Effect of renal function impairment of iproplatin pharmacokinetics and relation to toxicity.

The pharmacokinetics of iproplatin, a quadrivalent second-generation platinum complex the dose-limiting toxicity of which is myelosuppression, was studied in patients with different degrees of renal function impairment. The drug was administered in a 30-min i.v. infusion. The plasma decay of iproplatin was biphasic, with an overall median terminal phase half-life of 3.16 +/- 2.6 (SD) h. The overall mean volume of distribution (Vss) was 39.9 +/- 25.0 liters, with a total body clearance of 14.25 +/- 3.99 liters/h. The total body clearance of iproplatin showed a linear correlation, with renal function measured as creatinine clearance. The toxicity of the drug, expressed as percentage of reduction in platelet count, correlated linearly with the area under the concentration X time curve.

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.

Phase I chemotherapy study of biochemical modulation of folinic acid and fluorouracil by gemcitabine in patients with solid tumor malignancies.

PURPOSE: This phase I biochemical modulation study evaluated the maximum-tolerated dose (MTD), toxicity, and effectiveness of the combination of folinic acid (FA)/fluorouracil (5-FU) followed by escalated dose levels of gemcitabine (FFG) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients were refractory to primary treatment and/or without effective treatment options. Twenty-eight patients received an intravenous (IV) infusion of FA 100 mg/m(2) over 1 hour and a 5-FU 450 mg/m(2) IV bolus in the middle of the FA infusion. After the FA infusion, gemcitabine was administered at a steady rate of infusion of 10 mg/m(2)/min over initially 30 minutes and with increases of an additional 15 minutes at each given level. One cycle consisted of six weekly treatments followed by a 2-week rest. RESULTS: The MTD of gemcitabine was established at 900 mg/m(2) given over 90 minutes. Eight patients of 21 with metastatic colorectal cancer achieved responses (one complete response; seven partial responses), for a response rate of 38%. Responses were seen across the gemcitabine doses of 300 to 900 mg/m(2). One patient had prior treatment with FA/5-FU for advanced disease. Patients with colorectal carcinoma had a median survival of 18 months, and the patient with lung carcinoma has been alive for 24+ months. CONCLUSION: The combination chemotherapy of FFG was well tolerated and may benefit patients with advanced colorectal carcinoma. A phase II evaluation in this patient population is in progress.

Oral ondansetron for the control of cisplatin-induced delayed emesis: a large, multicenter, double-blind, randomized comparative trial of ondansetron versus placebo.

PURPOSE: To investigate the efficacy and safety of oral ondansetron in the control of cisplatin-induced delayed emesis in patients who do not require rescue antiemetic therapy for acute emesis. PATIENTS AND METHODS: Five hundred thirty-eight chemotherapy-naive patients who received cisplatin chemotherapy (> or = 70 mg/m2), and who were not rescued for acute emesis, were eligible to be randomized to receive one of the three oral regimens to control delayed emesis. Group I received placebo on days 2 to 6; group II received ondansetron 8 mg twice daily on days 2 and 3 and placebo on days 4 to 6; group III received ondansetron 8 mg twice daily on days 2 to 6. All patients received intravenous ondansetron (0.15 mg/kg every 4 hours for three doses) for the control of acute emesis on day 1. The number of emetic episodes on days 2 and 3 combined (days 2/3, when incidence and severity of delayed emesis were expected to be greatest) was considered the primary measure of efficacy. RESULTS: Patients who received odansetron had significantly fewer emetic episodes on days 2/3, 4, and 5 than those who received placebo (P < or = .002 on each day). Additionally, significantly more patients who received ondansetron had a complete plus major response (C+MR; < or = two two emetic episodes) than those who received placebo on days 2/3 (56% v 37%, P = .001), 4 (94% v 85%, P = .005), and 5 (98% v 88%, P = .006). Patients who received ondansetron had significantly less nausea on day 2/3 when day-1 nausea was used as the baseline score (P = .025). Patients who received ondansetron also had significantly less nausea on day 4 (P = .042) and the results approached significance on day 5 (P = .066). CONCLUSION: Oral ondansetron had a significant effect in the control of cisplatin-induced delayed emesis and nausea in patients who had not required rescue antiemetics during the acute emesis period. The control of delayed nausea and vomiting was most notable in the immediate 2 days following cisplatin administration, with the clinical difference narrowing between the two treatment arms on subsequent days.

