Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion

Our plain-English summary of Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion, by I. Rassmann, R. Thödtmann, M. Mross, et al (Investigational New Drugs, 1998).

The study

• Authors: I. Rassmann, R. Thödtmann, M. Mross, A. Hüttmann, W.E. Berdel, C. Manegold, H.H. Fiebig, A. Kaeser-Fröhlich, K. Burk, A.R. Hanauske
• Journal: Investigational New Drugs
• Published: 1998;16(4):319-24
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: NK611 is a novel podophyllotoxin derivative. Compared with etoposide, NK611 carries a dimethylamino group at the D-glucose moiety. The antitumor activity of NK611 showed to be equal or superior to etoposide in a variety of in vitro and in vivo tumor models. The aim of our present study was to determine the maximum tolerated dose and the dose-limiting toxicities of NK611 administered as intravenous infusion over 30 min every 28 days.

Patients And Methods: 45 patients (7 female, 38 male; median age 54 [range 37-73]) were enrolled. In a first stage, NK611 was administered without hematopoietic growth factor support; in a second stage, G-CSF was used for further dose escalation. Toxicities were assessed using WHO-criteria.

Results: Initially, the dose was escalated from 60 mg/m2 to 120 mg/m2. In a second patient cohort, doses were further escalated with G-CSF support with doses ranging from 140 mg/m2 to 250 mg/m2. Dose-limiting toxicities were granulocytopenia and thrombocytopenia. Non-hematologic toxicities consisted of alopecia, mild nausea, and infection. Four partial responses were observed: two at 200 mg/m2 (pleural mesothelioma, response duration 7 months, and non-small cell lung cancer, response duration 13 months), and two at 250 mg/m2 (hepatocellular carcinoma, response duration 7 months, and non-small cell lung cancer, response duration 2 months). Pharmacokinetic analyses were performed in all patients. Using an open 3-compartment model, the terminal half-life (t1/2gamma) was 14.7 +/- 3.7 h. The AUC at 250 mg/m2 was determined to be 330 +/- 147 microg/mlh, the plasma clearance of NK611 was 16.2 +/- 8.2 ml/min x m2 and the V(ss) was 16.8 +/- 3.3 l/m2. Protein binding of NK611 was 98.7%.

Conclusion: the recommended dose for clinical Phase II studies is 120 mg/m2 without G-CSF support and 200 mg/m2 with G-CSF support.

In plain English

This Phase I trial tested NK611, an experimental chemotherapy drug related to etoposide, in 45 patients (38 male, 7 female) with solid tumors that had no proven treatment. It did not study asbestos exposure. The drug was given as a 30-minute intravenous infusion every 28 days, first at 60 to 120 mg/m2, then at 140 to 250 mg/m2 together with the growth factor G-CSF. Without G-CSF, the dose-limiting effect was a severe drop in granulocytes (a type of white blood cell); with G-CSF, low platelets became an additional dose-limiting effect alongside low white blood cells. All patients had grade 2 hair loss. Four patients had partial responses, two at 200 mg/m2 and two at 250 mg/m2. One had newly diagnosed pleural mesothelioma and responded after two courses at 200 mg/m2; the response lasted seven months. The authors concluded that the maximum tolerated dose with G-CSF was 250 mg/m2. They recommended 120 mg/m2 without G-CSF and 200 mg/m2 with G-CSF for Phase II studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Two-stage Phase I dose-escalation clinical and pharmacokinetic trial (stage one without and stage two with G-CSF support)
• Who was studied: 45 patients (38 male, 7 female; median age 54) with histologically proven solid tumors with no proven treatment option, entered over a period of 42 months by the German AIO Phase I Study group; calendar dates not given
• Exposure: No asbestos exposure was studied. The exposure was the drug NK611, given intravenously over 30 minutes every 28 days at 60 to 120 mg/m2 without G-CSF, then 140, 170, 200 and 250 mg/m2 with G-CSF support
• Main results:
  • Without G-CSF, the dose-limiting toxicity was grade 4 granulocytopenia
  • In the second stage, with G-CSF, thrombocytopenia (low platelets) was found as an additional dose-limiting toxicity; leukopenia/granulocytopenia remained dose-limiting at the maximum tolerated dose of 250 mg/m2
  • Grade 2 alopecia (hair loss) occurred in all patients
  • A total of 100 cycles were given, median 2 cycles per patient, range 1 to 7
  • Of the 45 patients, 36 left the study due to disease progression, three due to toxicity and six at their own wish
  • Four patients had antitumor responses, two at 200 mg/m2 and two at 250 mg/m2; none of the responders had received prior chemotherapy
  • One patient with newly diagnosed pleural mesothelioma had a partial remission after two courses at 200 mg/m2, lasting seven months
  • The mean terminal half-life of NK611 rose from 10.2 hours at 140 mg/m2 to 20.3 hours at 250 mg/m2
  • NK611 clearance fell from 60.8 ml/min at 140 mg/m2 to 32.6 ml/min at 250 mg/m2
• The authors' conclusion: The authors concluded that the maximum tolerated dose (with G-CSF) was 250 mg/m2, with leukopenia/granulocytopenia and thrombocytopenia as dose-limiting toxicities. They recommended 120 mg/m2 without G-CSF and 200 mg/m2 with G-CSF for Phase II studies
• Limitations the authors state:
  • The authors noted considerable variation between patients in drug levels at all doses. At higher doses requiring G-CSF they found no clear linear relationship between dose and drug exposure (AUC)

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Non-Small Cell Lung Cancer, Carcinoma.

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