Effect of food on exposure to napabucasin: Data from two phase I studies.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 477-477
Author(s):  
Xiaoshu Dai ◽  
Naoto Noda ◽  
Yuran Xie ◽  
Bo Xu ◽  
Matthew Hitron ◽  
...  
Keyword(s):  
Two Phase ◽  
Fed State ◽  
Investigational Agent ◽  
Fasted State ◽  
Japanese Male ◽  
Advanced Malignancies ◽  
The Us ◽  
Effect Of Food ◽  
Clinical Trial Information ◽  
Japanese Diet

477 Background: Napabucasin is an orally-administered NAD(P)H quinone dehydrogenase 1–bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including STAT3. Methods: Food effects on napabucasin pharmacokinetics were evaluated in two studies: one at two sites in Japan (Study 1; JapicCTI-205447) and the other at two sites in the US and three in Canada (Study 2; NCT01775423). Study 1 enrolled healthy Japanese male volunteers (HJMV) who received napabucasin 480 mg (formula 2) per sequential design — fasting on Day (D) 1 followed by a Japanese diet (JD) on D8 — with a 6-D intervening washout. In Study 2, patients (pts) with advanced malignancies received napabucasin 500 mg (formula 1) on D1 in the fasted state, then napabucasin 500 mg (formula 2) on D4 and D8 with a high-fat breakfast [HFB] or in the fasted state per the randomized sequence per crossover design. Results: In Study 1, mean plasma napabucasin levels 6–10 h after napabucasin 480 mg administration were higher in fed (JD) vs fasted states; in the fed state, Cmax increased by 15% and AUClast by ~60% (Table), while tmax decreased by ~1.4 hours. Adverse events (AEs) in Study 1 occurred in 5/6 (83.3%) HJMVs (fasted, n=3; fed, n=5; all grade [gr] 1). In Study 2, mean concentration profiles were comparable in fasted and fed (HFB) states for napabucasin 500 mg. When comparing fasted and fed states, Cmax increased by 21% and AUClast by 39% in the fed state (Table). Interpatient variability was high: geometric CV% for CL/F was 75.9% (fed) and 141% (fasted). AEs in Study 2 occurred in 68% (17/25) of fasted pts (gr 1: n=7; gr 2: n=8; gr 3, n=2) and 50% (7/14) of pts fed an HFB (gr 1: n=2; gr 2: n=3; gr 3, n=2). Conclusions: In HJMVs, napabucasin 480 mg administered with a JD increased exposure (Cmax; AUClast; AUCinf) and decreased tmax vs the fasted state. In pts with advanced malignancies, napabucasin 500 mg administered with an HFB increased exposure (Cmax; AUClast) vs the fasted state. These exposure increases are not considered to be of clinical relevance. Clinical trial information: JapicCTI-205447; NCT01775423. [Table: see text]

Single-Dose Pharmacokinetics of Indinavir and the Effect of Food

1998 ◽  
Vol 42 (2) ◽  
pp. 332-338 ◽  
Author(s):  
Kuang C. Yeh ◽  
Paul J. Deutsch ◽  
Heidi Haddix ◽  
Michael Hesney ◽  
Vicki Hoagland ◽  
...  
Keyword(s):  
Single Dose ◽  
Renal Clearance ◽  
Dose Range ◽  
Systemic Circulation ◽  
Tubular Secretion ◽  
Fed State ◽  
Fasted State ◽  
Indinavir Sulfate ◽  
Effect Of Food ◽  
Intrinsic Solubility

