Phase I clinical study of NK105, paclitaxel-encapsulating micelles, on a weekly schedule, in patients with malignant tumors (dose-escalation phase).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3082-3082 ◽  
Author(s):  
Ken Kato ◽  
Hirofumi Mukai ◽  
Taito Esaki ◽  
Shozo Ohsumi ◽  
Yasuo Hozumi
Keyword(s):  
Gastric Cancer ◽  
Cancer Patient ◽  
Phase I ◽  
Polymeric Micelles ◽  
Malignant Tumors ◽  
Sensory Neuropathy ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Weekly Schedule

3082 Background: NK105 is the formulation of a novel drug delivery system that encapsulates paclitaxel (PTX) in polymeric micelles and possibly resolves the safety issues associated with the additives contained in the conventional PTX formulation. In the phase II study of NK105 administered to gastric cancer patients on a 150Emg/m2 triweekly schedule, peripheral sensory neuropathy was mitigated compared to prior data for conventional PTX, without any reduction in efficacy. Based on the dose-density theory, we conducted a phase I study of NK105 on a weekly schedule to determine the dose-limiting toxicity (DLT) and recommended dosage (RD), and to evaluate the pharmacokinetic profile. Methods: Patients with advanced solid tumors refractory to standard therapy received NK105 at dosage levels of 50-100 mg/m2 as a 30-min infusion without premedication, once a week for three weeks, followed by one week of rest. Pharmacokinetic analysis was conducted in cycles 1 and 2. Results: Sixteen patients were enrolled in the study. In the 100Emg/m2 cohort (n=7), one patient experienced DLT (grade 4 neutropenia lasting 5 days), and dose reduction or delay was necessary in 4 of the 7 patients during the first course due to neutropenia. It was decided that 100 mg/m2 was the maximum tolerated dosage, and the RD was set at 80 mg/m2. Grade 3 or more severe adverse drug reactions reported for the 80Emg/m2 cohort were neutropenia, anemia, fatigue, hearing impaired and ataxia. Comparison of the pharmacokinetic parameters of NK105 with those of PTX at the same dosage (100 mg/m2) showed that the AUC0-inf. and Vdss of NK105 were approximately 50-fold and 1/15 of the reported PTX values, respectively. A refractory gastric cancer patient and an esophageal cancer patient each showed a partial response, at dosages of 80 mg/m2 and 100 mg/m2, respectively. Conclusions: 80Emg/m2 weekly administration of NK105 was well tolerated and showed anti-tumor activity, including partial responses and several occurrences of stable disease. The expansion phase of the study is ongoing at the RD of 80 mg/m2. Clinical trial information: JapicCTI-101233.

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

1998 ◽  
Vol 16 (7) ◽  
pp. 2494-2499 ◽  
Author(s):  
A M Langevin ◽  
D T Casto ◽  
P J Thomas ◽  
S D Weitman ◽  
C Kretschmar ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Malignant Tumors ◽  
Hepatic Metabolism ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Recommended Phase Ii Dose

PURPOSE A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

Analysis of phase I pharmacokinetic studies with targeted molecules based on gender and age

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2521-2521
Author(s):  
S. Di Segni ◽  
I. Sperduti ◽  
A. Cinquina ◽  
M. Contestabile ◽  
B. Nuvoli ◽  
...  
Keyword(s):  
Phase I ◽  
Clinical Parameter ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Targeted Agents ◽  
Female Population ◽  
Male And Female ◽  
Age Related ◽  
The Impact

2521 Background: Pharmacokinetic parameters are usually not sufficiently correlated with patient characteristics, such as age, gender, or excretory organ function, and with outcome measures. Female sex has been shown to be a risk factor for clinically relevant adverse drug reactions and acting as a predictive/prognostic factor. Methods: We analyzed Phase I/II oncology trials of solid tumors with targeted agents enrolling Male and Female population (age>18yrs), reporting pharmacokinetic analysis, published between 2000 and 2007. We excluded trials involving Radiation therapy alone, Hematological malignancies, and trials of Gender related pathology (ovarian, prostate and breast cancer). Standard descriptive statistics was used. Results: 160 phase I and II trials involving 48 targeted agents has been selected. 44%, 37% and 19% of the population enrolled for PK analysis is respectively male, female or unknown gender. 65% of the trials have male preponderance. Authors did not specified number of male and female if only a group of patients enrolled in the trial was submitted to pharmacokinetic analysis. 95% of the trials enrolled patients > 65years, while 16% of the trials enrolled patients >80years. But only 3% of studies specified individual patient age and less than 6% of papers showed the number of male and female for each dose level, while about 10% of studies considered ethnicity as a characteristic. Conclusions: What emerged from our analysis is the irregularity and the lack of important informations when reported for publication. Knowing the impact of important prognostic/predictive factor of such clinical parameter (age, gender) we believe that more informations should be reported in the trials in order to evaluate if Toxicity and Efficacy could be gender or age related. Definitive data will be presented at the meeting. No significant financial relationships to disclose.

