Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors

Our plain-English summary of Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors, by C.A. Johnson, D. Kilpatrick, R. von Roemeling, et al (Journal of Clinical Oncology, 1997).

The study

• Authors: C.A. Johnson, D. Kilpatrick, R. von Roemeling, C. Langer, M.A. Graham, D. Greenslade, G. Kennedy, E. Keenan, P.J. O'Dwyer
• Journal: Journal of Clinical Oncology
• Published: 1997;15(2):773-80
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose And Methods: Tirapazamine (SR4233, WIN 59075) is a benzotriazine-di-N-oxide bioreductive agent that is selectively activated to a reactive DNA-damaging species in hypoxic tumors. Preclinical studies show that synergistic antitumor activity results from a schedule-dependent interaction between tirapazamine and several cytotoxic drug classes, including cisplatin. In a phase I combination study, tirapazamine (130 to 260 mg/m2) was administered as a 1-hour intravenous (IV) infusion beginning 3 hours before cisplatin (75 to 100 mg/m2). Thirteen patients received 41 courses of therapy. These patients had an excellent performance status and were not heavily pretreated. The predominant diagnosis was lung cancer.

Results: The major acute side effects were nausea and vomiting, which were controlled with an intensive antiemetic regimen. Other acute effects included diarrhea and muscle cramping, while with repeated dosing, anorexia and fatigue predominated. Full doses of each agent were well tolerated in combination, although in this previously treated population, fatigue increased markedly after three cycles of therapy. Partial responses were observed in two patients (one with non-small-cell lung cancer and one with breast cancer), and a minor response occurred in a patient with mesothelioma. Tirapazamine pharmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (Cmax) of 5.97 +/- 2.25 microg/mL and an area under the concentration-time curve (AUC) of 811.4 +/- 311.9 microg/mL.min at 260 mg/m2. These results are consistent with other ongoing single-agent and combination studies and indicate that therapeutically relevant levels of tirapazamine are achievable in patients based on animal models. The mean cisplatin AUC was 285.6 +/- 46.4 microg/mL.min with mean Cmax values of 3.38 +/- 0.43 microg/mL at 75 mg/m2. The clearance of cisplatin was unaffected by coadministration with tirapazamine.

Conclusion: This trial shows that in previously treated patients, full doses of cisplatin are well tolerated with increasing doses of tirapazamine up to 260 mg/m2. The observation of clinical responses in this trial supports the phase II investigation of this regimen.

In plain English

This was a phase I trial of an experimental drug, tirapazamine, given with the chemotherapy drug cisplatin every 3 weeks to patients with solid tumors judged refractory to standard therapy. It did not study asbestos exposure. Thirteen patients (nine men, four women; median age 60) received 41 treatment cycles; twelve had received previous chemotherapy and one had no prior treatment. Five had lung cancer and one had mesothelioma. Tirapazamine doses rose from 130 to 260 mg/m2, with cisplatin at 75 or 100 mg/m2. Nausea and vomiting occurred in all patients. Fatigue appeared to build up over repeated cycles. Four of seven patients who received more than three cycles developed grade 3 (severe) fatigue, and doses were not raised further because of this cumulative toxicity. Two patients had partial responses, one with non-small-cell lung cancer and one with breast cancer. A patient with pleural mesothelioma who had no prior therapy had a minor response. That patient stopped after five cycles because of fatigue and was lost to follow-up 1 month later. The authors concluded that the regimen was suitable for phase II testing.

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 clinical trial (dose-escalation study of a drug combination)
• Who was studied: 13 patients (9 men, 4 women; median age 60, range 39 to 73) with solid tumors, treated at Fox Chase Cancer Center, Philadelphia. Eligibility required a tumor refractory to standard therapy. Primary sites were lung (5), ovary (2), and breast, endometrium, head and neck, mesothelioma, pancreas and unknown (1 each). Twelve had received previous chemotherapy and one had no prior treatment. Study dates are not given.
• Exposure: No asbestos exposure was studied. Patients received intravenous tirapazamine at 130, 195 or 260 mg/m2 followed by cisplatin at 75 mg/m2 (dose levels one to three) or 100 mg/m2 (level four), repeated every 3 weeks.
• Main results:
  • Twelve of the 13 patients had received previous chemotherapy, and three had received prior radiation.
  • Nausea and vomiting occurred in all patients; two patients had grade 4 vomiting.
  • Fatigue was the dose-limiting toxicity and appeared cumulative: 4 of 7 patients who received more than three cycles developed grade 3 fatigue, and five patients stopped the study because of it.
  • Tirapazamine doses were not raised above 260 mg/m2 because of cumulative toxicity.
  • Among the 13 patients, there were two partial responses (one non-small-cell lung cancer, one breast cancer) and one minor response.
  • The minor response was in a patient with pleural mesothelioma who had no prior therapy. This patient received five cycles, stopped because of fatigue, and was lost to follow-up 1 month after withdrawal.
  • Hematologic (blood count) toxicity was not significant, and no patient had ototoxicity (hearing damage).
  • At 260 mg/m2, the mean tirapazamine maximum plasma concentration was 5.97 plus or minus 2.25 micrograms/mL. The mean area under the concentration-time curve was 811.4 plus or minus 311.9 micrograms/mL.min (range 479 to 1,426).
  • The authors reported that tirapazamine at doses up to 260 mg/m2 had no significant effect on the renal clearance of cisplatin.
• The authors' conclusion: The authors concluded that they had described a regimen of tirapazamine and cisplatin suitable for phase II testing, and that the responses suggest it may be promising for further development.

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Performance Status, Lung Cancer, Mesothelioma.

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