Effect of TKI258 on plasma biomarkers and pharmcokinetics in patients with advanced melanoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9020-9020 ◽  
Author(s):  
M. Shi ◽  
K. B. Kim ◽  
J. Chesney ◽  
X. Wang ◽  
M. Motwani ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Dose Schedule ◽  
Maximum Tolerated Dose ◽  
Advanced Melanoma ◽  
Plasma Exposure ◽  
Meso Scale Discovery ◽  
Plasma Biomarkers ◽  
Continuous Dose ◽  
Pharmacodynamic Biomarkers ◽  
Soluble Vegfr1

9020 Background: TKI258 (dovitinib lactate), is a multi-tyrosine kinase inhibitor of VEGF receptors-1,2,3, FGF receptors-1, 2, 3, PDGFR-β, and c-KIT. A phase I study was conducted to determine the maximum tolerated dose (MTD), the biological activity and the preliminary efficacy of TKI258 in patients with advanced melanoma. A panel of plasma biomarkers of angiogenesis and soluble receptors were evaluated to determine the pharmacodynamic effect of TKI258. Methods: Patients were treated orally with 200, 300, 400 or 500 mg/day on a once daily continuous dose schedule. The MTD was defined at 400 mg/day. Plasma samples from 43 patients were collected. Plasma concentration of TKI258 was measured by LC/MS/MS. Plasma VEGF, placental growth factor (PLGF), basic FGF (bFGF), and soluble VEGFR1 and VEGFR2 (sVEGFR1 and 2), and c-Kit were measured by multiplex assays using the Meso-Scale Discovery platform. Plasma FGF23 was evaluated by ELISA as a pharmcodynamic marker of FGFR1 inhibition. Results: Following 400 mg or 500 mg continuous daily dosing, the mean plasma exposure (AUC24hr) was approximately 3000 ng/mL*h and 4100 ng/mL*h, respectively. No accumulation in TKI258 plasma exposure was observed at doses of 400mg or below, while accumulation up to 2.5-fold was observed on day 15 following the 500 mg daily dose. At the end of the first treatment cycle, mean plasma VEGF, PLGF and FGF23 levels increased over baseline by 100%, 198% and 68%, respectively, while mean plasma sVEGFR2 levels decreased by 15% in patients treated with 400 and 500 mg/day TKI258. Further analysis of correlations with pharmacokinetic and clinical parameters is ongoing. Conclusions: TKI258 therapy is associated with increases of plasma VEGF and PLGF as well as decreases of sVEGFR2 suggesting VEGFR inhibition. Induction of plasma FGF23 suggest that FGFR may be inhibited at doses of 400 mg/day and above. This panel of circulating proteins may have utility as pharmacodynamic biomarkers of TKI258 activity in patients with advanced melanoma. [Table: see text]

A phase I study (CA180021-Segment 2) of dasatinib in patients (pts) with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14042-14042 ◽  
Author(s):  
F. M. Johnson ◽  
A. Chiappori ◽  
H. Burris ◽  
L. Rosen ◽  
B. McCann ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Fdg Pet ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Biopsy Material ◽  
Tumor Biopsy ◽  
Pharmacodynamic Biomarkers

14042 Background: SPRYCEL™ is a potent, orally active, multi-targeted kinase inhibitor, active against BCR-ABL and SRC family kinases. We report the results of a Phase I dose-escalation study evaluating safety, tolerability, pharmacokinetics, and biomarkers of dasatinib in pts with advanced solid tumors. Methods: Pts with adequate hematologic, renal, cardiac and liver function received oral dasatinib once daily for 7 days per week. Three doses and schedules were examined: 90 mg BID; 140 mg QD; and 180 mg QD. Pharmacokinetics and pharmacodynamic biomarkers were collected on Days 1 and 26 of Cycle 1. Tissue biomarkers were assessed at screening. CT was performed at least every 8 weeks, and FDG-PET at weeks 4, and 8. Results: 26 pts [M=15, F=11] ECOG PS ≤ 2 with epithelial tumors (n=14) or other solid tumors (n=12) have been treated in escalating dose levels. Toxicity was generally mild; most patients came off study for progressive disease. DLTs of pleural effusions were seen in 3/9 subjects on the 180 mg cohort, 2 of whom had pre-existing effusions. Patients with pleural effusion have been excluded from future enrollment. The maximum tolerated dose has not been identified. There have been no objective responses on CT. Six patients have had stable disease with continued study treatment for 2–10 months. Conclusions: Dasatinib can be safely administered at doses of 140 and 180 mg QD. Clinical efficacy, pharmacokinetics, and correlative studies of tumor biopsy material and early FDG-PET results will be reported. No significant financial relationships to disclose.