Stratified, randomized, double-blind comparison of intravenous ondansetron administered as a multiple-dose regimen versus two single-dose regimens in the prevention of cisplatin-induced nausea and vomiting.

PURPOSE: This study compares the efficacy and safety of two single-dose regimens with the approved three-dose regimen of ondansetron in the prevention of cisplatin-induced emesis. PATIENTS AND METHODS: This multicenter study was a stratified, randomized, double-blind, and parallel group design. Chemotherapy-naive inpatients were randomized to receive intravenous (IV) ondansetron (Zofran; Glaxo Inc, Research Triangle Park, NC) 0.15 mg/kg times three doses, every 4 hours or a single 8-mg or 32-mg dose followed by two saline doses that began 30 minutes before cisplatin administration. Cisplatin (high-dose > or = 100 mg/m2 or medium-dose 50 to 70 mg/m2) was given as a single infusion (< or = 3 hours). Patients were monitored for emetic episodes, adverse events, and laboratory safety parameters for 24 hours after cisplatin administration. RESULTS: A total of 699 patients (359 high-dose, 340 medium-dose) were enrolled. Of these, 618 were assessable for efficacy (15 ineligible, 66 protocol deviations). The 32-mg dose was superior to the 8-mg single dose with regard to total number of emetic episodes (high-dose, P = .015; medium-dose, P < .001), complete response (no emetic episodes: high-dose, 48% v 35%; P = .048; medium-dose, 73% v 50%; P = .001) and failure rate (> 5 emetic episodes, withdrawn or rescued: high-dose, 20% v 34%; P = .018; medium-dose, 9% v 23%; P = .005). The 32-mg single dose was also superior to the 0.15 mg/kg times three dose regimen with regard to total number of emetic episodes (medium-dose, P = .033) and failure rate (high-dose, 20% v 36%; P = .009; medium-dose, 9% v 22%; P = .011). Ondansetron was well tolerated. The most common adverse event was headache. An approximate 10-fold increase in the incidence of clinically significant transaminase elevations was observed in the high-dose versus medium-dose cisplatin strata (aspartate aminotransferase [AST], 6.5% v 0.7%; serum alanine aminotransferase [ALT], 5.0% v 0.3%). CONCLUSION: A 32-mg single dose of ondansetron is more effective than a single 8-mg dose and is at least as effective as the standard regimen of 0.15 mg/kg times three doses in the prevention of cisplatin-induced acute emesis.

Treatment of metastatic bone pain with tin-117m Stannic diethylenetriaminepentaacetic acid: a phase I/II clinical study.

The physical characteristics of Sn-117m combined with the biodistribution of the compound tin-117m (Stannic, 4+) diethylenetriaminepentaacetic acid (Sn-117m DTPA) suggest that it should be an excellent agent for the palliation of pain from bony metastases. Prior work has established the dosimetry and the safety for the material in human beings. The presence of low-energy conversion electrons should result in the relative sparing of the bone marrow while delivering a high radiation dose to sites of bony metastatic disease. Forty-seven patients with painful bone metastases from various malignancies were treated with Sn-117m DTPA. The patients were assigned to five different dose levels ranging from 2.64 to 10.58 MBq (71-286 microCi) per kg of body weight. Follow-up included review of pain diaries, performance scores, analgesic requirements, blood chemistries, and hematological assessment. Three patients received a second treatment. There was an overall response rate for relief of pain of 75% (range, 60-83%) in the 40 treatments that could be evaluated. No correlation was apparent in this limited series between response rate and the five dose levels used. The relief was complete in 12 patients (30%). The time to onset of pain relief was 19 +/- 15 days with doses < or = 5.29 MBq/kg and 5 +/- 3 days with doses > or = 6.61 MBq/kg. Myelotoxicity was minimal, with only one patient having a marginal grade 3 WBC toxicity. On the basis of our data, Sn-117m DTPA should be an effective and safe radiopharmaceutical for palliation of painful bony metastases. A large-scale trial is warranted to evaluate it in comparison to other similar agents.

