Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin

Our plain-English summary of Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin, by R. Thödtmann, H. Depenbrock, H. Dumez, et al (Journal of Clinical Oncology, 1999).

The study

• Authors: R. Thödtmann, H. Depenbrock, H. Dumez, J. Blatter, R.D. Johnson, A. van Oosterom, A.R. Hanauske
• Journal: Journal of Clinical Oncology
• Published: 1999;17(10):3009-16
• Cited by: 117 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: Multitargeted antifolate (MTA; LY231514) has broad preclinical antitumor activity and inhibits a variety of intracellular enzymes involved in the folate pathways. This study was designed to (1) determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of MTA combined with cisplatin; (2) determine a recommended dose for phase II studies; and (3) collect anecdotal information on the antitumor activity of MTA combined with cisplatin.

Patients And Methods: Patients with solid tumors received MTA intravenously over 10 minutes and cisplatin over 2 hours once every 21 days. In cohort 1, both agents were administered on day 1 starting with MTA 300 mg/m(2) and cisplatin 60 mg/m(2). In cohort 2, MTA (500 or 600 mg/m(2)) was administered on day 1, followed by cisplatin (75 mg/m(2)) on day 2.

Results: In cohort 1, 40 assessable patients received 159 courses of treatment. The MTD was MTA 600 mg/m(2)/cisplatin 100 mg/m(2). DLTs were reversible leukopenia/neutropenia and delayed fatigue. Hydration before cisplatin therapy did not influence MTA pharmacokinetics. Eleven objective remissions included one complete response in a patient with relapsed squamous cell head and neck carcinoma, and partial responses in four of ten patients with epithelial pleural mesothelioma. In cohort 2, 11 assessable patients received 23 courses of treatment. The MTD was MTA 600 mg/m(2) and cisplatin 75 mg/m(2). DLTs were neutropenic sepsis, diarrhea, and skin toxicity. Two patients died of treatment-related complications during the study. Two patients had objective remissions (one mesothelioma patient, one colon cancer patient).

Conclusion: The combination of MTA and cisplatin is clinically active, and administering both agents on day 1 is superior to a split schedule. Further development of this combination for mesothelioma is warranted.

In plain English

This phase I study, from a hospital in Leuven, Belgium, tested the drug multitargeted antifolate (MTA, LY231514) given with the chemotherapy drug cisplatin. It did not examine asbestos exposure. Of 54 patients with solid tumors who were entered, 40 in cohort 1 (both drugs on day 1) and 11 in cohort 2 (MTA on day 1, cisplatin on day 2) were assessable. In cohort 1, the main dose-limiting side effects were low white blood cell and neutrophil counts. The maximum tolerated dose was MTA 600 mg/m2 with cisplatin 100 mg/m2 when only the first cycle was counted, or with cisplatin 75 mg/m2 when all cycles were counted. In cohort 2, two patients died of treatment-related complications. The timing of cisplatin did not appear to change how the body handled MTA. Four patients with pleural mesothelioma in cohort 1 and one mesothelioma patient in cohort 2 had partial responses. The authors noted that a phase I design generally does not allow response rates to be estimated. The authors concluded that MTA may be safely combined with cisplatin. They recommended MTA 500 mg/m2 plus cisplatin 75 mg/m2 for phase II studies and judged giving both drugs on day 1 superior with regard to toxicity.

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: Clinical and pharmacokinetic phase I dose-finding study of a drug combination, with two treatment schedules (cohorts)
• Who was studied: 54 patients with solid tumors for which no proven therapeutic option was available, treated at Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium. 42 were entered in cohort 1 (40 assessable) and 12 in cohort 2 (11 assessable). Mesothelioma was the most common tumor type: 10 patients in cohort 1 and 3 in cohort 2. Study dates were not given.
• Exposure: No asbestos exposure was studied. The exposure was treatment with MTA (intravenously over 10 minutes) plus cisplatin (over 2 hours) every 21 days. In cohort 1 both drugs were given on day 1 at MTA/cisplatin dose levels from 300/60 to 600/100 mg/m2. In cohort 2, MTA was given on day 1 and cisplatin on day 2 at 500/75 and 600/75 mg/m2.
• Main results:
  • Cohort 1 (both drugs on day 1): the dose-limiting toxicity was myelosuppression, mainly leukopenia and neutropenia.
  • Cohort 1: the maximum tolerated dose was MTA 600 mg/m2 and cisplatin 100 mg/m2 when only the first cycle was evaluated. It was MTA 600 mg/m2 and cisplatin 75 mg/m2 when all cycles were evaluated.
  • Cohort 2 (split schedule): one patient at MTA 500/cisplatin 75 mg/m2 developed grade 4 diarrhea, severe dehydration and sepsis and died of these treatment-related complications.
  • Cohort 2: a second patient, with recurrent head and neck cancer, at MTA 600/cisplatin 75 mg/m2 died on study. The cause was most likely a catheter-related bacterial sepsis.
  • Pharmacokinetics (4 patients in cohort 1, 11 in cohort 2): MTA pharmacokinetics did not depend on when cisplatin and its hydration were given.
  • Cohort 1: 11 objective tumor responses were seen.
  • Cohort 1: one patient with relapsed squamous cell carcinoma of the head and neck had a complete response, which was short-lasting.
  • Cohort 1: four patients with pleural mesothelioma had partial remissions, which an independent radiology reviewer confirmed.
  • Cohort 2: one mesothelioma patient and one colon cancer patient had confirmed partial responses.
  • Across the study, the authors reported partial responses in five of 11 assessable pleural mesothelioma patients, and four more patients had stable disease.
• The authors' conclusion: The authors concluded that MTA may be safely combined with cisplatin and that the schedule is clinically active. They recommended MTA 500 mg/m2 plus cisplatin 75 mg/m2 for phase II studies, considered giving both drugs on day 1 superior to the split schedule with regard to toxicity, and called for further studies in malignant mesothelioma and head and neck cancer.
• Limitations the authors state:
  • A phase I design generally does not allow response rates to be estimated.
  • The sample size for the pharmacokinetic comparison was small in each treatment regimen.
  • In cohort 1, blood samples were collected for only 24 hours, so a prolonged terminal elimination phase could not be observed in that cohort.
  • Future studies are needed to support the pharmacokinetic findings.

Topics

Medical terms in this study, explained in our Lexicon: Antifolate, Cisplatin, Neutropenia, Squamous Cell, Carcinoma, Pleural Mesothelioma, Mesothelioma, Colorectal Cancer.

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