Phase I clinical study with pharmacokinetic analysis of 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC 286193) administered as a five-day infusion

A Phase I trial of 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC 286193, tiazofurin) was conducted using a 5-day continuous infusion schedule. Twenty-four patients with advanced cancer were entered on this trial. Dose levels ranged from 360 to 2350 mg/sq m/day for 5 days. Neurotoxicity was dose limiting and occurred in six patients. Neurotoxicity was expressed as confusion, lethargy, or obtundation and was associated with focal neurological deficits in four of six patients: hemiparesis, three; cortical blindness and bilateral upper extremity weakness, one. Neurotoxicity was not clearly dose related, occurring at 900 mg/sq m/day for 5 days (two patients), 1100 mg/sq m/day for 5 days (two patients), 1850 mg/sq m/day for 5 days, and 2350 mg/sq m/day for 5 days (one patient each). Other toxicities seen were myelosuppression, desquamation of palms and soles, malar erythema, and hyperpigmentation, stomatitis, chest pain, drug fever, and increased serum creatine phosphokinase. Administered drug [71.5 +/- 11.2% (SE)] was recovered intact in the urine within 24 h of administration. Terminal-phase mean harmonic half-life was 8.0 h. The unpredictable neurotoxicity seen following continuous infusion therapy with tiazofurin suggests that Phase II trials of this schedule are not indicated until better understanding of the biochemical effects of tiazofurin is achieved.     

A phase I trial of cisplatin in hypertonic saline and escalating doses of 5-fluorouracil by continuous intravenous infusion in patients with advanced malignancies

Thirty-four patients with incurable solid tumors were treated in a Phase I trial with a fixed dose of high-dose cisplatin (CDDP) administered in hypertonic saline and escalating doses of infusional 5-fluorouracil (5-FU). Five treatment levels of 5-FU, ranging from 500 to 900 mg/m2/day for 5 days, were studied. Leukopenia, thrombocytopenia, and oral mucositis were the dose-limiting toxicities encountered. Nephrotoxicity was minimal. Ototoxicity and peripheral neuropathies were rare and mild in this patient group, but most patients received only a small number of treatment cycles. Diarrhea was not dose-limiting. Two complete responses (one non-small cell lung cancer and one sweat gland carcinoma) were observed. No other major responses were noted. With the dose of CDDP set at 35 mg/m2/day for 5 consecutive days, the maximum tolerated dose (MTD) of a concurrent 5-day 5-FU infusion was found to be 900 mg/m2/day. The recommended dosages for Phase II trials are 35 mg/m2/day CDDP and 800 mg/m2/day 5-FU for 5 consecutive days. Cancers of the lung, breast, gastrointestinal tract, and genitourinary tract would be reasonable targets for Phase II studies.     

Pharmacokinetics and dosage reduction of cis-diammine(1,1-cyclobutanedicarboxylato)platinum in patients with impaired renal function

cis-Diammine(1,1-cyclobutanedicarboxylato)platinum (CBDCA) is a nonnephrotoxic but myelosuppressive analogue of cisplatin (DDP) with greatly reduced protein binding and greatly increased renal excretion. Thus, CBDCA might produce undue toxicity in patients with decreased renal function. Twenty-two patients [14 females and 8 males; median age, 66 (range, 35 to 83); median Karnofsky performance status, 70 (range, 40 to 90)] with refractory tumors and renal dysfunction [creatinine clearance (CCr) 6 to 83 ml/min] were treated with 31 courses of i.v. bolus CBDCA every 4 to 5 weeks. Dosages were determined by pretreatment CCr. Patients with CCr greater than or equal to 40 ml/min received 400 mg/sq m; patients with CCr 20 to 39 ml/min received 250 mg/sq m; and patients with CCr 0 to 19 ml/min received 150 mg/sq m. Toxicities were assessed by weekly clinical and laboratory assessment. Responses were assessed in patients with measurable disease. Plasma pharmacokinetics and urinary excretion of total and ultrafilterable platinum were measured with flameless atomic absorption spectrometry. Observed toxicities were similar to those in patients with normal renal function. Myelosuppression, especially thrombocytopenia, was the major toxicity. Nausea and vomiting were mild to moderate. There was no ototoxicity, neurotoxicity, or nephrotoxicity or reduction in CCr due to CBDCA. Total body clearance of ultrafilterable platinum correlated highly with CCr. The percentage of reduction in platelet count correlated highly and linearly with the area under the curve (AUC) of plasma-ultrafilterable platinum. However, for any AUC, there was 17% greater platelet reduction in patients who had previously received extensive myelosuppressive chemotherapy than in nonpretreated patients. Since total body clearance is proportional to CCr, platelet reduction is proportional to AUC, and total body clearance = dosage/AUC, we have derived an equation to calculate a dosage that will produce a desired reduction in platelet count. Calculations for theoretical patients (both pretreated and nonpretreated) with CCr of 100 ml/min produce dosages very close to maximum tolerated dosages derived in actual Phase I trials. The actual clinical utility of these predictive equations must await validation in prospective studies with larger numbers of patients.     