Correlation Between the Tyrozinkinazine Inhibitor Sunitinib - Dose, Schedule of Administration and Adverse Events

2017 ◽  
Vol 68 (7) ◽  
pp. 1652-1659
Author(s):  
Dana Lucia Stanculeanu ◽  
Raluca Ioana Mihaila ◽  
Daniela Zob ◽  
Oana Catalina Toma ◽  
Raluca Ioana Mihaila ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Dose Reduction ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Dose Schedule ◽  
Prophylactic Measures ◽  
Hand Foot Syndrome

Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, has demonstrated survival benefit in patients with metastatic renal cell carcinoma (mRCC) and is generally well tolerated with most adverse events, manifesting as mild to moderate in severity. The most frequent related adverse events include hand-foot syndrome (HFS), hypertension, proteinuria, cardiac toxicities, myelosuppression, fatigue/asthenia, hypothyroidism, diarrhea and hepatotoxicity. The study aims to determine incidence of adverse events among patients with metastatic renal cell carcinoma (mRCC) treated Sunitinib within five years from 2010 to 2015 and comparing the results with data from literature. The study included a total of 56 patients treated with Sunitinib, with a dose of 50 mg (Schedule 4/2). Due to adverse events and individual safety and tolerability, at the indication of the personal clinician, 11 patients needed dose reduction, with a continuous dose of 37.5 mg, daily and 28 patients continued the dose of 50 mg taken daily, on a different schedule (2/1 schedule). The most important toxicities were anemia, leukopenia, thrombocytopenia, gastrointestinal effects (diarrhea), fatigue and hypertension. After dose reduction or modified schedule the incidence of the most frequent toxicities (HFS, leukopenia, thrombocytopenia and fatigue) decreased, but hypertension was still observed in 30% of patients. The results are similar with data from literature. Early identification of individuals at risk and monitoring patients during Sunitinib treatment is very important and it can facilitate early intervention with prophylactic measures or supportive treatment, thus increasing quality of life and adherence to treatment. Further studies need to establish which targeted population can benefit the most from adjusted regimens and to correlate them with prognostic factors for survival.

scholarly journals Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial

Haematologica ◽  
2012 ◽  
Vol 97 (5) ◽  
pp. 731-738 ◽  
Author(s):  
F. Guilhot ◽  
T. P. Hughes ◽  
J. Cortes ◽  
B. J. Druker ◽  
M. Baccarani ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Clinical Response ◽  
Kinase Inhibitor ◽  
Plasma Exposure

Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma.

1998 ◽  
Vol 16 (6) ◽  
pp. 2169-2180 ◽  
Author(s):  
A L Yu ◽  
M M Uttenreuther-Fischer ◽  
C S Huang ◽  
C C Tsui ◽  
S D Gillies ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Dose Schedule ◽  
Maximum Tolerated Dose ◽  
Target Cells ◽  
Complement Dependent Cytotoxicity ◽  
Clinical Responses

PURPOSE To evaluate the toxicity, immunogenicity, and pharmacokinetics of a human-mouse chimeric monoclonal antibody (mAb) ch 14.18 directed against disialoganglioside (GD2) and to obtain preliminary information on its clinical efficacy, we conducted a phase I trial in 10 patients with refractory neuroblastoma and one patient with osteosarcoma. PATIENTS AND METHODS Eleven patients were entered onto this phase I trial. They received 20 courses of mAb ch 14.18 at dose levels of 10, 20, 50, 100, and 200 mg/m2. Dose escalation was performed in cohorts of three patients; intrapatient dose escalation was also permitted. RESULTS The most prevalent toxicities were pain, tachycardia, hypertension, fever, and urticaria. Most of these toxicities were dose-dependent and rarely noted at dosages of 20 mg/m2 and less. Although the maximum-tolerated dose was not reached in this study, clinical responses were observed. These included one partial (PR) and four mixed responses (MRs) and one stable disease (SD) among 10 assessable patients. Biologic activity of ch 14.18 in vivo was shown by binding of ch 14.18 to tumor cells and complement-dependent cytotoxicity of posttreatment sera against tumor target cells. An anti-ch 14.18 immune response was detectable in seven of 10 patients studied. CONCLUSION In summary, with the dose schedule used, ch 14.18 appears to be clinically safe and effective, and repeated mAb administration was not associated with increased toxicities. Further clinical trials of mAb ch 14.18 in patients with neuroblastoma are warranted.

