Cancer Research and Treatment

Original Articles

Phase I Study of Axitinib in Combination with Cisplatin and Capecitabine in Patients with Previously Untreated Advanced Gastric Cancer: Do-Youn Oh, Toshihiko Doi, Kuniaki Shirao, Keun-Wook Lee, Sook Ryun Park, Ying Chen, Liqiang Yang, Olga Valota, Yung-Jue Bang; Cancer Res Treat. 2015;47(4):687-696. Published online February 12, 2015; DOI: https://doi.org/10.4143/crt.2014.225

Purpose
This phase I trial evaluated the question of whether the standard starting dose of axitinib could be administered in combination with therapeutic doses of cisplatin/capecitabine in patients with previously untreated advanced gastric cancer, and assessed overall safety, pharmacokinetics, and preliminary antitumor activity of this combination.
Materials and Methods
Patients in dose level (DL) 1 received axitinib 5 mg twice a day (days 1 to 21) with cisplatin 80 mg/m2 (day 1) and capecitabine 1,000 mg/m2 twice a day (days 1 to 14) in 21-day cycles. Maximum tolerated dose (MTD) was the highest dose at which ≤ 30% of the first 12 patients experienced a dose-limiting toxicity (DLT) during cycle 1. Ten additional patients were enrolled and treated at the MTD in order to obtain additional safety and pharmacokinetic data.
Results
Three DLTs occurred during cycle 1 in three (25%) of the first 12 patients: ruptured abdominal aortic aneurysm, acute renal failure, and > 5 consecutive days of missed axitinib due to thrombocytopenia. DL1 was established as the MTD, since higher DL cohorts were not planned. Common grade 3/4 non-hematologic adverse events in 22 patients treated at DL1 included hypertension (36.4%) and decreased appetite and stomatitis (18.2% each). Cisplatin/capecitabine slightly increased axitinib exposure; axitinib decreased capecitabine and 5-fluorouracil exposure. Eight patients (36.4%) each had partial response or stable disease. Median response duration was 9.1 months; median progression-free survival was 3.8 months.
Conclusion
In patients with advanced gastric cancer, standard doses of axitinib plus therapeutic doses of cisplatin and capecitabine could be administered in combination. Adverse events were manageable.

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Heng Yun, Fangde Dong, Xiaoqin Wei, Xinyong Yan, Ronglong Zhang, Xiuyu Zhang, Yulin Wang
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Construction of a hypoxia-immune-related prognostic panel based on integrated single-cell and bulk RNA sequencing analyses in gastric cancer
Cuncan Deng, Guofei Deng, Hongwu Chu, Songyao Chen, Xiancong Chen, Xing Li, Yulong He, Chunhui Sun, Changhua Zhang
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Pranshu Sahgal, Brandon M. Huffman, Deepa T. Patil, Walid K. Chatila, Rona Yaeger, James M. Cleary, Nilay S. Sethi
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Clinical Pharmacokinetics of Tegafur Administered with Epirubicin and Cisplatin in Patients with Advanced Gastric Cancer: Jin Hyung Kang, Yoo Lim Kim, Hea Kyoung Cho, Eun Sook Lee, Soo Jin Cha, Young Sun Hong, Kyung Shik Lee, Hyo Jeong Kuh; Cancer Res Treat. 2003;35(3):224-231. Published online June 30, 2003; DOI: https://doi.org/10.4143/crt.2003.35.3.224

