An open-label phase I dose escalation study of KRN951, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 1 in a 4 week on, 2 week off schedule in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2034-2034 ◽  
Author(s):  
F. A. Eskens ◽  
A. Planting ◽  
L. Van Doorn ◽  
T. Isoe ◽  
K. Hayashi ◽  
...  
Keyword(s):  
Growth Factor ◽  
Drug Exposure ◽  
Kinase Inhibitor ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Growth Factor Receptor ◽  
Pharmacokinetic Analysis ◽  
Dose Escalation Study ◽  
Once Daily ◽  
Grade 3

2034 Background: KRN951 inhibits VEGF induced phosphorylation of VEGF receptors (VEGFR)2 and 1 (IC50 of 0.16 and 0.21 nM) and phosphorylation of c-Kit and Platelet Derived Growth Factor Receptor (PDGFR), (IC50 of 1.63 and 1.72 nM). Methods: The principal objectives of this study were (1) to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of KRN951 administered once daily (OD) for 28 days followed by 14 days off treatment, (2) to characterize safety and tolerability, (3) to characterize single and multiple dose pharmacokinetics, (4) to explore inhibitory effects on tumor blood flow, and (5) to look for evidence of antitumor activity. Results: 10 male and 5 female patients, median age 57 yrs (28–72) have been enrolled at dose levels of 1 mg (n=6), 2 mg (n=8), and 1.5 mg (n=1). The total number of courses given is 63 (1–15 per patient) At 2 mg DLT consisting of grade 3 asymptomatic proteinuria, grade 3 ataxia and grade 4 intracranial hemorrhage was seen in three patients. In the next-lower dose level of 1 mg one DLT (grade 3 fatigue) was seen. An intermediate dose of 1.5 mg is currently studied. Hypertension occurred in 14/15 patients but could be medically controlled. Pharmacokinetic analysis revealed dose dependent drug exposure and peak plasma concentrations. Plasma levels of sVEGFR2 decreased following exposure to KRN951. Exploratory analysis by means of Dynamic Contrast Enhanced MRI analysis indicated a decrease in tumorperfusion in selected patients. One confirmed partial response lasting more than 80 weeks in a patient with renal cell carcinoma was seen, and stable disease lasting more than 2 courses of treatment was seen in 6 patients. Conclusion: Once daily KRN951 can be administered safely when given for 28 days followed by 14 days off treatment. The recommended phase II dosing is currently being defined. No significant financial relationships to disclose.

Phase I dose escalation study of continuous oral dosing of OSI-906, an insulin like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor, in patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2559-2559
Author(s):  
C. R. Lindsay ◽  
E. Chan ◽  
T. R. Evans ◽  
S. Campbell ◽  
P. Bell ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Median Number ◽  
Insulin Like Growth Factor ◽  
Dose Escalation Study ◽  
Molecule Inhibitor ◽  
Grade 3

2559 Background: OSI-906 is a potent small molecule inhibitor of IGF-1R, a receptor tyrosine kinase activated by insulin like growth factor, which is overexpressed in numerous malignancies and implicated in resistance to chemotherapy. Methods: Patients with advanced cancer entered escalating dose cohorts of OSI-906. Study objectives included assessment of: safety; determination of MTD; pharmacokinetics (PK), pharmacodynamics (PD) including IGF-1R levels in peripheral blood cells; and tumor response (RECIST). Results: To date, 32 pts have been treated (22M/10F, median age 62y) at 10, 20, 40, 75, 150, and 300 mg QD and at 20, 40 mg and 75 mg BID. Median number of weeks on trial was 6 (range 0–44). No DLTs have been observed. Hyperglycemia (5/20 pts) related to OSI-906 was transient and mild (grade 1 only). In addition to hyperglycemia, grade 1–2 nausea and vomiting (5/20 pts) were the most frequent related adverse events (AEs). There was grade 3 elevated lipase in 1 pt. At doses of 10–150 mg, OSI-906 exhibited linear PK, median terminal t1/2 ranged from 2.18–4.30 hr, AUC0-inf from 284–10200 ng.hr/mL, and Cmax 76.6–1440 ng/mL. There was no relationship between glucose or insulin levels and OSI-906 plasma concentrations. Stable disease > 12 weeks was seen in 7/20 pts (range 12–34 weeks), including 1 pt each with thymic (27 w), adrenocortical (28w), and colorectal (34w) cancer. PD data on IGF-1R phosphorylation will be presented. Conclusions: Plasma concentrations of OSI-906 achieved in this trial exceed concentrations required for antitumor efficacy in preclinical models. PD target modulation and preliminary anti-tumor activity have been observed. It is interesting to note that clinically meaningful hyperglycemia has yet to occur. Minimal toxicity was observed and further dose escalation is in progress. [Table: see text]

