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Endpoint:
specific investigations: other studies
Type of information:
experimental study
Adequacy of study:
other information
Cross-reference
Reason / purpose:
reference to same study
Reference
Endpoint:
basic toxicokinetics, other
Remarks:
Pharmacokinetics in a Phase I clinical trial in adults with advanced solid tumors
Type of information:
other: Phase I clinical trial
Adequacy of study:
weight of evidence
Study period:
The study was published in 1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Objective of study:
other: pharmacokinetics
Qualifier:
no guideline followed
Principles of method if other than guideline:
This Phase I dose-escalation clinical trial of a lyophilized formulation of titanocene dichloride (MKT4) was conducted to determine the maximum tolerated dose, the doselimiting
toxicity (DLT), and pharmacokinetics of titanium (Ti) after a single i.v. infusion of MKT4.The study was performed according to German drug regulations.
The protocol was approved by the ethical boards of the universities of Berlin, Essen, and Hannover.
GLP compliance:
no
Remarks:
Study was performed according to good clinical practice guidelines
Specific details on test material used for the study:
Substance referred to as MKT4: a lyophilized formulation of titanocene dichloride, was supplied by medac GmbH in 25-mg vials.
Radiolabelling:
no
Species:
other: human
Strain:
other: not applicable
Details on species / strain selection:
Eligible for the study were patients with histological proof of malignancy for which conventional treatment had failed or was not available. Measurable disease was not required but, when present, was evaluated before dosing and every 22 days. Other eligibility criteria were: age between 18 and 75 years; Karnofsky-performance index _70%; life expectancy >3 months; no chemotherapy or radiotherapy within the 4 weeks preceding the study; written informed consent; adequate bone marrow (leukocyte, >3.500/mm3; platelet count, >100.000/mm3); and renal (serum creatinine, <1.5 mg/l00 ml)
and hepatic (serum bilirubin, <1.5 mg/l00 ml; alanine aminotransferase and aspartate aminotransferase less than two times the upper limit of normal values, unless secondary to metastatic liver disease) function. Exclusion criteria were: acute infectious disease, left ventricular hypertrophy, persistent toxicity of prior therapy (except alopecia or actinic dermatitis), and refusal of informed consent. The patients were hospitalized for treatment.
Sex:
male/female
Route of administration:
intravenous
Vehicle:
other: malic acid
Dose / conc.:
15 other: mg/m^2
Dose / conc.:
30 other: mg/m^2
Dose / conc.:
50 other: mg/m^2
Dose / conc.:
75 other: mg/m^2
Dose / conc.:
105 other: mg/m^2
Dose / conc.:
135 other: mg/m^2
Dose / conc.:
180 other: mg/m^2
Dose / conc.:
240 other: mg/m^2
Dose / conc.:
315 other: mg/m^2
Dose / conc.:
420 other: mg/m^2
Dose / conc.:
560 other: mg/m^2
Details on study design:
Study Design.
Baseline values before treatment comprised complete blood cell count with differential and reticulocytes, sodium, potassium, calcium, creatinine, creatinine clearance, urea, uric acid, cholinesterase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, alkaline phosphatase, -y-GT, lactic dehydrogenase, serum glucose, triglycerides, thyroid hormones, and plasmatic coagulation parameters. Complete physical examination and history, chest X-ray, electrocardiogram, and tumor measurements as appropriate were performed in addition.
After infusion, patients had weekly assessments including all laboratory tests mentioned above. Physical examination, evaluation of performance status and drug-related toxicity according to the WHO criteria were assessed before each treatment course. Response evaluation was performed according to the WHO criteria in patients with measurable disease after each treatment cycle.
Details on dosing and sampling:
Drug Administration.
Immediately before infusion, MKT4 was reconstituted in 25 ml of 50 mM malic acid to a final concentration of 1 mg of titanocene dichloride/ml of malic acid (pH = 3.5). After reaching the 420 mg/m2 dose level, the increased infusion volume necessitated an increase of the titanocene dichloride concentration. Three patients then received 75-mg vials. The
content was reconstituted in 37.5 ml of 25 mM malic acid to a final concentration of 2 mg of titanocene dichloride/ml of malic acid (pH = 3.0). The MKT4 infusion was given light-protected via a central iv. line over 30 mm (15-180 mg/m2) or over 60 mm (180-560 mg/m2). Blood pressure, pulse, and temperature were recorded before therapy and 1, 4, 8, and 24 h after therapy. Serum glucose monitoring was performed every 6 h up to 24 h after MKT4 infusion. Subsequent courses were repeated every 21 days. A delay of 1 week was permitted. Individual therapy was continued until there was objective evidence of disease
progression, nephrotoxicity WHO grade 2, other nonhematological toxicity WHO grade 3, hematological toxicity WHO grade 4, or a >20% treatment-related decline of the Karnofsky performance index. Treatment was also discontinued at the discretion of the treating physician or according to the patient’s decision. Antiemetics were only used if there was nausea/vomiting during the previous treatment course.