Pharmacokinetics of cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) in patients with normal and impaired renal function

cis-Diammine-1,1-cyclobutane dicarboxylate platinum(II) (CBDCA, JM8) is a nonnephrotoxic analogue of cisplatin currently undergoing clinical evaluation. Pharmacokinetic studies have been performed in patients receiving CBDCA (20 to 520 mg/sq m) as a 1-hr infusion without hydration or diuresis. Following the end of the infusion, plasma levels of total platinum and ultrafilterable (Mr less than 50,000) platinum (free platinum) decayed biphasically with first-order kinetics (total platinum t alpha 1/2 = 98 min; t beta 1/2 range, 399 to greater than 1440 min; free platinum t alpha 1/2 = 87 min; t beta 1/2 = 354 min). During the first four hr, binding of platinum to plasma protein was limited (24%), with most of the free platinum in the form of unchanged CBDCA (94%). However, by 24 hr, the majority of platinum was protein bound (87%). The major route of elimination was renal, 65% of the platinum administered being excreted in the urine within 24 hr, with 32% of the dose excreted as unchanged CBDCA. No evidence was found from studies on the renal clearance of free platinum to indicate renal tubular secretion (mean free platinum renal clearance, 69 ml/min). However, the plasma clearance of free platinum did correlate positively with glomerular filtration rates (p = 0.005). None of the pharmacokinetic parameters determined were dose dependent. In vitro studies with plasma and urine demonstrated that, in contrast to cisplatin, CBDCA is a stable complex [t 1/2 - 37 degrees; plasma, 30 hr, and urine (range), 20 to 460 hr]. The differences in the pharmacokinetics of cisplatin and CBDCA may explain why the latter complex is not nephrotoxic.     

Phase I study of single-dose oxaliplatin in Japanese patients with malignant tumors

BACKGROUND: Oxaliplatin, a platinum compound, has been commonly used around the world for treating advanced colorectal cancer. The generally recommended dose and schedule of oxaliplatin monotherapy is 130 mg/m(2) every 3 weeks. This trial was conducted to evaluate the safety and pharmacokinetics of oxaliplatin monotherapy in Japanese patients with solid tumors. METHODS: Oxaliplatin was administered as a 2-h intravenous infusion every 3 weeks at a dose of 90 and 130 mg/m(2). Blood was collected to determine the total platinum and the ultrafiltrate platinum concentrations in plasma in all cycles. RESULTS: Nine patients were enrolled; three were given oxaliplatin monotherapy at 90 mg/m(2) and six received 130 mg/m(2). All tumors were colorectal cancer. The major adverse reactions included myelosuppressive, neurological and gastrointestinal toxicities, although most were grades 1 and 2 at both dose levels. Peripheral sensory neuropathy of without movement disturbance (grade 1 or 2) was observed in all patients at both dose levels. The 130 mg/m(2) dose level was not found to be the maximum tolerated dose, but was judged to be the recommended dose. No objective responses were seen and five cases of no change were observed. A bi-exponential open model best described the disappearance of platinum in the plasma, and a tri-exponential open model best described the disappearance of ultrafilterable platinum in the plasma at both dose levels. No racial difference was suggested in the pharmacokinetics of oxaliplatin. CONCLUSIONS: The oxaliplatin monotherapy dose schedule of 130 mg/m(2) every 3 weeks, recommended worldwide, is acceptable for Japanese patients.     

