Phase I study of the novel distamycin derivative tallimustine (FCE 24517)

Our plain-English summary of Phase I study of the novel distamycin derivative tallimustine (FCE 24517), by C. Sessa, O. Pagani, M.G. Zurlo, et al (Annals of Oncology, 1994).

The study

• Authors: C. Sessa, O. Pagani, M.G. Zurlo, J. de Jong, C. Hofmann, M. Lassus, P. Marrari, M. Strolin Benedetti, F. Cavalli
• Journal: Annals of Oncology
• Published: 1994;5(10):901-7
• Cited by: 47 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Tallimustine, a benzoyl nitrogen mustard derivative of the antiviral agent distamycin A, is a new alkylating agent which binds to A-T rich regions of DNA in the minor groove producing highly sequence-specific alkylations. Its main preclinical features are a significant antitumor activity in animal models and a lack of cross-resistance in vitro and in vivo with L-PAM. Myelotoxicity was dose-limiting in animals, with a more than 100-fold difference in bone marrow sensitivity between mice and dogs.

Patients And Methods: Forty adult patients (pts) with solid malignancies were entered in the study. The drug was administered as an IV bolus every 4 weeks. CBC was repeated twice a week and serial assessments of renal function were performed in the week following the first cycle. From the starting dose of 50 micrograms/m2, corresponding to 1/3 of the highest non-toxic dose (HNTD) in dogs, there were increases through 10 dose levels, with reliance only on the features of the myelotoxicity observed.

Results: The main toxic effect was neutropenia which was dose-limiting, selective and short-lasting. Only previously-untreated pts received doses of 750 micrograms/m2 or more, with grade 4 neutropenia occurring in > or = 75% of the cycles. The maximally tolerable dose (MTD) was defined as 1250 micrograms/m2, with 3 of 3 pts developing febrile neutropenia requiring IV antibiotics. A platelet count of < 100 x 10(3)/microliters was observed in only one pt. Bone marrow aspiration performed in selected pts on days 8 and 15 confirmed a highly selective impairment by tallimustine of the myeloid lineage, with rapid recovery of the proliferative compartment. Pharmacokinetic studies performed at 1000 micrograms/m2 and 1250 micrograms/m2 showed a rapid fall of the plasma levels within the first 2 hours with drug concentrations between 100 ng/ml and 400 ng/ml within the first hour. A partial response of 4 months' duration was reported in one previously-untreated pt with cutaneous recurrences of malignant mesothelioma.

Conclusions: The report of some antitumour efficacy, the high selectivity of neutropenia, the lack of significant non-hematological toxic effects and the occurrence of detectable but still low plasma drug concentrations suggest that further clinical evaluation of higher doses of tallimustine in combination with colony-stimulating factors would be justified.

In plain English

This was a phase I trial of tallimustine, an experimental cancer drug. A phase I trial is an early trial looking for a tolerable dose. It was run in Bellinzona, Switzerland. It is not a study of asbestos exposure. Forty adults with solid tumours entered the study, most often non-small cell lung cancer (20 patients). Doses were raised through 10 levels, from 50 to 1250 micrograms per square metre, given as a one-minute intravenous injection every four weeks. The main side effect was a short-lasting fall in neutrophils, a type of white blood cell. At 1250 micrograms per square metre, 3 of 3 patients had fever with low neutrophils needing intravenous antibiotics, so the authors set this as the maximally tolerable dose for patients without prior treatment. Platelets fell below 100 x 10^3 per microlitre in only one patient. One patient with malignant mesothelioma had a partial response lasting 4 months at 1250 micrograms per square metre. This patient had tumour nodules in and under the skin near a chest surgery scar. The authors concluded that higher doses with colony-stimulating factors deserved further clinical evaluation.

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: Phase I dose-escalation trial of a new cancer drug
• Who was studied: 40 adult patients with solid tumours (26 male, 14 female; median age 55, range 33-74), treated at the Division of Oncology, Ospedale San Giovanni, Bellinzona, Switzerland. 20 had non-small cell lung cancer. 39 were evaluable for toxicity. Study dates are not given.
• Exposure: Not an asbestos exposure. Patients received the drug tallimustine as a 1-minute intravenous bolus every 4 weeks, at doses escalated through 10 levels from 50 to 1250 micrograms per square metre.
• Main results:
  • Neutropenia (low neutrophil count) was the main and dose-limiting toxic effect, and it was short-lasting.
  • Grade 4 neutropenia occurred in 66%, 75%, 75% and 100% of patients at 600, 750, 1000 and 1250 micrograms per square metre respectively.
  • The authors defined 1250 micrograms per square metre as the maximally tolerable dose in patients without prior treatment, because 3 of 3 patients treated at that dose had febrile neutropenia requiring intravenous antibiotics.
  • A platelet count below 100 x 10^3 per microlitre was seen in only 1 patient, treated at 1000 micrograms per square metre.
  • Creatinine clearance and the sodium clearance to creatinine clearance ratio on day 6 or day 8 were not significantly different from baseline at any dose level.
  • Alopecia (hair loss) was the most frequent non-blood side effect. It was first seen at 1000 micrograms per square metre in 1 patient and was universal at 1250 micrograms per square metre.
  • In 4 patients sampled at 1000 and 1250 micrograms per square metre, plasma drug levels fell rapidly within the first 2 hours, with concentrations between 100 and 400 ng/ml within the first hour.
  • One patient with malignant mesothelioma treated at 1250 micrograms per square metre had a partial remission lasting 4 months. This patient had cytologically proven subcutaneous/cutaneous nodules near the thoracotomy scar.
• The authors' conclusion: The authors concluded that the antitumour efficacy reported, the high selectivity of the neutropenia, the lack of significant non-blood toxic effects and the detectable but low plasma drug levels suggest that further clinical evaluation of higher doses of tallimustine combined with colony-stimulating factors would be justified. They recommended a phase II dose of about 750 to 1000 micrograms per square metre in previously untreated patients only.
• Limitations the authors state:
  • Only patients with limited or no previous treatment were given the higher doses, so a phase II dose could only be recommended for good-risk patients.
  • The drug assay became available only at the 1000 micrograms per square metre dose level.
  • The short sampling period prevented estimating main pharmacokinetic parameters. The small number of patients prevented conclusions on how drug exposure varied or related to dose.

Topics

Medical terms in this study, explained in our Lexicon: Neutropenia, Malignant Mesothelioma.

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