Phase I Dose Escalation Study of Telatinib, a Tyrosine Kinase Inhibitor of Vascular Endothelial Growth Factor Receptor 2 and 3, Platelet-Derived Growth Factor Receptor β, and c-Kit, in Patients With Advanced or Metastatic Solid Tumors

2009 ◽  
Vol 27 (25) ◽  
pp. 4169-4176 ◽  
Author(s):  
Ferry A.L.M. Eskens ◽  
Neeltje Steeghs ◽  
Jaap Verweij ◽  
Johan L. Bloem ◽  
Olaf Christensen ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Phase I ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Vascular Endothelial ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Endothelial Growth Factor

PurposeTelatinib (BAY 57-9352) is an orally available tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -2, VEGFR-3, platelet-derived growth factor receptor-β, and c-Kit. This phase I dose escalation study was conducted to evaluate the safety and tolerability of telatinib, with additional pharmacokinetic, pharmacodynamic, and efficacy assessments.Patients and MethodsPatients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Doses of continuously administered telatinib were escalated from 20 mg once daily to 1,500 mg twice daily.ResultsFifty-three patients were enrolled. Most frequently observed drug-related adverse events were nausea (26.4%; grade ≥ 3, 0%) and hypertension (20.8%; grade 3, 11.3%; grade 4, 0%). Two dose-limiting toxicities were observed: one poorly controlled hypertension (600 mg twice daily), and one grade 2 weight loss, anorexia, and fatigue (1,500 mg twice daily). A formal maximum-tolerated dose was not reached. Telatinib was rapidly absorbed, with median time to peak concentration (tmax) lower than 3 hours after dose. A nearly dose-proportional increase in exposure was observed with substantial variability. Telatinib half-life averaged 5.5 hours. Biomarker analyses showed dose-dependent increase in VEGF levels and decrease in plasma soluble VEGFR-2 levels, with a plateau at 900 mg twice daily. A decrease in tumor blood flow (Ktransand IAUC60) was observed with dynamic contrast-enhanced magnetic resonance imaging. Best tumor response was stable disease, observed in 50.9% of patients.ConclusionTelatinib was safe and well tolerated up to 1,500 mg twice daily. Based on pharmacodynamic and pharmacokinetic end points, telatinib 900 mg twice daily is the recommended dose for subsequent phase II studies.

scholarly journals ZD1839, a Selective Oral Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor, Is Well Tolerated and Active in Patients With Solid, Malignant Tumors: Results of a Phase I Trial

2002 ◽  
Vol 20 (9) ◽  
pp. 2240-2250 ◽  
Author(s):  
Malcolm Ranson ◽  
Lisa A. Hammond ◽  
David Ferry ◽  
Mark Kris ◽  
Andrew Tullo ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Malignant Tumors ◽  
Growth Factor Receptor ◽  
Once Daily ◽  
Epidermal Growth ◽  
Grade 3 ◽  
Solid Malignant Tumors

PURPOSE: To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 in patients with solid malignant tumors. PATIENTS AND METHODS: This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. RESULTS: Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non–small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for ≥ 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for ≥ 6 months. CONCLUSION: ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.

A phase I study of a novel spectrum selective kinase inhibitor (SSKI), XL880, administered orally in patients (pts) with advanced solid tumors (STs)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3041-3041 ◽  
Author(s):  
J. P. Eder ◽  
L. Appleman ◽  
E. Heath ◽  
L. Malburg ◽  
A. Zhu ◽  
...  
Keyword(s):  
Single Dose ◽  
Growth Factor ◽  
Drug Exposure ◽  
Kinase Inhibitor ◽  
Peak Plasma ◽  
Growth Factor Receptor ◽  
Papillary Renal Cell Carcinoma ◽  
Orally Bioavailable ◽  
To Receive