Dose-Escalation Procedures.
The starting dose of titanocene dichloride was 15 mg/m2. The dose increase was based
on a modified Fibonacci scheme and proceeded as follows: 30,
50, 75, 105, 135, 180, 240, 315, 420, and 560 mg/m2. A minimum of three patients were entered at each dose level. There was no dose escalation in individual patients. MTD was defined as the titanocene dichloride dose leading to DLT in at least two of six patients. DLT was defined as nephrotoxicity grade 2, other nonhematological toxicity grade 3, or hematological toxicity grade 4. The titanocene dichloride dose was only escalated to the next dose level if there was no toxicity or no
more than one case of nephrotoxicity (elevation of serum creatinine)
grade 1, other nonhematological toxicity grade 2, or hematological toxicity grade 3. If one patient had nephrotoxicity grade 2, nonhematological toxicity grade 3, or hematological toxicity grade 4, further evaluation of toxicity at this level was performed by treating three additional patients.
Details on distribution in tissues:
The pharmacokinetics of total Ti were concomitantly determined in plasma and whole blood in six comparative analyses in the first four patients treated with titanocene dichloride doses between 135 and 240 mg/m2. A constant ratio of 1:2 was obtained for AUC0-x in plasma and whole blood in four of six patients, and analysis was then carried out in plasma alone.
The pharmacokinetics of total Ti were analyzed in plasma and urine for 14 cycles in 10 patients. The biological half-life t1/2β in plasma was thus 22.8 ± 11.2 h (harmonic mean xh ± pseudo-SD), and the peak plasma concentration cmax was ~30 µg/ml at a dose of 420 mg/m2. The distribution volume Vss was 5.34 ± 2.1 L (arithmetic mean xa ± SD), and the total clearance Cltotal was 2.58 ± 1.23 ml/min.
There was a good correlation between the concentration time curves of Ti in plasma and the MKT4 dose administered. This was confirmed when the Ti AUC0-∞ in plasma was plotted against the titanocene dichloride dose and resulted in linear regression analysis with a 0.8856 correlation coefficient.
Comparing the AUC0-∞ of total Ti in plasma and ultrafiltrate reveals a plasma protein binding of Ti in the range of 70-80%.
Details on excretion:
The determination of the AUC0-∞ of total Ti in urine showed that between 3% and 16% of the total Ti administered is renally excreted during the first 36 h after administration.

The mean number of courses/patient was two. Thirteen patients received one treatment course; one of these patients (dose level 420 mg/m2) died of unexpected rapid tumor progression 5 days after treatment and, thus, can not be evaluated. Of the other patients, 20 received two treatment courses, 4 received three courses, 2 received four courses, and 1 received five courses.

Thirty-seven patients were treated with a 1 -mg/ml-concentrated solution of titanocene dichloride in malic acid buffer up to the level of 560 mg/m2. The infusion time was extended, and the concentration increased with further dose and infusion volume increases. Subsequently, the next three patients (38-40) were infused at dose level 315 mg/m2 with a concentrated solution of 2 mg/ml titanocene dichloride. To prevent nephrotoxicity, prehydration with I liter of isotonic saline over 2 h and posthydration with 2 liters of isotonic saline over 4 h was administered to these patients.