Treatment of cancer-associated hypercalcemia. Double-blind comparison of rapid and slow intravenous infusion regimens of pamidronate disodium and saline alone.

BACKGROUND: We assessed the effects of 60-mg single doses of pamidronate disodium compared with saline alone in the treatment of cancer-associated hypercalcemia. METHODS: After pretreatment hydration, patients with corrected serum calcium concentrations of 3.0 mmol/L (12 mg/dL) or greater secondary to cancer were randomized to double-blind treatment with a single infusion of pamidronate disodium, 60 mg, over either 4 or 24 hours or continued infusions of 0.9% saline alone (n = 23 per group). Corrected serum calcium levels were measured daily for 7 days of inpatient evaluation. RESULTS: Response rates for both of the pamidronate regimens were significantly (P < .05) higher than that for saline alone. A complete response to treatment (corrected serum calcium concentration normalized) was observed for five (22%), 18 (78%), and 14 (61%) patients, respectively, who received saline alone, 4-hour infusion of pamidronate, and 24-hour infusion of pamidronate. There were no significant differences between the two pamidronate regimens. Median durations of complete response were 6, 6, and 11 days, respectively, and median times to relapse (includes complete plus partial responders and nonresponders) were 0, 7, and 7 days, respectively. Pamidronate was well tolerated as assessed by all clinical and laboratory measures, regardless of the time of infusion. CONCLUSIONS: A 4-hour infusion of pamidronate disodium, 60 mg, was as safe and effective as a 24-hour infusion, and both were superior to saline alone in lowering corrected serum calcium concentrations in patients with cancer-associated hypercalcemia.

A Comparison of Oral Ondansetron and Intravenous Granisetron for the Prevention of Nausea and Emesis Associated with Cisplatin-Based Chemotherapy.

PURPOSE: To compare the efficacy and safety of oral ondansetron with i.v. granisetron each given as a single dose prior to administration of highly emetogenic cisplatin chemotherapy. PATIENTS AND METHODS: Chemotherapy-naive patients with histologically confirmed malignancies were randomized to receive a single 24 mg ondansetron hydrochloride tablet plus a 50 ml i.v. infusion of normal saline, or a single 10 µg/kg (50 ml) i.v. infusion of granisetron plus a placebo tablet in this multicenter, double-blind, parallel-group trial. Study drug was administered 30 min prior to a single i.v. infusion of cisplatin (50-75 mg/m²), given over a period of

Insulin-induced growth hormone responses in patients with prostatic carcinoma.

Insulin-induced pituitary growth hormone (GH) response was studied in 12 patients with prostatic carcinoma. Three patients demonstrated significant abnormal GH release associated with concentrations which remained on a high plateau during the study. The patients subsequently presented clinically with rapidly progressing disease. Such observations are compatible with the viewpoint that abnormally high or low GH levels systemically present, may be associated with a particularly bad clinical prognosis. Further studies will clarify this relationship.

Pharmacokinetics of cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum IV (CHIP) in patients with advanced cancer.

The pharmacokinetics of a second-generation platinum (Pt) analog cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum IV (CHIP) have been studied in 12 patients at doses from 20 to 350 mg/m2. Three Pt species have been measured: total Pt and non-protein-bound Pt by atomic absorption spectrophotometry, and unchanged CHIP by separation on high-performance liquid chromatography followed by atomic absorption spectrophotometry. Plasma decay of total Pt was biexponential at all doses with a beta-phase half-life of 32.1-124 h. Plasma decay of filterable Pt was monoexponential at low doses but biexponential at high doses, with a terminal-phase half-life of 17.8-54.6 h. Plasma decay of unchanged CHIP was monoexponential at all doses, with a half-life of 0.64-1.27 h. Excretion of Pt after CHIP was rapid up to 10 h after the end of infusion and then slow. The total recovery of Pt was 15%-61% of the dose at 24 h in 19 patients. The data indicated that essentially all plasma Pt after 12 h is in the form of metabolites, most of which are protein-bound. The most striking difference between CHIP and reported data for cisplatin is the biexponential decay of non-protein-bound Pt.