3041 Background: XL880 is a sub-nM inhibitor of the hepatocyte growth factor receptor (Met) and vascular endothelial growth factor (VEGF) family receptor tyrosine kinase (RTK). PDGFRβ, KIT, FLT3, and Tie-2 are also inhibited at low nM concentrations in vitro. XL880 is the 1st orally bioavailable small molecule Met inhibitor to enter the clinic. Methods: Pts with advanced STs were enrolled in successive cohorts to receive XL880 orally as a single dose on Day (D) 1 with pharmacokinetic (PK) sampling, followed by 5 consecutive daily doses (DD) starting on D 4 with additional PK sampling. Pts then continued to receive XL880 for 5 consecutive days, repeated every 14 days. Results: Nineteen pts have been treated across 5 dose levels: 0.1, 0.2, 0.4, 0.8, and 1.6 mg/kg. No dose-limiting toxicities have been observed. Two pts have demonstrated grade 2 hypertension, at 0.8 and 1.6 mg/kg respectively. PK analysis indicated that systemic drug exposure (AUC) and peak plasma levels (Cmax) increased approximately dose-proportionally (r2 values = .89 and .87 respectively) with increasing XL880 dose (0.1–1.6 mg/kg). Following 5 consecutive DD, AUC values were 175–304% higher and Cmax values were 30–203% higher than following a single XL880 dose, suggesting possible drug accumulation with repeat dosing. Terminal half-life values were ∼60 hours (hrs) following 5 consecutive DD (D 8 range: 40–66 hrs), were more variable following a single dose (D 1 range: 26–87 hrs), and appeared to be unaffected by dose. A pt with papillary renal cell carcinoma has a partial response (DD = 0.2 mg/kg) and pts with carcinoid and melanoma have had minor responses. Conclusions: XL880 is a RTK inhibitor with a novel spectrum of activity that targets both tumor cells and tumor-associated vasculature. XL880 is well tolerated up to the 1.6 mg/kg dose, with continued dose escalation ongoing. XL880 demonstrates biologic activity through hypertension and antitumor activity. [Table: see text]

Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 Is Generally Well-Tolerated and Has Activity in Non–Small-Cell Lung Cancer and Other Solid Tumors: Results of a Phase I Trial

2002 ◽  
Vol 20 (18) ◽  
pp. 3815-3825 ◽  
Author(s):  
Roy S. Herbst ◽  
Anne-Marie Maddox ◽  
Mace L. Rothenberg ◽  
Eric J. Small ◽  
Eric H. Rubin ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Antitumor Activity ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Once Daily ◽  
Epidermal Growth

PURPOSE: To investigate safety, tolerability, dose-related pharmacologic properties, and pharmacodynamics of ZD1839 (gefinitib, Iressa; AstraZeneca Pharmacueticals, Wilmington, DE), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with solid tumor types known to express or highly express EGFR. METHODS: This was an open-label, phase I, dose escalation safety/tolerability trial of oral ZD1839 (150 to 1,000 mg/d), administered once daily for 28-continuous-day cycles until disease progression or undue toxicity. RESULTS: Of 71 (69 assessable for safety; 58 for efficacy) patients at seven dose levels, most had non–small-cell lung (n = 39) or head and neck (n = 18) cancer, and 68 of 71 patients received prior cancer therapy (two or more regimens in 54 patients [78%]). Diarrhea and rash, the primary dose-limiting toxicities (DLTs), occurred at 800 mg. Frequent treatment-related grade 1/2 adverse events were diarrhea (55%), asthenia (44%), and acne-like follicular rash (46%). At doses ≥ 800 mg, 45% of patients required dose reductions. No increased or cumulative toxicity was observed over 250 patient-months of exposure. Pharmacokinetic analysis showed that steady-state occurred by day 7, interpatient exposure was more variable than intrapatient exposure, and variability of exposure did not change with dose. One patient experienced a partial response, but antitumor activity manifested mainly as prolonged stable disease (45% of patients ≥ 3 months, 22% ≥ 6 months, and 7.2% ≥ 1 year). No relationship between dose, response, or duration on study was observed. CONCLUSION: Rash and diarrhea, generally mild and tolerable at doses ≤ 600 mg/d, were DLTs at 800 mg/d (maximum-tolerated dose). Antitumor activity was observed at all doses. Pharmacokinetic analyses confirmed suitability of once-daily oral dosing.