Phase I Trial of 72-Hour Continuous Infusion UCN-01 in Patients With Refractory Neoplasms

2001 ◽  
Vol 19 (8) ◽  
pp. 2319-2333 ◽  
Author(s):  
Edward A. Sausville ◽  
Susan G. Arbuck ◽  
Richard Messmann ◽  
Donna Headlee ◽  
Kenneth S. Bauer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Protein Binding ◽  
Phase I ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Large Cell ◽  
Maximum Tolerated Dose

PURPOSE: To define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the novel protein kinase inhibitor, UCN-01 (7-hydroxystaurosporine), administered as a 72-hour continuous intravenous infusion (CIV). PATIENTS AND METHODS: Forty-seven patients with refractory neoplasms received UCN-01 during this phase I trial. Total, free plasma, and salivary concentrations were determined; the latter were used to address the influence of plasma protein binding on peripheral tissue distribution. The phosphorylation state of the protein kinase C (PKC) substrate alpha-adducin and the abrogation of DNA damage checkpoint also were assessed. RESULTS: The recommended phase II dose of UCN-01 as a 72-hour CIV is 42.5 mg/m2/d for 3 days. Avid plasma protein binding of UCN-01, as measured during the trial, dictated a change in dose escalation and administration schedules. Therefore, nine patients received drug on the initial 2-week schedule, and 38 received drug on the recommended 4-week schedule. DLTs at 53 mg/m2/d for 3 days included hyperglycemia with resultant metabolic acidosis, pulmonary dysfunction, nausea, vomiting, and hypotension. Pharmacokinetic determinations at the recommended dose of 42.5 mg/m2/d for 3 days included mean total plasma concentration of 36.4 μM (terminal elimination half-life range, 447 to 1176 hours), steady-state volume of distribution of 9.3 to 14.2 L, and clearances of 0.005 to 0.033 L/h. The mean total salivary concentration was 111 nmol/L of UCN-01. One partial response was observed in a patient with melanoma, and one protracted period ( > 2.5 years) of disease stability was observed in a patient with alk-positive anaplastic large-cell lymphoma. Preliminary evidence suggests UCN-01 modulation of both PKC substrate phosphorylation and the DNA damage-related G2 checkpoint. CONCLUSION: UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.

Phase I and Pharmacologic Study of the Tyrosine Kinase Inhibitor SU101 in Patients With Advanced Solid Tumors

1999 ◽  
Vol 17 (4) ◽  
pp. 1095-1095 ◽  
Author(s):  
S. Gail Eckhardt ◽  
Jinee Rizzo ◽  
Kevin R. Sweeney ◽  
Gillian Cropp ◽  
Sharyn D. Baker ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Dose Schedule ◽  
Malignant Neoplasms ◽  
Pharmacokinetic Studies ◽  
Entire Treatment Period ◽  
Moderate Nausea

PURPOSE: To evaluate the clinical feasibility and pharmacologic behavior of the platelet-derived growth factor (PDGF) tyrosine kinase inhibitor SU101, administered on a prolonged, intermittent dosing schedule to patients with advanced solid malignancies. PATIENTS AND METHODS: Twenty-six patients were treated with SU101 doses ranging from 15 to 443 mg/m2 as a 24-hour continuous intravenous (IV) infusion weekly for 4 weeks, repeated every 6 weeks. Pharmacokinetic studies were performed to characterize the disposition of SU101 and its major active metabolite, SU0020. Immunohistochemical staining of PDGF-α and -β receptors was performed on malignant tumor specimens obtained at diagnosis. RESULTS: Twenty-six patients were treated with 52 courses (187 infusions) of SU101. The most common toxicities were mild to moderate nausea, vomiting, and fever. Two patients experienced one episode each of grade 3 neutropenia at the 333 and 443 mg/m2 dose levels. Dose escalation of SU101 above 443 mg/m2/wk was precluded by the total volume of infusate required, 2.5 to 3.0 L. Individual plasma SU101 and SU0020 concentrations were described by a one-compartment model that incorporates both first-order formation and elimination of SU0020. SU101 was rapidly converted to SU0020, which exhibited a long elimination half-life averaging 19 ± 12 days. At the 443 mg/m2/wk dose level, trough plasma SU0020 concentrations during weeks 2 and 4 ranged from 54 to 522 μmol/L. Immunohistochemical studies revealed PDGF-α and -β receptor staining in the majority (15 of 19) of malignant neoplasms. CONCLUSION: SU101 was well tolerated as a 24-hour continuous IV infusion at doses of up to 443 mg/m2/wk for 4 consecutive weeks every 6 weeks. Although further dose escalation was precluded by infusate volume constraints, this SU101 dose schedule resulted in the achievement and maintenance of substantial plasma concentrations of the major metabolite, SU0020, for the entire treatment period.

