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 trial of bevacizumab plus sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5099-5099 ◽  
Author(s):  
D. R. Feldman ◽  
G. V. Kondagunta ◽  
E. A. Ronnen ◽  
P. Fischer ◽  
R. Chang ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Rapid Progression ◽  
Hematologic Toxicity ◽  
Phase Ii Trials ◽  
Dose Levels

5099 Background: Bevacizumab, an intravenous monoclonal antibody against VEGF, and sunitinib, an oral multi-targeted tyrosine kinase inhibitor of VEGF and PDGF receptors, both have activity in mRCC [NEJM 349:427–434; JAMA 295:2516–2524]. Combining bevacizumab and sunitinib may increase antitumor efficacy by maximizing inhibition of the VEGF pathway. The safety and maximum tolerated dose (MTD) of sunitinib in combination with bevacizumab was assessed in this Phase I trial. Methods: Cohorts of 3–6 pts with mRCC received escalating doses of sunitinib (dose levels: 25, 37.5, and 50 mg po) daily for 4 weeks (wks) followed by 2 wks off with fixed- dose bevacizumab (10 mg/kg iv) every 2 wks continuously. Pre-determined dose-limiting toxicities (DLTs) in the first 6-wk cycle included Grade (Gr) 4 neutropenia, ≥Gr 3 thrombocytopenia of ≥7 days, Gr 4 hypertension or proteinuria, and other Gr 3 non-hematologic toxicity of ≥7 days. Pts who came off study prior to completion of cycle 1 for any reason other than a DLT were replaced. Serum VEGF levels were measured before and during cycles 1 and 2. Results: 16 pts (11 male, 5 female, median age 57) were enrolled. Of 8 patients entered at the first dose level (sunitinib 25 mg, bevacizumab 10 mg/kg), 2 were replaced; 1 never received treatment and 1 did not complete cycle 1 due to rapid progression of disease (PD). No DLTs occurred in the remaining 6 evaluable pts in this cohort. At the 2nd dose level (n =6, sunitinib 37.5 mg, bevacizumab 10 mg/kg), 1 pt receiving low molecular weight heparin had a DLT of Gr 4 hemorrhage. 2 pts have enrolled in the 3rd dose level (sunitinib 50 mg, bevacizumab 10 mg/kg) but are not yet evaluable for toxicity or response. Gr 3/4 toxicities over all cycles included Gr 3 hypertension (n=4), Gr 3 proteinuria (n=2), Gr 3 abdominal pain (n=2), Gr 4 hemorrhage (n=1), and Gr 3 hand/foot syndrome (n=1). 13 pts were evaluated for best response–4 had partial responses, 7 had stable disease, and 2 had PD. Serum VEGF levels decreased during cycle 1 in all pts. Conclusions: The combination of sunitinib and bevacizumab in mRCC pts was tolerable at the first 2 dose levels. Once the MTD is identified, further testing of this combination in phase II trials may be indicated for mRCC as well as other malignancies. [Table: see text]

Toxicokinetic Studies and Analytical Toxicology of the New Synthetic Opioids Cyclopentanoyl-Fentanyl and Tetrahydrofuranoyl-Fentanyl

2020 ◽  
Vol 44 (5) ◽  
pp. 449-460 ◽  
Author(s):  
Tanja M Gampfer ◽  
Lea Wagmann ◽  
Matthias J Richter ◽  
Svenja Fischmann ◽  
Folker Westphal ◽  
...  
Keyword(s):  
Protein Binding ◽  
Phase I ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
New Psychoactive Substances ◽  
Analytical Toxicology ◽  
Rat Urine ◽  
Analytical Strategy ◽  
Synthetic Opioids