ABSTRACT Indinavir sulfate is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor indicated for treatment of HIV infection and AIDS in adults. The purpose of this report is to summarize single-dose studies which characterized the pharmacokinetics of the drug and the effect of food in healthy volunteers. Indinavir concentrations in plasma and urine were obtained by high-pressure liquid chromatography and UV detection assay methods. The results indicate that indinavir was rapidly absorbed in the fasting state, with the time to the maximum concentration in plasma occurring at ∼0.8 h for all doses studied. Over the 40- to 1,000-mg dose range studied, concentrations in plasma and urinary excretion of unchanged drug increased greater than dose proportionally. The nonlinear pharmacokinetics were attributed to the dose-dependent oxidative metabolism of first-pass metabolism as well as to metabolism in the systemic circulation. Renal clearance slightly exceeded the glomerular filtration rate, suggesting a net tubular secretion component. At high concentrations in plasma, tubular secretion appeared to be lowered because there was a trend for a decreased renal clearance. Administration of 400 mg of indinavir sulfate following a high-fat breakfast resulted in a blunted and decreased absorption (areas under the concentration-time curves [AUCs], 6.86 μM·h in the fasted state versus 1.54 μM·h in the fed state; n = 10). However, two types of low-fat meals were found to have no significant effect on the absorption of 800 mg of indinavir sulfate (AUCs, 23.15 μM·h in the fasted state versus 22.71 and 21.36 μM·h, respectively, in the fed state; n = 11). Immediately following dosing, the concentrations of indinavir in urine often exceeded its intrinsic solubility. To reduce the risk of nephrolithiasis, it is recommended that indinavir sulfate be administered with water.

Does a food intervention makes abiraterone treatment affordable?

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16523-e16523
Author(s):  
Nielka P. Van Erp ◽  
Guillemette Emma Benoist ◽  
Winald R. Gerritsen ◽  
Niven Mehra ◽  
David Burger ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Fold Increase ◽  
Plasma Exposure ◽  
Time Curve ◽  
Large Variability ◽  
Fasted State ◽  
Effect Of Food ◽  
Multi Center Study ◽  
Clinical Trial Information

e16523 Background: Abiraterone is registered for metastatic prostate cancer. It is used in a fixed oral dose of 1000mg OD in a fasted state in combination with 10mg prednisone daily. Although large differences in the effect of food on abiraterone exposure are reported (ranging from 1-10 fold increase in area under the concentration time curve (AUC)) it is generally accepted that abiraterone is much better absorbed in the presence of food. By administering abiraterone with food a reduced dose can be given while maintaining equivalent abiraterone exposure. Moreover aadministering abiraterone with food is more patient friendly and it could significantly reduce the treatment costs of abiraterone.The aim of this study was to establish the bio-equivalent lower dose of abiraterone when taken with a continental breakfast compared to the standard intake of 1000mg OD in fasted state. Methods: In this phase I cross-over multi-center study abiraterone pharmacokinetics (PK) were evaluated in patients with metastatic prostate cancer who were treated with 1000 mg abiraterone in a fasted state, followed by 500 mg taken with a continental breakfast. After both periods of 14 days, abiraterone plasma exposure was measured. Bioequivalence was assumed when the GMR (fed/fasted) of the AUC0-24h and Cmax and their 90% confidence interval (CI) were within the range of 0.8 and 1.7. Results: 14 patients were enrolled into the study, of whom 12 were eligible for PK analysis. GMR (fed/fasted) AUC0-24h was 0.88 (90% CI 0.73-1.07), GMR Cmax was 1.03 (CI 0.79-1.34) and the GMR of Ctrough was 0.81 (90% CI 0.60-1.10). Conclusions: Ingesting 500mg abiraterone with a continental breakfast was not considered bio-equivalence when compared to 1000mg taken fasted. The criteria for bio-equivalence could not be met due to the large variability in pharmacokinetics of abiraterone within and between patients. Due to this large variability in abiraterone exposure, we believe that dose optimization by food intake is not a feasible strategy for abiraterone. The intake of abiraterone with food could not be advised based on the results presented in our study. Clinical trial information: NCT02883166. [Table: see text]

