Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer.

Christodoulou, Constantina; Ferry, David; Fyfe, D.; Young, Anna-Mary; Doran, J.; Sheehan, T. M. T.; Eliopoulos, Aristides G.; Hale, K.; Baumgart, Joachim; Sass, G; Kerr, David

doi:10.1200/jco.1998.16.8.2761

Cited by 104 publications

(58 citation statements)

References 9 publications

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“…Significant nephrotoxic and hepatotoxic side effects were observed in accordance with previous reports, and a dose reduction to 240 mg/m 2 is recommended. Hematotoxicity was confirmed to be negligible, but in contrast to previous clinical trials [10,11,13] treatment-related neurotoxic side effects were evident. This study was conducted according to the two-stage optimal Simon design.…”

Section: Discussioncontrasting

confidence: 67%

“…Titanocene dichloride showed antitumor activity in cisplatinum-resistant cell lines, indicating a different molecular mode of action than described for platinum complexes [7][8][9]. Two clinical phase I trials have been conducted, indicating nephrotoxicity, hepatotoxicity and fatigue as dose-limiting toxicities [10,11]. A phase II dose recommendation of 270 mg/m 2 MKT4 was suggested for intravenous administration at intervals of 3 weeks.…”

Section: Introductionmentioning

confidence: 99%

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Phase II Clinical Trial of Titanocene Dichloride in Patients with Metastatic Breast Cancer

Kröger¹,

Kleeberg²,

Mross³

et al. 2000

Oncol Res Treat

193

174

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Background: Titanocene dichloride (MKT4) is a recently developed cytostatic agent that shows preclinical activity against human breast cancer xenograft models in nude mice. A phase II trial was conducted to evaluate the clinical activity of this inorganic early-transition metal complex in patients with metastatic breast cancer. Patients and Methods: Fifteen patients were enrolled into this multicenter phase II trial. Twelve patients with a median age of 58 years were eligible for toxicity and response. All 12 patients had prior surgery and metastatic disease at study entry. Seven patients had prior radiotherapy, 9 patients had prior hormone therapy, and 8 patients had prior adjuvant chemotherapy. No previous chemotherapy for metastatic disease was allowed. Titanocene dichloride was intravenously administered at a dose of 270 mg/m² every 3 weeks. Results: Among the 12 eligible patients evaluable for response, no objective remission was observed. Two patients (17%) showed a ‘minor remission’, and 5 patients (42%) experienced a ‘no change’ situation of their disease. Moderate to severe drug-related toxicities (CTC grade II–III) affecting the gastrointestinal, neurological, hepatic and renal system occurred in the majority of patients. Therefore, in 5 patients the dose had to be reduced to 240 mg/m². Conclusion: MKT4, given at a dose of 240–270 mg/m² in this schedule, was not effective in patients with metastatic breast cancer. The tolerability of the 3-weekly dosing regimen was acceptable when the MKT4 dose was reduced to 240 mg/m².

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Section: Discussioncontrasting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Phase II Clinical Trial of Titanocene Dichloride in Patients with Metastatic Breast Cancer

Kröger¹,

Kleeberg²,

Mross³

et al. 2000

Oncol Res Treat

193

174

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“…The maximum tolerated dose (MTD) was 315 mg/m 2 , and the recommended dose for phase II studies was 240 mg/m 2 . The second phase I study evaluated a weekly administration schedule [6]. The DLT was again renal toxicity.…”

Section: Titanocendichlorid · Phase-i-studiementioning

confidence: 99%

Phase I Clinical Trial of a Day-1, -3, -5 Every 3 WeeksPhase I Clinical Trial of Day-1, -3, -5 Every 3 Weeks Schedule with Titanocene Dichloride (MKT 5) in Patients with Advanced Cancer. (Phase I Study Group of the AIO of the German Cancer Society)