Thirty-five patients were withdrawn from the study with progressive disease. In three of those patients, renal toxicity was an additional reason for treatment discontinuing. One patient (dose level 30 mg/m2) decided to discontinue the study after five treatment courses at his own request, despite stable disease. One patient treated with a 2-mg/ml concentration of 315 mg/m2 titanocene dichlonide was taken out of the study because of renal toxicity (WHO grade 3). There were three deaths on study. A patient with hepatocellular carcinoma died 20 days after one course at the 1 5 mg/m2 dose level due to gastrointestinal bleeding in conjunction with tumor infiltration into the bowel, as confirmed by autopsy. Another patient suffering from testicular cancer with multiple lung metastases died of respiratory failure 5 days after one treatment course at the 420 mg/m2 dose level. Pulmonary embolism was suspected, but no further diagnostic evaluations were performed in this patient. The third patient who had biliary cancer with multiple liver metastases developed fatal hepatic and renal failure 10 days after an infusion of 420 mg/m2 titanocene dichloride. The early deaths of the first two patients were clearly related to rapid tumor progression. In the third patient, an additional influence of the study drug could not be excluded. Thus, possibly one death was at least partially drug-related due to grade 4 hepatotoxicity.

Determining the clinical pharmacokinetics of titanocene dichlonide was one of the objectives of the present Phase I study. However, up to the 135 mg/m2 level, titanocene dichloride could not be clearly identified in plasma or urine by high-performance liquid chromatography with spectrophotometric detection at 250 nm used according to in vitro investigations of titanocene dichlonide solutions. Thus, it is necessary to develop effective methods for ex vito stabilization in whole blood as well as further sensitization of titanocene dichloride detection. In consequence, we determined total Ti as the method applied in the early pharmacokinetic investigations of cisplatin to determine total platinum in plasma by atomic absorption spectroscopy before development of intact cisplatin detection methods. Thus, only 14 pharmacokinetic investigations in 10 patients treated with a dose range of 135-560 mg/m2 titanocene dichlonide could be performed.

Executive summary:

This Phase I dose-escalation clinical trial of a lyophilized formulation of titanocene dichloride (MKT4) was conducted to determine the maximum tolerated dose, the dose limiting toxicity (DLT), and pharmacokinetics of titanium (Ti) after a single i.v. infusion of MKT4. Forty patients with refractory solid malignancies were treated with a total of 78 courses. Using a modified Fibonacci scheme, 15 mg/m2initial doses of titanocene dichloride were increased in cohorts of three patients up to level 11(560mg/m2) if DLT was not observed. The maximum tolerated dose was 315 mg/m2, and nephrotoxicity was DLT. Two minor responses (bladder carcinoma and non-small cell lung cancer) were observed.

The pharmacokinetics of plasma Ti were assessed in 14 treatment courses by atomic absorption spectroscopy. The ratio for the area under the curve0-∞in plasma and whole blood was 1.2. The following pharmacokinetic parameters were determined for plasma, as calculated in a two-compartment model: biological half-lifet1/2β,in plasma was 22.8 ± 11.2 h (xh± pseudo-SD), peak plasma concentration cmax~30 µg/ml at a dose of 420 mg/m2, distribution volume Vss= 5.34 ± 2.1 L (xa± SD), and a total clearance Cltotal=2.58 ±1.23 mI/min (xa± SD). There was a linear correlation between the area under the curve0-∞of Ti in plasma and the titanocene dichloride dose administered with a correlation coefficientr2of 0.8856. Plasma protein binding of Ti was in the 70-80% range. Between 3% and 16% of the total amount of Ti administered were renally excreted during the first 36 h. The recommended dose for Phase II evaluation is 240 mg/m2given every 3 weeks with i.v. hydration to reduce renal toxicity.