Phase I pharmacokinetic(PK)/food effect and safety study of satraplatin in patients (pts) with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12014-12014
Author(s):  
B. J. George ◽  
A. D. Ricart ◽  
E. Calvo ◽  
Q. Chu ◽  
J. Sarantopoulos ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Phase Iii ◽  
Fed State ◽  
Fasted State ◽  
Heavily Pretreated ◽  
Effect Of Food ◽  
Hormone Refractory ◽  
Grade 3 ◽  
Tumor Types

12014 Background: Satraplatin (S) is a novel oral platinum analog that has demonstrated preliminary activity in hormone refractory prostate cancer (HRPC). A large (950 pts) worldwide, randomized phase III trial evaluating S as 2nd line therapy for HRPC recently completed enrollment. The current study was designed to determine the PKs of S under fasted and fed conditions, as well as treatment efficacy and toxicity. Methods: S was administered orally at 80 mg/m2/day (d) on d1–5 q 35 days, with prophylactic antiemetics. For the 1st cycle, pts were randomized to receive d1 and d5 doses of S in either the fed or fasted state when PK sampling was performed. The fed/fasted state was reversed for the 2nd cycle. Subsequent doses of S were given in the fasted state. Results: 17 pts were enrolled (9M/8F), median age 62 (range 33–78) and tumor types: HRPC (7), breast (3), 1 each with anal, parotid, leiomyosarcoma, Merkel cell, ovarian, mesothelioma, and neuroendocrine tumor. The median no. of prior regimens was 3 (range 1–8). A total of 58 cycles of S were given. Grade 3–4 hematologic toxicities (1st 2 cycles) included: neutropenia (11%), thrombocytopenia (24%) and anemia (24%). The hematologic nadir occurred during week 4. There was no grade 3–4 nausea, vomiting or diarrhea. No significant cardiac, renal, hepatic, or neurologic toxicity was observed. The peak plasma concentration (Cmax) for platinum in plasma ultrafiltrate (PUF) was decreased by 20% when S was administered following a high fat meal compared to the fasting condition. There was no effect of food on AUC0–24 hr. The time of Cmax (Tmax) was delayed in the fed state. Table shows PK parameters. One PR (HRPC) and 4 SD ≥ 5 months (breast, ovarian, parotid and HRPC) were confirmed. Conclusions: There is an effect of food on the Cmax, however the clinical implications are unknown at this time. For this reason, it is recommended that S be administered to pts in the fasting state. At the dose of 80 mg/m2/day, S was well tolerated in this group of heavily pretreated patients. [Table: see text] [Table: see text]

scholarly journals Effects of Food on the Relative Bioavailability of Lapatinib in Cancer Patients

2009 ◽  
Vol 27 (8) ◽  
pp. 1191-1196 ◽  
Author(s):  
Kevin M. Koch ◽  
Nandi J. Reddy ◽  
Roger B. Cohen ◽  
Nancy L. Lewis ◽  
Bonnie Whitehead ◽  
...  
Keyword(s):  
Systemic Exposure ◽  
Random Order ◽  
Relative Bioavailability ◽  
High Fat ◽  
Low Fat ◽  
Time Curve ◽  
Fed State ◽  
Fasted State ◽  
Concentration Time ◽  
Effect Of Food

Purpose This study was conducted to characterize the effect of food on the relative bioavailability of lapatinib. Patients and Methods A single 1,500-mg, oral dose of lapatinib was administered to 27 patients with advanced solid tumors on each of three occasions that were 1 week apart, in random order: after an overnight fast, with a low-fat breakfast, and with a high-fat breakfast. Results The low-fat breakfast produced mean increases in lapatinib area under the concentration-time curve (AUC) of 167% (2.67-fold) and maximum concentration (Cmax) of 142% (2.42-fold). The high-fat breakfast produced mean increases in lapatinib AUC of 325% (4.25-fold) and Cmax of 203% (3.03-fold) compared with the fasted state. Increased bioavailability in the fed state did not significantly decrease relative variability. Therefore, absolute variability in systemic exposure was increased. Conclusion These large increases in lapatinib bioavailability and absolute variability support the recommendation for dosing in the fasted state to achieve consistent therapeutic exposure. Prescribers and patients should consider the potential consequences of toxicity or diminished efficacy that might result from dosing without regard to variations in diet.

