Phase I, dose-finding, and pharmacokinetic study of raltitrexed combined with oxaliplatin in patients with advanced cancer

Our plain-English summary of Phase I, dose-finding, and pharmacokinetic study of raltitrexed combined with oxaliplatin in patients with advanced cancer, by K. Fizazi, M. Ducreux, P. Ruffié, et al (Journal of Clinical Oncology, 2000).

The study

• Authors: K. Fizazi, M. Ducreux, P. Ruffié, M. Bonnay, C. Daniel, J.C. Soria, C. Hill, A. Fandi, M. Poterre, M. Smith, J.P. Armand
• Journal: Journal of Clinical Oncology
• Published: 2000;18(11):2293-300
• Cited by: 59 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of the raltitrexed plus oxaliplatin combination regimen, to explore its safety and pharmacokinetics, and to assess its antitumor activity in patients with advanced solid tumors.

Patients And Methods: Forty-eight patients received the combination of raltitrexed plus oxaliplatin. Raltitrexed was administered as a 15-minute infusion followed by oxaliplatin as a 2-hour infusion 1 hour later, repeated every 3 weeks. Seven dose levels were explored, ranging from 2 to 3.75 mg/m(2) and from 85 to 130 mg/m(2) for raltitrexed and oxaliplatin, respectively. The pharmacokinetics of both raltitrexed and oxaliplatin was assessed at the last three dose levels.

Results: Forty-six patients were assessable for toxicity. Severe toxicities usually occurred from dose level V (raltitrexed 3 mg/m(2) and oxaliplatin 130 mg/m(2)). This combination was not myelosuppressive, eliciting only sporadic grades 3 and 4 neutropenia and/or thrombocytopenia without complications. There was no alopecia. DLTs were asthenia and nausea/vomiting, despite systematic antiemetic prophylaxis. Dose level VI (raltitrexed 3.5 mg/m(2) and oxaliplatin 130 mg/m(2)) was deemed to be the MTD. Eight confirmed partial responses were observed: six patients with malignant mesothelioma (both pretreated and nonpretreated), one with fluorouracil-refractory pancreatic carcinoma, and one with renal carcinoma. Evaluation of the pharmacokinetics of both drugs did not suggest any drug interaction.

Conclusion: The combination of raltitrexed and oxaliplatin given as consecutive short infusions every 3 weeks seems to be an acceptable regimen that allows a dose-intensity as high as the sum of the recommended doses of each agent given alone. The dose recommended for further phase II studies is raltitrexed 3 mg/m(2) and oxaliplatin 130 mg/m(2) every 3 weeks. Promising antitumor activity has been observed in patients with malignant mesothelioma.

In plain English

This was a phase I study at one French cancer center. It tested raltitrexed followed by oxaliplatin, given every 3 weeks to 48 patients with advanced solid tumors and no viable treatment alternative. It did not study asbestos exposure. Seventeen had malignant mesothelioma and 11 colorectal cancer. Doses rose over seven levels to find the highest tolerable dose. Peripheral neurotoxicity, a nerve side effect, occurred in 83% of patients and was usually mild and rapidly and fully reversible. Nausea and vomiting affected 75.0%, and asthenia (weakness) 60.4%. Blood-count side effects were uncommon, and no febrile neutropenia was reported. Dose level VI was judged the maximum tolerated dose. The authors recommended raltitrexed 3 mg/m2 with oxaliplatin 130 mg/m2 for further studies. Of 17 mesothelioma patients, 6 had partial responses (35%; 95% CI 14% to 59%), four of whom were considered cisplatin-refractory. None of the 11 heavily pretreated colorectal cancer patients had an objective response, though six had disease stabilization lasting at least 3 months. The authors noted that response was not the study's main goal. They concluded the combination showed promising activity in malignant mesothelioma.