Evaluation of the nephrotoxicity of iproplatin (CHIP) in comparison to cisplatin by the measurement of urinary enzymes.

Levels of three enzymes, leucine aminopeptidase (LAP), N-acetyl-beta-D-glucosaminidase (NAG), and beta-glucuronidase (BGA) were measured in the urine of patients receiving hematologically toxic doses of iproplatin (a) with or (b) without pretreatment hydration. The maximum post-treatment increases in the levels of each of the enzymes were compared between these two groups of patients. In addition, the maximum increases in urinary enzyme levels in iproplatin-treated patients were compared with those in patients treated with 40 mg/m2 cisplatin, a known nephrotoxic agent. Increases in LAP levels after cisplatin treatment in the periods studied are significantly higher than those after iproplatin treatment (P less than 0.05). No differences were found in the increases in BGA and NAG levels between iproplatin treatment and cisplatin treatment. No differences were found in the increases in levels of any of the enzymes between patients receiving iproplatin with pretreatment hydration and no prior hydration.

Phase I clinical trial of 1-(2-[2-(4-pyridyl)-2-imidazoline-1-yl]-ethyl)-3-(4-carboxy-phenyl) urea (CGP 15720A).

A phase I clinical trial of the intravenous administration of a novel pyridyl imidazoline ethyl carboxy phenyl urea was carried out in 42 patients with advanced solid tumors. Five schedules were evaluated: I, daily X 5; II, daily X 10; III, daily X 15; IV, continuous infusion for 5 days; V, continuous infusion for 7 days. Toxicity was not seen in schedule I (maximum dose 3 g/m2/day) and was minimal in schedule IV (6 g/m2/day). In schedule II it was seen at 2 and 3 g/m2/day, in schedule III at 2 g/m2/day and in schedule V at 6 g/m2/day. Dose-limiting toxicity consisted of a syndrome of lethargy and fatigue. There were no definitely drug-related changes in hematologic or serum chemistry parameters. No responses were seen, but relief of pain in three patients with prostate cancer was noted. Pharmacokinetics indicate a short half-life, limited volume of distribution, and rapid renal clearance. The recommended dose for phase II studies is 3 g/m2/day X 10 or 2 g/m2/day X 15 days.

Efficacy and tolerability of oral ondansetron versus prochlorperazine in the prevention of emesis associated with cyclophosphamide-based chemotherapy and maintenance of health-related quality of life.

This study compared the efficacy and tolerability of oral ondansetron (8 mg twice daily [BID] for up to 3 days) with those of phenothiazine prochlorperazine (10 mg BID for up to 3 days) in 133 cancer patients receiving cyclophosphamide-based chemotherapy. In addition, the study evaluated the impact of these treatments on patients' health-related quality of life, measured with both the Functional Living Index--Cancer and the Functional Living Index--Emesis questionnaires. The first dose of study drug was administered 30 minutes before initiation of chemotherapy. Patients received a rescue antiemetic at their request or if the investigator deemed it necessary. There was a statistically significant difference in the number of patients with no emetic episodes over the 3-day study period: 60% in the ondansetron group compared with 21% in the prochlorperazine group. Twenty-five percent of ondansetron-treated patients compared with 68% of prochlorperazine-treated patients experienced three or more emetic episodes, rescue medication use, or withdrawal from the study due to adverse events or lack of efficacy of the study drug. Among patients with at least one emetic episode, the mean time to emesis was significantly longer (13 hours and 37 minutes) in the ondansetron group compared with the prochlorperazine group (9 hours and 30 minutes). Nausea and appetite scores did not differ significantly between groups. The score on the vomiting subscale of the Functional Living Index--Emesis was significantly more favorable in the ondansetron group compared with the prochlorperazine group, indicating better maintenance of health-related quality of life in ondansetron-treated patients. Both treatments were well tolerated. The most common potentially drug-related adverse event was headache, which occurred in significantly more (16%) ondansetron-treated patients compared with prochlorperazine-treated patients (3%). The results of this study demonstrate that oral ondansetron 8 mg BID for up to 3 days is more effective than prochlorperazine 10 mg BID for up to 3 days in the prevention of emesis associated with moderately emetogenic chemotherapy.

