Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer.

INTRODUCTION: Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours. METHODS: This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer. RESULTS: Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m(-2) on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1-147.3 weeks). Common treatment-emergent adverse events (all grades/grade ≥3) included diarrhoea (92%/29%; none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9-81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan-Meier median progression-free survival was 57.0 weeks (95% CI: 47.7-81.6 weeks). Pharmacokinetic analyses indicated no interaction between neratinib and paclitaxel. CONCLUSION: The combination of neratinib and paclitaxel was associated with higher toxicity than that of neratinib as a single agent, but was manageable with antidiarrhoeal agents and dose reductions in general. The combination therapy also demonstrated a high rate of response in patients with HER2-positive breast cancer. A phase III trial is ongoing to assess the benefit and risk of this combination in the first-line setting.

Epirubicin and ifosfamide in advanced soft tissue sarcoma: a phase II study.

Thirty patients with previously untreated and measurable or evaluable advanced soft tissue sarcoma entered this phase II study. Median age was 53 years (range: 24-71 years). Starting dose of Epirubicin was 100 mg/m2 IV bolus on day 1 combined with Ifosfamide, 2.5 g/m2, as a 6-hr IV infusion on day 1 and day 2 with uroprotection with Uromitexan, 1.6 g/m2, on day 1 and day 2. This schedule was repeated every 3 weeks. In case of minimal myelosuppression, the dose of Epirubicin was increased by 10 mg/m2 up to 130 mg/m2. Ifosfamide dosage was not increased. Mean cumulative dose of Epirubicin received was 477 +/- 272 mg/m2 (range: 200-1200 mg/m2). Of 27 evaluable patients (WHO criteria), 13 had a partial response (48%), 4 showed no change (15%), and 10 had progressive disease (37%). Median time to progression was 27 weeks. Of 27 patients evaluable for toxicity, hematological toxicity at day 21 was mild. Nonhematological toxicities consisted of nausea and vomiting in 82% of patients (WHO grade 3-4 = 19%), stomatitis in 44.5% (WHO grade 3 = 7.5%), and alopecia in 96% (WHO grade 2-3 = 89%). Appearance of cardiac dysfunction without heart failure during the treatment led to discontinuation of this chemotherapy in 3 patients. The results of this study show that the combination of Epirubicin and Ifosfamide is effective in advanced soft tissue sarcoma with an acceptable toxicity. However, we cannot conclude from this trial whether combination Epirubicin and Ifosfamide is superior to Epirubicin alone.

Premenopausal patients with node-positive resectable breast cancer. Preliminary results of a randomised trial comparing 3 adjuvant regimens: FEC 50 x 6 cycles vs FEC 50 x 3 cycles vs FEC 75 x 3 cycles. The French Adjuvant Study Group.

Anthracyclines are among the most active drugs for the treatment of advanced breast cancer. Epirubicin has been found to be as effective as doxorubicin at equimolar doses but significantly better tolerated, especially in terms of alopecia, leucopenia, and cardiac toxicity. The role of anthracycline-containing regimens in adjuvant treatment of breast cancer has been studied by only a few clinical trial teams. In 1986, the French Adjuvant Study Group (FASG) began a randomised trial aimed to investigate the concept of dose intensity as well as the optimal duration of treatment in patients with early breast cancer. Between 1986 and 1990, 621 patients were included in the trial, of whom 595 were evaluable. Patients were randomised to 1 of 3 treatment groups: Group A (n = 207) received FEC 50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2 plus cyclophosphamide 500 mg/m2) every 21 days for 6 cycles; Group B (n = 193) received FEC 50 every 21 days for 3 cycles; Group C (n = 195) received FEC 75 (fluorouracil 500 mg/m2, epirubicin 75 mg/m2 plus cyclophosphamide 500 mg/m2) every 21 days for 3 cycles. Locoregional radiotherapy was administered after the third cycle of chemotherapy in all treatment arms. Clinical prognostic factors were similar between treatment groups. Approximately 62% of all patients had 1 to 3 positive lymph nodes; 50% of patients were hormone receptor positive and 73% were Scarff-Bloom Richardson (SBR) grade 2 to 3. Toxicity was evaluated in 595 patients (207, 193 and 195 patients in Groups A, B and C, respectively), who received a total of 2301 chemotherapy cycles.(ABSTRACT TRUNCATED AT 250 WORDS)

Improved bioavailability of a new oral preparation of medroxyprogesterone acetate.

