ME-143, a novel inhibitor of tumor-specific NADH oxidase (tNOX): Results from a first-in-human phase I study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3067-3067
Author(s):  
Carla Kurkjian ◽  
Shubham Pant ◽  
Howard A. Burris ◽  
Johanna C. Bendell ◽  
Suzanne Fields Jones ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Nadh Oxidase ◽  
Testicular Atrophy ◽  
Pharmacokinetic Analysis ◽  
In Vivo Models ◽  
Human Dose

3067 Background: ME-143, a second generation isoflavone-derived compound, specifically binds tNOX, shifting the ceramide-S1P equilibrium and resulting in prompt apoptosis via pleotrophic caspase activation. A first generation compound, phenoxodiol (PXD), showed promising phase II activity with cisplatin in ovarian cancer. ME-143 is broadly active against human cancers in both in vitro and in vivo models, with IC50’s 1-2 logs lower than PXD. Toxicology studies up to 140mg/kg (human dose equivalent ~23mg/kg) showed no STD level. The only significant findings were dose dependent hypospermia and testicular atrophy in rats. We report clinical and PK results from the first-in-human phase I study. Methods: A 3+3 dose escalation design was used with 4 dose cohorts: 2.5, 5, 10, and 20mg/kg IV over 30 minutes weekly times 3, followed by a 1 week break, and then continuous weekly dosing in patients with advanced solid tumors. Dense PK sampling was performed at 0, 5, 10, 20, 30, 60, 90, 120, 180, 240, 300, 360 minutes, and 24 hours post-infusion day 1 and 15 of the first treatment cycle. Results: To date, 9 patients have been enrolled, 3 in each of the first 3 cohorts. Median time on treatment is 56 days (range 6 to 62). Five patients have discontinued protocol therapy, all due to PD. No DLT’s have been observed. Related AE’s include grade 1: myalgia (1), anorexia (1), fatigue (2), headache (1), diarrhea (1), vomiting (1) and grade 2: fatigue (1). Preliminary PK analyses in the first 2 cohorts is shown in table below. Conclusions: ME-143 appears to be well tolerated when administered IV. Preliminary PK data suggest that drug levels achieve target concentration extrapolated from pre-clinical studies (AUC0-t ~10mg*hr/mL) and exceed levels obtained with IV PXD in the phase II study (AUC0-t ~2mg*hr/mL) . Updated clinical data from all planned dose cohorts, including the final pharmacokinetic analysis and planned phase II dose, will be presented. [Table: see text]

Effects of Ofloxacin Administration on the Reliability of Urine Glucose Testing

1996 ◽  
Vol 30 (5) ◽  
pp. 469-472
Author(s):  
Tsong-Mei Tsai ◽  
Brian F Shea ◽  
Paul F Souney ◽  
Fred G Volinsky ◽  
Joseph M Scavone ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Tertiary Care ◽  
Urine Samples ◽  
Care Hospital ◽  
Open Label ◽  
Urine Glucose ◽  
Glucose Testing

OBJECTIVE: TO study the effects of ofloxacin on the reliability of urine glucose testing. DESIGN: Open-label, nonrandomized. SETTING: A university-affiliated tertiary care hospital, ambulatory clinic. PARTICIPANTS: Ten healthy volunteers (8 men and 2 women) aged 22-39 years. MAIN OUTCOME MEASURES: Phase I (in vitro) involved the addition of selected amounts of ofloxacin to a set of standard 50-mL urine samples prepared to simulate glycosuria. Phase II (in vivo) involved the oral administration of ofloxacin 400 mg to 10 subjects. Urine was collected: (1) immediately predose, (2) pooled 0–4 hours postdose, and (3) pooled 4–8 hours postdose. Known glucose concentrations were then added to these samples. Clinitest and Diastix tests were performed on all samples. The accuracy of these tests in determining glucose concentrations was compared among urine samples taken before and after ofloxacin dosing. RESULTS: None of the ofloxacin concentrations in phase I (0,25,50, 100, 200,400, and 800 μg/mL) influenced these testing methods at the urine glucose concentrations of 0.0%, 0.5%, 1%, and 2%. Likewise, the accuracy of these two tests was unaffected by ofloxacin administration in phase II. CONCLUSIONS: In single-dose administration, ofloxacin does not interfere with Clinitest or Diastix for determining urine glucose concentrations. Supported by a grant from the RW Johnson Pharmaceutical Research Institute. Presented in abstract form at the American College of Clinical Pharmacy 1994 Winter Practice and Research Forum, February 6–9, 1994, San Diego. CA.