Efficacy and tolerability of oral ondansetron versus prochlorperazine in the prevention of emesis associated with cyclophosphamide-based chemotherapy and maintenance of health-related quality of life.

This study compared the efficacy and tolerability of oral ondansetron (8 mg twice daily [BID] for up to 3 days) with those of phenothiazine prochlorperazine (10 mg BID for up to 3 days) in 133 cancer patients receiving cyclophosphamide-based chemotherapy. In addition, the study evaluated the impact of these treatments on patients' health-related quality of life, measured with both the Functional Living Index-Cancer and the Functional Living Index-Emesis questionnaires. The first dose of study drug was administered 30 minutes before initiation of chemotherapy. Patients received a rescue antiemetic at their request or if the investigator deemed it necessary. There was a statistically significant difference in the number of patients with no emetic episodes over the 3-day study period: 60% in the ondansetron group compared with 21% in the prochlorperazine group. Twenty-five percent of ondansetron-treated patients compared with 68% of prochlorperazine-treated patients experienced three or more emetic episodes, rescue medication use, or withdrawal from the study due to emesis or adverse events. Among patients with at least one emetic episode, the mean time to emesis was significantly longer (13 hours and 37 minutes) in the ondansetron group compared with the prochlorperazine group (9 hours and 30 minutes). Nausea and appetite scores did not differ significantly between groups. The score on the vomiting subscale of the Functional Living Index-Emesis was significantly more favorable in the ondansetron group compared with the prochlorperazine group, indicating better maintenance of health-related quality of life in ondansetron-treated patients. Both treatments were well tolerated. The most common potentially drug-related adverse event was headache, which occurred in significantly more (16%) ondansetron-treated patients compared with prochlorperazine-treated patients (3%). The results of this study demonstrate that oral ondansetron 8 mg BID for up to 3 days is more effective than prochlorperazine 10 mg BID for up to 3 days in the prevention of emesis associated with moderately emetogenic chemotherapy.

Phase I clinical trial of ethyl 6-deoxy-3,5-di-O-methyl 6-(3 methyl-3-nitrosoureido)-alpha-D-glucofuranoside (CGP 6809).

A phase I study of single i.v. doses of a new sugar containing nitrosourea 6-deoxy-3,5 di-O-methyl 6-(3 methyl-3-nitrosoureido)-alpha-D-glucofuranoside (CGP 6809, EDMN) has been carried out in 47 patients with advanced solid tumors. Nine dose levels between 200 and 4500 mg/m2 were examined. Nausea and vomiting were seen in most patients but were controlled with antiemetics. Myelosuppression was minimal. The dose-limiting toxicity was hepatotoxicity, occurring early (peak at days 2-4) and resolving rapidly. No cumulative toxicity was seen with an every 6 weeks schedule. Other toxicities were abdominal pain, diarrhea, arm pain, restlessness, and headache. Pharmacokinetic studies in 20 patients using an HPLC assay and in 5 patients using [14C]EDMN showed a short half-life, rapid plasma clearance, rapid metabolism, and minimal excretion of unchanged drug. There was one partial response in a patient with colon carcinoma. The recommended dose for phase II studies in 3750 mg/m2 every 6 weeks.

Phase I clinical trial and human pharmacokinetics of 2,4-diamino-5-adamantyl-6-methyl pyrimidine ethane sulfonate (DAMP-ES): a lipid-soluble antifolate.

A phase I and pharmacokinetic study of a novel lipid-soluble antifolate, 2,4 diamino-5-adamantyl-6-methyl pyrimidine ethane sulfonate (DAMP-ES) has been carried out on two schedules: I--daily x5; II--24-h continuous infusion. In schedule I, doses of 10-90 mg/m2 per day were evaluated. Dose-limiting toxicity was hematologic, but nausea and vomiting, skin rash, diarrhea, anorexia, alopecia, mucositis, and neurotoxicity were also noted. In schedule II, doses of 192 and 240 mg/m2 were evaluated. Dose-limiting toxicity was neurotoxicity, but hematologic toxicity was also marked. Recommended starting doses for phase II studies are 75 mg/m2 per day for 5 days or 192 mg/m2 by continuous infusion for 24 h. Pharmacokinetic studies indicated a beta-phase plasma half-life of 12.4-24 h and a large and variable volume of distribution.