A phase I dose escalation study of sunitinib plus capecitabine in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3592-3592 ◽  
Author(s):  
C. Sweeney ◽  
C. Verschraegen ◽  
G. Chiorean ◽  
F. Lee ◽  
S. Jones ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Antiangiogenic Therapy ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Curative Therapy ◽  
Grade 3

3592 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. This phase I study assesses the safety, tolerability and pharmacokinetics (PK) of SU in combination with capecitabine (C). Methods: Pts with advanced solid tumors not amenable to curative therapy, previously treated with =2 prior chemotherapy regimens, and ECOG PS =1 were eligible. Prior antiangiogenic therapy was not permitted. Three SU schedules were evaluated: 4 wks on treatment followed by 2 wks off in 6-wk cycles (4/2 schedule); 2 wks on followed by 1 wk off in 3-wk cycles (2/1 schedule), and continuous dosing (CD schedule). In all cases C was administered orally bid on days 1–14. SU and C doses were alternately escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of SU for all schedules using a standard 3 + 3 design. PK and antitumor efficacy were also assessed. Results: A total of 50 pts have been enrolled; 28 pts have been treated on the 4/2 schedule: SU 50 mg + C 1,000 mg/m2, and SU 37.5 mg + C 1,250 mg/m2 were not tolerated. Dose limiting toxicities (DLTs) included: grade 3 myalgia (n=1), grade 3 fatigue (n=2), and grade 3 hand- foot syndrome (n=2). The MTD for the 4/2 schedule was SU 37.5 mg/day + C 1,000 mg/m2. No DLTs nor dose reductions were observed among 9 pts treated at the MTD. Preliminary PK data do not indicate drug-drug interactions between SU and C. 3 pts (1 each with breast cancer, neuroendocrine carcinoma, and thyroid carcinoma) achieved confirmed partial responses. On the 2/1 schedule patients are being accrued to SU 37.5 or 50 mg + C 1,000 mg/m2 and doses of SU 37.5 mg + C 1,000 mg/m2 or SU 25 mg + C 1,250 mg/m2 are being explored on the CD schedule. Conclusions: The combination of SU 37.5 mg/day (4/2 schedule) with C 1,000 mg/m2 in pts with advanced solid tumors appears tolerable. SU may be administered in combination with C with no apparent drug-drug interaction. Subsequent cohorts will define the MTD of SU administered on the 2/1 and CD schedules. Further studies of this combination in breast cancer are warranted. No significant financial relationships to disclose.

Pharmacokinetics (PK) of CR011-vcMMAE, an antibody-drug conjugate (ADC), in a phase (Ph) I study of patients (pts) with advanced melanoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9063-9063
Author(s):  
M. Sznol ◽  
O. Hamid ◽  
P. Hwu ◽  
H. Kluger ◽  
T. Hawthorne ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Advanced Melanoma ◽  
Terminal Phase ◽  
Maximum Plasma ◽  
Additional Dose ◽  
Toxicity Data ◽  
Liquid Chromatography Mass Spectrometry ◽  
Antibody Drug Conjugate ◽  
Dose Limiting Toxicity