Abstract PDF: PURPOSE
Tegafur, an oral prodrug of 5-fluorouracil (5-FU), has been used in the treatment of gastric cancers. UFT (tegafur + uracil) has been developed to enhance the efficacy of tegafur. This study was conducted to assess the pharmacokinetics (PK) of tegafur in gastric cancer patients given the ECU-E regimen (epirubicin, cisplatin, UFT-E, an enteric-coated formula of UFT). A preliminary evaluation of antitumor efficacy and toxicity of ECU-E regimen was also performed. MATERIALS AND METHODS: Of the 32 gastric cancer patients registered for the ECU-E regimen, 8 participated in the PK study. The plasma concentration of tegafur was determined using HPLC. RESULTS: Seven out of the 8 patients were evaluable for response after 2 cycles, and showed 3 partial responses, 1 stable disease and 3 progressive diseases. No major toxicities were observed. Plasma profiles of the tegafur after the first dose showed significant differences in the amount and rate of absorption, i.e., rapid absorption group vs. slow absorption group. The level of C(max) in the rapid absorption group was 1.8 fold higher, and the AUC(0-5h) 4 fold greater, than those in the slow absorption group, nonetheless, the steady state concentrations showed no significant difference. These data indicate that the different absorption rates may not affect the overall exposure to tegafur. The patients with low Cp(ss, peak) showed poor efficacy compared to those with high Cp(ss, peak), suggesting that the concentration of tegafur may be one of the pharmacodynamic determinants in patients administered with ECU-E. CONCLUSION: This study evaluated the pharmacokinetics of tegafur in gastric patients given the ECU-E regimen, and provides preliminary data on the relationship between the plasma tegafur level and the efficacy, which warrants further evaluation.

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Phase I and Pharmacokinetic Study of Intraoperative Intraperitoneal Heptaplatin in Patients with Surgically Resected Advanced Gastric Cancer: Wansik Yu, Ho Young Chung, So Hyang Park, Yong Baik Cho, Yang Soo Lim; Cancer Res Treat. 2003;35(1):25-29. Published online February 28, 2003; DOI: https://doi.org/10.4143/crt.2003.35.1.25

Abstract PDF: PURPOSE
Heptaplatin, a new platinum analog, has favorable toxicity profiles and antitumor activity, comparable to those of cisplatin, in the treatment of gastric cancer. This study was designed to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of heptaplatin administered by an intraperitoneal route in patients with resected advanced gastric cancer. MATERIALS AND METHODS: Seventeen patients with resected advanced gastric cancer were entered onto the study. After completion of a curative resection and an astomosis, heptaplatin was administered intraperiton eally in one liter of 5% dextrose solution. The starting heptaplatin dose was 400 mg/m2 of the body surface area, and was escalated in 200 mg/m2 increments, to cohorts of three patients. A pharmacokinetic analysis was carried out to determine the total and ultrafiltratable platinum concentrations in the plasma, peritoneal fluid, and urine. RESULTS: Patients were unable to tolerate a 1, 000 mg/m2 dose level, and at 800 mg/m2, reVersible Grade III toxic ities, including elevated creatinine, proteinuria, hypon- atremia, abdominal pain, and intraabdominal bleeding were noted. No significant toxicity was noted up to a 600 mg/m2 dose level. The ratio of the peak peritoneal to peak plasma drug concentrations were 19.4, 16.6 and 22.8 at doses of 400 mg/m2, 600 mg/m2 and 800 mg/m2, respectively. The pharmacological advantage, expressed as the peritoneal to plasma AUC ratio ranged from 4.3 to 7.0. CONCLUSION: Heptaplatin can be delivered by an intra peritoneal route, with both an acceptable toxicity profile and a major pharmacokinetic advantage for cavity exposure. The MTD of intraperitoneal heptaplatin was 800 mg/m2. The major DLTs were nephrotoxicity and intraabdominal bleeding. The recommended starting dose for a subsequent study would be 600 mg/m2.

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Chemotherapy with Five-Day Continuous Infusion of 5-Fluorouracil (5-FU) Plus Cisplatin for Advanced Gastric Cancer; Significance of 5-FU Concentration Monitoring: Yeon Hee Park, Bong Seog Kim, Baek Yeol Ryoo, Tae You Kim, Young Hyuck Im, Ho Sang Shin, Yoon Koo Kang; J Korean Cancer Assoc. 2000;32(3):516-523.

