Phase I clinical and pharmacological study of oral methoxymorpholinyl doxorubicin (PNU 152243).

PURPOSE: The methoxymorpholinyl doxorubicin analogue PNU 152243 was brought into clinical studies because of preclinical observations of its non-cross-resistance in mdr tumor cells, dose-limiting neutropenia, lack of cardiotoxicity, and antitumor activity after oral administration. METHODS: PNU 152243 was given orally every 4 weeks to 21 adults with a variety of solid tumors at doses ranging from 59 to 940 microg/m(2). Antiemetic prophylaxis with 5-HT3 antagonists and steroids, given i.v. on day 1 and orally on days 2-8, was required beginning with the dose of 118 microg/m(2). The plasma pharmacokinetics of PNU 152243 were determined by an HPLC method with fluorescence detection. The in vitro myelotoxic effects on granulocyte macrophage-colony forming cells (GM-CFC) of the plasma from 11 patients, obtained 4 and 6 h after treatment at all dose levels, were also assessed. RESULTS: Neutropenia was the main hematologic toxic effect and the maximum tolerated dose (MTD) for myelotoxicity was 940 microg/m(2), with neutropenia grade 3-4 in two of three patients. Dose-dependent nausea and vomiting were dose-limiting and the MTD for gastrointestinal toxicity was fixed at 820 microg/m(2), with grade 4 vomiting in one of two patients. Other frequent toxic effects were diarrhea and fatigue. Peak levels of PNU 152243 were achieved 4 h after dosing. Dose-dependent Cmax and AUCExp, and significant interpatient variability of the main pharmacokinetic parameters were found. Very low levels of the 13-dihydrometabolite PNU 155051 were detected only at the highest doses. The hematotoxicity tests showed a <70% colony growth inhibition with no correlation between the growth inhibition effect and the degree of myelotoxicity in the same patient. Plasma concentrations of PNU 152243 were 1000 times lower than the concentration inhibiting the growth of 70% of colonies. No objective tumor responses were seen. CONCLUSIONS: Owing to the occurrence of severe and prolonged nausea and vomiting, the clinical development of oral PNU 152243 was discontinued. The higher-than-expected neutropenia and its lack of relationship with plasma levels of PNU 152243 and its 13-dihydroderivative PNU 155051 might be related to the formation of potent cytotoxic metabolites present in human plasma at undetectable concentrations and with prolonged half-life, as suggested by hematotoxicity tests performed with plasma from patients in GM-CFC assays.

Broad phase II and pharmacokinetic study of methoxy-morpholino doxorubicin (FCE 23762-MMRDX) in non-small-cell lung cancer, renal cancer and other solid tumour patients.

The aim was to perform a broad phase II and pharmacokinetic study of methoxymorpholino-doxorubicin (MMRDX), a drug active against multidrug-resistant tumour cells in vitro when given by i.v. bolus at 1.5 mg m(-2) every 4 weeks, in metastatic or unresectable solid tumour patients with known intrinsic drug resistance. Patients received a maximum of six cycles. Plasma, urine and leucocyte MMRDX and its 13-dihydro metabolite pharmacokinetic analysis was performed in patients without liver metastases. Patients (n = 48, 21 NSCLC, 19 renal cell, three head and neck tumour, three cervical cancer and two adenocarcinoma of unknown primary) received 132 cycles of MMRDX. Common toxicity criteria (CTC) grade III/IV thrombocytopenia (12% of cycles) and neutropenia (27% of cycles) occurred with median nadir on day 22. Transient transaminases elevation > grade III/IV was observed in 7% of cycles, late and prolonged nausea > or = grade II in 34% and vomiting > or = grade II in 39%. In two patients, the left ventricular ejection fraction was reduced > or = 15%. Of 37 evaluable patients, one out of 17 NSCLC had a partial response. Mean (+/- s.d.) MMRDX AUC0-infinity calculated up to 24 h after dosing was 20.4 +/- 6.2 microg h l(-1) (n = 11) and t(1/2, gamma) was 44.2 h. Mean plasma clearance (+/- s.d.) was 37.2 +/- 7.3 l h(-1) m(-2) and volume of distribution 1982 +/- 64 l m(-2). MMRDX leucocyte levels 2 and 24 h after infusion were 450 to 600-fold higher than corresponding MMRDX plasma levels. In urine, 2% of the MMRDX dose was excreted unchanged, and 2% as metabolite. The main side-effects of 1.5 mg m(-2) every 4 weeks of MMRDX are delayed nausea and vomiting and haematological toxicity. MMRDX is characterized by extensive clearance and rapid and extensive distribution into tissues. A low response rate was observed in patients with tumours with intrinsic chemotherapy resistance.

