Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent.

The antitumour action of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is mediated through tumour-selective antivascular effects and cytokine induction. This clinical phase I trial was conducted to examine its toxicity, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). A secondary objective was to assess its antitumour efficacy. DMXAA was administered every 3 weeks as a 20-min i.v. infusion. Dose escalation initially followed a modified Fibonacci schema but was also guided by PK and toxicity. A total of 63 patients received 161 courses of DMXAA over 19 dose levels ranging from 6 to 4900 mg m(-2). DMXAA was well tolerated at lower doses and no drug-related myelosuppression was seen. Rapidly reversible dose-limiting toxicities were observed at 4900 mg m(-2), including confusion, tremor, slurred speech, visual disturbance, anxiety, urinary incontinence and possible left ventricular failure. Transient prolongation of the corrected cardiac QT interval was seen in 13 patients evaluated at doses of 2000 mg m(-2) and above. A patient with metastatic cervical carcinoma achieved an unconfirmed partial response at 1100 mg m(-2), progressing after eight courses. The results of PK and PD studies are reported separately. DMXAA has antitumour activity at well-tolerated doses.

Phase I study of the cytotoxic agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA) is a new DNA-intercalating drug with a dual mode of cytotoxic action that is thought to involve topoisomerases I and II. On the basis of novelty of action and promising preclinical activity against solid tumours in mice, DACA was selected for clinical trial under the auspices of the Cancer Research Campaign, United Kingdom. We report the phase I findings of a 3-h infusion regimen, repeated 3-weekly, of escalating doses through 18-1000 mg/m2 given to 31 patients with solid malignancies. A maximum tolerated dose (MTD) of 750 mg/m2 was identified, with 3 of 6 cycles being abandoned at 1000 mg/m2. Dose-limiting toxicity took the form of infusional arm pain, in some cases associated with facial discomfort, that was of rapid onset and subsided quickly on the cessation of infusion. The mechanism is unclear but is modulated to some extent by the rate of drug delivery, and it was unaffected in this study by concurrent anti-inflammatory or opiate medication. No host or tumour anti-proliferative activity was observed at these doses, and only minimal toxicity of any other kind was evident. Animal data suggest that the MTD achieved with this schedule may be sub-therapeutic in humans. It is therefore important that efforts be continued to explore methods of giving higher doses of DACA.

Plasma pharmacokinetics of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in a phase I trial.

DACA [N-[2-(dimethylamino)ethyl]acridine-4-carboxamide] is an acridine derivative with high activity against solid tumours in mice and a dual mode of cytotoxic action involving topoisomerases I and II. The plasma pharmacokinetics of DACA were studied in 28 patients with solid tumours in a phase I trial. A single dose was given every 3 weeks, being escalated from a starting dose of 18 mg/m2 (as the dihydrochloride trihydrate salt) to a maximal dose, limited by severe pain in the infusion arm, of 1000 mg/m2. Drug was given by constant intravenous infusion with a target delivery period of 3 h. Blood samples were taken from the contralateral arm before, during and for up to 72 h after the infusion. DACA was separated from plasma by solid-phase extraction and was analysed by reversed-phase high-performance liquid chromatography (C18 column) using fluorescence detection. A two-compartment pharmacokinetic model provided the best fit for the concentration-time profiles obtained for most patients showing clearance of 1.00+/-0.36 l h(-1) kg(-1), a volume of distribution of the central compartment of 0.72+/-0.55 l/kg, an initial half-life of 0.28+/-0.19 h and a terminal half-life of 2.04+/-0.94 h. All pharmacokinetic parameters were independent of dose, indicating first-order kinetics. As DACA binds strongly to alpha1-acid glycoprotein, plasma concentrations of this protein were determined and used to estimate free-drug fractions in plasma. Estimated values for the free fraction varied from 0.9% to 3.3% and were lower than those determined by equilibrium dialysis for mice and rats (15% and 16%, respectively). At the maximum tolerated dose (MTD) of 750 mg/m2, the area under the drug concentration-time curve (AUC) was 46.2+/-4.4 microM h, exceeding that obtained in mice treated at the MTD (23.4 microM h). On the other hand, the corresponding free-drug AUC was 0.92+/-0.03 microM h, much lower than the corresponding value (3.5 microM h) determined for mice. These results suggest that free-drug rather than total drug concentrations are more appropriate for interspecies dose comparisons when significant differences exist in the free plasma fraction.

Metabolism of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in cancer patients undergoing a phase I clinical trial.

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA) is an experimental antitumour agent that has just completed phase I clinical trials in New Zealand and the United Kingdom. Urine (0-72 h) was analysed from 20 patients receiving DACA infused over 3 h (dose range 60-1000 mg/m2, the latter being the highest dose achieved in the trial). Aliquots were analysed for DACA and its metabolites by high-performance liquid chromatography (HPLC). Over 72 h, 44+/-5% (range 20-60%) of the dose was recovered in the urine, with 0.8+/-0.3% (range 0-3.1%) occurring as DACA. The major urinary metabolite was DACA-N-oxide-9(10H)acridone, accounting for 34+/-3% of the dose. Minor metabolites were identified as N-monomethyl-DACA-9(10H)acridone (2.0+/-0.5%), DACA-9(10H)acridone (3.3+/-0.5%), N-monomethyl-DACA (0.2+/-0.1%) and DACA-N-oxide (0.5+/-0.1%). No ring-hydroxylated metabolite was detected. The urinary excretion of metabolites was greatest over 0-6 h in most patients. The composition of urinary metabolites was also independent of the delivered dose. Plasma was sampled at intervals throughout the infusion and at time points up to 48 h post-administration. The major plasma metabolites observed were DACA-9(10H)acridone and DACA-N-oxide-9(10H)acridone. These results indicate that, based on urinary excreted metabolites, the major biotransformation reactions for DACA in humans involve N-oxidation of the tertiary amine side chain and acridone formation, both of which appear to be detoxication reactions.