Medroxyprogesterone acetate (MPA) is widely used in the hormonal therapy of breast cancer. So far, oral formulations of MPA commercially available present a very low bioavailability, with a less than 10% extent of oral absorption. A new oral preparation of MPA has been recently developed. Based on a pilot study, an open, randomized, crossover trial has been performed on 22 breast and endometrial cancer patients to evaluate the relative bioavailability of this new oral formulation (200-mg sachet, twice daily) as compared with a standard formulation (Farlutal, 500-mg tablet, twice daily). The bioavailability evaluation was mainly based on the area under the curve measured between two administrations at steady state, after 15 days of continuous therapy. Wide interpatient variability of MPA plasma levels after oral MPA administration was confirmed. The MPA plasma levels were higher in patients treated with the new formulation than in patients treated with Farlutal. The relative bioavailability of the new preparation was 3.5 times higher than that of the standard. This new formulation represents a great improvement in the extent of oral absorption of MPA and could lead to better management of hormone-responsive tumors by hormonal therapy.

Phase II study of epirubicin in advanced soft tissue sarcoma.

Thirty-seven patients (pts) with previously untreated and measurable advanced soft tissue sarcoma entered this phase II study: 22 men and 15 women were included. Median age was 58 (range: 20-71). The starting dose of epirubicin was 100 mg/m2 IV bolus every 3 wks. In the case of minimal myelosuppression, the dose was increased by 10 mg/m2 to 130 mg/m2 (Mean dose per cycle: 105 mg/m2). Median cumulative dose of epirubicin administered was 445 mg/m2 (range: 200-1320 mg/m2). From 32 evaluable pts, one had a complete response (CR), 5 a partial response (PR), (CR + PR = 18.7% +/- 13.8%), 12 showed no change (37.5%) and 14 had progressive disease. The number of complete or partial responses observed was not modified by increasing the doses of epirubicin. Median time to progression was 4 months. From 32 pts evaluable for toxicity, hematologic toxicity at d 21 was mild. Non hematological toxicities consisted of nausea and vomiting in 74% of pts (WHO grade 3 = 5%), stomatitis in 12.2% (WHO grade 3 = 3%) and alopecia in 91% (WHO grade 2-3 = 72%). No cardiac dysfunction was recorded during the treatment, even though 7 patients received more than 800 mg/m2 of epirubicin (median: 850 mg/m2, range: 810-1320 mg/m2). The results of this study show that epirubicin is an active drug in advanced soft tissue sarcoma.

[An analog of gonadoliberin in the treatment of prostatic carcinoma]. / Un analogue de la gonadolibérine dans le traitement des carcinomes prostatiques.

Twenty-five patients with prostatic carcinoma were involved in a Gehan's oriented phase II trial of D-Trp6-LH-RH in daily doses of 500 mcg for 7 days and 100 mcg for 3 months, this lapse of time being considered optimal for evaluation of the short-term response to treatment in this disease. Serum levels of LH and testosterone decreased rapidly. After 3 months of treatment, pain had disappeared in 14/21 patients; urinary symptoms had completely regressed in 10/22 patients and partially regressed in 9. A more than 50% reduction in prostatic enlargement was detected by ultrasonography in 7/19 patients, and the overall proportion of regression at scintigraphy was 43%. Prostatic acid phosphatases decreased by more than 50% in 10/15 patients. The results obtained with this LH-RH agonist were equivalent to those of orchidectomy and oestrogen therapy. The new drug was well tolerated. Although some of the patients treated are still responding after more than 15 months of treatment, further studies are required to evaluate the duration of response.

An oriented phase-II trial of D-Trp6-LH-RH in patients with prostatic carcinoma.

An oriented phase II trial of D-Trp6-LH-RH was conducted according to Gehan's statistical method on 25 patients suffering from prostatic carcinoma. LH and testosterone serum levels decreased rapidly. Pain disappeared during the third month in 14 out of the 21 patients and markedly decreased in 5. Prostatism completely regressed in 10 out of the 22 subjects presenting it and markedly decreased in 9. Prostate hypertrophy regressed, as shown by ultrasonography, in 84% and by more than 50% in 37% of the patients. The overall regression rate of bone scintigraphy images was 43%; a regression of more than 50% was only registered in 12.5% of the patients; this may be explained by the long time which is necessary before bone image disappearance occurs. Prostatic acid phosphatase levels regressed in 75% and by more than 50% in 66.7% of the patients.