9063 Background: CR011-vcMMAE, an ADC of fully-human monoclonal anti-GPNMB antibody (Ab) with monomethylauristatin E (MMAE), is in Ph I/II trials in pts with melanoma and breast cancer. We report PK and toxicity data from a Ph I study in melanoma pts treated every (q) 3 weeks (w), qw, or 2 of 3w. Methods: Enzyme-linked immunosorbent assays were used to measure ADC, total Ab (TA), soluble GPNMB (sGPNMB), and anti-ADC Ab in pt samples. Free MMAE was measured by liquid chromatography/mass spectrometry. Results: Initially, 32 pts were treated in 9 cohorts of 0.03 to 2.63 mg/kg iv q3w using standard 3+3 dose escalation. Noncompartmental PK analysis showed dose-proportional TA, ADC and free MMAE levels. As previously reported, maximum tolerated dose (MTD) was 1.88 mg/kg iv q3w; dose limiting toxicity (DLT) was rash. At MTD (n=15), terminal phase half life (T½) of TA was 41 ± 25h and T½ of ADC was 29 ± 13h. Mean maximum plasma concentrations of free MMAE was 1.3–2.9% of TA concentration across all doses. Mean sGPNMB at baseline was 12 ng/ml (range 1.3–32 ng/ml), corresponding to 0.024 % of TA concentration at MTD. Anti-ADC Ab were detectible in 8/240 (3.3%) samples (n=54). Based on the T½, two additional dose schedules (qw and 2 out of 3w) were initiated (n=14). Pts received 0.75 mg/kg (n=3) and 1.0 mg/kg (n=5) in the qw schedule and 1.25 mg/kg (n=3) and 1.5 mg/kg (n=3) in 2 of 3w. The most common adverse events (AEs) were rash (n=6), pruritus (n=5) and fatigue (n=4). 1 DLT (Gr 3 rash) was observed at 1.0 mg/kg qw. Enrollment is ongoing in both schedules. Conclusions: The relatively short T½ of CR011-vcMMAE (∼40h) does not appear to be due to immunogenicity or sGPNMB-mediated clearance. Preliminary data suggest that weekly dosing is tolerated at higher per-cycle cumulative doses than the q3w schedule. [Table: see text]

TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies: A phase I/II dose finding and biomarker study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3563-3563 ◽  
Author(s):  
E. Angevin ◽  
J. A. Lopez ◽  
A. Pande ◽  
C. Moldovan ◽  
M. Shi ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Sinus Bradycardia ◽  
Safety Data ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Primary Objective ◽  
Dose Finding ◽  
Minor Response ◽  
Suprarenal Mass

3563 Background: TKI258 is a potent receptor tyrosine kinase inhibitor (TKI) that selectively targets VEGFR, PDGFR, FGFR, CSF1R, c-KIT, RET, TrKA, and FLT3. Compared to other TKI agents, TKI258 additionally targets FGFR. FGF has been reported as an important escape mechanism of anti-VEGFR therapies. Methods: The primary objective of this phase I was to determine the maximum tolerated dose (MTD) of TKI258, administered orally on a 5 days on / 2 days off schedule in repeated 28 day cycles, in mRCC pts refractory to standard therapies. A two-parameter Bayesian logistic regression model and safety data for at least 21 pts will be used to determine MTD. Results: A phase I study is ongoing. As of December 2008, 11 pts (9 m, 2 f), median age: 55 (29–66 yrs) have been enrolled. Four pts have been treated at 500 mg/day (start dose): 2 are ongoing at cycle (C) 7; 1 pt discontinued due to PD and 1 due to sinus bradycardia. Five pts received 600 mg/day: 2 DLTs (G4 hypertension and G3 fatigue - pts discontinued) leading to dose reduction of all patients to 500mg/day; 2 pts in C5 and C4, 1 pt discontinued for PD. Two pts just entered the extension cohort at 500 mg. Other toxicities ≥G2 included fatigue, nausea, vomiting, diarrhea, neutropenia, folliculitis and dizziness. PK data showed CMax range (180–487 ng/mL, n = 8), and AUC range (2200–8251 ng/mL*h). Preliminary biomarker data indicated pts had high baseline VEGF (506 ± 203 pg/ml, n=6) and bFGF (220 ± 185 pg/ml, n = 6) levels, which may reflect failure of previous anti-VEGF agents. Induction of plasma FGF23 levels, a pharmacodynamic biomarker of FGFR1 inhibition, was observed in pts from the first 500 mg/day dosing cohort. Preliminary evidence of efficacy is observed with one minor response (-17% at C4), 4 stable disease and 1 dramatic shrinkage/necrosis of some target lesions (lymph node & suprarenal mass). Conclusions: TKI258 500mg/day seems a feasible schedule in heavily pre-treated mRCC patients with some indications of clinical benefit. These preliminary findings will be confirmed in the extension cohort. [Table: see text]

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