Mross¹,

Robben-Bathe²,

Edler³

et al. 2000

Oncol Res Treat

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Background: Titanocene dichloride (TD) is an organometallic compound with antiproliferative properties in vitro and promising antitumor activity in preclinical in vivo models. The drug interferes with DNA, blocks the S/G₂ phase of the cell cycle and shows antiangiogenic properties. The purpose of this study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of a ‘split’ dose administration schedule (days 1, 3, 5 q 3 weeks). Patients and Method: Patients with progressive advanced cancer and a creatinine clearance > 60 ml/min qualified for a treatment with TD after standard therapies (radio-, chemo-, hormone therapy) failed. A total of 10 patients (4 females, 6 males) with a median age of 58 (range 49–68) years were treated with 80 mg/m² TD at days 1, 3 and 5 (repeated at day 22). The drug was administered as light-protected infusion within 1 h. Results: Significant side effects were as follows: nausea/vomiting, appetite loss, renal toxicity (elevation of serum creatinine and proteinuria) and liver toxicity (bilirubin and alkaline phosphatase elevation), but no myelosuppression. At the starting dose (3 x 80 = 240 mg/m² TD), renal (3 patients) or liver toxicity (1 patient) of grade 3 was judged as DLT. No further dose escalation was possible. No objective tumor remission was observed. Conclusion: The tolerability of TD cannot be improved by splitting the total dose in to three treatments every other day. Compared to previous phase I data using a 3-weekly and a 1-weekly schedule, the ‘split’ dose administration allowed no further increase of the total drug dose per treatment cycle. Thus, dose intensification by alterations of the application mode does not seem to be possible.

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“…For instance, titanocen dichloride has undergone clinical trials as anticancer drug [14,15]. According to the work of Becker et al [16] metalloproteins are ambitious targets for therapy and diagnosis of tumour growth or neurodegenerative diseases like stroke.…”

Section: Introductionmentioning

confidence: 99%

Positron and γ-ray intensities in the decay of ⁴⁵Ti

Kuhn¹,

Schölten²,

Spahn³

et al. 2015

Radiochimica Acta

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Abstract:To evaluate the PET-imaging properties of the promising positron emitter 45 Ti, its + -and -ray intensities were measured. Use of the cation-exchange resin DOWEX 50W×8 (H + -form) enabled the isolation of radiochemically pure, no-carrier-added 45 Ti from "bulk" scandium after proton bombardment. Thin, no-carrier-added 45 Ti samples were prepared. The combination of -ray and X-ray spectrometry with -coincidence counting allowed for the first time the experimental determination of the positron intensity as (85.67 ± 2.23)% and the absolute intensity of the 720.22 keV -ray as (0.1171 ± 0.0057)%.

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Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer.

Abstract: The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.

Cited by 104 publications

References 9 publications

Phase II Clinical Trial of Titanocene Dichloride in Patients with Metastatic Breast Cancer

Phase II Clinical Trial of Titanocene Dichloride in Patients with Metastatic Breast Cancer

Phase I Clinical Trial of a Day-1, -3, -5 Every 3 WeeksPhase I Clinical Trial of Day-1, -3, -5 Every 3 Weeks Schedule with Titanocene Dichloride (MKT 5) in Patients with Advanced Cancer. (Phase I Study Group of the AIO of the German Cancer Society)

Positron and γ-ray intensities in the decay of ⁴⁵Ti

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Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer.

Abstract: The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.

Cited by 104 publications

References 9 publications

Phase II Clinical Trial of Titanocene Dichloride in Patients with Metastatic Breast Cancer

Phase II Clinical Trial of Titanocene Dichloride in Patients with Metastatic Breast Cancer

Phase I Clinical Trial of a Day-1, -3, -5 Every 3 WeeksPhase I Clinical Trial of Day-1, -3, -5 Every 3 Weeks Schedule with Titanocene Dichloride (MKT 5) in Patients with Advanced Cancer. (Phase I Study Group of the AIO of the German Cancer Society)

Positron and γ-ray intensities in the decay of 45Ti

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Positron and γ-ray intensities in the decay of ⁴⁵Ti