Abstract PDF: PURPOSE
To investigate the therapeutic effects and toxicities of 5-day continuous infusion of 5-FU plus cisplatin FP chemotherapy in advanced gastric adendegrees Carcinoma and to elucidate the relationship between the pharmacokinetic (PK) parameters and therapeutic outcome.
MATERIALS AND METHODS
Patients with previously untreated advanced stomach cancer were treated with FP chemotherapy. Plasma concentrations of 5-FU were measured using gas chro matography method for 5 days. Correlation of PK parameters of 5-FU with clinical outcome after FP chemotherapy was studied.
RESULTS
Response rate of FP chemotherapy was 46% (95% C.I.: 30~62%). There was a wide range of difference in the concentration and area under the curve (AUC) of 5-FU from patient to patient. We could find significant differences in AUC of 5-FU between the responders and the non-responders (p<0.05).
CONCLUSION
We could confirm that FP chemotherapy was effective and tolerable for the treatment of advanced stomach cancer. The monitoring of plasma 5-FU concentration after chemotherapy and the adjustment of subsequent 5-FU dose seems to be necessary to improve the treatment outcome of FP chemotherapy.

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Pharmacokinetics and Toxicities of High - Dose Methotrexate in the Treatment of Primary Osteogenic Sarcoma: Goo Hyun Baek, Soo Yong Lee, Seok Il Hong; J Korean Cancer Assoc. 1990;22(3):386-395.

Abstract PDF: From December 1989 to July l990, we have tried 70 courses of high-dose methotrexate therapy, which was combined with adriamycin and cisplatin, in the treatment of 13 patients with primary wteogenic sarcoma. The dosage of methotrexate in our protocol was 8 grams per square meter of body surface and the intravenous infusion was done for 4 hours. Using fluorescence polarization immunoassay (FPI) method, we measured the plasma level of methotrexate at 4, 5, 6, B, 24, 48 and 72 hours from the start of infusian. The toxicities were analyzed according to the WHO guidelines. The mean plasma level was 1343.89uM/L at 4 hours (S.D.: 474.63, range: 795.40 to 2870.00), 736.58 (S.D.:291.33, range: l53.00 to 1495.90) at 5 hours, 601.26 (S.D.:329.69, range:36.10 to 1251.20) at 6 hours, 353.44 (S.D.: 179.02, range: 3.60 to 720.23) at 8 hours, 7.32 (S.D.: 9.79, range: 0.08 to 68.50) at 24 hours, 0.40(S.D.: 0.55, range: 0.02 to 3.90) at 48 hours and 0.15 (S.D.: 0.09, range: 0.01 to 0.63) at 72 hours. Twenty two point nine percents at 24 hours and 17.1 percents at 48 hours needed increase of citrovorum factor rescue and 14.3 percents needed prolonged administration of citrovorum factor at 72 hours. Myelosuppression, alteration of hepatic function such as increase of sGOT and sGPT, and other infrequent toxicities were observed, but they were reversible and did not result in permanent dysfunction.

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Phase 1b Clinical Trial and Pharmacokinetic Evaluation of Recombinant Human Granulocyte - Macrophage Colony: Jae Kyung Roh, Jin Hyuk Choi, Hyung Keun Roh, Sun Young Rha, Kyung Hee Lee, Hye Ran Lee, Jee Sook Hahn, Pum Soo Kim, Byung Soo Kim; J Korean Cancer Assoc. 1994;26(3):495-510.

Abstract PDF: To define the clinical safeties and hematologic effects of subcutaneously administered yeast- derived recombinant human granulocyte-macrophage colony stimulatina factor(rh GM-CSF, LBD-005h and to determine the maximally tolerated dose(MTD) and the pharmacokinetics. Sngle arm open non-randomized phase Ib study was carried in 15 cancer patients#(14 patients evaluable) with chemotherapy induced bone marrow depression. Rh GM-CSF by once-daily subcutaneous administration to groups of 3-6 patients at doses of 50, 100, 150, 250, 350, 500, 700 ug/m/d for 10 consecutive days was escalated unless greater than WHO grade III toxicites were observed. Intrapatient dose escalation was permitted. Clinical safeties and toxicities were observed with frequent hematologic monitering. Blood and urine were collected on day 1, and 8 of rh GM-CSF administration to evaluate the parmacokinetic parameters. Of the 15 enrolled patients, 14 patients were evaluable. Male to female ratio was 8: 6 with median age 32 y-o(10~70 y-o). Seven patients had osteosarcoma, 2 malignant lymphoma, 2 gastric carcinoma, 2 lung cancer and 1 had uterine leiomyosarcoma. The total administered cycles of rh GM-CSF were 24. At each dose step, 3 patients were treated with exception of 6 patients at 500 ug/m/d dose. At all the doses administered, fever and flue-like syndrome were common side effects. Grade I fever and flue-like syndrome 50~150 pg/m dose, and grade II fever flue- like syndrome were observed at the dose of grater than 250 u/m(2)/d dose. Even at the 700 ug/m(2)/ d dose, no greater than grade III toxicities were observed. Leucocytosis were dose dependent with 120-480% increment of baseline. Pharmacokinetic parameters are as follows; Cmax were dose dependent(0.42-11.7 ng/ml) with 2-4 hours of Tmax. AUC were also dose dependent(3.93~87.9ng.hr/ml) with sustained serum levels(0.2-2ng/ml) up to 12 hours after rh GM-CSF administration. Urinary excretion(0-24 hours) after GM-CSF was less than 1% of administered dose. Yeast-derived rh GM-CSF induces leucocytosis in the dose range of 150~500ug/m(2)/d with tolerable side effects. Subcutaneously administered rh GM-CSF has sustained serum levels up to 12 hours after administration. The doses of 150-500 ug/m/d would be appropriated for the further trials.

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A Phase 1 Clinical Trial and Pharmacokinetic Evaluation of DA-125 ( A Novel Anthracycline Derivative ) in Advanced Carcer Patients: Jae Kyung Roh, Sun Young Rha, Jong In Lee, Kyung Hee Lee, Joon Oh Park, Jae Yong Cho, Nae Chun Yoo, Hyun Cheol chung, Joo Hang Kim, Jin Sik Min, Byung Soo Kim, Myung Geol Lee, Won Bae Kim, Joong Ik Y; J Korean Cancer Assoc. 1996;28(6):961-973.

Abstract PDF: Background
DA-125 {(7-0-12.6-dioxy-2-fluoro-2-L-talopyranosyl)- adriamycinone-14-b-alaninate HC1}, is a novel water soluble derivative of fluorinated doxorubicin. Our previous studies showed that DA-125 is more stable and effective than doxorubicin, especially to doxorubicin resistant tumor cell lines in vitro and in vivo. We initiated phase I clinical trial to evaluate the toxicities and the pharmacokinetics of DA-l25 in advanced cancer patients. Method: Advanced cancer patients who were refractory to the standard treatment with normal hepatic and renal functions were eligible after informed consent. Drug was administered intravenously for 5 minutes with initial starting dose of 20 mg/§³(10% of murine LD10). For each dose level, 3 patients were enrolled and the next increased dose was administered if there were no toxicities greater than WHO grade III. Blood, urine and bile (if possible) were collected for the pharmacokinetic evaluation. Result: Twenty three patients were enrolled with 22 evaluable patients (3 at 20 mg/§³, 3 at 40 mg/§³, 3 at 60 mg/§³, 6 at 80 mg/§³ and 7 at 100 mg/§³ of DA-125). All treated patients did not suffer from life-threatening side effects. Hematologic alterations especially neutropenia were major toxicities. Up to 60 mg/§³ dose, toxicities greater than WHO grade II were not observed. At 80 mg/§³ dose, one heavily pretreated patient developed grade III neutropenia. At 100 mg/§³ dose, one patient developed grade IV thrombocytopenia without evidence of clinical bleeding and 2 patients showed grade III neutropenia Grade I and II nausea and vomiting were observed at 80 mg/§³ and 100 mg/§³ dose level. Cardiac toxicities did not occur in any patient. DA-125 was rapidly hydralized to Ml(active metabolite), after IV administration. The plasma half life of M1 was 1.1~2.6 hours and that of M2 was 7.8~9.4 hours. The AUC of both metabolites were dose dependent(Ml: 0.154~0.638ug.hr/ml, M2: 0.684~3.07 ug.hr;ml). Urinary excretion of Ml wss less than 1% of administered dose until 96 hours and that of M2 was 10~22%. In one patient with periampullary cancer, 52.3% of the metabolites were excreted through bile. Conclusion: The results of the present study demonstrated that DA-125 was well tolerable to the advanced cancer patients and 100 mg/§³ was considered as maximally tolerated dose. We are planning the phase II trial on the basis of these results.

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Neoadjuvant Chemotherapy with High-dose Methotrexate , Adriamycin and Cisplatin for Non - Metastatic Osteosarcoma: Keun Seok Lee, Heung Moon Chang, Dae Seog Heo, Yung Jue Bang, Noe Kyeong Kim, Sang Hoon Lee, Eui Keun Ham, Han Ku Lee; J Korean Cancer Assoc. 1996;28(6):1092-1104.

Abstract PDF: three non-metastatic osteosarcoma patients were treated with high-dose methotrexate, adriamycin, and cisplatin from October 1987 to May 1993. Median age was 18. The ratio of male to female was 16: 7. The patients received methotrexate 8g/§³ IV, day 1 and 8 with leucovorin rescue, adriamycin 25mg/§³ IV day 16~18, and cisplatin 75mg/§³ IV day 16, After two cycles of neoadjuvant chemotherapy, operation was done and then six cycles of adjuvant chemotherapy were given with the same regimen. One patient developed lung metastasis after two cycles of neoadjuvant chemotherapy, and the other patient died from sepsis associated with chemotherapy-induced neutropenia before operation. Therefore, 21 patients underwent operation. Among them, l9 patients underwent limb salvage operation. Of the five patients who relapsed, two patients had lung metastasis and another two patients had local recurrence, and one patient had both lung and brain metastasis. One year, three year, and five year disease-free survival rate were 84%, 68%, and 68%. One year, three year, and five year survival rate were 91%, 64%, and 53%, respectively. The site of the primary lesion was the only significant prognosis factor. Patients with the lesion of distal femur had poor prognosis.Histologic responses were assessed in 17 patients. Observed histologic responses were grade I necrosis in 35%, grade II necrosis in 65%. There was no grade III or IV necrosis. The disease-free survival rates and overall survival rates were not significantly different between grade I necrosis group and grade II necrosis group. Toxicities grade III or IV were as follows: leukopenia 32%, thrombocytopenia 9%, hepatotoxicity 14%, and infection 6% with one chemotherapy-related death. The pharmacokinetics of high-dose methotrexate with leucovorin rescue were studied in l0 patients. The highest concentration was achieved at the end of infusion(6 hour). The decay of the plasma concentration of methotrexate after completion of the infusion followed a two-compartment model with a T(1/2)￥a of 3.4¡¾1.9 hours and T(1/2)￥a of 8.0¡¾2.6 hours. The clearance was 55¡¾13ml/min/§³ and the volume of distribution was 8.2¡¾3.0 L/§³. In conclusion, neoadjuvant chemotherapy with high-dose methotrexate, adriamycin, and cisplatin is effective for treatment of the patients of osteosarcoma with preserving the limb function.

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