Abstract The growing number of new synthetic opioids (NSO) on the new psychoactive substances (NPS) market bears new challenges in toxicology. As their toxicodynamics and particularly their toxicokinetics are usually unknown, impact on human health is not yet fully understood. Detection of the 2 NSO cyclopentanoyl-fentanyl (CP-F) and tetrahydrofuranoyl-fentanyl (THF-F) was first reported in 2016. Both were involved in several fatal intoxication cases, but no detailed information about their toxicological characteristics is available so far. The main purpose of this study was therefore to investigate the in vitro toxicokinetics and in vivo analytical toxicology of CP-F and THF-F by means of liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS). These studies included metabolic stability, phase I and II metabolism, isozyme mapping, plasma protein binding and detectability in LC-HRMS/MS standard urine screening approaches (SUSA) using rat urine samples. In total, 12 phase I metabolites of CP-F and 13 of THF-F were identified, among them 9 metabolites described for the first time. Overall, N-dealkylations, hydroxylations and dihydroxylations were the main metabolic reactions. The cytochrome P450 (CYP) isozymes mainly involved were CYP2D6 and CYP3A4, leading to elevated drug levels and intoxications in CYP2D6 poor metabolizers. CP-F showed a high plasma protein binding of 99%, which may increase the risk of toxicity by simultaneous intake of other highly bound drugs. Detectability studies showed that neither the parent compounds nor their metabolites were detectable in rat urine using LC-HRMS/MS SUSA. However, a more sophisticated analytical strategy was successfully applied and should be used for analytical confirmation of an intake of CP-F and/or THF-F.

scholarly journals Plasma protein binding of sorafenib, a multi kinase inhibitor: in vitro and in cancer patients

2011 ◽  
Vol 30 (6) ◽  
pp. 2096-2102 ◽  
Author(s):  
Maria Cristina Villarroel ◽  
Keith W. Pratz ◽  
Linping Xu ◽  
John J. Wright ◽  
B. Douglas Smith ◽  
...  
Keyword(s):  
Protein Binding ◽  
Cancer Patients ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Kinase Inhibitor

Phase I trial sunitinib plus everolimus in patients with metastatic renal cell carcinoma (mRCC).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 311-311 ◽  
Author(s):  
A. M. Molina ◽  
D. R. Feldman ◽  
M. S. Ginsberg ◽  
P. Fischer ◽  
M. J. Trinos ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Phase I ◽  
Cell Carcinoma ◽  
Dose Level ◽  
Renal Cell ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Clear Cell ◽  
Maximum Tolerated Dose ◽  
Grade 3

311 Background: Sunitinib a targeted tyrosine kinase inhibitor and everolimus an mTOR inhibitor both inhibit hypoxia-induced factor-dependent signaling and have activity in advanced renal cell carcinoma (RCC). The safety and maximum tolerated dose (MTD) of sunitinib in combination with everolimus was assessed in this phase I trial. Methods: Cohorts of 3–6 patients with mRCC received sunitinib at 37.5 or 50 mg daily for 4 weeks followed by 2 weeks off with everolimus administered either daily (2.5 or 5 mg) or weekly (20 or 30 mg). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine MTD. Results: 20 patients (13 clear cell and 7 non-clear cell RCC) were enrolled in five cohorts. Both patients in the 2nd dose level (everolimus 5 mg daily, sunitinib 37.5mg) experienced grade 3 DLT (thrombocytopenia and mucositis; vomiting). With weekly everolimus dosing, the MTD was everolimus 30 mg /sunitinib 37.5 mg (4th dose level). However, only one of six patients at this dose level tolerated treatment beyond 4 cycles. Grades 3 and 4 toxicities observed with chronic treatment included infection, gastrointestinal hemorrhage, and pulmonary embolism. A total of six patients were treated with everolimus 20b mg weekly/37.5 mg sunitinib (3rd dose level) with better tolerance as chronic therapy. Overall, 5 out of 20 patients achieved a partial response including 3 patients with non-clear cell histology. Conclusions: Partial responses were observed in both clear cell and non-clear cell histologies. However, due to toxicity the combination of sunitinib and everolimus could not be administered at full doses. [Table: see text]

BARIS: A phase I trial to evaluate the safety and tolerability of combined BIBF 1120 and RAD001 in solid tumors and to determine the maximum tolerated dose (MTD) of the combination.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS3115-TPS3115
Author(s):  
Matthias Scheffler ◽  
Lucia Nogova ◽  
Masyar Gardizi ◽  
Marc Christiaan Allardt Bos ◽  
Irini Papachristou ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Phase I ◽  
Solid Tumors ◽  
Growth Regulation ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dce Mri ◽  
Bibf 1120