Gas Chromatographic Determination of Poly chlorinated Biphenyls (as Aroclor 1254) in Serum: Collaborative Study

1989 ◽  
Vol 72 (4) ◽  
pp. 649-659
Author(s):  
Virlyn W Burse ◽  
Margaret P Korver ◽  
Larry L Needham ◽  
Chester R Lapeza ◽  
Elizabeth L Chester R ◽  
...  
Keyword(s):  
Phase I ◽  
Silica Gel ◽  
Phase Ii ◽  
Collaborative Study ◽  
Chlorinated Hydrocarbons ◽  
Aroclor 1254 ◽  
Relative Standard

Abstract A gas chromatographic-electron capture detection method for determining the concentration of polychlorinated biphenyls (PCBs) as Aroclor 1254 (AR 1254) in serum was evaluated through a 2-phase collaborative study. In Phase I, each collaborator's lot of Woelm silica gel (70-150 mesh) was evaluated for elution and recovery of AR 1254, which had been added in vitro at 25 ng/mL to a serum extract. In Phase II, each collaborator analyzed a series of bovine serum samples that contained the following: (1) in vitro-spiked AR 1254; (2) in vivo AR 1254 and 8 in vitro-spiked chlorinated hydrocarbons; (3) in vivo AR 1254 only; (4) 8 in vitro-spiked chlorinated hydrocarbons only; and (5) neither AR 1254 nor chlorinated hydrocarbons above the detection limit of the method. In Phase I, the average recovery of AR 1254 from silica gel for the 6 collaborators was 87.9 ± 15.44% (mean ± 1 SD; N = 18; range = 52.3-105.8%). In Phase II, the analysis of in vitro spikes of AR 1254 in serum at 8.58,16.8, 41.8, and 84.3 ppb gave mean (X) interlaboratory recoveries of 89.0, 83.3, 79.4, and 76.9%, respectively, with within-laboratory (repeatability) relative standard deviations (RSDr) of 18.8, 20.5, 10.2, and 14.1%, respectively, and among-laboratory (reproducibility) relative standard deviations (RSDR) of 21.5, 21.1, 14.6, and 20.8%, respectively. The determination of in vivo AR 1254 in samples containing approximately 10, 25, 50, and 100 ng/mL of AR 1254 resulted in interlaboratory means of 10,22,39, and 79 ng/mL, respectively, with RSDr = 6.7,9.7,6.4, and 5.8%, respectively, and RSDR = 20.6,16.0, 10.9, and 10.3%, respectively. The precision of the method for incurred AR 1254 showed a maximum RSDr of less than 10% and a maximum RSDR of less than 21% for a concentration range of 10-100 ng/mL. The accuracy of the method as demonstrated by the mean recovery of in vitro-spiked AR 1254 over a concentration range of 8.58-84.3 ng/mL was 82.2%. The method has been approved interim official first action.

Phase I Study of IMGN901 in Patients with Relapsed and Relapsed/Refractory CD56-Positive Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3689-3689 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Mecide Gharibo ◽  
Sundar Jagannath ◽  
Nikhil C. Munshi ◽  
Kenneth C Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Minor Response

Abstract Background: IMGN901 (huN901-DM1) is a novel conjugate of the cytotoxic maytansinoid, DM1, with the humanized CD56-binding monoclonal antibody, N901. Once bound to CD56 on a cancer cell, the conjugate is internalized and releases DM1. About 70% of multiple myeloma (MM) cases have surface expression of CD56. Preclinical investigations demonstrated significant in vitro and in vivo anti-myeloma activity of IMGN901. Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of increasing doses of IMGN901 given for MM on a weekly schedule. Methods: Patients with relapsed or relapsed/refractory MM who have failed at least one prior therapy and have CD56-expressing MM received a single IV infusion of IMGN901 on 2 consecutive weeks every 3 weeks. Patients are enrolled in cohorts of 3 at each dose level, with DLT triggering cohort expansion. Results: Eighteen patients have received IMGN901 to date in this study - 3 patients each at 40, 60, 75, 90, 112, and 140 mg/m2/week. One patient experienced a DLT (grade 3 fatigue) on 140 mg/m2/week, and this cohort is being expanded to enroll up to 6 patients. No patients have experienced serious hypersensitivity reactions or evidence of presence of humoral responses against the huN901 antibody component (HAHA) or against the DM1 component (HADA). Preliminary PK results indicate an approximately linear relationship between dosing and observed maximal serum concentration. A confirmed minor response (MR) was documented in 3 heavily pretreated patients (1 patient each at 60, 90, and 112 mg/m2/week) using the European Bone Marrow Transplant criteria. Durable stable disease was reported at doses of 60, 90, 112, and 140 mg/m2/week. Of the 18 patients treated in the study, eight patients remained on treatment with IMGN901 for at least 15 weeks, five of these 8 patients remained on treatment for at least 24 weeks, and two of these 5 patients remained on treatment for at least 42 weeks. This phase I study provides preliminary evidence of safety as well as clinical activity of IMGN901 in patients with CD56-positive MM who have failed established MM treatments. Updated results of this ongoing study will be presented.