Phase I trial of micronized formulation carboxyamidotriazole in patients with refractory solid tumors: pharmacokinetics, clinical outcome, and comparison of formulations.

1997 ◽  
Vol 15 (5) ◽  
pp. 1985-1993 ◽  
Author(s):  
E C Kohn ◽  
W D Figg ◽  
G A Sarosy ◽  
K S Bauer ◽  
P A Davis ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Performance Status ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Response Analysis ◽  
Minor Response ◽  
Similar Frequency ◽  
Disease Stabilization ◽  
Dose Limiting Toxicity

PURPOSE Cytostatic agents targeted against angiogenesis and tumor cell invasive potential form a new class of investigational drugs. Orally administered carboxyamidotriazole (CAI) (NSC609974) is both antiangiogenic and antimetastatic. An encapsulated micronized powder formulation has been developed to optimize CAI administration. A phase I dose escalation trial with pharmacokinetic analysis has been performed. PATIENTS AND METHODS Twenty-one patients with refractory solid tumors and good end organ function and performance status were enrolled onto the study. Patients received a test dose followed 1 week later by daily administration of CAI in the encapsulated micronized formulation at doses of 100 to 350 mg/m2. Patients remained on CAI until disease progression or dose-limiting toxicity. Plasma samples were taken to characterize the pharmacokinetic parameters of this formulation of CAI. RESULTS All patients were assessable for toxicity and 18 were assessable for pharmacokinetics and response analysis. Grade 1 and 2 gastrointestinal side effects were observed in up to 50% of patients. Dose-limiting toxicity was observed in both patients treated at 350 mg/m2/d, consisting of reversible grade 2 to 3 cerebellar ataxia (n = 1) and confusion (n = 1). One minor response (MR) was observed in a patient with renal cell carcinoma and another nine patients had disease stabilization (MR + SD = 47%). Pharmacokinetic analysis demonstrated reduced bioavailability (58% reduction) compared with the PEG-400 liquid formulation previously reported. CONCLUSION The better toxicity profile of encapsulated micronized CAI with similar frequency of disease stabilization and ease of administration compared with the liquid or gelatin capsule, suggests that the micronized formulation is a preferable formulation for subsequent studies. A dose of 300 mg/m2/d is proposed for phase II investigations.

scholarly journals First-In-Class CD13-Targeted Tissue Factor tTF-NGR in Patients with Recurrent or Refractory Malignant Tumors: Results of a Phase I Dose-Escalation Study

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1488 ◽  
Author(s):  
Christoph Schliemann ◽  
Mirjam Gerwing ◽  
Hauke Heinzow ◽  
Saliha Harrach ◽  
Christian Schwöppe ◽  
...  
Keyword(s):  
Blood Flow ◽  
Phase I ◽  
Tissue Factor ◽  
Malignant Tumors ◽  
Troponin T ◽  
Central Venous Access ◽  
Pharmacokinetic Analysis ◽  
Intratumoral Hemorrhage ◽  
Contrast Enhanced ◽  
Ngr Peptide

Background: Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. Truncated tissue factor (tTF) with a C-terminal NGR-peptide (tTF-NGR) binds to CD13 and causes tumor vascular thrombosis with infarction. Methods: We treated 17 patients with advanced cancer beyond standard therapies in a phase I study with tTF-NGR (1-h infusion, central venous access, 5 consecutive days, and rest periods of 2 weeks). The study allowed intraindividual dose escalations between cycles and established Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) by verification cohorts. Results: MTD was 3 mg/m2 tTF-NGR/day × 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides other relevant risk factors, were reversible upon anticoagulation. Imaging by contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) showed major tumor-specific reduction of blood flow in all measurable lesions as proof of principle for the mode of action of tTF-NGR. There were no responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), although some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR application. Pharmacokinetic analysis showed a t1/2(terminal) of 8 to 9 h without accumulation in daily administrations. Conclusion: tTF-NGR is safely applicable with this regimen. Imaging showed selective reduction of tumor blood flow and intratumoral hemorrhage and necrosis.