Plasma and tissue pharmacokinetics of fosfomycin in morbidly obese and non-obese surgical patients: a controlled clinical trial

2019 ◽  
Vol 74 (8) ◽  
pp. 2335-2340 ◽  
Author(s):  
Christoph Dorn ◽  
David Petroff ◽  
Nancy Neumann ◽  
Alexander Kratzer ◽  
Nahed El-Najjar ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Peak Plasma ◽  
Subcutaneous Tissue ◽  
Plasma Concentrations ◽  
Surgical Patients ◽  
Pharmacokinetic Analysis ◽  
Controlled Clinical Trial ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Tissue Pharmacokinetics

Abstract Objectives To assess the pharmacokinetics and tissue penetration of fosfomycin in obese and non-obese surgical patients. Methods Fifteen obese patients undergoing bariatric surgery and 15 non-obese patients undergoing major intra-abdominal surgery received an intravenous single short infusion of 8 g of fosfomycin. Fosfomycin concentrations were determined by LC-MS/MS in plasma and microdialysate from subcutaneous tissue up to 8 h after dosing. The pharmacokinetic analysis was performed in plasma and interstitial fluid (ISF) by non-compartmental methods. Results Thirteen obese patients (BMI 38–50 kg/m2) and 14 non-obese patients (BMI 0–29 kg/m2) were evaluable. The pharmacokinetics of fosfomycin in obese versus non-obese patients were characterized by lower peak plasma concentrations (468 ± 139 versus 594 ± 149 mg/L, P = 0.040) and higher V (24.4 ± 6.4 versus 19.0 ± 3.1 L, P = 0.010). The differences in AUC∞ were not significant (1275 ± 477 versus 1515 ± 352 mg·h/L, P = 0.16). The peak concentrations in subcutaneous tissue were reached rapidly and declined in parallel with the plasma concentrations. The drug exposure in tissue was nearly halved in obese compared with non-obese patients (AUC∞ 1052 ± 394 versus 1929 ± 725 mg·h/L, P = 0.0010). The tissue/plasma ratio (AUCISF/AUCplasma) was 0.86 ± 0.32 versus 1.27 ± 0.34 (P = 0.0047). Conclusions Whereas the pharmacokinetics of fosfomycin in plasma of surgical patients were only marginally different between obese and non-obese patients, the drug exposure in subcutaneous tissue was significantly lower in the obese patients.

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Trial of ZD1839, a Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Five Selected Solid Tumor Types

2002 ◽  
Vol 20 (21) ◽  
pp. 4292-4302 ◽  
Author(s):  
J. Baselga ◽  
D. Rischin ◽  
M. Ranson ◽  
H. Calvert ◽  
E. Raymond ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Egfr Signaling ◽  
Epidermal Growth ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Limiting Toxicity

PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non–small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for ≥ 3 months; seven of these patients remained on study drug for ≥ 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.

scholarly journals Osimertinib Rechallenge With Bevacizumab vs. Chemotherapy Plus Bevacizumab in EGFR-Mutant NSCLC Patients With Osimertinib Resistance

2022 ◽  
Vol 12 ◽  
Author(s):  
Qingli Cui ◽  
Yanhui Hu ◽  
Qingan Cui ◽  
Daoyuan Wu ◽  
Yuefeng Mao ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Vegf Inhibitors ◽  
Clinical Benefits ◽  
Grade 3 ◽  
Egfr Mutant

At present, treatment options for osimertinib resistance are very limited. Dual inhibition of the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) significantly improved the progression-free survival (PFS) of advanced EGFR-mutant non–small cell lung cancer (NSCLC). After EGFR-tyrosine kinase inhibitor (TKI) resistance, EGFR-TKI continuation combined with VEGF inhibitors still had clinical benefits. It is unclear whether the addition of bevacizumab after osimertinib progresses will prolong the duration of the osimertinib benefit. We screened 1289 patients with NSCLC and finally included 96 patients to evaluate osimertinib combined with bevacizumab (osi + bev) versus chemotherapy combined with bevacizumab (che + bev) for patients with acquired resistance to osimertinib. The overall response rate (ORR) for osi + bev and chem + bev was 15.8% (6 of 38) and 20.7% (12 of 58), respectively. The median PFS for osi + bev and che + bev was 7.0 and 4.9 months (HR 0.415 95%CI: 0.252–0.687 p = 0.001). The median OS for osi + bev and che + bev was 12.6 and 7.1 months (HR 0.430 95%CI: 0.266–0.696 p = 0.001). Multivariate analyses showed that no brain metastases and osi + bev treatment after osimertinib resistance correlated with longer PFS (p = 0.044, p = 0.001), while the median PFS of osimertinib less than 6 months (p = 0.021) had a detrimental effect on sequent treatment. Only osi + bev treatment was identified as an independent predictor of OS (p = 0.001). The most common adverse events (AEs) of grade ≥3 were hypertension (13.2%) and diarrhea (10.5%) in the osi + bevacizumab group. Neutropenia (24.1%) and thrombocytopenia (19%) were the most common grade ≥3 AEs in the che + bev group. The overall incidence of serious AEs (grade ≥3) was significantly higher in the chemotherapy plus bevacizumab group. Our study has shown the superiority of osi + bev compared to che + bev after the failure of osimertinib, making it a preferred option for patients with acquired resistance to osimertinib.

