Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors

Our plain-English summary of Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors, by A.A. Adjei, C. Erlichman, J.A. Sloan, et al (Journal of Clinical Oncology, 2000).

The study

• Authors: A.A. Adjei, C. Erlichman, J.A. Sloan, J.M. Reid, H.C. Pitot, R.M. Goldberg, P. Peethambaram, P. Atherton, L.J. Hanson, S.R. Alberts, J. Jett
• Journal: Journal of Clinical Oncology
• Published: 2000;18(8):1748-57
• Cited by: 104 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: Multitargeted antifolate (MTA) is an investigational agent that, like gemcitabine, exhibits broad activity in solid tumors. A phase I trial of MTA and gemcitabine was undertaken, based on the demonstration of preclinical cytotoxic synergy.

Patients And Methods: Thirty-five patients (group I) received 164 courses (median, four; range, one to 14 courses) of treatment of gemcitabine at doses of 1,000 and 1,250 mg/m(2) on days 1 and 8 and MTA at doses of 200, 300, 400, 500, and 600 mg/m(2), given 90 minutes after gemcitabine on day 1. Courses were repeated every 3 weeks. Because the day 8 dose of gemcitabine was reduced or omitted in 57% of courses due to neutropenia, 21 patients (group II) were treated on an alternate schedule, with MTA administered on day 8 rather than day 1. This group received 85 treatment courses (median, four; range, one to 10 courses).

Results: The most common and dose-limiting toxicity was neutropenia. Other toxicities included nausea, fatigue, rash, and elevated hepatic transaminases. The maximum-tolerated dose was gemcitabine/MTA 1,000/500 mg/m(2) for group I and 1,250/500 mg/m(2) for group II. Thirteen objective responses were documented (colorectal cancer, n = 3; non-small-cell lung cancer, n = 3; cholangiocarcinoma, n = 2; ovarian carcinoma, n = 2; mesothelioma, n = 1; breast cancer, n = 1; and adenocarcinoma of unknown primary site, n = 1). Gemcitabine had no effect on the disposition of MTA.

Conclusion: The gemcitabine/MTA combination is broadly active and warrants further evaluation. The sequence of gemcitabine administered on days 1 and 8 with MTA administered on day 8 is better tolerated and is recommended for further study at doses of gemcitabine/MTA 1,250/500 mg/m(2).

In plain English

This was a phase I trial at the Mayo Clinic. It tested two chemotherapy drugs given together, gemcitabine and an investigational drug called multitargeted antifolate (MTA, also called LY231514 or ALIMTA), in 56 patients with advanced solid tumors. Three of the patients had mesothelioma. The study did not look at asbestos exposure. In group I (35 patients), MTA was given on day 1. Low white blood cell counts (neutropenia) often forced the day 8 gemcitabine dose to be cut or skipped, so group II (21 patients) received MTA on day 8 instead. Neutropenia was the dose-limiting side effect in both groups. The highest tolerated gemcitabine/MTA doses were 1,000/500 mg/m2 in group I and 1,250/500 mg/m2 in group II. Confirmed tumor responses occurred in 13 of 55 assessable patients. One of them had pleural mesothelioma and kept the response for 11 months. There were no treatment-related deaths. The authors concluded that the combination should be studied further in phase II trials and recommended the group II schedule. They also noted that clinical activity is hard to define in a phase I study of mixed tumor types.

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 clinical trial with pharmacokinetic study, preceded by laboratory (cell culture) experiments
• Who was studied: 56 patients with advanced solid tumors treated at the Mayo Clinic, Rochester, MN: 35 in group I and 21 in group II. Three had mesothelioma (2 in group I, 1 in group II). The other tumors included colorectal, lung, pancreatic and bile duct cancers. Study dates are not given.
• Exposure: Not an asbestos exposure study. Patients received gemcitabine (1,000 or 1,250 mg/m2) on days 1 and 8, plus MTA (200 to 600 mg/m2) given 90 minutes after gemcitabine on day 1 (group I) or day 8 (group II), every 3 weeks
• Main results:
  • Neutropenia was the dose-limiting toxicity in both groups
  • Maximum tolerated dose of gemcitabine/MTA: 1,000/500 mg/m2 for group I and 1,250/500 mg/m2 for group II
  • In group I, the planned treatment could be given to only 16 (45%) of 35 patients. In group II, the day 8 treatment was not omitted for any patient.
  • There were no treatment-related deaths in the study
  • Liver enzyme (transaminase) elevations occurred in 178 (71%) of 249 courses
  • Confirmed objective responses occurred in 13 of 55 assessable patients, including one with mesothelioma
  • One patient with pleural mesothelioma, previously treated with two chemotherapy regimens, maintained a response for 11 months
  • Giving gemcitabine first did not alter the pharmacokinetics of MTA (assessed in four patients)
• The authors' conclusion: The authors concluded that the responses seen across a broad range of tumor types suggest the regimen should be studied in phase II trials. They recommended gemcitabine 1,250 mg/m2 on days 1 and 8 with MTA 500 mg/m2 on day 8, every 21 days.
• Limitations the authors state:
  • The small number of patients could have hidden a moderate drug interaction
  • With mixed tumor types and different dose levels, it is difficult to define the clinical activity of the regimen

Topics

Medical terms in this study, explained in our Lexicon: Gemcitabine, Antifolate, Neutropenia, Colorectal Cancer, Lung Cancer, Carcinoma, Mesothelioma, Adenocarcinoma.

Related studies

• Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin — R. Thödtmann, H. Depenbrock, et al. (1999)
• Phase I study of gemcitabine, docetaxel and imatinib in refractory and relapsed solid tumors — B. Saraiya, R. Chugh, et al. (2012)
• Phase I dose-escalation study of milciclib in combination with gemcitabine in patients with refractory solid tumors — S. Aspeslagh, K. Shailubhai, et al. (2017)
• Phase I combination study of the PARP inhibitor veliparib plus carboplatin and gemcitabine in patients with advanced ovarian cancer and other solid malignancies — H.J. Gray, K. Bell-McGuinn, et al. (2018)
• Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors — A.R. Hanauske, V. Chen, et al. (2001)
• Sunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies--results of a phase I dose-escalation study — N. Blais, D.R. Camidge, et al. (2013)

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