Linda D. Marks

Phase II trial of trimetrexate in patients with stage III and IV non-small-cell lung cancer.

Trimetrexate is a nonclassical antifolate with greater preclinical antitumor activity than methotrexate. Fourteen patients with stage III or IV non-small-cell lung cancer who had not previously received chemotherapy were given trimetrexate (12 mg/m2 intravenously daily for 5 days) every 3 weeks. No major objective responses were observed (95% confidence limits: 0–20%). Ten of the 14 patients had grade 2 or greater toxicity, with 50% experiencing grade 2 or greater leukopenia and/or thrombocytopenia. Nausea, vomiting, rash, mucositis, diarrhea, and serum glutamic-oxaloacetic transaminase (SGOT) elevations were also seen. At the dosage and schedule of trimetrexate used, no responses occurred in this population of patients with non-small-cell lung cancer. With the low response rate and the observed degree of myelosuppression, trimetrexate appears to have limited utility in this disease.

Oral piritrexim : a phase II study in patients with advanced soft tissue sarcoma

Piritrexim is a lipid soluble dihydrofolate reductase (DHFR) inhibitor that rapidly and passively diffuses into cells [1,2]. It has been synthesized as an antifolate compound potentially capable of circumventing methotrexate resistance from arising via various mechanisms [3]. A phase II evaluation of this drug was organized at the Memorial Sloan Kettering Cancer Center (MSKCC) to evaluate the anti-tumor activity and toxicity in patients with advanced soft tissue sarcoma. Preliminary results have been previously presented [4]. Adult patients with soft tissue sarcoma with a clearly measurable indicator lesion(s) and a Karnofsky Performance Status of 70% or greater were eligible for entry regardless of prior treatment. Classic oncologic response criteria were used. Patients were scheduled to receive a dose of 160 mg/m 2, administered orally twice daily for five consecutive days every three weeks. Following unexpected severe toxicity in two patients (both with prior pelvic irradiation who initiated treatment at a dose of 120 mg/m2), the protocol was amended to initiate treatment at a dose of 120 mg/m 2 in all patients and 80 mg/m 2 in those patients with prior radiation to the pelvis. The dose was subsequently escalated or deescalated based on toxicity. Twenty-six patients with soft tissue sarcoma were entered on study. Table 1 summarizes the demographic data and the results. One-hundred and thirty-one courses of therapy were administered to the 26 patients for a mean of 5 courses and a median of 3.5 courses per patient. Fourteen of the patients initiated treatment at a dose of 120 mg/m 2 bid, eleven initiated treatment at a dose of 80 mg/m 2 bid and one initiated treatment at a dose of 160 mg/m z. Two patients obtained a partial response. Of twelve evaluable patients with leiomyosarcoma, one patient obtained a partial response (for response rate of leiomyosarcoma upper limit 95% confidence interval = 34%). The other patient who obtained a partial response was the only patient entered with endometrial stromal sarcoma. Grade 2 or greater toxicity was observed in 80% of patients. Severe (grade 3 -4 ) myelopoietic toxicity was associated with 17 courses of treatment in nine patients, severe oral mucositis with nine courses of treatment in seven patients, severe maculo-papular pruritic rash with four courses in four patients and severe emesis with three courses in three patients. Generally, these toxicities occurred concurrently. This complex of toxicities represents the dose limiting toxicity of piritrexim. Piritrexim was evaluated in this phase II study because of its activity in the sarcoma 180 preclinical model, because of the activity of methotrexate in patients with soft tissue sarcoma and because of the anti-tumor efficacy of metoprine in previous studies in patients with sarcoma. Two clinically beneficial objective responses were observed, an overall response rate of 11%. Piritrexim is a potentially active agent in the treatment of soft tissue sarcoma but with an upper limit of a 95~ confidence

PHASE II TRIAL OF AMONAFIDE IN PATIENTS WITH STAGE III AND IV NON-SMALL-CELL LUNG CANCER

Amonafide (benzisoquinolinedione, nafidimide, NSC 308847) is an anticancer agent that functions as a DNA intercalator. Sixteen patients with stage III or IV non-small-cell lung cancer who had not previously received chemotherapy were given amonafide at an initial dose of 300 mg/m2 i.v. daily for 5 days every 21 days. No major objective responses were observed among the 14 patients adequately treated (95% confidence limits 0–20%). Local reactions at the injection site or phlebitis were seen in 14 of the 16 patients. Leukopenia (44%), nausea or vomiting (38%), and thrombocytopenia and rash (each 25%) were also noted. With the low response rate and the toxicity observed, amonafide at this dosage and schedule has limited use in the treatment of non-small-cell lung cancer.

Taxol (paclitaxel) plus recombinant human granulocyte colony-stimulating factor in the treatment of metastatic breast cancer.

We treated 28 patients who had no prior chemotherapy for stage IV breast cancer and 51 patients with extensive prior exposure to other chemotherapeutic agents with a 24-hour infusion of Taxol (paclitaxel) as a single agent. Prophylactic recombinant human granulocyte colony-stimulating factor was administered routinely to ameliorate the anticipated dose-limiting toxicity of neutropenia. Nonhematologic toxicity was mild to moderate in most cases. Taxol was more active in patients with chemotherapy-naive stage IV disease, but activity was also observed in extensively treated patients as well. There is a strong clinical suggestion of at least partial noncross-resistance with doxorubicin. Taxol is a very promising agent for the treatment of metastatic breast cancer; its optimal application in this disease will be the subject of future trials.

Phase II trial of esorubicin (4' deoxydoxorubicin, DxDx) in patients with small cell lung cancer

SummaryEsorubicin (4′-deoxydoxorubicin or DxDx) is an analog of doxorubicin with preclinical antitumor activity and no significant cardiotoxicity in model systems. Eleven patients with small cell lung cancer who had previously received chemotherapy were given esorubicin (25 mg/m2 intravenously) every 3 weeks. No major objective responses were observed (95% confidence limits: 0–25%). Nine of the 11 patients had grade 2 or greater toxicity, with 55% of the patients experiencing grade 3 or greater toxicity [myelosuppression (4/11), anemia (2/11) or elevated liver enzymes (3/11)]. Nausea, vomiting, alopecia and intravenous site phlebitis were also seen. Three of the 11 patients received 3 or more course of esorubicin without evidence of significant cardiotoxicity. At this dose and shedule, no significant antitumor response were seen in this population of patients. Esorubicin, with this low response rate and significant toxicity, appears to be of limited utility in this disease.