Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women

Aromatase inhibitors are a useful therapeutic option in the management of endocrine-dependent advanced breast cancer. A single-dose administration of exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17 dione), a new irrversible aromatase inhibitor, was investigated in 29 healthy postmenopausal female volunteers. The compound, given at p.o. doses of 0.5,5,12.5,25,50,200,400, and 800 mg (n=3-4), was found to be a well tolerated, potent, long-lasting, and specific inhibitor of estrogen biosynthesis. The minimal dose which produced the maximum suppression of plasma estrogens was 25 mg, reducing plasma estrone, estradiol, and estrone sulfate to 35,28 and 39 per cent of basal values, respectively. This maximum suppression, observed at 3 days, persisted for at least 5 days after administration of a single dose. However, there was no interference on cortisol, aldosterone, 17-hydroxyprogesterone, or dehydroepiandrostenedione sulfate plasma levels. Peak plasma exemestane concentrations of 27, 221, 343, and 414 ng/ml were reached within 2 h after administration of 50, 200, 400, and 800 mg, respectively. Plasma concentrations declined rapidly and fell under teh detection limit (10 ng/ml) at 4 (50 mg) or 24 h (200 and 400 mg). No clinically significant adverse events which could be attributed to the drug were reported. Apart from transient eosinophilia in 3 patients, al biochemical and hematological laboratory parameters were within 1.25-fold of the normal ranges

Phase I study of carboplatin in patients with advanced cancer, intermitten intravenous bolus, and 34-hour infusion

We undertook a phase 1 study of Carboplatin (CBDCA) on an intermitten single intravnous (IV) bolus (schedule A) and a 24-hour continous infusion schedule (schedule B). Hydration and forced diuresis were not performed. Patients were not premedicated for anticipated vomiting. Thirty-eight adult patients with solid tumors received a total of 71 courses. In schedule A, doses were escalated from 20 to 600 mg/m2. The dose-limiting tosicity was myelosuppression. At doses of 270 mg/m2 and higher, leukopenia and thrombocytopenia were reproducibly seen. The dose of 600 mg/m2 was the maximally tolerated dose, producing severe thrombocytopenia (platelet counts <30,000/uL). Other toxicities included a fall in hemoglobin levels and tolerable nausea and vomiting. Schedule B produced comparable hematologic and emetogenic toxicities to those in schedule A. In three patients audiograms became abnormal with hig frequency hearing loss without overt deafness. Two patients developed hypomagnesemia without irreversivle renal dysfunction. Patients with poor performance status, preexisting renal dysfunction, a third fluid space, or bone metastases seemed to develop increased hematologic toxicity. The recommended phase 2 dose for good risk patients is 400 mg/m2 IV bolus and for poor tisk patients 270 mg/m2 IV bolus. Responses were seen in one patient each with head and neck carcinoma (partial response), small cell lung cancer (minor response), and breast cancer (minor response)

Isolation perfusion for malignant melanoma of the extremity : a review

The role of perfusion, normothermic and hypothermic, in the curative treatment of melanoma remains controversial. Survival appears to be somewhat improved over that of surgery alone in all stages, especially with hyperthermic perfusion, but all comparisons have been retrospective and uncontrolled. In addition to the usual problems with historical controls, melanoma presents its own special problems because of its unpredictable natural history in any given individual and the multiplicity of factors known to affect prognosis. It is unfortunate that hundreds of patients have been treated in uncontrolled studies. Randomized trials continue to be necessary to define this role and even then careful attention will have to be paid to the distribution of known prognostic factors in each group to insure a comparable cohort of patients. The response of melanoma to perfusion is clearly significant, however, and the response rate seems to be improved with hyperthermic perfusion. Hyperthermic perfusion appears to be a useful palliative treatment for locally advanced melanoma of the extremity, especially for which the alternative surgical therapy would be amputation

Prostate-specific antigen : a surrogate endpoint for screening new agents against prostate cancer?

