PK parameters and adverse events (AEs). Results: BCD-017 induced a fast and significant increase of ANC. Median maximum ANC (ANCmax) for BCD-017 1, 3, 9 mg and filgrastim was 18.68 (10.62-21.02), 25.92 (15.43-28.07), 32.22 (18.22-45.79), and 28.21 (21-31.95) ×103 cells/mm3, respectively; median time to ANCmax was 24 (12-24); 48 (24-72); 72 (48-72); and 132,5 (12-169) h, respectively; median increase in СD34+ cells number 96 h post dose was 4.7 (1.2-6.5), 6.5 (1.7-12.3), 40.9 (24.5-102), and 17.8 (3.3-35.2) times, respectively. Filgrastim serum concentration was analyzed using ELISA. Median Cmax for BCD-017 3 and 9 mg and filgrastim was 45 (31-65), 446 (191-649), and 40 (20-54) ng/mL, respectively; median Tmax was 48 (24-72), 36 (24-48), and 8 (6-8) h respectively; median T1/2 was 65 (51-70), 46 (41-57), and 6.7 (6.2-7.6) h, respectively. BCD-017 was well tolerated. No dose-limiting AEs were observed. AEs included headache, back pain, myalgia, arthralgia, thrombocytopenia, hyperuricemia, alkaline phosphatase/LDH increased. All AEs were of grade 1-2. Compared to filgrastim, the best tolerability was observed in 3 mg group. Conclusions: BCD-017 is shown to be a potent stimulator of granulopoiesis. BCD-017 3 mg did not differ from filgrastim in terms of ANC increase and its safety was shown in healthy volunteers. Further phase II study of BCD-017 for treatment and prophylaxis of neutropenia in patients receiving cytotoxic chemotherapy is necessary.

A phase I/II study of lenalidomide (Len) in combination with rituximab (R) in relapsed/refractory mantle cell lymphoma (MCL) with early evidence of efficacy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8030-8030 ◽  
Author(s):  
M. Wang ◽  
L. Fayad ◽  
F. Hagemeister ◽  
S. Neelapu ◽  
N. Bell ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Prior Therapy ◽  
Mantle Cell ◽  
Open Label Phase ◽  
To Receive ◽  
Ongoing Phase

8030 Background: MCL remains a therapeutic challenge. R targets CD20 antigen on MCL cells while Len may target the microenvironment of MCL cells and enhance the ADCC activity of R. To test this hypothesis, we initiated a single-center; open label, phase I/II study. We now report the completed phase I. Methods: Eligible patients (pts) had 1–4 lines of prior therapy including prior thalidomide or R, regardless of resistance. Each cycle of treatment consisted of Len given orally daily on days 1–21 of a 28-day cycle and R 375 mg/m2 by IV infusion weekly for 4 weeks. A standard 3+3 dose escalation was used to determine MTD with Len doses at 10 mg, 15 mg, 20 mg, and 25 mg. DLT was defined as grade (G) 3 or 4 non-hematologic or G4 hematologic toxicity during the first cycle. Results: The phase I portion completed enrollment with 15 pts (4 at 10 mg, 3 at 15 mg, 6 at 20 mg and 2 at 25 mg). Thirteen pts were evaluable. Median age was 73 (62–84); median prior lines of therapy were 3 (1–4); median cycles received to date were 2 (1–7). Two DLT's occurred at 25 mg. One pt had G3 hypercalcemia. The other had G4 neutropenic fever and died of sepsis (G5) during the first cycle. Three additional pts were therefore enrolled at 20 mg. Common non-hematologic toxic events included pruritis (21 G1–2), hypercalcemia (9 G1–2, 1 G3), fatigue (9 G1–2), constipation (8 G1), diarrhea (6 G1–2), fever (6 G1–2), myalgias (4 G1–2, 1 G3) and elevated LDH (4 G1–2, 1 G3). Hematologic events included neutropenia (20 G1–2, 4 G3), thrombocytopenia (6 G1–2, 2 G3) and anemia (6 G1). There were no responses at 10 mg or 15 mg. At 20 mg after 2 cycles, 5 out of 6 pts achieved responses including 1 CR, 1 PR, 3 minor responses (MRs) and only 1 pt progressed. The 1 pt with PR went on to achieve a CR after 6 cycles. The 3 pts with MRs had tumor reductions by 43%, 40% and 38% respectively. These 3 patients with MRs continue to receive Len and might later achieve PR or CR. Conclusions: The MTD for Len with R in relapsed/refractory MCL was 20 mg, orally daily on days 1–21 of a 28-day cycle. Responses observed at 20 mg are promising with a favorable toxicity profile and are being evaluated further in an ongoing phase II study. [Table: see text]

scholarly journals ACTR-59. A PHASE 1 STUDY OF BPM31510 PLUS VITAMIN K IN SUBJECTS WITH HIGH-GRADE GLIOMA THAT HAS RECURRED ON A BEVACIZUMAB-CONTAINING REGIMEN

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi27-vi27
Author(s):  
Lawrence Recht ◽  
Reena Thomas ◽  
Sophie Bertrand ◽  
Priya Yerballa ◽  
Gordon Li ◽  
...  
Keyword(s):  
Phase I ◽  
Vitamin K ◽  
Phase I Study ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

Abstract BACKGROUND High-grade gliomas (HGG) are characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone (coenzyme Q10) containing lipid nanodispersion, causes a switch in cancer energy sourcing from glycolysis towards mitochondrial oxidative phosphorylation in vitro, reversing the Warburg effect and suggesting potential as an anti-tumor agent. The current study is a phase I study of BPM31510 + vitamin K in GB with tumor growth after bevacizumab (BEV). METHODS This is an open-label phase I study of BPM31510 continuous infusion with weekly vitamin K (10mg IM) in HGG patients using an mTPI design, starting at 110mg/kg, allowing for a single dose de-escalation and 2 dose-escalations. Patients had received first-line ChemoRadiation and were in recurrence following a BEV containing regimen. RESULTS 9 eligible and evaluable patients completed the 28 day DLT period. 8 patients had primary GB, 1 had anaplastic astrocytoma with confirmed pathologic transformation to GB. Median age was 55 years (27–67) and median KPS 70 (60–90) at enrollment. 4 patients were treated at the highest dose 171mg/kg, where there was a single DLT: Grade 3 AST & ALT. The most common grade 1–2 AEs possibly, probably or definitely related to drug were elevated AST, rash, and fatigue, each occurring in 3 patients. Median OS for 9 eligible/evaluable patients was 128 days (95% CI: 48–209) while PFS was 34 days (CI of mean 8.9). 3 patients are currently alive; 2 patients have survived >1 year. PK/PD data are being processed and will be presented. CONCLUSION This study confirms that BPM 31510 + vitamin K is safe and feasible in treatment-refractory HGG patients. Though this study demonstrates safety at 171mg/kg, the proposed dose for future studies in GB, based on additional pre-clinical and non-GB clinical data is 88mg/kg.

scholarly journals Effect of renal function on the pharmacokinetics of fimasartan: a single-dose, open-label, Phase I study

2014 ◽  
pp. 1723 ◽  
Author(s):  
Seokuee Kim ◽  
Jongtae Lee ◽  
Donghoon Shin ◽  
Kyoung Soo Lim ◽  
Yon Su Kim ◽  
...  
Keyword(s):  
Renal Function ◽  
Single Dose ◽  
Phase I ◽  
Phase I Study ◽  
Open Label ◽  
Open Label Phase

scholarly journals Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer

2020 ◽  
Vol 26 (18) ◽  
pp. 4814-4822 ◽  
Author(s):  
Zev A. Wainberg ◽  
Howard S. Hochster ◽  
Edward J. Kim ◽  
Ben George ◽  
Aparna Kaylan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Phase I Study ◽  
Advanced Pancreatic Cancer ◽  
Open Label ◽  
Open Label Phase

Randomized, open-label, phase II study comparing five-weekly S-1 plus cisplatin (SP) with tri-weekly capecitabine plus cisplatin (XP) in chemotherapy-naïve patients with HER2 negative advanced gastric cancer (AGC): OGSG 1105 HERBIS-4A trial.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 102-102
Author(s):  
Atsushi Takeno ◽  
Youichi Makari ◽  
Shunji Endo ◽  
Jin Matsuyama ◽  
Ryohei Kawabata ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Open Label ◽  
Group 13 ◽  
Common Grade ◽  
Open Label Phase ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
To Receive

102 Background: This phase II study aimed to investigate the safety and efficacy of XP compared to SP in the first-line treatment of HER2 negative AGC. Methods: Patients were randomly assigned to receive either SP (S-1 at 40–60 mg twice daily for 21 days plus cisplatin at 60 mg/ m2 on day 8, every 5 weeks) or XP (capecitabine 1,000 mg/m2 twice daily for 14 days plus cisplatin 80 mg/m2 on day 1, every 3 weeks). Primary endpoint was response rate (RR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), and adverse events. Results: 84 eligible patients were randomly assigned to receive SP ( N = 41) or XP ( N = 43). No statistical difference was observed in overall RR between the SP and XP groups [51.2% (95% CI, 35.1% to 67.1%) vs. 53.5% (95% CI, 37.7% to 68.8%), P = 1.000]. Despite not significant, however, SP vs. XP showed a trend toward better PFS [median, 5.9 months vs. 4.1 months; hazard ratio (HR), 0.763; 95% CI, 0.462 to 1.259; P = .284] and OS (median, 13.5 months vs. 10.0 months; HR, 0.776; 95% CI, 0.485 to 1.244; P = .290). This trend in the SP vs. XP comparison was more pronounced in TTF (median, 4.5 months vs. 3.1 months; HR, 0.651; 95% CI, 0.421 to 1.006; P = .052). Common grade 3 to 4 hematological toxicities were neutropenia and anemia (SP group, 23% and 23%; XP group, 35% and 28%). Grade 3-4 anorexia and hyponatremia were more frequently seen in the XP group (31% and 16%) compared to the SP group (13% and 5%). Treatment-related deaths occurred in one patient (2.3%) in the XP group. Conclusions: XP failed to demonstrate the superior efficacy over SP. Higher incidence of severe toxicities by XP suggests SP as the standard 1st line chemotherapy for HER2 negative AGC in Japan. Clinical trial information: UMIN000006755.

Phase I study of BPM31510 and vitamin K in patients with high grade glioma recurrent after a bevacizumab-containing regimen.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2543-2543
Author(s):  
Seema Nagpal ◽  
Reena Parada Thomas ◽  
Sophie Bertrand ◽  
Hari Priya Yerraballa ◽  
Michael Iv ◽  
...  
Keyword(s):  
Phase I ◽  
Vitamin K ◽  
Phase I Study ◽  
High Grade Glioma ◽  
Clinical Development ◽  
High Grade ◽  
Open Label ◽  
Tumor Bed ◽  
Mitochondrial Superoxide ◽  
Open Label Phase

2543 Background: BPM31510 is an ubidecarenone-lipid conjugate nanodispersion in clinical development for advanced malignancies, including high grade glioma (HGG). BPM31510’s anti-cancer effect is mediated by induction of mitochondrial superoxide and activation of cell death in glioblastoma models. Herein, we present preliminary pharmaco-kinetic and dynamic data, and survival from a phase I study of BPM31510 + Vitamin K in HGG with progression after bevacizumab (BEV). Methods: This was an open-label phase I study of BPM31510 continuous infusion with Vitamin K (10mg IM qweek) using a mTPI design, starting at 110mg/kg 2X/week, allowing 2 dose escalations & 1 de-escalation. Patients had received ChemoRT and were in recurrence after BEV. Results: Of 12 patients treated with BPM31510, 9 completed the 28-day DLT period. 2 patients came off study for progressive disease; 1 patient after asymptomatic hemorrhage into tumor bed (G1). 10 patients had primary GB, 2 had AA. Median age was 54.5yo (27-67) and KPS 70 (60-90). On Day 1 of BPM31510, a dose dependent increase in Cmax was observed; Tmax values were similar for all doses. AUC was linear with dose escalation. For all doses, Day 4 Cmax values were higher compared to Day 1. In contrast there was variable decrease in Tmax (table). Of evaluable patients, 4 patients received the highest dose 171mg/kg, where a single patient experienced DLT: G3 AST & ALT. The most common grade 1/2 AEs were elevated AST, rash, and fatigue, each occurring in 4 patients. The mOS for 9 eligible/evaluable patients was 128 days (95% CI: 48-209) while PFS was 34 days (95% CI of mean 8.9). Two patients are currently alive >12 months. Conclusions: BPM31510 + vitamin K demonstrated a safe profile to maximum dose of 171mg/kg twice/week with potential therapeutic utility in treatment-refractory HGG patients. Multi-omic molecular profiles characterizing AE and response to be reported from the study will be investigated for next phase of clinical development. Clinical trial information: NCT03020602 . [Table: see text]

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