The effect of food on cabergoline pharmacokinetics and tolerability in healthy volunteers.

The effect of food on the pharmacokinetics and tolerability of cabergoline in man was investigated. For this purpose an open, randomized, single-dose study was conducted in 12 healthy male volunteers who received 1 mg cabergoline as tablets both under fasting conditions and after a breakfast containing a substantial amount of carbohydrates, fat, and proteins, in a crossover fashion. The two treatments were separated by a 4 week washout period. Plasma and urine were collected up to 336 and 168 h respectively after administration and cabergoline concentration was measured in both fluids using a validated radioimmunoassay. Tolerability assessment included haematology, blood chemistry, and urinalysis, blood pressure and heart rate measurements, and ECG. Under both fasting and fed conditions low but persistent cabergoline plasma levels were observed in the present study up to 2 weeks after drug intake, in agreement with the long-lasting prolactin-lowering activity of the drug. In subjects receiving cabergoline under fed or fasting conditions, Cmax values averaged 44 and 54 pg mL(-1), AUC(0-336 h) averaged 6392 and 5331 pg h mL(-1), Ae(0-168 h) averaged 12.7 and 11.9 micrograms, and t1/2 averaged 109.7 and 101.3 h, respectively. No statistically significant difference was found when Cmax, AUC(0-336 h), t1/2, and Ae(0-168 h) from subjects treated under fasting and fed conditions were compared. Median tmax values in subjects treated under fasting or fed conditions were identical (2.5 h). The statistical analysis applied to the parameters chosen to evaluate the variations in the blood pressure profiles observed either supine or standing did not show any significant difference between the fed and fasting conditions. Heart rate values were not significantly modified after cabergoline under either fed or fasting conditions. Laboratory evaluation showed some minor deviations from normal, which were not clinically relevant (only one subject showed an occasional and transient elevation in alkaline phosphatase which disappeared in the subsequent laboratory evaluations) and were considered for the most part not to be drug related. Eleven subjects reported adverse events (one after both treatments, five only after drug intake under fasting conditions, and five only after drug intake with food.

Phase I clinical and pharmacokinetic study of 3'-deamino-3'-(2-methoxy-4-morpholinyl)doxorubicin (FCE 23762).

Methoxymorpholinyldoxorubicin (FCE 23762) is a novel, highly lipophilic doxorubicin analogue. It possesses potent in vitro and in vivo antitumor activity including efficacy in multidrug-resistant tumor cell lines. It is also metabolically activated in vivo resulting in an 80-fold increase in potency over the parent drug. In this phase I study the drug was administered by i.v. bolus injection at 3-week intervals. Fifty-three patients with refractory solid tumors were treated; 133 courses of FCE 23762 were administered at doses ranging from 30 to 2250 micrograms/m2. The dose limiting toxicity was reversible myelo-suppression (granulocytopenia and thrombocytopenia), demonstrating a delayed nadir and recovery in comparison to doxorubicin. Other toxicities included transient elevation of hepatic transaminases, delayed and prolonged nausea and vomiting, mucositis, anorexia, fatigue, and diarrhea. Heavily pretreated patients demonstrated more myelosuppression than previously untreated patients at 1250 micrograms/m2. No cardiotoxicity was observed. Four objective tumor responses were seen: one complete response in a patient with pelvic recurrence of cervical cancer; one partial response in a patient with cutaneous and lymph gland metastases from head and neck cancer; and two minor responses in patients with liver metastases from colorectal cancer. Plasma concentrations of FCE 23762 and its 13-dihydro metabolite, FCE 26176, were measured in 20 patients at doses > or = 675 micrograms/m2, using HPLC with fluorescence detection. The area under the plasma concentration-time curve ranged from 30 to 80 ng/h/ml; plasma data suggested linear kinetics in the range of tested doses (although there was considerable interpatient variability). The maximum tolerated dose defined in this study using this schedule is 1500 micrograms/m2. A safe phase II dose for previously untreated patients using this schedule is 1250 micrograms/m2; however, this may actually be below the optimal dose for this patient population.

Pharmacokinetics, pharmacodynamics, and tolerability of cabergoline, a prolactin-lowering drug, after administration of increasing oral doses (0.5, 1.0, and 1.5 milligrams) in healthy male volunteers.

Cabergoline (CAB) a long-acting dopaminergic ergoline derivative, was given orally, in single doses of 0.5, 1.0, and 1.5 mg, to 12 healthy men in order to evaluate its PRL-lowering effect as well as its plasma pharmacokinetics and urinary excretion. Drug administrations were separated by 5-week washout periods. Blood samples for PRL and CAB determination were taken at baseline and for 840 h thereafter (every 1 h up to 4 h, every 4 h up to 12 h, every 24 h up to 168 h, and weekly up to 5 weeks). Fractional urine collections for CAB excretion were taken immediately before drug administration, every 4 h up to 12 h, and every 12 h up to 168 h. During the study period, blood pressure and heart rate were monitored at the same time periods of plasma sampling for CAB, and electrocardiographic tracings and hematological evaluations were performed before and after each treatment period. All CAB doses (0.5, 1.0, and 1.5 mg) produced in all subjects a complete PRL suppression (PRL < 1.0 micrograms/L), that occurred earlier and persisted longer with the two higher doses. PRL secretion areas [area under the curve (AUC) 0-48 h and 48-840 h] were higher after 0.5-mg than after 1.0- and 1.5-mg doses. In particular, in the first portion of the area, the difference between 0.5 mg and both 1.0 and 1.5 mg was highly statistically significant (P < 0.01) without significant differences between the two highest doses. Mean CAB maximal plasma concentrations (Cmax) were 33.3 +/- 3.69, 40.3 +/- 2.49, and 67.0 +/- 9.79 ng/L after 0.5, 1.0, and 1.5 mg CAB, respectively; time to Cmax was 2 h (median) for all doses; CAB AUC(0-168 h) after 0.5 mg CAB was significantly lower (P < 0.01) than after 1.5 mg CAB. The percentages of the administered doses of CAB excreted in urine were 1.1 +/- 0.1%, 1.1 +/- 0.1%, and 1.2 +/- 0.1% for the 0.5-, 1.0-, and 1.5 mg doses, respectively (P = NS). CAB AUCs(0-168 h) and Cmax normalized to the 1.0-mg dose were compared by two-way analysis of variance; no significant differences were found for CAB AUCs(0-168h); Cmax after 0.5 mg was significantly higher (P < 0.01) than after 1.0 and 1.5 mg CAB. A progressive decrease of systolic and diastolic blood pressure was observed, and symptomatic hypotension after the 1.0-mg dose did not allow one subject to receive the 1.5-mg dose. Other mild to moderate adverse events occurred only after 1.0 and 1.5 mg CAB. These results indicate that, in the dose range of 0.5-1.5 mg, the pharmacokinetics of CAB are dose independent, and that the pharmacodynamic data and the frequencies of adverse events of CAB are dose related, with no significant differences in the PRL-lowering effect of the 1.0- and 1.5-mg doses.

High-dose epirubicin for untreated patients with advanced tumours: a phase I study.

In a phase I study, epirubicin was administered as an intravenous bolus at an initial dose of 105 mg/m2 in untreated patients with advanced tumours considered resistant to antineoplastic treatment. A 15 mg/m2 dose escalation was done every 3 patients if toxicity was below grade 3 or every 6 patients if at least 1 patient had grade 3 toxicity. 18 patients entered the study. The dose was (mg/m2): 105 (3 patients), 120 (3), 135 (3), 150 (6) and 165 (3). The maximally tolerated dose was 165 mg/m2. The dose-limiting toxicity was neutropenia. Other side-effects were nausea/vomiting (78%) and alopecia (100%). 4 patients stopped treatment because of a decrease in left ventricular ejection function, without clinical signs of cardiotoxicity. A complete response was observed in a patient with abdominal metastases from unknown origin at 105 mg/m2 and a partial response in 2 out of 7 patients with non-operable non-small cell lung cancer, at 135 and 150 mg/m2, respectively. The recommended dose for phase II trial is 135-150 mg/m2.

Clinical evaluation of the cardiac toxicity of 4'-deoxy-doxorubicin.

4'-deoxy-doxorubicin, a new doxorubicin analog, was tested in 65 phase II patients with advanced malignancies. Cardiac toxicity evaluation was performed by means of electrocardiography (ECG), left ventricular systolic time intervals, echocardiography and radionuclide left ventricular ejection fraction. ECG abnormalities were observed in a lower percentage of patients (23%) compared to that described for doxorubicin and other anthracycline analogs such as 4'-epi-doxorubicin and 4-demethoxy-daunorubicin. Other functional parameters serially measured to evaluate chronic cardiotoxicity in 23 patients, who received more than 200 mg/m2 were not significantly different from mean pretreatment values. No patient developed congestive heart failure but some of them exhibited a fall of left ventricular function parameters more than 15% from pretreatment values. These data suggest that this new analogue is probably less cardiotoxic than the parent compound doxorubicin but not completely devoid of cardiotoxicity.

Phase II study of esorubicin (4'-deoxydoxorubicin) in locally advanced or metastatic head and neck carcinoma.

Sixteen patients with locally advanced or metastatic head and neck cancer were treated with esorubicin (4'-deoxydoxorubicin) at a dose of 30-35 mg/m2 i.v. every 3 weeks. One patient was lost to the follow up after one cycle, whereas in the 15 evaluable cases a total of 34 courses were administered (median per patient: 2, range: 1-6). Pretreatment for parameter lesions consisted of radiotherapy in 5, chemotherapy in 3 and both treatments in 1 patients respectively. Overall, one partial response, one stable disease and 13 progressions were documented. Severe (grade 3 and 4) leukopenia, thrombocytopenia and anemia were noted in 3, 1 and 1 patients respectively. The only patient developing leukopenia and thrombocytopenia of grade 4 subsequently died because of pneumonia. On the other hand, non-hematologic toxicity was generally mild. At this dose and schedule, esorubicin demonstrated an activity less than 20% in head and neck cancer and therefore, no further evaluation is warranted.

Pharmacokinetic study of intravenous and oral idarubicin in cancer patients.

Idarubicin (4-demethoxydaunorubicin) is a new anthracycline analogue which lacks the methoxyl group at the C-4 position of the aglycone moiety. The present study was undertaken to investigate the pharmacokinetics and bioavailability of idarubicin in man. The drug was administered at 3-week intervals to six patients by both intravenous and oral routes. Doses used were 13-15 mg/m2 intravenous and 45 mg/m2 p.o. Plasma levels of unchanged idarubicin and of its metabolite idarubicinal were assayed by high performance liquid chromatography (HPLC). After intravenous administration the plasma levels of the unchanged drug declined very rapidly reaching the sensitivity limits of the analytical method (1-2 ng/ml) 24 h after dosing. Plasma levels of idarubicinal reached a peak of about 10 ng/ml within two hours then decreased very slowly with a plasma t1/2 of about 2.5 days. After the oral dose of 45 mg/m2, the plasma level patterns of both parent compound and the idarubicinal were roughly similar to those after 15 mg/m2 intravenous except for the obvious difference linked to the absorption of idarubicin. The absorption of oral idarubicin was rapid and, in terms of area under curve of the metabolite, the availability after oral administration can be estimated as about 30% of the dose. The urine findings reflected the plasma situation. The metabolite levels were much higher and longer lasting than those of the parent compound. Urinary recovery after intravenous (16% of the dose in four days) and oral administration (approximately 5% of the dose) confirmed the 30% absorption estimated on the basis of plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)

A pilot study of oral idarubicin in metastatic melanoma.

Seventeen patients with disseminated melanoma were treated with Idarubicin (IDA) at the dose of 15 mg/m2 daily for 3 consecutive days every 4 weeks by oral route. One complete remission and one partial remission were achieved (remission rate: 12%). The treatment was well tolerated. We conclude that oral IDA may be considered for a pilot trial in a regimen of combination therapy in patients with metastatic melanoma.

Preliminary observations on intravenous idarubicin (4-demethoxydaunorubicin) in the chronic and accelerated phase of chronic myelogenous leukemia.