An early phase II trial combining cisplatin, carboplatin and vindesine in patients with inoperable non-small cell lung cancer

We conducted an early phase II trial of advanced non-small cell lung cancer (NSCLC) to evaluate the response efficacy of a combination of cisplatin (CDDP), carboplatin (CBDCA) and vindesine (VDS). The twenty-four patients in the study had had no previous treatment. CDDP (15 mg/m2), CBDCA (200 mg/m2) and VDS (3 mg/m2) were administered on Day 1, CDDP (15 mg/m2) was administered on Days 2-5, and VDS (3 mg/m2) was administered on Day 8. We observed 9 partial responses (PR), with a total response rate of 39%. The overall median survival was 72 weeks, and the 1-year survival rate was 57%. Major toxicities were hematologic; leukopenia of grades 3 and 4 occurred in 25% patients, and thrombocytopenia occurred in 21%. Therefore, the combination of CBDCA with CDDP and VDS chemotherapy was effective against inoperable NSCLC with tolerable toxicities and a favorable median survival time.     

Phase I-II trial of high-dose calcium leucovorin and 5-fluorouracil in advanced colorectal cancer

Twenty-six patients with metastatic colorectal adenocarcinoma were entered into a Phase I-II study of 5-fluorouracil (5-FUra)-high-dose leucovorin (CF). The starting dose of 5-FUra was 300 mg/sq m with escalation to 750 mg/sq m/week in 6 doses given by rapid i.v. injection midway during a 2-hr infusion of CF, 500 mg/sq m. Partial responses were seen in 9 of 23 patients (6 of 12 who had had previous 5-FUra). Complete normalization of liver enzymes was seen in two of these patients. Side effects were seen sporadically with 5-FUra doses up to 600 mg/sq m. At a 600-mg/sq m 5-FUra dose, 8 of 18 patients had diarrhea, and 2 of 18 had white blood cell counts less than 3000/microliter. At a 750-mg/sq m dose of 5-FUra, 6 of 11 patients had severe diarrhea and 6 of 11 had white blood cell counts less than 3000/microliter. Other toxicities were mild conjunctivitis and lacrimation, thinning of the nails, and alopecia. In bioavailability studies of CF p.o., no plasma CF could be detected. After CF i.v., mean plasma peak was 111.3 +/- 40.3 (S.D.) microM. 5-FUra-CF appears to be effective in patients clinically resistant to 5-FUra. This study is being extended to randomized trial of 5-FUra-CF versus 5-FUra alone.     

Cisplatin combined with carboplatin: a new way of intensification of platinum dose in the treatment of advanced ovarian cancer. Belgian Study Group for Ovarian Carcinoma

We performed a phase I-II trial of escalating doses of cisplatin (CDDP: 50-100 mg/m2 per course) plus carboplatin (CBDCA: 300-400 mg/m2 per course) as a potential way in which to maximize platinum doses without causing excessive toxic effects in patients with advanced ovarian cancer. Thirty-three patients with nonoptimally debulked disease of FIGO (International Federation of Gynecology and Obstetrics) stages IIc-IV [median age: 60 yr; median WHO (World Health Organization) performance status: 2; no prior chemotherapy] received a median of six courses of therapy. CBDCA was infused on day 1 and CDDP on day 2 with an aggressive 48-hour hydration regimen. Myelosuppression was dose-limiting: at the highest dose levels, WHO grade 4 neutropenia and thrombocytopenia led to dose reduction and/or treatment delay in 45% of the patients. Nonhematologic toxic effects included acute nausea and vomiting (97% of the patients), mild alopecia (45%), ototoxic effects (39%), neurotoxic effects (21%), and renal toxic effects (serum creatinine greater than 1.5 mg/dL: 12.5%). The pathologic complete response rate was 22%. We conclude that CBDCA and CDDP can be given safely in combination at reasonably high doses (CBDCA at 300 mg/m2 per course and CDDP at 100 mg/m2 per course) over a 6-month period, provided a close hematologic follow-up is conducted. Randomized clinical trials are needed to define whether this regimen is any better than standard combination chemotherapy.     