Combination of 5-azacytidine (5-AZA) and valproic acid (VPA) in advanced solid cancers: A phase I study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3547-3547 ◽  
Author(s):  
A. O. Soriano ◽  
F. Braiteh ◽  
G. Garcia-Manero ◽  
L. H. Camacho ◽  
D. Hong ◽  
...  
Keyword(s):  
Phase I ◽  
Histone Acetylation ◽  
Phase I Study ◽  
Mononuclear Cells ◽  
Neutropenic Fever ◽  
Dna Hypomethylation ◽  
Peripheral Blood Mononuclear ◽  
Western Blots

3547 Background: 5-AZA is a DNA hypomethylating agent. VPA is a histone deacetylase inhibitor (HDACI). The combination of hypomethylating agents and HDACI has synergistic anticancer activity in vitro and in vivo. Based on this, we conducted a phase I study of the combination of 5-AZA and VPA in patients with advanced solid cancers. Methods: 5-AZA was administered SQ daily for 10 days. VPA was given orally daily titrated to 75–100 mcg/ml. Cycles were 28 days long. 5-AZA was started at 20 mg/m2 and escalated using an adaptive algorithm based on toxicity in the prior cohort. Each cohort included 6 patients (pts). Global DNA methylation was estimated with the LINE pyrosequencing assay in peripheral blood mononuclear cells on days 1 and 10 of each cycle. Histone H3 and H4 acetylation was assessed with western blots. Results: Forty seven patients were evaluable. Median age was 60 years (15–77). 5- AZA dose levels included 20, 25, 37.5, 47, 59, 75 and 94 mg/m2. One DLT occurred at 37.5 (Neutropenic fever (NF)). At 75 mg/m2, 1 grade 3 NF and at 94 mg/m2, 3 DLTs (2 NF and 1 thrombocytopenia) were observed. The MTD was 75 mg/m2 SQ daily for 10 days. Other toxicities included drowsiness (N=6), tremor (N=6), hypomagnesemia (N=1), anemia (N=2) and vomiting (N=1). Stable disease (SD) was observed in 16 pts (34%). One pt with rapidly progressive renal cell carcinoma had SD for 6 months (mos). Two pts with leiomyosarcoma of the uterus had SD for 8 and 6 mos. One pt with melanoma and two pts with uveal melanoma had SD for 4 mos. One pt with sinus adenoid cystic carcinoma and 1 with thymic carcinoma had SD for 4 mos. SD was also observed in pts with colon (N=3), sarcoma (N=2), papillary thyroid (N=2) and breast cancer (N=1). Global DNA hypomethylation was demonstrated in all of the doses of 5- AZA. Median LINE methylation pretreatment was 65% (59–70%), it declined to 61% (53–63%) by day 10 (p=0.001) and returned to baseline by day 0 of the next cycle. Histone acetylation was observed in 53% of the pts. Conclusions: The combination of 5-AZA and VPA in patients with advanced solid tumors is safe. The MTD of 5-AZA in combination with VPA was 75 mg/m2 SQ daily for 10 days. DLTs were neutropenic fever and thrombocytopenia. Clinical benefit (SD) was observed in 16 pts (34%). Transient global hypomethylation and histone acetylation were demonstrated. No significant financial relationships to disclose.

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]

scholarly journals Urinary Excretion Kinetics of 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) and Its Phase I and Phase II Metabolites in Humans following Controlled MDMA Administration

2011 ◽  
Vol 57 (12) ◽  
pp. 1748-1756 ◽  
Author(s):  
Andrea E Schwaninger ◽  
Markus R Meyer ◽  
Allan J Barnes ◽  
Erin A Kolbrich-Spargo ◽  
David A Gorelick ◽  
...  
Keyword(s):  
Urinary Excretion ◽  
Phase I ◽  
Phase Ii ◽  
Urine Analysis ◽  
Liver Microsomes ◽  
Forensic Toxicology ◽  
Urinary Metabolites ◽  
Phase Ii Metabolites

