Phase I Pharmacokinetic Study of S-1 Plus Cisplatin in Patients With Advanced Gastric Carcinoma

2005 ◽  
Vol 23 (28) ◽  
pp. 6957-6965 ◽  
Author(s):  
Jaffer A. Ajani ◽  
Josephine Faust ◽  
Kazumasa Ikeda ◽  
James C. Yao ◽  
Hiroshi Anbe ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Cancer Patients ◽  
Pharmacokinetic Study ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Highly Active ◽  
Advanced Gastric Carcinoma ◽  
Level 1 ◽  
Gastric Cancer Patients

Purpose The conversion rate of tegafur (a component of S-1) to fluorouracil (FU) differs in Asians and whites because of polymorphic differences in the CYP2A6 gene. S-1 with cisplatin is considered highly active in Japanese gastric cancer patients. Therefore, we initiated a phase I pharmacokinetic study of this combination in our gastric cancer patients. Patients and Methods Patients received cisplatin intravenously on day 1 and S-1 orally, twice daily, on days 1 to 21 every 28 days. At level 1, the S-1 dose was 25 mg/m2/dose (50 mg/m2/d), but it was increased by 5 mg/m2/dose for the next level. Cisplatin was administered at 75 mg/m2 (for levels 1 and 2) but was then reduced to 60 mg/m2 (level 1A). At every level, a cohort of three patients, which could be expanded to six patients, was studied. Maximum-tolerated dose (MTD) was determined based on the dose-limiting toxicity (DLT) in the first cycle. Patients with histologic proof of gastric adenocarcinoma and near-normal organ function were studied. Results Sixteen patients were enrolled. No DLTs occurred at level 1. However, DLTs occurred at levels 2 and 1A. The area under the curve for FU correlated significantly with DLT (P = .006) and grade 3 to 4 diarrhea (P = .004). Six partial responses were confirmed, including three at the MTD. Conclusion At the established MTD of S-1 plus cisplatin, the S-1 dose (50 mg/m2/d for 21 days) is lower in our study than in the Japanese study (80 mg/m2/d for 21 days). A multi-institutional phase II study of this active combination is currently accruing patients.

Phase I study of biweekly intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel for gastric cancer with peritoneal metastasis.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 139-139
Author(s):  
H. Ishigami ◽  
J. Kitayama ◽  
S. Kaisaki ◽  
H. Yamaguchi ◽  
H. Yamashita ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Cancer Patients ◽  
Dose Level ◽  
Peritoneal Metastasis ◽  
Phase I Study ◽  
Level 1 ◽  
Grade 3 ◽  
Gastric Cancer Patients ◽  
Experienced Grade

139 Background: Intraperitoneal (IP) chemotherapy is promising for the treatment of gastric cancer with peritoneal metastasis. We previously verified the safety and efficacy of IP paclitaxel (PTX) combined with S-1 and intravenous (IV) PTX in phase I and phase II studies (Oncology. 2009; Ann Oncol. 2010). Secondly, we developed a new IP-containing chemotherapy regimen, IV PTX plus IP cisplatin (CDDP) and PTX, for patients who have failed S-1-based chemotherapy. We performed a phase I study to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients. Methods: A total of 9 gastric cancer patients were enrolled who had shown progression of peritoneal metastasis after S-1-based chemotherapy. PTX was administered intravenously at a dose of 100 mg/m2 and intraperitoneally over 1 hour with an initial dose of 20 mg/m2 (level 1), stepped up to 30 or 40 mg/m2 depending on observed toxicity. CDDP was subsequently administered intraperitoneally at a dose of 30 mg/m2 over 24 hours after PTX infusion. PTX and CDDP were administered on days 1 and 15 in 4-week cycles. Results: At dose level 1, dose-limiting toxicities (DLTs) were observed in 2 of 3 patients. One patient experienced grade 4 leukopenia, and the other grade 3 vomiting. Because of higher toxicities than anticipated, the initial dose-escalation schedule was abandoned, and the doses of IV PTX and IP CDDP were reduced to 80 mg/m2 and 25 mg/m2, respectively, while keeping the dose of IP PTX at 20 mg/m2 (level 0). At dose level 0, one of the first 3 patients experienced grade 3 nausea, and an additional 3 patients experienced no DLTs. Consequently, the MTD and RD were determined to be dose level 1 and dose level 0, respectively. No patients experienced complications related to the peritoneal access device or IP infusion. Conclusions: Combination chemotherapy of IV PTX plus IP CDDP and PTX was shown to be a safe regimen that should be further explored in clinical trials. No significant financial relationships to disclose.

scholarly journals Correlation between the Expression Levels of miR-21 and miR-192 and Clinicopatological Features in Plasma of Patients with Gastric Cancer in Iran