Background. And endpoint for clinical trials of prostate cancer which simplifies traditional endpoints (response of measurable lesions, progression rates and death) is urgently needed. This is especially true for hormone-unresponsive disease for which may new drugs are presently in a development phase. This paper presents a rationale for the use of prostate-specific antigen (PSA) in clinical trials of progressive prostate cancer under endocrine treatment. Methods. The study is based on 84 patients who progressed after radical prostatectomy or node dissection, of whom 24 showed increasing PSA levels under subsequent endocrine treatment. An average linear relationship between (log-transformed) PSA and time and a subject-specific deviation from this average relationship were assessed. The predictive value of the subject-specific parameters of the linear fit with respect to time to prostate cancer-specific death was determined. The outcomes of the fitting procedure were used to calculate sample sized for future studies (duration, 6 months) using PSA increase over time in hormone-unresponsive prostate cancer as a marker for treatment efficacy.Results. The average PSA doubling time in this population was 4 months (corresponding time constant =0.25). The assessed variance of the time constants equalled 0.04; the overall residual variance equalled 0.265. The subject-specific rate of change of the log-transformed PSA value in hormone-unresponsive prostate cancer was a highly significant predictor of prostate cancer-specific death. This suggests the potential usefulness of PSA as an endpoint in trials of hormone-unresponsive prostate cancer. Depending on conditions chosen (e.g, desired power and changes in log PSA slope), 18-70 participants per arm will be necessary in future phase III studies. A suggestion (algorithm) for the use of PSA in drug development is presented. Conclusions. Relatively small PSA-based trials in patients with hormone-unresponsive prostate cancer are possible if a a similar patient population is utilized. As long as surrogacy is not established, such studies cannot be considered conclusive with respect to effectiveness of treatment, but are likely to be useful as a screening tool for new drugs. Experimental confirmation in human prostate cancer model systems of synergism between PSA decrease and tumor control by a given test treatment is likely to enhance the level of certainty of PSA-based drug evaluation

Menogaril : a new anthracycline agent entering clinical trials

Menogaril (menogarol, 7(R)-O-methylnogarol, 7-OMEN) is a new anthracycline agent which was chosen for clinical trials based on: a) broad spectrum activity against a panel of murine tumors, b) lower cardiotoxicity than doxorubicin in the chronic rabbit model, c) differences in biochemical effects from other anthracyclines suggesting a possible difference in mechanism of action, d) murine antitumor activity by oral as well as parenteal routes. Biochemical studies indicated that, in comparison to doxorubicin, menogaril is bound weakly to DNA, inhibits RNA synthesis less, and has different cell cycle phase-specific cytoxicity. Pharmacology studies in the mouse and dog using HPLC analytical methodology have shown multiexponential clearance from plasma and metabolism of menogaril to a material which co-chromatographs with N-demethylmenogaril in addition to at least two other metabolites of unknown structure. Oral bioavailability studies in the mouse showed significant absorption of menogaril from the grastrointestinal tract followed by first.pass metabolism. In acute toxicity studies in the rat, the dog, and the monkey, dose-related myelosuppression and gastrointestinal toxicity predominated. Phase I clinical trials on menogaril are currently in progress on a variety of schedules

Phase I-II study of high-dose epirubicin in advanced non-small cell lung cancer

Purpose: A phase I multicenter trial was performed to determine the maximum-tolerated dose (MTD) of epirubicin, given on 3 consecutive days every 3 weeks to previously untreated patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods: After appropriate staging and a baseline multiple-gated angiogram (MUGA) scan, at least four patients were entered at each dose level, starting at 35 mg/m2 of epirubicin given intravenously(IV) daily for 3 days (105 mg/m2) and escalating by 5 mg/m2 per injection in each dose level (15 mg/m2 per course). Epirubicine was administered up to a maximum dose of 60 mg/m2/d for 3 days (180 mg/m2). The MTD was determined to be 55 mg/m2/d for 3 days (165 mg/m2) after treating a total of 35 (33 assessable) patients. Nadir granulocyte counts and associated febrile episodes comprised the dose-limiting toxicity, but there were no treatment-related deaths. A phase II trial was performed using a dose of 50 mg/m2/d for 3 days (150 mg/m2) every 3 weeks with no dose escalation, but with dose reduction for toxicity as required. A total of 30 patients were entered onto this phase of the study. Results: The major toxicity, as in the phase I trial, was neutropenia with five febrile episodes, again with no-treatment-related deaths. An overall response rate of 12 of 63 (19 per cent) was noted in the combined patient population of the phase I-II trial, with 95 per cent confidence interval of 10 per cent to 31 per cent. When the response rate was analyzed by histology, only one of 17 (6 per cent) patients with squamous histology, as compared with 11 of 46 (24 per cent with non-squamous histology, responded, but this did not reach statistical significance (P=.15). Conclusions: High-dose epirubicin is tolerable and is an active single agent in NSCLC. It should be combined with relatively nonmyelosuppressive agents such as cisplatin to try to obtain higher response rates and extend the survival in this disease

Superior efficacy of letrozole versus tamoxifen as first.line therapy for postmenopausal women with advanced breast cancer : results of a phase III study of the International Letrozole Breast Cancer Group

Purpose: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. Patients and Methods: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor-and/or progesterone receptor-positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. Results: TTP was significantly longer for letrozole than for tamoxifen (median, 41 vs 26 weeks). Treatment with letrozole reduced the risk of progression by 30 per cent (hazard ratio, 0.70; 95 per cent confidence interval, 0.60 to 0.82, P=.0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median 40, 40 v 25 weeks). ORR was higher for letrozole (30 per cent v 20 per cent; P=.0006), as was the rate of clinical benefit (49 per cent v 38 per cent; P=.001). Survival data are currently immature and not reported here. Both treatments were well tolerated. Conclusion: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer