1109 Phase II Clinical Trial of SKI-2053R, a New Platinum Analog, in the Treatment of Patients with Advanced Gastric Adenocarcinoma Noe K. Kim, M.D. Seock-Ah Im, M.D. Dong-Wan Kim, M.D. Moon H. Lee, M.D. Chul W. Jung, M.D. Eun K. Cho, M.D. Jong T. Lee, M.D. Jin S. Ahn, M.D. Dae S. Heo, M.D. Yung-Jue Bang, M.D. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea. BACKGROUND. SKI-2053R (SK Chemicals, Kyungki-Do, South Korea) is a new platinum derivative with antitumor activity against various cell lines, including cisplatin-resistant tumor cell lines. Preclinical studies have suggested that it is less nephrotoxic than cisplatin. This study evaluated the efficacy and toxicity of SKI2053R in the treatment of patients with advanced gastric adenocarcinoma. METHODS. Thirty-seven patients with advanced gastric adenocarcinoma that was unresectable or metastatic were treated. No prior chemotherapy or radiotherapy was allowed. Patients received SKI-2053R 360 mg/m2 by 1-hour infusion on Day 1. After the first cycle, subsequent doses were adjusted according to the toxicity. Courses were repeated every 28 days. RESULTS. Thirty-five patients were evaluable for response and toxicity. Six patients achieved a major response (17%; 95% confidence interval, 8 –33%); 2 were complete and 4 were partial responses. The median duration of response was 7.2 months, with a range of 1–20 months. Patients could tolerate the treatment without significant toxicity. No patients had Grade 3 or 4 toxicity. The most frequent toxicity was Grade 1 or 2 proteinuria (26% of cycles), but it was mild and transient. Leukopenia, thrombocytopenia, azotemia, nausea and vomiting, and neurotoxicity were not frequent. These low toxicity profiles indicated that the dose of SKI-2053R could be increased in future studies. CONCLUSIONS. SKI-2053R was active in the treatment of patients with gastric adenocarcinoma and had favorable toxicity profiles. Cancer 1999;86:1109 –15. © 1999 American Cancer Society. KEYWORDS: SKI-2053R, gastric carcinoma, chemotherapy, clinical trial, Phase II study. G Presented in abstract form at the 33rd annual meeting of the American Society of Clinical Oncology, Denver, Colorado, May 1997. Supported by Grant HMP-98-D-1-0002 from the ’98 Good Health R & D Project, Ministry of Health and Welfare, Republic of Korea. Address for reprints: Noe Kyeong Kim, M.D., Department of Internal Medicine, Seoul National University College of Medicine, 28, Yongon-dong, Chongno-gu, Seoul, 110-744, South Korea. Received December 7, 1998; revision received April 22, 1999; accepted April 22, 1999. © 1999 American Cancer Society astric adenocarcinoma is the most common malignancy in Korea,1 and it is one of the most prevalent malignancies in many countries.2 The prognosis of gastric adenocarcinoma is very grave; only 20 –30% of patients survive longer than 5 years. The causes of the poor prognosis are adjacent organ invasion and distant metastasis at diagnosis. Thus, the development of effective chemotherapeutic agents for locally advanced and metastatic gastric carcinoma is essential. For many years, a few single agents, such as 5-fluorouracil, doxorubicin, mitomycin C, and nitrosourea, have been considered to have significant antitumor activity in patients with gastric carcinoma.3 However, the response rate has been less than 30% and complete remission has been rare. To improve treatment outcomes, several combination chemotherapy regimens with these agents have been tried. FAM (5-fluorouracil, doxorubicin, and mitomycin C) chemo- 1110 CANCER October 1, 1999 / Volume 86 / Number 7 FIGURE 1. Structures of SKI-2053R, cisplatin, and carboplatin are shown. therapy showed a response rate of 42% in a nonrandomized Phase II study.4 There was no evidence that combination chemotherapy could increase the survival rate of patients.5 In mid-1980s, it was suggested that cisplatin was effective in treating gastric carcinoma, with a response rate of 19%.6 Recently, some cisplatin-based combination chemotherapy regimens showed high response rates of 40 –70%.7–11 Despite the effectiveness of cisplatin against gastric carcinoma, there were two major problems with this agent. First, cancer cells showed primary or acquired resistance to cisplatin.12 Second, significant side effects were observed, such as severe nausea and vomiting, nephrotoxicity, and neurotoxicity.13 To overcome these drawbacks of cisplatin, extensive efforts have been made to develop new cisplatin analogs with equivalent or greater antitumor activity and lower toxicity.14 –17 Among them, carboplatin has reduced renal and gastrointestinal toxicities as compared with cisplatin.14,18 However, carboplatin has no enhanced therapeutic efficacy over cisplatin and has not circumvented acquired resistance to cisplatin due to its cross-resistance.19 SK Chemicals (Kyungki-Do, South Korea) has developed many cisplatin analogs, including SKI-2053R (Fig. 1). Preclinical studies with SKI-2053R showed antitumor effects on various cancer cell lines comparable to cisplatin.20 –22 Moreover, it was effective against gastric carcinoma cell lines. SKI-2053R especially showed an antitumor effect on L1210-CPR cells, which are from an experimentally induced, cisplatinresistant cell line.20,21 No remarkable toxicity was found in a general pharmacologic evaluation of pre- clinical trials.23 A toxicity evaluation of beagle dogs showed a milder nephrotoxicity than cisplatin but showed major toxicity in bone marrow suppression and mucositis.24 It was expected that bone marrow suppression and mucositis would be dose-limiting toxicities in clinical trials. We performed a Phase I clinical trial based on these preclinical data.25 SKI-2053R was administered intravenously as a 1-hour infusion on Day 1 and every 4 weeks after that. The starting dose of the Phase I study was 40 mg/m2, which was one-tenth of LD10 in mouse (LD10 in mouse was 380 mg/m2). The dose of drug was increased up to 480 mg/m2 using a modified Fibonacci method. There was no significant toxicity with dosages up to 360 mg/m2. At 480 mg/m2, twothirds of patients developed Grade 4 hepatotoxicity, Grade 3 leukopenia, thrombocytopenia, Grade 2 azotemia, and proteinuria. Other toxicity included nausea/vomiting and mucositis. It was suggested that peripheral neuropathy could be present with long term administration. By these results, the initial dose of Phase II clinical trial was recommended as 360 mg/m2 (75% of maximal tolerable dose, 480 mg/m2). The purpose of this clinical trial was to evaluate the efficacy and toxicity of the SKI-2053R chemotherapy in patients with advanced gastric adenocarcinoma. PATIENTS AND METHODS This study was performed at the Seoul National University Hospital (SNUH), Seoul, South Korea, and patients were accrued only at SNUH. Patients were eligible if they had histologic evidence of unresectable or metastatic gastric adenocarcinoma. Patients were required to have measurable disease, which was defined as follows: 1) a tumor mass that could be evaluated by physical examination in two perpendicular dimensions (e.g., skin nodule or lymph node), 2) a clearly measurable lung nodule on chest radiography, or 3) a hepatic lesion with a maximal dimension of over 2 cm that could be measured by computed tomography (CT) scan. Prior surgical treatment, such as gastrectomy, was allowed, but only if it was performed at least 3 weeks before enrollment in the study. Patients’ ages ranged from 20 to 70 years. All patients signed an informed consent form. Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status of 0 –2 and a life expectancy of 3 months or longer. Adequate hematologic function (hemoglobin level $6.2 mmol/liter [10 g/dL]), white blood cell count $4.0 3 109/liter, platelet count $100 3 109/liter), renal function (serum creatinine level #132.6 mmol/liter [1.5 mg/dL] or creatinine clearance $65 mL/min), and hepatic function (biliru- SKI-2053R for Gastric Adenocarcinoma/Kim et al. TABLE 1 Dose Modification of Subsequent Cycle According to the Toxicity after the First Cycle Leukocyte (3 109/liter) Platelet (3 109/liter) Hepatotoxicity Dose .3.0 2.0–3.0 ,2.0 .75 50–75 ,50 Grade 0–1 Grade 2 Grade 3 400 mg/m2 (escalation by 11%) 360 mg/m2 (same as first cycle) 320 mg/m2 (reduction by 11%) bin level #25.65 mmol/liter [1.5 mg/dL] or serum alanine aminotransferase/aspartate aminotransferase [ALT/AST] level less than 2 times of reference value) were required. No prior chemotherapy, immunotherapy, or radiation therapy were allowed. Patients with the following conditions were excluded: 1) active bacterial infection that required antibiotic treatment; 2) the presence of psychiatric disease, brain metastasis, or seizure disorder; or 3) pregnancy or lactation. Treatment was administered in the inpatient setting. SK Chemicals provided SKI-2053R. SKI-2053R was administered by intravenous injection into a peripheral vein over 1 hour on Day 1. It was diluted with 500 mL of 5% dextrose water. The 1500 mL of 0.9% saline was infused over 12 hours before the administration of SKI-2053R. To prevent emesis, 8 mg of ondansetron were given by intravenous route 3 times (15 minutes before, 4 hours after, and 8 hours after SKI2053R infusion). The course was repeated every 28 days. The starting dose was 360 mg/m2 and subsequent dosage was modified according to the hematologic and hepatic toxicity after the first cycle, as shown in Table 1. Pretreatment evaluation included taking a complete history, physical examination, and documentation of performance status. Pretreatment laboratory evaluation included a complete blood count; partial thromboplastin time; prothrombin time; urinalysis (specific gravity, pH, albumin, glucose, ketone, blood, urobilinogen, bilirubin, nitrite, and microscopy); blood chemistry, including liver function tests (calcium, phosphate, magnesium, glucose, uric acid, blood urea nitrogen, creatinine, cholesterol, protein, albumin, bilirubin, alkaline phosphatase, ALT/AST, sodium, potassium, and chloride); and a viral hepatitis marker study (hepatitis B surface antigen, antibodies to the hepatitis B surface antigen, antibodies to the hepatitis B core antigen, and antibodies to the hepatitis C virus). All patients were evaluated with 12-lead electrocardiogram (EKG), audiogram, and stool occult blood test. Measurement of creatinine clearance by 24-hour urine collection was performed if it was indi- 1111 cated. Chest radiograph was performed on every patient. CT scan and other studies were performed to measure lesions before treatment. During the first 4 weeks of the study, history-taking, physical examination, and complete blood count and blood chemistry were performed every week. These studies were performed every 4 weeks while patients were on therapy. Partial thromboplastin time and prothrombin time were evaluated every 2 weeks. Urinalysis, 12-lead EKG, and creatinine clearance test were performed every 4 weeks. Chest radiograph, stool occult blood test, CT scan, and other studies to measure the lesion were performed at the fourth week of study and then every 4 – 8 weeks. Audiogram was obtained at the end of treatment. The evaluation of tumor response was performed every 4 weeks. The criteria for response were as follows: 1) A complete response (CR) was defined as disappearance of all the evidence of tumor for at least 4 weeks and no evidence of newly developed lesions. 2) A partial response (PR) was defined as a greater than 50% reduction in the sum of the products of the longest perpendicular dimensions of indicator lesions for a period of at least 4 weeks, and no evidence of enlargement of other lesions or development of new lesions. 3) Stable disease (SD) was defined as a less than 50% reduction or less than 25% increase in measurable tumor area and no evidence of newly developed lesions for at least 4 weeks. 4) Progressive disease (PD) was defined as a greater than 50% increase in the sum of the products of the longest perpendicular dimensions of indicator lesions or the presence of newly developed lesions. The evaluation of treatment efficacy was performed at the end of treatment. The efficacy of treatment was defined as the best response of tumor during treatment. Toxicity was graded according to the World Health Organization scoring system of Miller et al.26 Periodic history-taking, physical examination, and laboratory tests were performed to evaluate toxicity. Toxicity was properly managed if it occurred. Treatment was stopped if the disease progressed, Grade 4 toxicity occurred, the ECOG performance status of patients was 4, or the patient refused further treatment. Statistical Analysis The trial was designed by using a two-stage procedure.27 Assuming a true response rate of at least 20%, initially 14 patients were accrued. If no response was observed, the trial would be closed because if the true response rate was at least 20%, then the probability of obtaining no response in 14 patients was less than 0.05. The decision was made to continue the study if at 1112 CANCER October 1, 1999 / Volume 86 / Number 7 TABLE 2 Patient Characteristics Characteristic No. of patients Total no. of patients Evaluable for response Evaluable for toxicity Ineligible Age, yrs Median Range ECOG Performance status 0 1 2 Men/women Prior therapy None Surgery Site of measurable lesion Intraabdominal lymph nodes Cervical lymph nodes Liver mass Ovarian mass Intraabdominal mass Pelvic mass 37 35 35 2 53 33–65 5 27 5 28/9 26 11 27 6 14 2 1 1 ECOG: Eastern Cooperative Oncology Group. least 1 treatment response was observed and 11 additional patients were to be included according to the rules, to obtain an accuracy of 0.10 of the final response rate; however, accrual was continued to a total of 35 patients so that the response proportion would be better defined. According to this design, the probability of completing the trial was greater than 95% if the true response rate was at least 20%. The proportion of patients who responded was used to estimate the true response rate, with a 95% confidence interval based on a multistage testing procedure. Survival times were calculated from the start of chemotherapy until death. Duration of response was evaluated depending on response: PR duration was calculated from the start of chemotherapy to the date of PD; CR duration was calculated from the date of the evaluation of the CR to the date of PD. Actuarial survival was determined by the Kaplan–Meier method.28 RESULTS Baseline Characteristics of Patients Patients’ characteristics are listed in Table 2. Thirtyseven patients were accrued from January 1995 until August 1996 at SNUH. Thirty-five patients were evaluable for response and toxicity. Two patients were ineligible due to inadequate hemoglobin level and hepatic transaminase (ALT/AST) level. The median age of patients was 53 years (range, 33– 65 years). Twentyeight patients were male and 9 were female. Most of the patients had good performance status. No patient had received prior chemotherapy or radiotherapy. Eleven patients had received palliative surgical treatment before SKI-2053R treatment. All patients had bidimensionally measurable lesions. The measurable lesions of patients were intraabdominal lymph nodes (27 patients), cervical lymph nodes (6 patients), metastatic lesions in liver (14 patients), ovarian masses (2 patients), an intra-abdominal mass (1 patient), and a pelvic mass (1 patient). Response The median number of cycles of chemotherapy was 2 (range, 1–17cycles). Nine patients completed three or more courses of chemotherapy. Thirty-five patients were evaluable for response. Six of 35 evaluable patients achieved major responses (17%; 95% confidence interval, 8 –33), including 4 partial (11%) and 2 complete responses (6%). Partial responses were seen after a median of 2 cycles (range, 1–2 cycles) and complete responses were seen after 6 and 8 cycles. The duration of response ranged from 1 to 20 months (median, 7.2 months), with partial responses that lasted for 1–20 months (median, 7.2 months) and complete responses that lasted for 3.2 and 6.2 months. Responses were seen in patients with liver mass, intraabdominal lymph nodes, and cervical lymph nodes. Complete responses were observed in two patients with unresectable perigastric lymph nodes. One patient achieved a complete response after 8 cycles of therapy. The patient subsequently underwent gastrectomy to control the primary lesion. There was no evidence of residual tumor on surgical pathology. However, the disease recurred in cervical lymph nodes and liver 3 months after operation. The other patient achieved a complete response after six cycles of therapy. When the operation was recommended to control the primary lesion, the patient refused. The disease recurred in the stomach 6 months after the complete response. Four patients achieved partial responses. Three of these patients had metastatic liver disease and one patient had cervical and perigastric lymph node disease. SKI-2053R was administered until disease progressed. Three have died of disease and one remains alive with disease. The median duration of survival from the first cycle of chemotherapy was 9.1 months (range, 1.4 – 34.21 months) for all patients and 20.6 months (range, 9.1–34.21 months) for responders (median follow-up time, 22.2 months). Eleven patients survived for more SKI-2053R for Gastric Adenocarcinoma/Kim et al. 1113 TABLE 4 Nonhematologic Toxicity per Patient (Total of 35 Patients) Grade 1 FIGURE 2. Kaplan–Meier overall survival is shown for all eligible patients (35 patients, 10 censored). The median survival was 9.1 months. Marks indicate last follow-up. Grade 2 Grade 3 Grade 4 Toxicity No. % No. % No. % No. % Nausea/vomiting Diarrhea Constipation Stomatitis Hepatic Elevation of BUN/Cr Proteinuria Hematuria Peripheral neuropathy Auditory neuropathy Alopecia 19 4 5 1 5 4 10 10 5 0 1 54 11 14 3 14 11 29 29 14 0 3 8 0 0 0 2 0 18 0 0 0 0 23 0 0 0 6 0 51 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 BUN: blood urea nitrogen; Cr: creatinine. TABLE 5 Renal Toxicity per Cycle (Total of 94 Cycles) TABLE 3 Hematologic Toxicity per Cycle (Total of 94 Cycles) Grade 1 Grade 2 Grade 3 Grade 1 Grade 4 Toxicity No. % No. % No. % No. % Anemia Leukopenia Thrombocytopenia 30 13 3 32 14 3 12 3 0 13 3 0 0 0 0 0 0 0 0 0 0 0 0 0 Grade 2 Grade 3 Grade 4 Toxicity No. % No. % No. % No. % Elevation of BUN/Cr Proteinuria Hematuria 4 19 12 4 20 13 0 24 0 0 26 0 0 0 0 0 0 0 0 0 0 0 0 0 BUN: blood urea nitrogen; Cr: creatinine. than 12 months and 7 patients survived for more than 24 months. Actuarial survival is shown in Figure 2. Toxicity Thirty-five patients were assessable for toxicity and a total of 94 cycles were delivered. Hematologic and nonhematologic toxicities are listed in Tables 3 and 4. Patients tolerated the treatment without serious toxicity. Grade 3– 4 toxicity was not experienced by any patient, and none of the patients were removed from the study due to toxicity. Dose reduction was not required in any of the cycles, and the dose was escalated for 12 patients (34%). The most common hematologic toxicity was anemia. Grade 1 and 2 anemia occurred at 32% and 13% of treatment cycles, respectively. Leukopenia of Grade 1 or 2 was experienced in 17% of cycles. Thrombocytopenia was experienced in 3% of all cycles. The most common nonhematologic toxicity was proteinuria of Grade 1 or 2. Proteinuria occurred in 28 of 35 patients (80%), including 10 patients with Grade 1 proteinuria and 18 patients with Grade 2 proteinuria (defined as 11 ; 111 on urine stick test; 0.3–1.0 g/dL). Despite the frequency of proteinuria, Grade 2 proteinuria occurred in only 24 of 94 cycles (26%) (Table 5). No patient experienced symptomatic proteinuria. When the urinalysis was performed serially, the proteinuria resolved completely after the treatment. Another renal toxicity was Grade 1 hematuria (29%), which was transient. Azotemia occurred in 4 of 35 patients (11%) and was Grade 1 in all cases. Gastrointestinal toxicity included nausea/vomiting, diarrhea, constipation, and stomatitis of Grade 1 or 2. Mild nausea/vomiting was observed transiently in 27 of the 35 patients and could be well controlled with antiemetic medication. No patient experienced Grade 3 or 4 nausea/vomiting. Diarrhea, constipation, and stomatitis were reported infrequently and were mild. Reversible elevation of hepatic transaminase of Grade 1 or 2 occurred in 7 patients (20%). Transient alopecia was reported in one patient. Neurotoxicity was rare and transient. Five patients had Grade 1 peripheral neuropathy but tolerated it well. All of them experienced peripheral neuropathy during the first cycle of treatment, and it completely resolved subsequently. Nine patients received more 1114 CANCER October 1, 1999 / Volume 86 / Number 7 than three cycles of treatment and did not experience neuropathy. Ototoxicity did not occur in any patient. All chemotherapy toxicities were reversible, and there were no chemotherapy-related deaths. DISCUSSION Cisplatin is an effective chemotherapeutic agent in the treatment of advanced gastric adenocarcinoma. However, its clinical usefulness has frequently been limited by undesirable side effects13 and by the development of resistance.12 Carboplatin has modified the problems of toxicity, but it does not possess the ability to overcome cross-resistance.19 Therefore, there is a pressing need to identify new active agents that can overcome toxicity and resistance in the treatment of gastric carcinoma patients. SKI-2053R demonstrated antitumor activity superior to that of cisplatin against a variety of tumor cell lines, including cisplatin-resistant tumor cell lines.20 –22 Preclinical studies suggested that it was less nephrotoxic than cisplatin, and bone marrow suppression was a predominant toxicity in animals.24 A Phase I clinical trial showed that the dose-limiting toxicities of this agent were hepatotoxicity and bone marrow suppression.25 Based on these results, we expected that SKI-2053R had antitumor activity in gastric carcinoma with less nephrotoxicity than cisplatin. We performed this study to evaluate the efficacy and toxicity of SKI-2053R in patients with advanced gastric adenocarcinoma. The result of this study showed that SKI-2053R had antitumor activity comparable to that of cisplatin in gastric adenocarcinoma. Objective responses occurred in 6 of 35 evaluable patients (response rate, 17%). The response rate in this study was similar to that of single-agent treatment with cisplatin.6 Two patients achieved complete responses, and one of them had no evidence of disease on surgical pathology. Responses occurred in metastatic sites as well as regional lymph nodes. Although the median duration of response was 7.2 months, the response was more durable in some patients. SKI-2053R could be safely administered to all patients. The toxicity profiles of this agent were more favorable than those of other platinum agents. No patient experienced Grade 3 or 4 toxicity. Dose reduction due to toxicity was not required in any of the cycles. Bone marrow suppression, which is common with carboplatin,29 was generally mild. Anemia of Grade 1 or 2 was relatively common. Thrombocytopenia occurred in only 3% of cycles. Nephrotoxicity was generally milder with SKI2053R than with cisplatin, as expected in preclinical and Phase I studies. In spite of less aggressive hydration, the azotemia was less frequent and milder than with cisplatin, and cumulative nephrotoxicity did not appear. Only Grade 1 azotemia occurred in 11% of the patients. However, mild proteinuria was frequent, and it was the most remarkable toxicity in this study. Proteinuria occurred in 26% of cycles. However, the grade of proteinuria was mild, and the toxicity was transient. Grade 3– 4 proteinuria did not occur in any patient. When we performed serial urinalysis of patients with proteinuria, the results showed that most proteinuria occurred during the first week of the cycle and gradually decreased with time. Proteinuria completely resolved after discontinuation of treatment for all patients. We concluded that proteinuria was mild and reversible, but further evaluation is warranted. Nausea/vomiting was infrequent and mild with SKI-2053R. It may reflect the antiemetic effect of ondansetron. Other gastrointestinal toxicities, including diarrhea, constipation, and stomatitis, were also uncommon with this agent. Neuropathy was not significant. Ototoxicity, a cumulative and irreversible side effect of cisplatin,13 was not observed with SKI-2053R. Peripheral neuropathy was also a cumulative side effect of cisplatin. However, only 5 patients had Grade 1 peripheral neuropathy, and they tolerated it well. It was remarkable that neuropathy occurred only in the first cycle and that it was reversible in all cases. Cumulative neurotoxicity was not reported even in the patients who had more than three cycles of treatment. Low toxicity profiles suggested that the starting dose of this agent could be increased up to 400 mg/m2 in further trials. Despite low toxicity, the response rate was comparable to that achieved with cisplatin. It was expected that SKI-2053R might show antitumor activity superior to that of cisplatin at higher doses. Preclinical studies showed that continuous infusion (over 12–24 hours) of this agent was more effective than infusion for a short period (over 1–3 hours).30 Phase I and II clinical trials with continuous infusion of higher dose SKI-2053R are being conducted. In conclusion, SKI-2053R was a safe and active agent in the treatment of advanced gastric adenocarcinoma patients in this study. REFERENCES 1. 2. Ministry of Health and Social Affairs, Republic of Korea. Five year’s report for cancer registry program in Republic of Korea (July 1, 1982 to June 30, 1987). J Korean Cancer Assoc 1989;21:151–216. Alexander HR, Kelsen DP, Tepper JC. Cancer of the stomach. In: DeVita VT Jr., Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th edition. Philadelphia: Lippincott-Raven, 1997:818 – 48. SKI-2053R for Gastric Adenocarcinoma/Kim et al. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Wills J, Bleiberg H. Current status of chemotherapy for gastric cancer. Eur J Cancer Clin Oncol 1989;25:3– 8. MacDonald JS, Schein PS, Woolley PV, Smythe T, Ueno W, Hoth D, et al. 5-Fluorouracil, doxorubicin and mitomycin (FAM) combination chemotherapy for advanced gastric cancer. Ann Intern Med 1980;93:533– 6. Cullinan SA, Moertel CG, Fleming TR, Rubin JR, Krook JE, Everson LK, et al. A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs. fluorouracil and doxorubicin vs. fluorouracil, doxorubicin, and mitomycin. JAMA 1985;253:2061–7. Lacave AJ, Wils J, Diaz-Rubio E, Clavel M, Planting A, Bleiberg H, et al. Cisplatinum as second-line chemotherapy in advanced gastic adenocarcinoma: a phase II study of the EORTC gastrointestinal tract cancer cooperative group. Eur J Cancer Clin Oncol 1985;21:1321– 4. Moertel CG, Rubin J, O’Connell MJ, Schutt AJ, Wieand HS. A phase II study of combined 5-fluorouracil, doxorubicin and cisplatin in the treatment of advanced upper gastrointestinal adenocarcinomas. J Clin Oncol 1986;4:1053–7. Wilke H, Preusser P, Fink U, Gunzer U, Meyer HJ, Meyer J, et al. Preoperative chemotherapy in locally advanced and nonresectable gastric cancer: a phase II study with etoposide, doxorubicin and cisplatin. J Clin Oncol 1989;7:1318 –26. Lacave AJ, Baron FJ, Anton LM, Estrada E, De Sande LM, Palacio I, et al. Combination chemotherapy with cisplatin and 5-fluorouracil 5-day infusion in the therapy of advanced gastric cancer: a phase II trial. Ann Oncol 1991;2:751– 4. Kim NK, Park YS, Heo DS, Suh C, Kim SY, Park KC, et al. A phase III randomized study of 5-fluorouracil and cisplatin versus 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil alone in the treatment of advanced gastric cancer. Cancer 1993;71:3813– 8. Ohtsu A, Shimada Y, Yoshida S, Saito H, Morise K, Kurihara M, et al. Phase II study of protracted infusional 5-fluorouracil combined with cisplatinum for advanced gastric cancer: report from the Japan Clinical Oncology Group (JCOG). Eur J Cancer 1994;30A:2091–3. Fram RJ. Cisplatin and platinum analogues: recent advances. Curr Opin Oncol 1992;4:1073–9. Reed E, Dabholkar M, Chabner BA. Platinum analogues. In: Chabner BA, Longo DL, editors. Cancer chemotherapy and biotherapy: principles and practice. 2nd edition. Philadelphia: Lippincott-Raven, 1996:357–78. Harrap KR. Preclinical studies identifying carboplatin as a visible cisplatin alternative. Cancer Treat Rev 1985;12(Suppl A):21–33. MacKeage MJ, Higgins JD III, Kelland LR. Platinum and other metal coordination compounds in cancer chemotherapy. A commentary on the sixth international symposium, San Diego, Califonia, January 23-26, 1991. Br J Cancer 1991; 64:788 –92. Kracker AJ, Hoeschele JD, Elliott WL, Showalter HD, Sercel AD, Farrell NP, et al. Anticancer activity in murine and 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 1115 human tumor cell lines of bis(platinum)complexes incorporating straight-chain aliphatic diamine linker groups. J Med Chem 1992;35:4526 –32. Mellish KJ, Kelland LR, Harrap KR. In vitro platinum drug chemosensitivity of human cervical squamous cell carcinoma cell lines with intrinsic and acquired resistance to cisplatin. Br J Cancer 1993;68:240 –50. Rose WC, Schurig JE. Preclinical antitumor and toxicologic profile of carboplatin. Cancer Treat Rev 1985;12(Suppl A):1– 19. Gore ME, Fryatt I, Wiltshaw E, Dawson T, Robinson BA, Calvert AH. Cisplatin/carboplatin cross-resistance in ovarian cancer. Br J Cancer 1989;60:767–9. Kim D-K, Kim G, Gam J, Cho Y-B, Kim H-T, Tai J-H, et al. Synthesis and antitumor activity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes. J Med Chem 1994;37:1471– 85. Kim D-K, Kim H-T, Cho Y-B, Tae JH, Ahn JS, Kim T-S, et al. Antitumor activity of cis-malonato[(4R, 5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II), a new platinum analogue, as an anticancer agent. Cancer Chemother Pharmacol 1995;35:441–5. Kim D-K, Kim H-T, Tae JH, Cho Y-B, Kim T-S, Kim KH, et al. Pharmacokinetics and antitumor activity of a new platinum compound, cis-malonato[(4R, 5R)-4,5-bis(aminomethyl)-2isopropyl-1,3-dioxolane]platinum(II), as determined by ex vivo pharmacodynamics. Cancer Chemother Pharmacol 1995;37:1– 6. Kim D-K, Ahn JS, Ryu G, Kim KH, Park CW, Kim MS, et al. General pharmacology of cis-malonato[(4R, 5R)-4,5bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II). Arzneimittelforschung 1994;44:1080 – 8. Lee Y-S, Kang K-S, Shin D-J, Cho J-J, Kim H-O, Kim B-H, et al. Subacute toxicity of cis-malonato[(4R, 5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI 2053R) in beagle dogs. Korean J Toxicol 1992;8:235–54. Kim NK, Bang Y-J, Heo DS, Kim TY, Lee JA, Park YI, et al. A phase I clinical and pharmacokinetic study of SKI 2053R, a new platinum analog, in patients with malignancies. Proc Am Soc Clin Oncol 1995;14:479. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207–14. Gehan EA. The determination of the number of patients required in a preliminary and follow-up trial of a new chemotherapeutic agent. J Chronic Dis 1961;13:346 –53. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 81. Muggia FM. Overview of carboplatin, complementing, and extending the therapeutic horizon of cisplatin. Semin Oncol 1989;16(Suppl 5):7–13. Kim H-T, Kim D-K, Cho Y-B, Kim T-S, Jung I, Kim KH, et al. Influence of exposure and infusion times on the cytotoxicity and pharmacokinetics of cis-malonato[(4R, 5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane] platinum(II). Cancer Chemother Pharmacol 1998;41:109 –16.