TPS3115 Background: Simultaneious inhibition of several signallingpathways involved in angiogenesis as well as in tumor cell growth regulation by kinase inhibitor combination therapy may increase therapeutic efficacy. Here we evaluate the combination of the mTOR-inhibitor RAD001 (everolimus) and the triple kinase (FGFR, VEGFR, PDGFR) inhibitor BIBF 1120in a phase I trial in advanced solid tumors.In addition we use DCE-MRI for early identification of patients with benefit from BIBF 1120. Methods: This is an open-label, monocentric phase I trial with three dosage arms in a classical "3+3" design: Patients in arm A receive 5 mg of RAD001 and 2 x 150 mg BIBF 1120, in arm B 10 mg RAD001 and 2 x 150 mg BIBF 1120 will be administered, whereas in arm C, 10 mg of RAD001 and 2 x 200 mg BIBF 1120 will be given. There is no interindividual dose escalation, and the enrollment of the patients will be performed sequentially. Eligible are all patients with relapsed or refractory advanced/metastatic solid tumors (UICC stage IV) and an ECOG performance state of 0-1 for whom no further standard therapies are available and who have predefined adequate organ functions. All patients will start with a 2-week run-in phase of 2 x 200 mg BIBF 1120. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scans will be performed at baseline staging, on day 3 and day 14. On day 14, there will also be 12 hours-pharmacokinetic (PK) assessment. Combination therapy within the forementioned dosage arms starts on day 15. After two weeks of combination therapy, on day 29, a DCE-MRI scan and 12-hours PK will be performed. Restaging for the evaluation of the efficacy will be performed on day 57. The safety of this combination will be assessed throughout the complete therapy phase using CTC-AE V4.0, with predefined dose-limiting toxicities (DLTs) being assessed until day 42. Patients who experience clinical benefit (i.e., response or stable disease) on day 57 with adequate tolerability of the combination will further receive the medication, as long as the benefit lasts. The trial is registered under NCT01349296 (clinicaltrials.gov). Recruitment in arm A has started in February 2012.

scholarly journals Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors

2015 ◽  
Vol 33 (30) ◽  
pp. 3409-3415 ◽  
Author(s):  
Khanh Do ◽  
Deborah Wilsker ◽  
Jiuping Ji ◽  
Jennifer Zlott ◽  
Tomoko Freshwater ◽  
...  
Keyword(s):  
Dna Damage ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Brca Mutations ◽  
Wee1 Kinase ◽  
Tumor Biopsies

Purpose Wee1 tyrosine kinase phosphorylates and inactivates cyclin-dependent kinase (Cdk) 1/2 in response to DNA damage. AZD1775 is a first-in-class inhibitor of Wee1 kinase with single-agent antitumor activity in preclinical models. We conducted a phase I study of single-agent AZD1775 in adult patients with refractory solid tumors to determine its maximum-tolerated dose (MTD), pharmacokinetics, and modulation of phosphorylated Tyr15-Cdk (pY15-Cdk) and phosphorylated histone H2AX (γH2AX) levels in paired tumor biopsies. Patients and Methods AZD1775 was administered orally twice per day over 2.5 days per week for up to 2 weeks per 21-day cycle (3 + 3 design). At the MTD, paired tumor biopsies were obtained at baseline and after the fifth dose to determine pY15-Cdk and γH2AX levels. Six patients with BRCA-mutant solid tumors were also enrolled at the MTD. Results Twenty-five patients were enrolled. The MTD was established as 225 mg twice per day orally over 2.5 days per week for 2 weeks per 21-day cycle. Confirmed partial responses were observed in two patients carrying BRCA mutations: one with head and neck cancer and one with ovarian cancer. Common toxicities were myelosuppression and diarrhea. Dose-limiting toxicities were supraventricular tachyarrhythmia and myelosuppression. Accumulation of drug (t1/2 approximately 11 hours) was observed. Reduction in pY15-Cdk levels (two of five paired biopsies) and increases in γH2AX levels (three of five paired biopsies) were demonstrated. Conclusion This is the first report of AZD1775 single-agent activity in patients carrying BRCA mutations. Proof-of-mechanism was demonstrated by target modulation and DNA damage response in paired tumor biopsies.

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