2021 ◽  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patients ◽  
Area Under The Curve ◽  
Tumor Stage ◽  
Expression Levels ◽  
The North ◽  
Study Results ◽  
Noninvasive Biomarker ◽  
North Of Iran ◽  
Gastric Cancer Patients

Background: Gastric cancer (GC) is the most prevalent malignancy worldwide and a common cause of death in Iran. Studies have proved that a variety of dysregulated microRNAs is involved in the development and progression of gastric cancer. The present study aimed to evaluate the expression levels of plasma circulating oncogenic miR-21 and miR-192 and their association with clinical phenotypes of patients with gastric cancer in the north of Iran. Material and Methods: Clinico-pathological analysis was conducted using a standard protocol and pathological tests. The expression levels of miR-21 and miR-192 were measured using quantitative reverse transcription-polymerase chain reaction in the plasma of twenty pre/post-operative gastric cancer patients and twenty healthy subjects. The receiver operating characteristic (ROC) curve of these microRNAs was analyzed to investigate their diagnosis properties. Results: The study results indicated that plasma miR-21 expression was significantly associated with tumor stage and helicobacter pylori infection status (P=0.024, P=0.0004, respectively). However, no association was observed between clinic-pathological characteristics and miR-192 expression. The results showed that the plasma levels of miR-21 (P=0.0001) and miR-192 (P=0.0007) were significantly higher in GC patients compared to those in healthy individuals. Furthermore, the ROC analyses yielded the area under the curve (AUC) values of 0.9525±0.03 (P<0.0001) and 0.5925±0.09 (P=0.316) for miR-21and miR-192, respectively. Pearson regression analysis showed that there was no significant correlation between the expression of miR-21 and miR-192 (P=0.1507). Conclusion: Based on the obtained results, the expression of the plasma level of miR-21 was significantly higher in gastric cancer patients compared to that in the healthy group. Furthermore, the higher levels of AUC in miR-21 indicated the potential role of miR-21 as a noninvasive biomarker for the prognosis of gastric cancer in the population of the north of Iran.

Phase 1 Study of Combined Chemotherapy of Nab-Paclitaxel, S-1, and Oxaliplatin for Gastric Cancer with Peritoneal Metastasis (NSOX Study)

Oncology ◽  
2020 ◽  
Vol 99 (1) ◽  
pp. 57-61
Author(s):  
Masaki Nakamura ◽  
Toshiyasu Ojima ◽  
Masahiro Katsuda ◽  
Keiji Hayata ◽  
Junya Kitadani ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dose Level ◽  
Peritoneal Metastasis ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Antitumor Effects ◽  
Phase 1 Study ◽  
Tumor Tissues ◽  
Level 1 ◽  
Gastric Cancer Patients

<b><i>Objectives:</i></b> A regimen of S-1 combined with oxaliplatin (SOX) has been widely used as the first-line regimen for advanced gastric cancer. To further improve the antitumor efficacy for gastric cancer patients with peritoneal metastasis, we added nab-paclitaxel to the established SOX regimen (NSOX). Nab-paclitaxel (nanoparticle albumin-bound paclitaxel) has effective transferability to tumor tissues and strong antitumor effects for peritoneal metastasis. We performed a phase 1 study of this regimen to determine the maximum tolerated dose (MTD) and the recommended dose (RD) in patients with gastric cancer with peritoneal metastasis. <b><i>Methods:</i></b> The NSOX regimen involved 21-day cycles with escalated doses of nab-paclitaxel (50 [level 1] to 80 [level 4] mg/m<sup>2</sup> on days 1 and 8) and fixed doses of oxaliplatin (100 mg/m<sup>2</sup> on day 1) and S-1 (80 mg/m<sup>2</sup>/day for 2 weeks). <b><i>Results:</i></b> Six patients with gastric cancer with peritoneal metastasis were enrolled. The MTD was determined to be dose level 2, as 2 of 3 patients experienced dose-limiting toxicities (DLTs), grade 4 non-hematological toxicities. One patient experienced acute myocardial infarction, and the other patient developed jejunal perforation. There were no treatment-related deaths. No patients experienced DLTs, so the RD was determined to be dose level 1. <b><i>Conclusions:</i></b> The NSOX regimen was shown to be a tolerable regimen and may be a promising triplet therapy for patients with gastric cancer with peritoneal metastasis.