Phase I Clinical and Pharmacogenetic Study of Weekly TAS-103 in Patients With Advanced Cancer

2001 ◽  
Vol 19 (7) ◽  
pp. 2084-2090 ◽  
Author(s):  
Reginald B. Ewesuedo ◽  
Lalitha Iyer ◽  
Soma Das ◽  
Annette Koenig ◽  
Sridhar Mani ◽  
...  
Keyword(s):  
Phase I ◽  
Advanced Cancer ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Weekly Schedule ◽  
Uridine Diphosphate ◽  
Pharmacogenetic Study ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Ugt1a1 Genotype

PURPOSE: TAS-103 is an inhibitor of both topoiso-merase I and II enzymes with broad antitumor activity. It is metabolized to TAS-103-glucuronide (TAS-103-G) predominantly by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of TAS-103 when administered on a weekly schedule to patients with advanced cancer. In addition, we evaluated the influence of UGT1A1 genotype on the pharmacokinetics and toxicity of TAS-103. PATIENTS AND METHODS: Thirty-two patients were treated with escalating doses (50 to 200 mg/m2) of TAS-103, administered intravenously over 1 hour each week for 3 weeks. Pharmacokinetic analysis was performed at the 130-, 160-, and 200-mg/m2 dose levels. UGT1A1 genotypes were determined using reverse-transcription polymerase chain reaction techniques. RESULTS: DLT (grade 3 neutropenia) was observed in 5 of 12 patients at 160 mg/m2 and in 3 of 6 patients at 200 mg/m2. At 160 mg/m2, there was a significant correlation between areas under the curve (AUCs) for TAS-103 and TAS-103-G (r = 0.76, P < .05) and an apparent relationship between TAS-103 AUC and D 15 absolute neutrophil count (r = −0.63, P < .05, n = 11, one outlier excluded). UGT1A1 genotype did not influence clearance of TAS-103. CONCLUSION: We recommend a dose of 130 to 160 mg/m2, or 250 to 300 mg administered using the above weekly schedule for phase II studies. Further studies to characterize the pharmacodynamics and pharmacogenetics of TAS-103 are warranted.

Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies.

1998 ◽  
Vol 16 (4) ◽  
pp. 1458-1464 ◽  
Author(s):  
A F Ratliff ◽  
J Wilson ◽  
M Hum ◽  
M Marling-Cason ◽  
K Rose ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Oral Bioavailability ◽  
Endometrial Adenocarcinoma ◽  
Laboratory Data ◽  
Complete Response ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Weekly Schedule ◽  
Nerve Sheath Tumor

PURPOSE Aminopterin (AMT) is a potent folate analog that is no longer in routine clinical use. Because of laboratory data that suggests improved metabolism of AMT versus methotrexate (MTX) in lymphoblasts, we developed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of AMT. PATIENTS AND METHODS Twenty patients with refractory malignancies were treated. The starting dose of AMT was 2.5 mg/m2 every 12 hours for two doses weekly: the dose of AMT was decreased and leucovorin (LV) rescue was added after the DLT was observed. Pharmacokinetics were performed after both intravenous (i.v.) and oral AMT administration. RESULTS Mucosal toxicity was dose-limiting and resulted in the need for a dose reduction (dose level 2: AMT 2 mg/m2 every 12 hours for two doses weekly) and, subsequently, the addition of scheduled LV rescue (dose level 3: AMT 2 mg/m2 every 12 hours for two doses followed by LV 5 mg/m2 orally every 12 hours for two doses, starting 24 hours after the second dose of AMT). The mean areas under the curve (AUC) for the i.v. (n = 14) and oral (n = 13) doses were 1.20 +/- 0.09 (SE) and 1.05 +/- 0.14 micromol x h/L respectively. The half-life was 3.64 +/- 0.28 hours and the oral bioavailability in 12 matched subjects was 83.5% +/- 8.3%. One patient with endometrial adenocarcinoma achieved a complete response (CR) and remains on therapy at 11+ months. Seven patients had stable disease (SD) for 8 weeks or greater, which included one patient with a metastatic nerve sheath tumor who was stable for 9 months. CONCLUSION We conclude that AMT has good oral bioavailability and that, when given on a q12 hour x two weekly schedule, the MTD is 2 mg/m2 with delayed LV rescue.

A RARE CASE OF METASTASIS OF GASTRIC CANCER IN THE SPLEEN

2017 ◽  
Vol 63 (1) ◽  
pp. 153-154
Author(s):  
Oleg Kit ◽  
Yevgeniy Kolesnikov ◽  
Mikhail Kozhushko ◽  
Aleksandr Snezhko
Keyword(s):  
Gastric Cancer ◽  
Rare Case ◽  
Clinical Observation ◽  
Malignant Tumors

The spleen’s damage by metastases of malignant tumors is occasional. There is presented a clinical observation of rare isolated metastasis of gastric cancer in the spleen without concomitant dissemination that is interesting.

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