Doxorubicin, paclitaxel and gemcitabine: a Phase I study of a new sequential treatment in stage III B - IV breast cancer

Based on the synergistic interactions of the sequence doxorubicin-paclitaxel-gemcitabine obtained in our preclinical study, a Phase I trial was conducted to evaluate the feasibility of this new sequence in breast cancer. Patients with stage IIIB-IV breast cancer received doxorubicin on day 1, paclitaxel on day 2 and gemcitabine on day 6 and 13 (steps IIa, III and V) in cohorts of 3 patients. From March 1999 to December 2000, 9 patients were treated. The most important toxicity was hematological. The maximum tolerated dose was reached at the second level because dose-limiting toxicity occurred in 3 patients. Non hematological toxicities were alopecia, diarrhea, asthenia, nausea, mucositis, paresthesia and myalgia. A Phase II trial is ongoing to further investigate the activity of this new sequential treatment with doxorubicin (50 mg/m2 day 1), paclitaxel (160 mg/m2 day 2) and gemcitabine (800 mg/m2 day 6) in advanced breast cancer.     

Phase I and clinical pharmacological evaluation of pirozantrone hydrochloride (oxantrazole)

Pirozantrone hydrochloride, an anthrapyrazole analogue, was selected for clinical evaluation based on broad antitumor activity against murine tumor systems and on potentially less cardiotoxicity when compared to anthracyclines. This anthrapyrazole analogue is currently under clinical evaluation, and we now report results on a Phase I clinical trial incorporating a pharmacologically guided dose-escalation scheme. Dose escalation was designed to proceed by factors of 2 until the patient drug exposure (concentration x time) was 40% of the murine exposure at the LD10 dose (90 mg/m2). Thereafter, more moderate dose escalations were employed. The target concentration x time value (59 micrograms-min/ml) derived from preclinical pharmacology data was exceeded in all three patients at a dose of 90 mg/m2. A dose of 160 mg/m2 was found to reproducibly result in appropriate myelosuppression. This dose is recommended for further testing in Phase II studies. Nonhematological toxicities encountered in this trial were mild, the most notable being phlebitis at the infusion site. Objective responses were observed in two patients, one with metastatic breast cancer and another with metastatic melanoma. Following a 60-min infusion, pirozantrone hydrochloride plasma elimination was monoexponential, with a half-life of approximately 30 min, mean total body clearance of 1.29 liters/min/m2, and mean steady state volume of distribution of 29 liters/m2.     

Reduced ability to clear ultrafilterable platinum with repeated courses of cisplatin

Ultrafilterable plasma and urinary levels of platinum were quantitated for 24 hours after the first- and fourth-course infusion of cisplatin (CDDP) to seven patients. Four patients received 80 mg/m2 and three patients received 100 mg/m2 CDDP as a 2-hour infusion. The area under the curve (AUC) of ultrafilterable platinum, average renal clearance (CIR) of ultrafilterable platinum, and percentage of the platinum dose excreted in urine (% E) were determined for each infusion over the 26-hour period of the study. The AUC was higher in all patients after the fourth-course infusion, with a median increase of 74%. The median CLR was 494 mL/min (range, 214 to 996 mL/min) for the first course and decreased to 156 mL/min (range, 108 to 271 mL/min) for the fourth-course infusion (P less than .02). The median % E was 29.2% (range, 19.6% to 37.7%) for the first course and decreased to 19.9% (range, 12.4% to 25.9%) for the fourth-course infusion (P less than .02). There was no difference in creatinine clearance for the two infusions (median, 94 mL/min; P greater than .05). Urinary excretion of B2-microglobulin (B2-MG) and N-acetyl-B-glucosaminidase (NAG) was highly variable between patients and did not provide a useful predictor of changes in renal function. Four courses of CDDP therapy resulted in significantly reduced renal elimination of platinum in patients, probably through a reduction in the secretion of the drug in the proximal tubule of the kidney. The results suggest that increased antitumor effect and toxicity could occur in patients receiving sequential courses of cisplatin.     

Phase I study of escalating doses of edatrexate in combination with paclitaxel in patients with metastatic breast cancer.