BACKGROUND 3,4-Methylendioxymethamphetamine (MDMA) is excreted in human urine as unchanged drug and phase I and II metabolites. Previous urinary excretion studies after controlled oral MDMA administration have been performed only after conjugate cleavage. Therefore, we investigated intact MDMA glucuronide and sulfate metabolite excretion. METHODS We used LC–high-resolution MS and GC-MS to reanalyze blind urine samples from 10 participants receiving 1.0 or 1.6 mg/kg MDMA orally. We determined median Cmax, tmax, first and last detection times, and total urinary recovery; calculated ratios of sulfates and glucuronides; and performed in vitro–in vivo correlations. RESULTS Phase II metabolites of 3,4-dihydroxymethamphetamine (DHMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-dihydroxyamphetamine (DHA), and 4-hydroxy-3-methoxyamphetamine were identified, although only DHMA sulfates, HMMA sulfate, and HMMA glucuronide had substantial abundance. Good correlation was observed for HMMA measured after acid hydrolysis and the sum of unconjugated HMMA, HMMA glucuronide, and HMMA sulfate (R2 = 0.87). More than 90% of total DHMA and HMMA were excreted as conjugates. The analyte with the longest detection time was HMMA sulfate. Median HMMA sulfate/glucuronide and DHMA 3-sulfate/4-sulfate ratios for the first 24 h were 2.0 and 5.3, respectively, in accordance with previous in vitro calculations from human liver microsomes and cytosol experiments. CONCLUSIONS Human MDMA urinary metabolites are primarily sulfates and glucuronides, with sulfates present in higher concentrations than glucuronides. This new knowledge may lead to improvements in urine MDMA and metabolite analysis in clinical and forensic toxicology, particularly for the performance of direct urine analysis.

Efficacy of a novel cytotoxic polybisphosphonate for treatment of bone metastasis in castration-resistant prostate cancer (CRPC).

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 236-236
Author(s):  
Sten Nilsson ◽  
Henriette Lindberg ◽  
Camilla Thellenberg-Karlsson ◽  
Claes Nyman ◽  
Marcela Marquez ◽  
...  
Keyword(s):  
Phase I ◽  
Controlled Trial ◽  
Continuous Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Short Term Treatment ◽  
Double Blind ◽  
In Vivo Models ◽  
Continuous Growth

236 Background: A cytostatic polybisphosphonate was developed for Tx of mCRPC. It has a) anti-resorptive effects, osteoclast inhib., b) tum. cell spec./tox, confirmed in in-vivo models. Tox. study shows high tolerability. Animal PK study has shown T½ < 3 hrs; principal accumulation in liver, spleen, kidneys. Methods: Clin phase I/IIa (clinicaltrials.gov NCT01595087): Prim obj: to define MTD of ODX given every 3rd week. Sec. obj: OS, bone metab. and resp. markers, PSA, QoL and PK. Explorative in vitrostudies (basis for rand. phase IIb trial in pts. with docetax-res. mCRPC). A docetax-resist. cell-line was developed from DU145 in escalating conc. of docetax, then continuous growth in docetax 500 µg/ml. Cells subj. to cytotox. exp. with ODX (iCELLigence system and fluorom microculture cytotox assay). Results: Clin Phase I/IIa first-in-man trial (clinicaltrials.gov NCT01595087): 17/28 patients rec. 4-7 doses every 3rd week. No DLTs; max dose adm.: 3.0 mg/kg: no drug-related SAEs. Tx was well tolerated. Efficacy and QoL data w. considerable variability as to be expected in this population of pts. w. mCRPC. Max blood conc. ODX: 110-160 fmol/mL; 85-90 % cleared within first 1 hr. Efficacy of ODX in docetax-res DU145TR: A dose-dependent cytotox effect seen when adding ODX in “sub-clin.” doses. All cells were apparently killed in the clin. relevant dose 6 uM. Conclusions: ODX is a novel drug cand. w. high cytotox. efficacy in vivo and in vitro, even in highly docetax-res. cells. Animal studies and Phase I trial show excellent tolerability. Studies now ongoing to elucidate whether short-term treatment is as efficacious as continuous treatment and whether some cells de facto may develop resistance also to this new treatment concept. A multicenter rand. double-blind pbo. controlled trial (EudraCT 2014-002054-39) starts Q4 2014 in mCRPC pts failing docetax and/or cabazitaxel AND abiraterone and/or enzalutamide. Clinical trial information: NCT01595087.