A Phase 1, Open Label Study To Evaluate The Drug Interaction Potential With Ketoconazole and The Effect Of Food On The Plasma Pharmacokinetics Of The Smoothened Inhibitor PF-04449913

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3857-3857
Author(s):  
M.Naveed Shaik ◽  
Robert R LaBadie ◽  
Dan Rudin ◽  
Wendy J. Levin
Keyword(s):  
Geometric Mean ◽  
Random Effect ◽  
Geometric Mean Ratio ◽  
Open Label ◽  
Post Dose ◽  
Fed State ◽  
Fasted State ◽  
Effect Of Food ◽  
Plasma Pharmacokinetics ◽  
Anti Fungal

Abstract Introduction PF-04449913 is a potent and selective inhibitor of the Hedgehog signaling pathway through binding to the target, Smoothened (SMO). PF-04449913 inhibits Hedgehog (Hh) signaling ex vivo and has demonstrated anti-tumor activity in vivo. PF-04449913 is currently under clinical evaluation in the AML and high risk MDS patient populations, who receive anti-fungal agents routinely as prophylaxis. The preferred anti-fungal agents are azoles which are known strong CYP3A4 inhibitors. Preliminary assessment using individual recombinant P450 enzymes suggests that CYP3A4 plays a major role in mediating the metabolism of PF-04449913. Preliminary results show that PF-04449913 does not inhibit CYPs .Thus, one of the goals of this study was to understand the potential drug-drug interaction (DDI) impact of a strong CYP3A4 inhibitor (ketoconazole) on PF-04449913 plasma exposure to provide dosing guidance. An additional objective was to estimate the effect of a high fat, high calorie meal on single dose PF-04449913 plasma pharmacokinetics (PK). Methods This was an open label, 2-sequence, 3-period, 3-treatment arm, single dose, crossover study in healthy volunteers. Subjects were randomized to receive single doses of 200 mg PF-04449913 in either the fasted or fed state during Periods 1 or 2 with a washout period of at least 8 days between treatments. Subsequently, in Period 3, all subjects received a fixed regimen of ketoconazole (400 mg/day) from Days 1 to 7 and a co-administered single 200 mg PF-04449913 dose on Day 4. Serial blood sampling to determine plasma concentrations of PF-04449913 was performed to 120 hours post dose in Periods 1 and 2, and to 144 hours post dose in Period 3. PF-04449913 in the fasted state was the Reference treatment for both comparisons, while PF-04449913 in the fed state and PF-04449913 + ketoconazole were the Test treatments. Natural log transformed AUCinf (area under the plasma concentration versus time curve from time zero to infinity) and Cmax (maximum observed plasma concentration) for PF-04449913 were analyzed using a mixed effects model with sequence, period and treatment as fixed effects and subject within sequence as a random effect for the effect of food. For the DDI, natural log transformed AUCinf and Cmax for PF-04449913 were analyzed using a mixed effects model with treatment as a fixed effect and subject as a random effect. The adjusted mean differences and 90% confidence intervals (CIs) for the differences from both models were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. Results PF-04449913 exposure was increased in the presence of ketoconazole, with a geometric mean ratio for AUCinf of 2.40 (90% CI: 2.15 -2.68) and for Cmax of 1.40 (90% CI: 1.24-1.58). For PF-04449913 alone and with ketoconazole, Cmax occurred 1.0 and 2.0 hours after dosing, respectively. The geometric mean ratio for AUCinf for fed state compared to the fasted state was 0.87 (90% CI: 0.78 -0.97) and for Cmax was 0.66 (90% CI: 0.56-0.78). In the fasted and fed state, the PF-0444913 Cmax occurred at 1.0 and 4.0 hours after dosing, respectively. All adverse events (AE) were mild in severity except for one case of moderate AE accelerated idioventricular rhythm in an individual with underlying cardiac issues, which was classified as non-treatment related. Conclusions PF-04449913 plasma exposures and peak concentrations were increased (2.40-fold for AUCinf and 1.40-fold for Cmax) following concurrent administration of ketoconazole in healthy volunteers. These findings provide the upper limit for the PF-04449913 plasma exposures expected with potent metabolic inhibition and define PF-04449913 dosing parameters in AML and high-risk MDS patient trials. While PF-04449913 plasma exposures and peak concentrations were decreased following administration of PF-04449913 in the fed state, the difference in exposures under the fed and fasted conditions was not considered clinically meaningful. Disclosures: Shaik: Pfizer: Employment, Stock Other. LaBadie:Pfizer: Employment, Stock Other. Rudin:Pfizer: Employment. Levin:Pfizer Oncology Business Unit: Employment.