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 open-label, noncomparative, single-center, dose-escalation chemotherapy study with pharmacokinetic sampling
• Who was studied: 48 patients (31 men, 17 women) with histologically proven advanced solid tumors and no viable therapeutic alternative, treated at Institut Gustave-Roussy, Villejuif, France. 17 had malignant mesothelioma, 11 colorectal cancer, 6 renal carcinoma, 4 lung cancer and 10 other tumors. Study dates are not given.
• Exposure: Not asbestos. The exposure was the treatment: raltitrexed as a 15-minute infusion, then oxaliplatin as a 2-hour infusion, every 21 days. Seven dose levels were used, with raltitrexed from 2 to 3.75 mg/m2 and oxaliplatin from 85 to 130 mg/m2.
• Main results:
  • Among malignant mesothelioma patients, there were 6 objective partial responses among 17 assessable patients (35%; 95% CI, 14% to 59%).
  • Four of the six mesothelioma responders were considered cisplatin-refractory.
  • Overall response rate in all 48 treated patients was 17% (95% CI, 8% to 30%). This included one renal carcinoma and one pancreatic carcinoma partial response.
  • No objective responses occurred in the 11 colorectal cancer patients, all of whom were heavily pretreated.
  • Six of the 11 colorectal cancer patients, who had progressive disease before inclusion, had disease stabilization lasting at least 3 months.
  • Peripheral neurotoxicity was the most common adverse event and occurred in 83% of patients. It was usually mild and rapidly and fully reversible.
  • Grade 3 peripheral neurotoxicity occurred in three patients (6.3%).
  • Nausea and vomiting occurred in 36 of 48 patients (75.0%). Asthenia occurred in 29 patients (60.4%).
  • Grade 3 or 4 neutropenia occurred in three patients (6.3%). No febrile neutropenia was reported.
  • At dose level VI (raltitrexed 3.5 mg/m2, oxaliplatin 130 mg/m2), 5 of 14 patients had dose-limiting toxicities. This level was deemed the maximum tolerated dose.
  • At dose level VII, 3 of 6 patients had dose-limiting toxicities. This level was considered the toxic dose.
  • No patients died from study-related events.
  • Increasing raltitrexed doses did not seem to alter oxaliplatin pharmacokinetics.
• The authors' conclusion: The authors concluded that raltitrexed 3.0 mg/m2 plus oxaliplatin 130 mg/m2 every three weeks seems to be a safe regimen. They stated that promising antitumor activity was observed in patients with malignant mesothelioma.
• Limitations the authors state:
  • Response assessment was not the primary end point of this phase I study.
  • Blood sampling only up to 28 hours may not adequately define the terminal elimination phase of raltitrexed.
  • For maximal drug concentration, dose increments were small compared with the known variability in raltitrexed pharmacokinetics between patients.
  • Asthenia was difficult to grade.
  • All colorectal cancer patients were heavily pretreated, which the authors gave as the reason no responses were seen in that group.

Topics

Medical terms in this study, explained in our Lexicon: Raltitrexed, Neutropenia, Malignant Mesothelioma, Fluorouracil (5-FU), Carcinoma.

Related studies

• Combination raltitrexed (Tomudex(R))-oxaliplatin: a step forward in the struggle against mesothelioma? The Institut Gustave Roussy experience with chemotherapy and chemo-immunotherapy in mesothelioma — K. Fizazi, R. Caliandro, et al. (2000)
• Oxaliplatin and raltitrexed in the treatment of inoperable malignant pleural mesothelioma: results of a pilot study — R. Maisano, N. Caristi, et al. (2001)
• A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours — G. Mak, J.C. Soria, et al. (2019)
• Raltitrexed: current clinical status and future directions — E. Van Cutsem, D. Cunningham, et al. (2002)
• Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma — D.R. Camidge, N. Blais, et al. (2013)
• Phase I dose-escalation study of milciclib in combination with gemcitabine in patients with refractory solid tumors — S. Aspeslagh, K. Shailubhai, et al. (2017)

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