Galanis Evanthia, Buckner Jan C, Maurer Matthew J, Reid Joel M, Kuffel Mary J, Ames Matthew M, Scheithauer Bernd W, Hammack Julie E, Pipoly George, Kuross Steven A
Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Invest New Drugs. 2005 Oct;23(5):495-503. doi: 10.1007/s10637-005-2910-4.
Novel therapeutic agents in the treatment of recurrent gliomas are urgently needed. Pyrazoloacridine (PZA), a rationally synthesized acridine derivative, has shown promising antitumor activity against glioma lines in combination with platinum compounds. This phase I/II trial of the PZA/carboplatin combination in recurrent glioma patients consisted of two phase I studies (studies 1 and 2) and a phase II trial (study 3). The objectives of studies 1 and 2 were to (a) assess the safety and toxicity and to establish the phase II dose of the pyrazoloacridine/carboplatin combination for recurrent glioma patients on P450 inducing anticonvulsants, and (b) to confirm the phase II dose for patients not on P450 inducing anticonvulsants. The primary objectives of study 3 were to determine the efficacy of the pyrazoloacridine/carboplatin combination in patients with recurrent gliomas, to further assess the toxicity of the combination, and to evaluate the impact of enzyme-inducing anticonvulsants on the pyrazoloacridine metabolism.
Both carboplatin and pyrazoloacridine were administered intravenously every 28 days. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal.
14 patients were treated in the two phase I studies and 32 patients in the phase II trial. The phase II dose of the combination was PZA 400 mg/m(2) and carboplatin AUC of 5 every 28 days. Neutropenia (4 patients) and dyspnea (1 patient) was the dose limiting toxicity in the phase I studies. In the phase II trial, the most frequent toxicity was myelosuppression with grade 3 and 4 hematologic adverse events being observed in 22 and 19% of the patients, respectively. The antitumor activity of this regimen was limited; the response rate in the phase II trial was 0%, (95% CI:0-11%) while 12 of the 32 patients (38%) had stable disease with a median duration of 2 months. The percentage of phase II patients who were progression free at three months was 22% and at six months was 16%. Median survival from study entry was 5.0 months for phase I patients and 5.8 months for phase II patients. Pharmacokinetic analysis performed in 8 phase I patients demonstrated no significant impact of the enzyme-inducing anticonvulsants on the pharmacokinetics of pyrazoloacridine.
The phase II dose of the pyrazoloacridine/carboplatin combination is pyrazoloacridine 400 mg/m(2) in combination with carboplatin AUC of 5. Antitumor activity in patients with recurrent gliomas was limited. Initial disease stabilization occurred in approximately 38% of the patients, with median duration of 2 months. Enzyme-inducing anticonvulsants did not affect the pyrazoloacridine metabolism.
治疗复发性胶质瘤急需新型治疗药物。吡唑并吖啶（PZA）是一种合理合成的吖啶衍生物，与铂类化合物联合使用时，对胶质瘤细胞系显示出有前景的抗肿瘤活性。这项针对复发性胶质瘤患者的PZA/卡铂联合治疗的I/II期试验包括两项I期研究（研究1和研究2）和一项II期试验（研究3）。研究1和研究2的目的是：（a）评估安全性和毒性，并确定接受P450诱导性抗惊厥药治疗的复发性胶质瘤患者使用吡唑并吖啶/卡铂联合治疗的II期剂量；（b）确认未接受P450诱导性抗惊厥药治疗的患者的II期剂量。研究3的主要目的是确定吡唑并吖啶/卡铂联合治疗对复发性胶质瘤患者的疗效，进一步评估联合治疗的毒性，并评估酶诱导性抗惊厥药对吡唑并吖啶代谢的影响。
卡铂和吡唑并吖啶均每28天静脉给药一次。治疗持续进行，直至出现不可接受的毒性、肿瘤进展或患者退出。
两项I期研究中有14名患者接受治疗，II期试验中有32名患者接受治疗。联合治疗的II期剂量为每28天PZA 400 mg/m²和卡铂AUC为5。中性粒细胞减少（4例患者）和呼吸困难（1例患者）是I期研究中的剂量限制性毒性。在II期试验中，最常见的毒性是骨髓抑制，分别有22%和19%的患者出现3级和4级血液学不良事件。该方案的抗肿瘤活性有限；II期试验中的缓解率为0%（95%CI：0-11%），而32例患者中有12例（38%）疾病稳定，中位持续时间为2个月。II期患者在3个月时无进展的百分比为22%，6个月时为16%。I期患者从研究入组开始的中位生存期为5.0个月，II期患者为5.8个月。对8名I期患者进行的药代动力学分析表明，酶诱导性抗惊厥药对吡唑并吖啶的药代动力学没有显著影响。
吡唑并吖啶/卡铂联合治疗的II期剂量为吡唑并吖啶400 mg/m²联合卡铂AUC为5。复发性胶质瘤患者的抗肿瘤活性有限。约38%的患者最初疾病稳定，中位持续时间为2个月。酶诱导性抗惊厥药不影响吡唑并吖啶的代谢。
