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Preliminary results of a phase I study with MTA (LY231514) in combination with cisplatin in patients with solid
R Thödtmann1, H Depenbrock, J Blatter
1Universitair Ziekenhuis Gasthuisberg, Katholic University of Leuven, Belgium.
Abstract:
MTA (multitargeted antifolate, LY231514) is a novel antimetabolite resulting from structure/activity studies of the lometrexol-type antifolates. It has been shown to inhibit various enzymes of folate pathways and has broad antitumor activity in a variety of in vitro and in vivo tumor models. Clinical phase 1 studies have been performed using different administration schedules, and subsequently the every-21-days schedule has been selected for further development. We report the preliminary findings from a combination phase I study of MTA and cisplatin administered every 21 days. In the first cohort (34 patients), both agents were administered on day 1 with a starting dose of 300 mg/m2 MTA and 60 mg/m2 cisplatin. In a second cohort (10 patients), MTA (500 or 600 mg/m2) was administered on day 1 followed by cisplatin (75 mg/m2) on day 2. The maximum tolerated doses were reached at 600 mg/m2 MTA/100 mg/m2 cisplatin (cohort 1) and 600 mg/m2 MTA/75 mg/m2 cisplatin (cohort 2). In cohort 1, dose-limiting toxicities consisted of reversible myelosuppression with leukopenia and neutropenia. In addition, delayed fatigue also was of clinical significance. Pharmacokinetic analyses indicated that hydration administered before the administration of cisplatin did not influence the major pharmacokinetic parameters of MTA. Eleven objective remissions were observed, including one complete response in a patient with relapsed squamous cell carcinoma of the head and neck and partial responses in four of seven patients with mesothelioma In contrast, the dose-limiting toxicities in patient cohort 2 consisted of neutropenic sepsis, diarrhea, and skin toxicity with two possibly treatment-related deaths on study. No objective remissions are presently observed in cohort 2. We conclude that the combination of MTA and cisplatin is feasible and clinically active when both agents are administered on day 1 and that it should be pursued for further clinical development.
Insights
Multitargeted antifolate (MTA) combined with cisplatin shows clinical activity and feasibility. Administering both agents on day 1 resulted in objective remissions, supporting further development of this combination cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Multitargeted antifolate (MTA) is a novel antimetabolite with broad antitumor activity.
- Previous phase 1 studies established an every-21-days administration schedule for MTA.
- Combination chemotherapy is a common strategy to enhance antitumor efficacy.
Purpose of the Study:
- To evaluate the feasibility and preliminary efficacy of combining MTA with cisplatin in a phase 1 clinical trial.
- To determine the maximum tolerated doses (MTD) and dose-limiting toxicities (DLTs) of the combination therapy.
- To assess the clinical activity of MTA and cisplatin administered on different schedules.
Main Methods:
- A phase 1 clinical trial was conducted with two patient cohorts receiving MTA and cisplatin on different schedules.
- Cohort 1: MTA and cisplatin administered on day 1 every 21 days.
- Cohort 2: MTA administered on day 1, followed by cisplatin on day 2 every 21 days.
Main Results:
- The MTDs were determined as 600 mg/m2 MTA/100 mg/m2 cisplatin (cohort 1) and 600 mg/m2 MTA/75 mg/m2 cisplatin (cohort 2).
- Cohort 1 showed reversible myelosuppression and fatigue as DLTs, with 11 objective remissions, including one complete response in head and neck cancer.
- Cohort 2 experienced severe toxicities including neutropenic sepsis and diarrhea, with no observed objective remissions and two treatment-related deaths.
Conclusions:
- The combination of MTA and cisplatin is feasible and clinically active when administered on day 1.
- The day 1 administration schedule demonstrated promising antitumor activity and should be further investigated.
- Further clinical development of MTA and cisplatin combination therapy is warranted.