Motivated by the observation of preclinical synergy, a Phase I dose escalation study of edatrexate in combination with a 3-h paclitaxel infusion was performed in patients with advanced breast cancer to determine the maximum tolerated dose (MTD) of edatrexate and the toxicities associated with this combination and to report preliminary observations of efficacy with this novel combination. Thirty-six patients were enrolled in this Phase I trial. Thirty-five eligible patients were treated every 21 days in cohorts of at least three patients and were assessable for toxicity. One patient was ineligible due to hyperbilirubinemia. Stepwise dose escalations of edatrexate were administered until grade >3 nonhematological dose-limiting toxicities were reported. The initial dose level of edatrexate was 180 mg/m2; subsequent cohorts were treated with escalating doses of edatrexate (210, 240, 270, 300, 350, and 400 mg/m2). Edatrexate was administered by i.v. infusion over 1 h. Paclitaxel was administered 24 h later at a fixed dose of 175 mg/m2 as a 3-h infusion with standard dexamethasone, diphenhydramine, and cimetidine premedication. The MTD of edatrexate was reached at the 350 mg/m2 level in this study. Grade 3 diarrhea was seen in one patient at the 300 and 400 mg/m2 dose levels, requiring dose reductions. Two patients experienced grade 4 stomatitis at the 400 mg/m2 dose level and also required dose reduction, establishing the MTD as 350 mg/m2. Grade 3 nausea and vomiting were noted in two of three patients at the highest dose level. Of 35 patients, 4 patients reported grade 3 myalgias and 1 patient reported grade 3 neurosensory complaints, which were seen mostly at the 350 and 400 mg/m2 dose levels; however, 1 patient reported grade 3 myalgias at 180 mg/m2. No cumulative neurotoxicity was observed, and no patient experienced an allergic reaction to paclitaxel. In 23 patients with bidimensionally measurable disease, there were four complete (17%) and seven partial responses, with an overall response rate of 48% (95% confidence interval, 27-69%). All of the responses were seen in patients who had not received prior chemotherapy for stage IV disease. The median duration of response was not assessable because many responding patients went on to receive high-dose chemotherapy treatment with stem cell support. The combination of edatrexate and paclitaxel for treatment of metastatic breast cancer is a feasible and safe regimen. The MTD of edatrexate was 350 mg/m2 when combined with a 3-h infusion of paclitaxel (175 mg/m2) given 24 h later. Activity was noted even among patients who had relapsed shortly after receiving methotrexate- and/or doxorubicin-containing adjuvant regimens. Additional studies evaluating the sequences and dosing schema for this combination are warranted to improve the response proportion and define the duration of the response.     

Second-generation cisplatin analogs

Since the introduction into clinical practice in 1972, cisplatin (CDDP) has assumed an important role in the treatment of various tumors such as testicular, ovarian or pulmonary cancer. Its toxicities include emesis, renal impairment, neuropathy, hearing loss and anemia. In clinical trials renal toxicity has been proved to be dose limiting factor. Thus the total number of courses which may be given is limited. For this reason second-generation CDDP analogues with reduced toxicity have been tried to develop and are reaching clinical testing. A number of studies have now been published relating the results of these trials. The best studied of these analogues is carboplatin (CBDCA, JM-8) which was noted to be less nephrotoxic, but more myelosuppressive than CDDP in preclinical study. Phase I trials have shown that CBDCA is relatively free of renal toxicity and that its dose limiting factor is myelosuppression, especially thrombocytopenia. In phase II trials CBDCA has been shown to be an active agent in advanced carcinomas of the ovary, head and neck, lung and urogenital organs. Similar results have been obtained in clinical trials of iproplatin (CHIP, JM-9) which is synthesized as an analogue of CDDP. Two other analogues developed in Japan have been evaluated to be active for various mouse tumors in preclinical studies. Phase I trials of these agents is now ongoing.     

Phase I clinical study of combined cisplatin and carboplatin therapy in lung cancer]

A phase I clinical study (a dose escalation test) of combined cisplatin (CDDP) + carboplatin (CBDCA) therapy was carried out in patients with primary or secondary lung cancer (PS 0-2) who had given prior informed consent to the study. The dose level of CDDP was set at 80 mg/m2, while five dose levels (200, 250, 300, 350, 400 mg/m2) of CBDCA were used. Three patients were allocated to each CBDCA dose group. Blood samples were taken immediately before and 0.5, 1, 2, 4, 6 and 24 hours after injection, and were examined for total Pt and free Pt level. The maximum tolerated dose (MTD) was CDDP 80 mg/m2 + CBDCA 400 mg/m2. Thrombocytopenia and leukopenia served as dose limiting factors (DLF). Total Pt and free Pt levels in blood after this combined therapy were higher than those after treatment with CDDP alone. The results from this study suggest that CDDP 80 mg/m2 + CBDCA 350 mg/m2 would be a suitable dose for phase II study of this combined chemotherapy. A multi-center pilot study based on these findings is now under way.     

A phase I study of a combination of allopurinol, 5-fluorouracil and leucovorin followed by hydroxyurea in patients with advanced gastrointestinal and breast cancer

Twenty patients with advanced carcinomas of the colorectum, pancreas, stomach, and breast were enrolled in a Phase I study of a sequential administration of 5-fluorouracil-leucovorin (FU-LV) combination followed by hydroxyurea (HU) with allopurinol protection (HALF regimen). As a weekly regimen for 6 weeks, followed by a rest period of 2 weeks, FU was administered intravenously (i.v.) during infusion of a 2-hour i.v. infusion of LV at a dose of 500 mg/m2. Six hours following the FU-LV combination, HU (1 gm/m2) was administered orally. Allopurinol (300 mg every 8 hours, orally) was given the day before and on the day of the administration of the FU-LV combination. The starting dose of FU was 300 mg/m2, with escalations to 900 mg/m2. Mucositis, diarrhea, and hematologic toxicities were mild and sporadic with FU doses up to 750 mg/m2 and occurred in patients who had received prior treatment with FU and/or radiotherapy. Dose-limiting neurocerebellar toxicity was observed in 2 out of 6 patients who received a FU dose of 900 mg/m2. Three additional patients experienced moderate neuromotor toxicity at this dose level. Among 17 patients evaluable for response, partial responses were seen in 3 of the 9 patients with colorectal cancer, 1 of the 3 patients each with carcinoma of breast and pancreas. Three of the 5 responses occurred in patients who had received prior treatment with FU and/or radiation therapy. An FU dose of 750 mg/m2 is recommended for a Phase II trial of the HALF regimen.     

Infusion carboplatin treatment of relapsed and refractory acute leukemia: evidence of efficacy with minimal extramedullary toxicity at intermediate doses

Carboplatin (CBDCA) is a second-generation platinum analog with prominent myelotoxicity and modest extramedullary toxicity. We performed a phase I study of CBDCA in adult patients with relapsed acute leukemia. Therapy was administered as a five-day continuous infusion. The initial dose of 875 mg/m2 over five days was escalated in 15% increments to a final dose of 2,100 mg/m2 over five days. Twenty-eight patients received 35 induction courses of CBDCA, including two patients who achieved a complete remission (CR) following the first course, and received a second induction course at the time of relapse. Therapy was well tolerated. No grade 3 or 4 extramedullary toxicity was seen. Myelosuppression was regularly observed, with prolonged myelosuppression at 2,100 mg/m2 over five days being the indication to cease dose escalation. Eight of 28 patients (28.5%) responded to CBDCA therapy (six CR, two partial remission [PR]) or ten of 30 initial induction courses (33.3%). Continuous-infusion CBDCA has an advantage over other therapy for acute leukemia because of its highly selective myelotoxicity and minimal gastrointestinal and renal toxicity. A standard phase II study should be undertaken to establish a more accurate response rate.     

Phase I/II trial of hyperfractionated accelerated chemoradiotherapy for unresectable advanced pancreatic cancer

BACKGROUND: We conducted a Phase I/II study to evaluate the local efficacy and toxicity of hyperfractionated accelerated radiotherapy (HART) combined with 5-fluorouracil (5-FU) and cisplatin (CDDP) in patients with unresectable advanced pancreatic cancer. METHODS: Thirty-five patients (15 with Stage 4A and 20 with Stage 4B disease according to TNM classification) were enrolled between August 1997 and August 2001 into this Phase I/II trial. All patients received concurrent HART (1.5 Gy twice daily separated by 6 h for 5 days per week), 5-FU (375 mg/m(2) given as continuous intravenous infusion), and CDDP (2 mg/m(2) given as 30-min infusion just before each fraction of irradiation). In the Phase I trial, the total dose of radiation was escalated from 27 to 45 Gy. RESULTS: Twenty-one patients were enrolled in the Phase I study and six patients were given the final planned dose (45 Gy) which did not exceed the maximum tolerated dose. Eleven patients (52.4%) suffered from Grade 3 or worse neutropenia. Vomiting and mucositis were observed in 21 (100%) and 12 (57.1%) patients, respectively. An additional 14 patients were entered in the Phase II trial and received a total dose of 45 Gy, which is recommended in Phase I trial. Concerning the local tumor control of 20 patients with the recommended regimen, 7 patients (35%) achieved partial response, 10 (50%) remained stable and local progressive disease occurred in 3 (15%). The median survival time and the overall 1-year survival rate were 11.2 months and 40.0%, respectively, in 20 patients who received the recommended regimen. In Stage 4A patients, they were 13.0 months and 70.0%, respectively. The trend of toxicities in patients with the recommended regimen was almost the same as that observed in the Phase I study. CONCLUSION: The chosen combined modality treatment was well tolerated, and showed an expected local efficacy for the treatment of unresectable advanced pancreatic cancer.     