scholarly journals Estimation of the Effects of Food on the Pharmacokinetic Results in Bioequivalence Studies

2019 ◽  
Vol 70 (8) ◽  
pp. 2805-2810
Author(s):  
Ion Mircioiu ◽  
Valentina Anuta ◽  
Constantin Mircioiu ◽  
Victor Voicu ◽  
Roxana Sandulovici
Keyword(s):  
Statistical Analysis ◽  
Food Intake ◽  
Methylene Chloride ◽  
Internal Standard ◽  
Extraction Yield ◽  
Two Phase ◽  
Peak Areas ◽  
Effect Of Food ◽  
Lower Effect ◽  
Almost All

Paper presents the effect of food on the pharmacokinetics of omeprazole and on the extraction yield of its internal standard, lansoprazole. The experimental data were obtained over three bioequivalence studies performed by the authors. Statistical analysis of plasma level curves of omeprazole indicated that food induces a delay of the time of maximum concentrations, but had a lower effect on maximum concentration and area under curves. Peak areas of lansoprazole were not constant, presenting a similar pattern in all seven periods of the clinical experiment, both in feeding and fasting conditions: an increase after the standard meal at four hours from the administration of drug followed by relatively constant, but higher areas afterwards. Statistical analysis of data (1500 points) in the 3 - 6 h interval, i.e. from immediately before until two hours after food intake revealed a two phase effect: an initial decrease of areas followed by an increase to a higher level than in the preprandial conditions, leading to the appearance of a minimum in curves one hour after food intake. In almost all cases a good parabolic fitting of data was obtained, which is in agreement with authors previous results on extraction of ketoconazole from pasma in methylene chloride in the presence of bile salts. The increase of peak areas of lansoprazole from two hours after meal by 24 h lead to an artificial decrease of calculated omeprazole concentrations. This effect could explain the unexpected lack of food effect on the area under curve of omeprazole, observed in the comparison between areas in fasting and fed conditions.

Adipocyte lactate production remains elevated during refeeding after fasting

1990 ◽  
Vol 259 (6) ◽  
pp. E865-E871 ◽  
Author(s):  
F. D. Newby ◽  
L. K. Wilson ◽  
S. V. Thacker ◽  
M. DiGirolamo
Keyword(s):  
Adipose Tissue ◽  
Lactate Production ◽  
Hepatic Glycogen ◽  
Fed State ◽  
Fasted State ◽  
Rapid Restoration ◽  
Isolated Adipocytes ◽  
Elevated Rate ◽  
Total Glucose ◽  
Main Substrate