New potential treatment modalities for disseminated prostatic cancer.

The authors consider treatments that are applicable to disseminated prostatic cancer. Several types of potential developments in systemic therapy for prostatic cancer are considered: new hormonal agents, new cytotoxic agents, modulation of the antitumor efficacy or toxicity or both of standard agents, biologic response modifiers, drug delivery systems, and systems for prediction of response.

Positron emission tomography study of human prostatic adenocarcinoma using carbon-11 putrescine.

To evaluate [1-11C]putrescine ([11C]PUT) as a potential tracer for imaging and characterization of human prostatic adenocarcinoma, positron emission tomography (PET) was performed in eight patients and three normal controls. In addition, four of the patients and the three normal controls also had a prostate scan with 2-deoxy-2-[18F]fluoro-D-glucose (18FDG). Three of the patients had undergone resection of the prostate tumor and all of the patients except for one had bone metastasis. Carbon-11 rapidly accumulated in prostate, bone and rectum after injection of [11C]PUT. Maximal uptake was achieved 5 min after injection with minimal washout during the 50 min study period. The uptake of carbon-11 in the prostate of normal controls was significantly higher than that in the patients. However, three of the four patients scanned for metastatic bone lesions showed higher uptake in bone metastasis than in normal bone. Quantitation of 18FDG uptake in the prostate was hindered by the high accumulation of activity in the urinary bladder. [11C]PUT does not appear to be a useful tracer for assessing proliferation of human prostate adenocarcinoma. Its utility in the imaging of other cancers with high polyamine concentration remains to be investigated.

Clinical trials with 5-fluorouracil, folinic acid and cisplatin in patients with gastrointestinal malignancies.

Combination chemotherapy for advanced gastrointestinal malignancies remains unsatisfactory. Studies show a definite therapeutic advantage for folinic acid/5-fluorouracil (5-FU) regimen compared with single agent 5-FU given intravenously in the management of advanced colorectal cancer. Data on survival benefits vary. A definitive conclusion regarding this question must outweigh the maturation of the present studies and possibly generate further extensive investigations. The currently available data are insufficient from which to draw any conclusion on the effect of the attempt to modulate 5-FU activity further by the addition of cisplatin to the combination. Nevertheless, the combination appears to elicit some therapeutic advantage in patients with pancreatic carcinoma and rectal carcinoma. The paucity of data in gastric carcinoma is disappointing in light of sensitivity to both cisplatin and 5-FU.

Clinical development of iproplatin (CHIP).

The clinical development of the second generation platinum complex iproplatin (CHIP) is reviewed. The compound was virtually non-nephrotoxic in preclinical toxicology studies and had myelosuppression as its dose-limiting toxicity in rats and dogs. A phase I study of 20-350 mg/m2 given every 3-4 weeks showed the compound to have myelosuppression as its dose-limiting toxicity in humans, with thrombocytopenia being the most prominent feature. Nausea and vomiting were almost universal, but were less severe than with cisplatin. Diarrhoea and skin rash were also noted but nephrotoxicity, neurotoxicity and ototoxicity were not seen. The maximum tolerated dose was 350 mg/m2, with or without pretreatment hydration. In pharmacokinetic studies three platinum-containing species were measured: total Pt, non-protein bound Pt and unchanged iproplatin. Plasma decay of total Pt was biphasic with a beta-phase half-life of 69.3 h. Plasma decay of unchanged iproplatin was monophasic with a half-life of about 1.17 h. Plasma decay of filterable Pt followed a monophasic pattern at low doses and a biphasic pattern at high doses. Urinary excretion of Pt was widely variable and incomplete. Early data from phase II studies indicate a high degree of activity in small-cell lung cancer; high activity in ovarian carcinoma has been reported by others.