Evaluation of Pharmacokinetic-Pharmacodynamic (PKPD) Relationship of an Oral, Selective, First-in-Class, Potent IDH2 Inhibitor, AG-221, from a Phase 1 Trial in Patients with Advanced IDH2 Mutant Positive Hematologic Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3737-3737 ◽  
Author(s):  
Bin Fan ◽  
Yue Chen ◽  
Fang Wang ◽  
Katharine Yen ◽  
Luke Utley ◽  
...  
Keyword(s):  
Mouse Model ◽  
Phase I ◽  
Half Life ◽  
Phase I Study ◽  
Xenograft Model ◽  
Hematologic Malignancies ◽  
Plasma Exposure ◽  
Xenograft Mouse Model

Abstract Introduction: Isocitrate dehydrogenase (IDH) is a critical enzyme in the citric acid cycle, catalyzing the oxidative decarboxylation of isocitrate to produce alpha-ketoglutarate (a-KG). The mutant IDH are not catalytically inactive enzymes, but rather possess novel enzymatic activities, catalyzing the reduction of α-KG to the ‘oncometabolite' 2-hydroxyglutarate (2-HG), which has been found to be elevated in patients with several tumor types, including acute myelogenous leukemia (AML). AG-221 is an oral, selective, first-in class, potent inhibitor of the IDH2 mutant protein. The compound has been demonstrated to reduce 2-HG levels by >90% and reverse histone and DNA hypermethylation in vitro, and to induce differentiation in leukemia cell models. In vivo pharmacokinetic/pharmacodynamic (PK/PD) studies in a U87MG IDH2 (R140Q) xenograft mouse model demonstrated robust plasma 2-HG lowering, and the correlation between PK (AG-221 exposure) and PD (the inhibition of 2-HG production) was used for human efficacious exposure projection. The PK/PD correlation was further confirmed in a primary human AML xenograft model in mice. These results are compared to early PK/PD results from the ongoing first-in-human Phase I study of AG-221 in patients with advanced IDH2 mutant positive hematologic malignancies [NCT01915498]. Methods: This first-in-man Phase I study of oral AG-221 was designed to evaluate the safety, PK, and PD, including 2-HG levels, as well as clinical activity. AG-221 was administered orally once (QD) or twice (BID) per day in continuous 28-day cycles. Sequential cohorts of patients were enrolled at higher dose levels. Patients included in this analysis were enrolled to doses of 30, 50, 75 mg BID and 100 mg QD (total N=21). Patients bearing the two dominant IDH2 mutations, R140Q (85.7%) or R172K (14.3%), were enrolled in the Phase I study. Blood was collected at multiple time points for determination of the PK and PD effects of AG-221. The concentrations of AG-221and 2-HG in plasma samples were determined using a qualified LC-MS/MS based method. PK and PK/PD analyses were performed using WinNonLin®. In addition, PK/PD relationships and efficacy of AG-221 was evaluated in a U87MG IDH2-R140Q xenograft mouse model and a primary human AML xenograft mouse model carrying the IDH2-R140Q mutation following oral doses. Results: Preliminary analysis of PK demonstrated excellent oral AG-221 exposure in humans. The mean plasma half-life is greater than 40 hours. Plasma 2-HG concentrations decreased rapidly; substantial and constant plasma 2-HG inhibition was achieved following multiple AG-221 doses in patients, and the inhibition was dose and drug exposure dependent. Based on exposure-response analyses with R140Q patients, the AG-221 AUC0-10hr value of 47.1 hr•ug/mL is estimated to result in sustained 90% plasma 2-HG inhibition in human (Figure1) which is associated with IC90 of 66 ng/mL. This is consistent with an in vivo IC90 in an AML xenograft model, U87MG IDH2-R140Q. In addition, up to 50% plasma 2-HG inhibition was observed in limited number of patients with R172K mutation. Figure 1. AG-221 plasma exposure and 2-HG inhibition correlation in patients with IDH2-R140Q mutation Figure 1. AG-221 plasma exposure and 2-HG inhibition correlation in patients with IDH2-R140Q mutation Conclusions: The pharmacokinetic profile for AG-221 supports QD dosing based on the high plasma exposure and long half-life observed in this study. AG 221 suppressed the production of 2-HG in plasma to the normal range found in healthy volunteers. 2-HG inhibition in R140Q mutation was translated well from mice to humans as well as from in vitro to in vivo. Disclosures Fan: Agios Pharmaceuticals: Employment, Stockholder Other. Chen:Agios Pharmaceuticals: Employment, Stockholder Other. Wang:Agios Pharmaceuticals: Employment, Stockholder Other. Yen:Agios: Employment. Utley:Agios Pharmaceuticals: Employment, Stockholder Other. Almon:Agios Pharmaceuticals: Employment, Stockholder Other. Biller:Agios Pharmaceuticals: Employment, Stockholder Other. Agresta:Agios Pharmaceuticals: Employment, Stockholder Other. Yang:Agios Pharmaceuticals: Employment, Stockholder Other.

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