The metabolic state occurring with refeeding after fasting is characterized by the rapid restoration of hepatic glycogen. Recent evidence suggests that a main substrate for glycogenesis is lactate. Because adipose tissue is an active site of lactate production that increases with fasting, we examined the magnitude and duration of lactate production by isolated adipocytes from three adipose depots of rats fasted for 48 h and then refed for up to 96 h. The data show that 48 h of fasting results in a markedly elevated rate of adipocyte lactate production, which increased from 3-9% of total glucose metabolized in the fed state to 49-60% in the fasted state. During the refeeding period, lactate production remained elevated for 12-24 h and then declined. Mesenteric adipocytes had a higher rate and more prolonged elevation in lactate production than cells from the other two depots. We conclude that, with refeeding after a fast, adipocyte glucose conversion to lactate remains elevated during the time of hepatic glycogen restoration. This suggests that adipose tissue may actively produce lactate for glycogenesis during refeeding.

Effects of physical exercise on colonic motor activity

1991 ◽  
Vol 260 (4) ◽  
pp. G646-G652 ◽  
Author(s):  
M. Dapoigny ◽  
S. K. Sarna
Keyword(s):  
Physical Exercise ◽  
Motor Activity ◽  
Contractile Activity ◽  
Total Duration ◽  
Distal Colon ◽  
Proximal Colon ◽  
Fed State ◽  
Fasted State ◽  
Colonic Motor ◽  
Colonic Motor Activity

We investigated the effect of physical exercise on colonic motor activity in the fasted and fed states in six conscious dogs. Each dog was implanted with nine strain gauge transducers: three on the proximal, three on the middle, and three on the distal colon. The dogs ran for 1 h on a treadmill at 5 km/h (slope 5%). In the fasted state, the dogs exercised during the 5th h of recording after an overnight fast, and in the fed state during the 1st, 3rd, and 5th postprandial hour. In the fasted state, exercise significantly decreased the frequency of colonic migrating motor complexes (MMCs) but had no effect on the total or the mean duration of contractile states in the proximal, middle, and distal colon. Postprandially, exercise disrupted colonic MMCs and replaced them with nonmigrating motor complexes in all three periods of exercise (1st, 3rd, and 6th h). Exercise also increased the total duration per hour of contractile activity throughout the colon during the 1st and 3rd h and only in the distal colon during the 6th h after the meal. The dogs never defecated during rest in the fasted or the fed state. Shortly after the start of exercise in the fasted and fed states, giant migrating contractions (GMCs) occurred, and they were followed by defecation. In approximately 40% of the experiments, another GMC originated in the proximal colon, approximately 10 min after the first defecation, and migrated caudad up to the middle colon. These GMCs were not associated with defecation but caused mass movements.(ABSTRACT TRUNCATED AT 250 WORDS)

Novel organic arsenic molecule darinaparsin: Development of IV and oral forms

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8501-8501 ◽  
Author(s):  
I. Lossos ◽  
M. D. Craig ◽  
M. S. Tallman ◽  
R. V. Boccia ◽  
P. R. Conkling ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Complete Response ◽  
Median Number ◽  
Two Phase ◽  
Phase I Studies ◽  
Advanced Malignancies