Phase I Pharmacokinetic and Pharmacodynamic Dose-Escalation Study of RG7160 (GA201), the First Glycoengineered Monoclonal Antibody Against the Epidermal Growth Factor Receptor, in Patients With Advanced Solid Tumors

2011 ◽  
Vol 29 (28) ◽  
pp. 3783-3790 ◽  
Author(s):  
Luis G. Paz-Ares ◽  
Carlos Gomez-Roca ◽  
Jean-Pierre Delord ◽  
Andres Cervantes ◽  
Ben Markman ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Phase I ◽  
Dose Escalation ◽  
Growth Factor Receptor ◽  
Dose Escalation Study ◽  
Epidermal Growth ◽  
Grade 3

Purpose We conducted a phase I dose-escalation study to characterize the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic properties of RG7160 (GA201), a humanized and glycoengineered immunoglobulin G1 anti–epidermal growth factor receptor (EGFR) monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity. Patients and Methods Seventy-five patients with advanced EGFR-positive solid tumors received RG7160 (50 to 1,400 mg) administered every week, every 2 weeks, or every 3 weeks. Dose escalation followed a three-plus-three trial design. Results No maximum-tolerated dose was reached for any dosing schedule. Common adverse events (AEs) included rash (80% of patients), infusion-related reactions (77%), and hypomagnesemia (56%). Grades 3 and 4 AEs were rash (grade 3, 25%), infusion-related reaction (grade 3, 7%; grade 4, 1%), paronychia (grade 3, 3%), and hypomagnesemia (grade 3, 1%; grade 4, 1%). RG7160 exposure increased greater than proportionally over the 50- to 400-mg dose range (with greater than proportional decline in clearance) and approximately dose proportionally above 400 mg (where clearance plateaued). A marked reduction in circulating natural killer cells and increased infiltration of immune effector cells into skin rash were seen. Clinical efficacy included one complete response and two partial responses in patients with colorectal cancer (including one with KRAS mutation) and disease stabilization in 27 patients. Conclusion RG7160 had an acceptable safety profile with manageable AEs and demonstrated promising efficacy in this heavily pretreated patient cohort. On the basis of modeling of available PK parameters, the RG7160 dose selected for part two of this study is 1,400 mg on days 1 and 8 followed by 1,400 mg every 2 weeks.

Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results

2005 ◽  
Vol 23 (24) ◽  
pp. 5474-5483 ◽  
Author(s):  
Hope S. Rugo ◽  
Roy S. Herbst ◽  
Glenn Liu ◽  
John W. Park ◽  
Merrill S. Kies ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Vascular Endothelial Cell ◽  
Clinical Activity ◽  
Advanced Solid Tumors

Purpose We studied the safety, clinical activity, and pharmacokinetics (PK) of AG-013736, an oral receptor tyrosine kinase inhibitor of vascular endothelial cell growth factor, platelet-derived growth factor, and c-Kit, in patients with advanced cancer. Patients and Methods Patients received fixed doses of AG-013736 orally in 28-day cycles. In the first cohort, patients initially received two single test doses of AG-013736 (10 and 30 mg); subsequent dosing was determined by individual PK parameters. Doses in subsequent cohorts were assigned by using a traditional dose-escalation/de-escalation rule based on observed toxicities in the current and previous cohorts. PK analysis included evaluation of the effect of food and antacid. Results Thirty-six patients received AG-013736 at doses ranging from 5 to 30 mg by mouth twice daily. The dose-limiting toxicities observed included hypertension, hemoptysis, and stomatitis and were seen primarily at the higher dose levels. The observed hypertension was manageable with medication. Stomatitis was generally tolerable and managed by dose reduction or drug holidays. AG-013736 was absorbed rapidly, with peak plasma concentrations observed within 2 to 6 hours after dosing. The maximum-tolerated dose and recommended phase II dose of AG-013736 is 5 mg, twice daily, administered in the fasted state. No significant drug interaction with antacid was seen. There were three confirmed partial responses and other evidence of clinical activity. Conclusion In this study, we have demonstrated clinical activity and safety of AG-013736 in patients with advanced solid tumors and identified the dose for phase II testing. The unique phase I study design allowed early identification of important absorption and metabolic issues critical to phase II testing of this agent.

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