A phase I study of neoadjuvant chemoradiotherapy with S-1/oxaliplatin in patients with gastric cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 51-51
Author(s):  
D. Lee ◽  
J. Lee ◽  
D. Lim ◽  
S. Kim ◽  
S. Park ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Abdominal Pain ◽  
Antitumor Activity ◽  
Phase I ◽  
Neoadjuvant Chemoradiotherapy ◽  
Optimal Dose ◽  
Maximum Tolerated Dose ◽  
Neoadjuvant Chemoradiation ◽  
Level 1 ◽  
Grade 3

51 Background: To determine the maximum tolerated dose (MTD) of concurrent radiotherapy with S-1 and oxaliplatin, and antitumor activity of the combination treatment in patients with gastric cancer. Methods: This was a phase I, escalating multiple-dose tolerability trial. S-1 and oxaliplatin were administered concurrently with radiotherapy for 4 weeks before surgery. The dose escalation scheme is provided in the table below. S-1 was continuously administered during radiotherapy and oxaliplatin was administered weekly for 4 weeks during radiotherapy. Results: From March 2009 to June 2010, twelve patients were entered at two dose levels. The most common dose-related grade 1 and 2 adverse events were nausea, vomiting, anorexia and abdominal pain. Two of six patients treated at level 1 developed DLT (disabling abdominal pain, stomach perforation). The dose of S-1/oxaliplatin was reduced to 30 mg/m2 bid and 40 mg/m2 (Level -1). There one DLT (vomiting and anorexia, grade 3) observed in the expanded cohort of 6 patients at Level -1. Among 12 patients, 1 patient demonstrated pathological CR after neoadjuvant chemoradiation therapy. Conclusions: Neoadjuvant CCRT with S-1/oxaliplatin was well tolerated, at a dose 30 mg/m2 bid for S-1 and 40 mg/m2 for oxaliplatin that at which antitumor activity was seen. Phase II study is planned to investigate further the efficacy, tolerability and optimal dose. [Table: see text] No significant financial relationships to disclose.

Phase I clinical and pharmacokinetic study of thiotepa administered intraperitoneally in patients with advanced malignancies.

1989 ◽  
Vol 7 (1) ◽  
pp. 132-139 ◽  
Author(s):  
S Wadler ◽  
M J Egorin ◽  
E G Zuhowski ◽  
L Tortorello ◽  
K Salva ◽  
...  
Keyword(s):  
Phase I ◽  
Peritoneal Cavity ◽  
Pharmacokinetic Study ◽  
Peak Plasma ◽  
Eastern Cooperative Oncology Group ◽  
Intraperitoneal Administration ◽  
Area Under The Curve ◽  
Systemic Exposure ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies

An important subset of malignancies arising in the ovary or digestive organs remains confined to the peritoneal cavity throughout its natural course. These tumors constitute appropriate targets for loco-regional therapy. With this rationale a clinical phase I and pharmacokinetic study of intraperitoneally administered N, N', N'' triethylenethiophosphoramide (thiotepa), an alkylating agent with activity against ovarian carcinoma, was initiated with the objectives of determining the systemic and local toxicities, maximum-tolerated dose, and pharmacokinetic advantage associated with using the drug in this manner. A total of 13 patients received 15 courses of intraperitoneal thiotepa at doses ranging from 30 mg/m2 to 60 mg/m2. The only important systemic toxicity observed was myelosuppression. At 50 mg/m2 two patients developed Eastern Cooperative Oncology Group (ECOG) grade III myelosuppression. At 60 mg/m2, the maximum-tolerated dose, the mean nadir WBC and platelet counts were 2.7 X 10(3)/microliter and 110 X 10(3)/microliter, respectively. There were no instances of vomiting, stomatitis, or alopecia. Pharmacokinetic studies performed in nine patients revealed that thiotepa was rapidly lost from the peritoneal cavity in a biexponential fashion with a mean t1/2 alpha of 0.26 +/- 0.08 hour and a mean t1/2 beta of 2.13 +/- 0.52 hour. Concomitant with the rapid loss of drug from the peritoneal cavity was the rapid rise in drug levels in the plasma, with peak plasma values approaching those associated with intravenous administration. Peritoneal exposure to thiotepa expressed as the area under the curve (AUC)peritoneal fluid was 7 to 34 micrograms/mL X hour. Systemic exposure expressed as the AUCplasma ranged between 0.95 and 7.71 micrograms/mL X hour. The observed pharmacokinetic advantage of intraperitoneal administration calculated as AUCperitoneal fluid/AUCplasma was 4.3 +/- 0.6. This relatively small advantage, combined with our observation of rapid appearance of the active metabolite, tepa, into the plasma argue against an important role for intraperitoneal administration of thiotepa.

Phase II and pharmacokinetic study of GL331 in previously treated Chinese gastric cancer patients

2002 ◽  
Vol 49 (5) ◽  
pp. 425-428 ◽  
Author(s):  
Jacqueline Liu ◽  
Li Chen ◽  
Yee Chao ◽  
Anna Li ◽  
Chew Wu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patients ◽  
Phase Ii ◽  
Pharmacokinetic Study ◽  
Previously Treated ◽  
Gastric Cancer Patients
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