8501 Background: Darinaparsin (ZIO-101) is a novel organic arsenical active against diverse cancers in vitro, and in vivo. Darinaparsin i.v. activity in lymphoma is being evaluated in a phase II study. Darinaparsin is orally bioavailable; the oral form is being investigated in two phase I studies in patients with advanced malignancies. Methods: Phase II trial is being conducted in patients diagnosed with advanced lymphomas who had ≥ 1 prior therapy. Patients receive 300 mg/m2/day of darinaparsin i.v. for 5 consecutive days every 28 days. Efficacy and safety are evaluated by standard criteria. Phase I oral dose escalation studies are being conducted in patients with advanced malignancies and explore safety, MTD, DLTs and preliminary efficacy of continuous and intermittent dosing schedules. Starting continuous dose is 100 mg BID for 3 weeks with 1 week rest, starting intermittent dose is 300 mg twice weekly for 3 weeks followed by 1 week rest. Results: The phase II study has accrued 28 lymphoma patients (21 non-Hodgkin's, 7 Hodgkin's); median age at baseline 61 years, ECOG ≤2, median number of prior therapies 3. Seventeen subjects have received at least 2 cycles of darinaparsin and are evaluable for efficacy. Of these, 1 subject (PTCL) has achieved a complete response, 3 - partial responses (2 marginal zone, 1 Hodgkin's), and 4 stable disease (2 PTCL, 1 DLBCL, 1 Hodgkin's). A total of 63 cycles of darinaparsin have been administered to subjects with lymphoma. No Gr. 3 or higher drug-related AEs were reported. Two SAEs were considered possibly drug-related (fall; neutropenic fever). Phase I studies accrued 35 patients; median age at baseline 58 years, ECOG ≤2, median number of prior therapies 3. Predominant tumor types include: colorectal (17), pancreatic (3), NHL (3). Current darinaparsin dose levels: continuous 200 mg BID, 2× weekly 900 mg. Of 18 patients evaluable for efficacy, 10 demonstrate SD ≥ 3 cycles. Oral darinaparsin bioavailability is 58%. Drug-related AEs include nausea/vomiting, fatigue, decreased appetite/anorexia. Conclusions: Darinaparsin is active in heavily pretreated patients with advanced lymphoma and has been very well tolerated. Oral darinaparsin is also well tolerated, and shows early activity. [Table: see text]

Pharmacokinetics and safety of an oral ALK inhibitor, ASP3026, observed in a phase I dose escalation trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2602-2602 ◽  
Author(s):  
Amita Patnaik ◽  
Patricia LoRusso ◽  
Howard A. Ball ◽  
Erkut Bahceci ◽  
Geoffrey Yuen ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Expansion Phase ◽  
Advanced Malignancies ◽  
Grade 3 ◽  
Ecog Ps ◽  
Clinical Trial Information

2602 Background: ASP3026 (3026) is a selective, potent, ATP-competitive, small molecule oral inhibitor of ALK receptor tyrosine kinase that has not previously been tested in humans. A Phase 1 dose-escalation trial, using a 3+3 design, evaluating 3026 as an oral single agent was conducted to investigate PK (Day 1 and Day 28), safety and clinical activity in patients (pts) with advanced malignancies (excluding leukemias) of ECOG PS 2 or less. Methods: 3026 was administered under fasting conditions on a continuous schedule to pts in successive dose-escalating cohorts at doses ranging from 25 mg QD to 800 mg QD. Results: Thirty pts were enrolled into the dose escalation part of the study. The MTD was determined based on DLT data from cycle 1. Three DLTs were observed: grade 2 nausea and vomiting leading to dose reduction at 525 mg QD; grade 3 rash leading to dose reduction, and grade 3 ALT/AST increase leading to study withdrawal at 800 mg QD. The most common AEs were constipation, vomiting, diarrhea, nausea and abdominal pain, and all AEs were manageable and reversible. Median AUC and Cmax increased proportionally with dose from 25 mg QD to 800 mg QD. There was no evidence of non-linear PK at ASP3026 doses >25 mg QD. The median terminal half-life was approximately 10 - 41 hours. Overall, A3026 appears well absorbed with median Tmax around 3 hours for both Day 1 and Day 28. Terminal T1/2 appears adequate for one daily dosing with median values ranging from approximately 18 to 34 hours. Based on visual inspection of pre-dose (trough) values from Days 8, 15, 22, and 28 it appears that steady-state conditions are achieved by day 28. Conclusions: The MTD of 3026 is 525 mg QD. Treatment with 3026 resulted in a promising safety and PK profile in pts with advanced malignancies. Further evaluation of 3026 in pts with tumors harboring gene mutation or ALK fusion genes in the cohort expansion phase at the MTD is ongoing. Clinical trial information: NCT01401504.

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