Chemotherapy for small cell lung carcinoma: the Greenlane Hospital experience 1993-1995.

AIMS: 1. To compare treatment response and survival of patients with small cell lung carcinoma managed at Greenlane Hospital with published results. 2. To compare the outcome of patients with extensive disease treated with oral etoposide with those who received combination chemotherapy. METHODS: Case notes of all new patients assessed for small cell lung carcinoma between 1993 and 1995 were reviewed. RESULTS: Seventy-eight cases were identified. Sixty-three patients (81%) underwent chemotherapy, of whom 32 had limited disease, 28 extensive disease and three were inadequately staged. Twenty-six patients (81%) with limited disease received combination treatment (carboplatin, etoposide +/- vincristine) compared with 16 (57%) in the extensive disease group. Response rate was significantly higher in those with limited disease (87.5%) than with extensive disease (50%), (p = 0.006). Overall median survival was 56 weeks in the limited disease group and 32 weeks for extensive disease (p = 0.007). Of patients with limited disease who achieved complete or partial response, 41% (n = 9) developed cerebral metastases as the first sign of disease relapse. These patients relapsed late (mean = 56 weeks) compared with those who relapsed at other sites (31 weeks) (p = 0.002). Patients with extensive disease, who received more than one drug (n = 16), had better median survival than those treated with etoposide only (n = 8), 35 vs 12 weeks, respectively (p = 0.6). Severe treatment complications were uncommon in either group. Four patients required admissions for infection although none were neutropenic. Only one patient (12.5%) treated with etoposide and three (18%) with combination chemotherapy developed grade IV neutropenia. CONCLUSIONS: 1. The survival in our series was comparable with published data on other treatment regimes. 2. Patients with extensive disease who received etoposide only had poorer median survival compared with those treated with more than one drug. This is likely a result of selection bias and the role of etoposide in palliation needs to be further assessed. 3. In spite of achieving good local control in patients with limited disease, late relapse with cerebral metastases was common. Prophylactic cranial irradiation, particularly in responders, needs to be considered in planning future treatment strategies. Small cell lung carcinoma (SCLC) accounts for 15-20% of all primary lung carcinomas and has an aggressive natural history because of its short tumour-doubling time and early metastatic potential. Chemotherapy has been used as the primary treatment modality for SCLC at Greenlane Hospital since 1979. Carboplatin, etoposide and vincristine (CEV) is an effective combination for patients with limited disease and has been adopted as the standard regime at Greenlane Hospital since 1993. Oral etoposide has attracted attention as a single agent for palliation in patients with advanced small cell lung carcinoma. Aggressive chemotherapy may not be appropriate in these patients whose prognosis is poor in spite of treatment. Etoposide offers the advantage of being an active oral agent and avoids the need for repeated venous access. It has been perceived as less toxic than other regimes and thus a preferred option for frail patients with extensive disease. The aims of this study were to compare treatment response and survival of patients with small cell lung carcinoma treated in our service since the introduction of the CEV regime with published data and to compare the outcome of patients with extensive disease treated with combination chemotherapy with those who receive oral etoposide only.

Late seminomatous relapse of a mixed germ cell tumor of the testis on intensive surveillance.

We report a case of a pure seminomatous relapse in the retroperitoneum 6 years after orchiectomy for an apparent stage I mixed germ cell tumor of the testis. The 4 cm. metastatic mass was not imaged on computerized tomography, tumor markers were negative and confounding symptoms made diagnosis difficult. The propensity for seminomatous tumors to relapse later than nonseminomatous tumors has profound implications for intensive surveillance programs for apparent stage I disease in mixed germ cell tumors. These programs often involve routine computerized tomography only for the first 2 years and rely on physical examination, simple radiology and serum tumor markers thereafter. Such programs may fail to detect pure seminomatous relapse and delay the onset of curative treatment.

Resistance mechanisms determining the in vitro sensitivity to paclitaxel of tumour cells cultured from patients with ovarian cancer.

Paclitaxel, a drug which stabilises microtubules, demonstrates marked activity against ovarian cancer. We investigated the sensitivity to paclitaxel of tumour cells from disaggregated solid tumours or tumour-bearing ascites from 7 ovarian cancer patients, and 21 established tumour cell lines (ovarian, melanoma and lung). Response was quantitated by [3H]-thymidine incorporation in 96-well plates or by colony growth. Dose-response curves to paclitaxel were biphasic with a dose-dependent phase providing an IC50 value (50% reduction in incorporation) and dose-dependent "plateau" phase where the effect was independent of paclitaxel concentration. IC50 values ranged from 2.5 to 110 nM with evidence of multidrug resistance in the two most resistant cell lines. The "plateau" killing values varied from 0.1 log10 to > 3.4 log10 units reduction, and were found to be significantly correlated (r = 0.86; P < 0.0001) with logarithmic culture doubling times of the cell lines. Cellular glutathione levels were measured and found not to be significantly associated with response to paclitaxel. The results suggest that the ratio of paclitaxel exposure time to the culture doubling time is a major factor in paclitaxel cytotoxicity. The relationship between tumour cell cytokinetics and paclitaxel pharmacokinetics in vivo may therefore be crucial in determining clinical paclitaxel response.