Continuous infusion 5-fluorouracil with escalating doses of intermittent cisplatin and etoposide. A phase I study

Continuous infusion 5-fluorouracil (CI 5-FU) and the combination of cisplatin (CDDP) plus etoposide (VP-16) have emerged as salvage regimens for metastatic breast carcinoma (MBC). In this study, 18 patients (15 with MBC) were entered into a Phase I study to determine the maximum intermittent doses of CDDP and VP-16 that could be added to 200 mg/m2/d CI 5-FU. The maximum tolerated dose of the combination was 40 mg/m2 of CDDP and 60 mg/m2 of VP-16 weekly for the first 8 weeks and every other week thereafter. The dose-limiting toxicities of the regimen were myelosuppression and thrombocytopenia. Two complete responses (both patients had received no previous chemotherapy) and one partial response were noticed. This regimen at the doses described here is appropriate for Phase II trials as an alternative to doxorubicin-based regimens for MBC.     

Toxicological and tumoricidal evaluations of a new platinum complex, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato+ ++)platinum( II) monohydrate, in rats

The toxicities and antitumor activity of a new anticancer platinum compound, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +) platinum(II) monohydrate (DWA2114R), were examined in rats by single intravenous injection in comparison with those of cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (CDDP). The lethal dose (LD) of DWA2114R (100 mg/kg) or CBDCA (80 mg/kg) caused a slight decrease in body weight (less than 10%) and no significant change in the levels of blood urea nitrogen and urinary sugar and protein. In contrast, a sub-LD level of CDDP (8 mg/kg) seriously decreased body weight (20%) and markedly elevated the levels of these nephrotoxicity parameters. Monitoring the numbers of peripheral blood cells for 3 weeks after the drug injection revealed that all three drugs showed severe thrombocytopenia, moderate leukopenia and slight anemia. However, CBDCA induced the most severe thrombocytopenia among these drugs. The number of platelets was reduced by 60% in rats injected with a half LD of CBDCA. A moderate reduction in platelet count (35-43%) was caused by an equitoxic dose of DWA2114R or CDDP, but abated about 3 days faster than that caused by CBDCA. Interestingly, only CDDP caused an irreversible anemia. Each drug showed a potent antitumor activity at weakly toxic doses against Walker 256 carcinosarcoma transplanted intramuscularly into rats. These results indicate that DWA2114R could be a promising new platinum anticancer agent with an improved toxicity profile.     

A Phase I clinical and pharmacological study of cis-diamminedichloro(2-methylpyridine) platinum II (AMD473)

AMD473 is a novel sterically hindered platinum cytotoxic with demonstrated ability to overcome acquired resistance to cisplatin in vitro and in human tumour xenografts. A single-agent dose escalating Phase I study was performed. AMD473 was initially administered intravenously as a 1 h infusion every 21 days to patients with advanced solid tumours. In total, 42 patients received a total of 147 cycles (median 3, range 1-8) of treatment at doses of 12, 24, 48, 96, 110, 120, 130, and 150 mg m(-2). Dosing intervals of 21 and 28 days were explored at the recommended dose. Neutropenia and thrombocytopenia proved dose limiting. Other toxicities included moderate nausea, vomiting, anorexia, and a transient metallic taste. There was no significant alopecia. The maximum tolerated dose was 150 mg m(-2). Plasma pharmacokinetics were linear. Two patients with heavily pretreated ovarian cancer showed partial response. Five patients (mesothelioma, ovary, nonsmall cell lung, and melanoma) showed prolonged stable disease. AMD473 demonstrates encouraging activity in patients, including those with prior platinum exposure. Toxicity is predictable with linear pharmacokinetics, as was predicted by preclinical studies. A dose of 120 mg m(-2) every 21 days is recommended for Phase II evaluation although there is evidence that chemo-naive patients and those of good performance status may tolerate a higher dose.