Data source

Reference
Reference Type:
publication
Title:
Phase I Clinical and Pharmacokinetic Study of Titanocene Dichloride in Adults with Advanced Solid Tumors
Author:
Agnieszka Korfel, Max E. Scheulen, Hans-Joachim Schmoll, Olaf Grundel, Andreas Harstrick, Martin Knoche, Luder M. Fels, Matthias Skorzec, Ferdinand Bach, Joachim Baumgart, Gretel Safi, Sigfried Seeber, Eckhard Thiel, and Wolfgang E. Berdel
Year:
1998
Bibliographic source:
Vol. 4, 2701-2708, November 1998, Clinical Cancer Research

Materials and methods

Results and discussion

Applicant's summary and conclusion

Conclusions:
Nephrotoxicity proved to be dose-limiting in this study. Detailed investigation of the mechanisms responsible for the renal disturbance in patients treated at the 315 mg/m2-dose level with titanocene dichloride revealed both glomerular and, more strikingly, proximal-tubular impairment. These effects were still detectable 3 weeks after MKT4 infusion and seemed to be dependent on the total dose. On the basis of the results of this study, 3 5 mg/m2 is the maximum tolerated dose (MTD). Unlike the situation observed in preclinical trials, hepatotoxicity was rather uncommon (3 of 39 assessable patients). In addition, all these patients had rapidly progressive liver metastases, which may at least have contributed to the hepatic impairment observed during treatment. Other adverse events considered attributable to titanocene dichloride were: metallic taste with transient ageusia; anorexia; nausea; vomiting; asymptomatic hypoglycemia; and pain during the infusion. Although concomitant i.v. hydration with isotonic saline did not seem to have a beneficial effect on the incidence and severity of drug induced nephrotoxicity, it seemed to reduce gastrointestinal toxicity. The prophylactic and therapeutic potential of ondansetron could not be confirmed because only a few patients received standardized antiemetic therapy. Transient hypoglycemia was mainly observed in patients at lower dose levels. The mechanism responsible for this effect could be phosphorylation of the insulin receptor, as it was shown to be induced by vanadium salts. Also, the interaction of titanocene dichloride and related metabolites with the analytical methods of serum glucose has not been excluded. One patient who experienced hypoglycemia during both treatment courses had normal insulin concentration measured at the same time as serum glucose.
Executive summary:

This Phase I dose-escalation clinical trial of a lyophilized formulation of titanocene dichloride (MKT4) was conducted to determine the maximum tolerated dose, the dose limiting toxicity (DLT), and pharmacokinetics of titanium (Ti) after a single i.v. infusion of MKT4. Forty patients with refractory solid malignancies were treated with a total of 78 courses. Using a modified Fibonacci scheme, 15 mg/m2initial doses of titanocene dichloride were increased in cohorts of three patients up to level 11(560mg/m2) if DLT was not observed. The maximum tolerated dose was 315 mg/m2, and nephrotoxicity was DLT. Two minor responses (bladder carcinoma and non-small cell lung cancer) were observed.The pharmacokinetics of plasma Ti were assessed in 14 treatment courses by atomic absorption spectroscopy. The ratio for the area under the curve0-∞in plasma and whole blood was 1.2. The following pharmacokinetic parameters were determined for plasma, as calculated in a twocompartment model: biological half-lifet1/2β,in plasma was 22.8 ± 11.2 h (xh± pseudo-SD), peak plasma concentration cmax~30 μg/ml at a dose of 420 mg/m2, distribution volume Vss= 5.34 ± 2.1 L (xa± SD), and a total clearance Cltotal=2.58 ±1.23 mI/min (xa± SD). There was a linear correlation between the area under the curve0-∞of Ti in plasma and the titanocene dichloride dose administered with a correlation coefficientr2of 0.8856. Plasma protein binding of Ti was in the 70-80% range. Between 3% and 16% of the total amount of Ti administered were renally excreted during the first 36 h. The recommended dose for Phase II evaluation is 240 mg/m2given every 3 weeks with i.v. hydration to reduce renal toxicity.