The study included 13 patients with chronic myelogenous leukemia (8 in the chronic phase with high WBC counts at onset, and 5 in the accelerated phase, poorly responding to conventional drugs for the chronic phase). They were treated with 4-demethoxydaunorubicin (idarubicin), a new anthracycline analog more active than daunorubicin (DNR) and doxorubicin (DX) in experimental tumor models which offers a higher therapeutic index than existing anthracyclines. Idarubicin was administered i.v. at the dose of 8 mg/m2 on days 1, 3 and 5. All patients in the chronic phase (8/8) developed significant leukopenia. Five of these 8 patients showed complete reduction of splenomegaly, and 4 of hepatomegaly as well. In all the other cases, hepato-splenomegaly was reduced by more than 70%. Three of the 5 patients in the accelerated phase of chronic myelogenous leukemia also showed massive cytolysis. More important, all of them showed complete or major reduction of hepato-splenomegaly and renewed responsiveness to conventional drugs for the chronic phase of the disease. Idarubicin was fairly well tolerated by all patients with only minor gastrointestinal side effects and no liver damage or acute cardiotoxic effects. These findings indicate that idarubicin--although it cannot replace established drugs for the chronic phase of the disease--represents an added therapeutic resource for producing rapid cytolysis at onset and, above all, in the accelerated phase of chronic myelogenous leukemia.

Oral idarubicin in adult acute leukemia: a preliminary experience.

Twelve patients affected by different types of acute leukemia received idarubicin (4-demethoxy-daunorubicin) by oral route at the total dosage of 45, 60 or 90 mg/m2 distributed over three consecutive days. Drug response was assessed by the decrease in blast cells in peripheral blood and showed some variations between the different types of leukemia. Acute myelogenous leukemia patients and those with blastic crisis of chronic myeloid leukemia appeared to be the more responsive groups; however, the lower dose schedule could explain the less satisfactory results obtained in lymphatic leukemia patients. Data suggest that idarubicin is absorbed rapidly after oral ingestion, in spite of nausea and vomiting, which appeared 3-4 h later and were easily controlled by antiemetic therapy. The purpose of fractionating the drug dosage over three consecutive days is to prolong in the blood an elevated concentration of the main idarubicin metabolite (13-dihydro-derivative), which presents in experimental models an antileukemic potency similar to the parent compound. This study confirms that idarubicin is effective in acute leukemia also by oral route. This formulation could offer some advantages for subjects who cannot tolerate parenteral chemotherapy and it could be proposed in maintenance leukemia protocols.

Idarubicin (4-demethoxydaunorubicin). A preliminary overview of preclinical and clinical studies.

4-Demethoxydaunorubicin (4-DMDR, IMI 30, Idarubicin, NSC 256439) is a new analog of daunorubicin (DNR) with antileukemic activity in experimental systems that is superior to that of daunorubicin (DNR) or doxorubicin (DX). The drug is more potent than DNR and DX and is active by both the intravenous and the oral routes of administration. After i.v. and oral administration in humans, Idarubicin is rapidly metabolized to its 13-dihydroderivative (Idarubicinol) and the plasma levels of this metabolite are consistently higher than those of the unchanged drug. Idarubicinol has been shown to be an active metabolite in experimental models, being as potent and as active as the parent compound. Phase II clinical trials of Idarubicin have indicated that: By I.V. route Idarubicin is a potent antileukemic agent active in relapsed or refractory, ANLL, ALL (adult and pediatric) either as single agent or in combination with Ara-C at doses of 8-12 mg/m2 by i.v. day 1, 2 and 3 or 7-8 mg/m2 i.v. daily X 5 days (adults). There is evidence of lack of cross-resistance with parent drugs and other antileukemic agents. Phase III studies in previously untreated acute leukemias have been initiated. By oral route Idarubicin has antitumor activity in breast cancer at the doses of 35-45 mg/m2 q 3-4 weeks or 15 mg/m2 daily X 3 days q 3-4 weeks. Idarubicin has activity as a single agent in adult leukemias at the doses of 20-30 mg/m2/day X 3 days. The safety of administration (no risk of extravasation), the good tolerability and the reduced potential for cardiac toxicity, make oral Idarubicin particular attractive for further clinical development. Whether Idarubicin proves to be more effective and/or less cardiotoxic in clinical therapy than DNR or DX remains to be seen through prospective randomized studies which have been already initiated both in leukemias and solid tumors.

Low dose oral administration of 4-demethoxydaunorubicin (idarubicin) in advanced cancer patients. A pharmacokinetic study.

Data relating to 4-demethoxydaunorubicin (DMDR) pharmacokinetics after oral administration (10-15 mg/m2 per day for 3 days) were collected in a total of 12 patients with advanced breast cancer and melanoma. Drug absorption took place in the first 2-4 h after administration. Plasma levels of the reduced metabolite DMDRol were higher than those of the parent compound: Peak levels were 4-10 ng/ml for DMDR and 15-40 ng/ml for DMDRol. The dose-corrected area under the time-concentration curve (AUC) was consequently higher for DMDRol (12.3-74.7, mean 32.6 vs 2.4-7.4, mean 4.6 ng/ml.mg for DMDR). Apparent plasma terminal half-lives after the last dose administered were in the range of 13-36 (mean 23.7) h for DMDR and 30-81 (mean 58.9) h for DMDRol. Drug and the reduced metabolite accumulated in the blood cells; the ratio of AUC (blood) to AUC (plasma) was 1.40-3.75 (mean 2.80) for DMDR and 1.29-3.50 (mean 2.16) for DMDRol. The biliary excretion of the drug and of the fluorescent metabolites was studied in two additional patients with extrahepatic obstruction and percutaneous biliary drainage. In the first 7 days of therapy, biliary excretion (DMDR + DMDRol) accounted for 3.7%-4% of the administered dose. In contrast to our observations with doxorubicin and epirubicin, urinary excretion seems very likely to be more important for this drug than biliary excretion. In these patients urinary excretions were 2.2, 2.9 times (for DMDR) and 1.2, 3.4 times (for DMDRol) the biliary excretion.

Activity of 4-demethoxydaunorubicin by the oral route in advanced breast cancer.

The new anthracycline-analogue 4-demethoxydaunorubicin (4-DMDR) was administered orally at the dose of 15 mg/m2 daily for three consecutive days and repeated every 21-28 days on 29 patients with advanced pretreated breast cancer. A partial remission was observed in 7/25 evaluable patients (28%) for a median duration of 7 months. Side-effects include leukopenia in 93% of the patients (less than 1000 WBC/mm3 in 7%), nausea in 41%, mild vomiting in 17%, diarrhea in 10% and alopecia in 10% of the patients. No definitive conclusion is possible regarding cardiotoxicity. Only mild changes in ECG were observed in two patients. This study shows that 4-DMDR administered orally is well tolerated in the majority of patients and has antitumor activity in advanced breast cancer.

The new anthracycline 4-demethoxydaunorubicin by oral route in advanced pretreated breast cancer and melanoma. A pilot study.

4-Demethoxydaunorubicin (4-DMDR) was administered orally at the dose of 15 mg/m2 daily for 3 consecutive days at three-weekly intervals to 28 patients with advanced pretreated breast cancer and 9 patients with disseminated pretreated melanoma. A partial remission was observed in 6 out of 20 evaluable breast cancer patients (30%) for a median duration of 6 months and in one out of 7 evaluable patients with melanoma (14%) for a duration of 3 months. Side-effects included leucopenia in 78% of patients (less than 1000 wbc/cmm in 8%), nausea in 32% and mild vomiting in 16%. The preliminary results of this ongoing study on 4-DMDR administered orally show that the regimen is well tolerated in the majority of patients and that it has antitumour activity in advanced breast cancer.

Phase I trial of 4-demethoxydaunorubicin (idarubicin) with single oral doses.

Twenty-four patients with a variety of solid tumors entered a Phase I trial with 4-demethoxydaunorubicin, a new analogue of daunorubicin. The drug was given as a single oral dose of 10-60 mg/m2 repeated every 3-4 weeks. Leukopenia was the dose-limiting toxicity. Other toxic effects included mild to moderate nausea and vomiting. Sixty mg/m2 was found to be the maximum tolerated dose in patients with fair tolerance to chemotherapy and normal liver function. Similar hematologic toxicity was reported in patients with very extensive prior chemotherapy or diffuse bone and/or liver metastases receiving 50 mg/m2. However, the wide range of the WBC nadirs reported with the same dose in 'good risk' cases, suggest that 40 mg/m2, increased up to 50 mg/m2 in the absence of significant myelotoxicity, could be more safely proposed as starting dose for Phase II trials. Pharmacokinetic studies were performed in five patients given a single dose of 40-60 mg/m2. IMI-30 (NSC 256439) appears to be rapidly absorbed and rapidly eliminated from plasma by means of a rapid and extensive biotransformation to 13-OH-idarubicin. The 13-dihydroderivative was present at higher and more prolonged levels than the parent compound, with an elimination half-life of about 40 hours.