Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer.

PURPOSE: Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study. EXPERIMENTAL DESIGN: In ARMOR1, 49 patients received increasing doses (650-2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700-3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed. RESULTS: In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ≥50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events. CONCLUSIONS: The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition.

Phase II study of vinorelbine and low-dose docetaxel in chemotherapy-naive patients with hormone-refractory prostate cancer.

PURPOSE: Vinorelbine, a semisynthetic vinca alkaloid, and docetaxel, a semisynthetic taxane, are active single agents in hormone-refractory prostate cancer and have demonstrated synergy in tumor cell lines and animal models. This study was designed to assess the efficacy and tolerability of vinorelbine and low-dose docetaxel in chemotherapy-naive, hormone-refractory prostate cancer patients whose disease had progressed after withdrawal from anti-androgens, despite castrate testosterone levels. PATIENTS AND METHODS: Patients with histologically confirmed hormone-refractory prostate cancer despite testosterone levels < or = 50 ng/mL, Karnofsky performance status > 70, and adequate bone marrow reserve were enrolled. They received vinorelbine, 20 mg/m2, followed by docetaxel, 25 mg/m2, on days 1 and 8 of a 21-day cycle. Tumor response was defined by prespecified reductions from baseline prostate-specific antigen levels or bidimensionally measurable disease. Adjustments in the dose of either agent were based on > or = grade 2 toxicity according to standard criteria. RESULTS: Twenty-one patients with a mean age of 76 years (range, 60-83 years) and a median prostate-specific antigen level of 116 ng/mL (range, 10.4-4,262 ng/mL) were enrolled and received a total of 152 courses (median, 7.5 courses) of vinorelbine and docetaxel. Of the 19 patients who were evaluable for biochemical response, prostate-specific antigen reductions from baseline of > 75%, > or = 50% to < or = 75%, and < 50% were observed in eight, three, and seven patients, respectively (median prostate-specific antigen decrease, 60% +/- 31%). Of five patients with measurable disease, three were evaluable: one patient had a complete response, and two had partial responses at the site of measurable disease. The vinorelbine/docetaxel doublet was generally well tolerated. In the first two cycles of therapy, six patients had grade 3 and eight patients had grade 4 neutropenia as their worst-grade toxicities; all cases were manageable with granulocyte colony stimulating factor support. Acute respiratory distress syndrome was observed in one patient. There were few dose reductions or interruptions. DISCUSSION: Vinorelbine, 20 mg/m2, and low-dose docetaxel, 25 mg/m2, given on days 1 and 8 every 21 days, is a well-tolerated regimen with biochemical and objective response rates comparable to standard therapies in patients with hormone-refractory prostate cancer. A multicenter, randomized trial is under way to compare vinorelbine plus low-dose docetaxel with estramustine plus higher-dose docetaxel (60 mg/m2).

Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2(+) metastatic breast cancer.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) overexpression is associated with a more aggressive form of breast cancer that responds well to trastuzumab therapy. Trastuzumab-based combination regimens have shown greater antitumor activity than chemotherapy alone. These findings, coupled with the favorable antitumor activity and tolerability profile of vinorelbine in breast cancer, provided the rationale for investigating the novel combination of vinorelbine and trastuzumab. PATIENTS AND METHODS: A phase II, open-label trial of intravenous vinorelbine (30 mg/m(2) on day 1, then weekly) and trastuzumab (4 mg/kg on day 0, then 2 mg/kg weekly) was conducted in previously untreated HER2(+) metastatic breast cancer patients. Vinorelbine dose was adjusted for grade 3/4 neutropenia; patients remained on combination therapy until disease progression or patient withdrawal due to adverse events. RESULTS: Of 40 enrolled patients (median age 51 years, range 30-82), 37 were evaluable for response. Overall response rate was 78% (29/37, 95% confidence interval [CI] 62%-90%), including four (11%, 95% CI 3%-25%) complete and 25 (68%) partial responses. Objective tumor response correlated with degree of HER2 positivity: immunohistochemistry (IHC) 3(+) = 82% (18/22) response and IHC 2(+) = 58% (7/12) response. Median time to progression was 72 weeks (95% CI 37-138 weeks); median survival has not been reached. Grade 3/4 neutropenia was the most frequent serious toxicity and cause of dose reductions (9% of courses) and omissions (10% of courses). No patient experienced serious cardiac toxicity. CONCLUSIONS: Weekly vinorelbine/trastuzumab offers a high therapeutic index as initial therapy in patients with HER2(+) metastatic breast cancer. Further investigation of this novel regimen is planned.

Second Neoplasms in Patients With Hodgkin's Disease Following Combined Modality Therapy-The Yale Experience.

In the article by Koletsky et al "Second Neoplasms in Patients With Hodgkin's Disease Following Combined Modality Therapy-The Yale Experience" (Journal of Clinical Oncology 4:311-317, 1986), an error was made in the footnote on page 311 which described the composition of MVVPP. The corrected footnote appears below. *MVVPP = nitrogen mustard (0.4 mg/kg on day 1 of cycle); vinblastine (6 mg/m2 on days 22, 29, and 36); vincristine (1.4 mg/m2, 2 mg maximum dose, on days 1, 8, and 15); procarbazine (100 mg/d on days 22 through 42); prednisone (40 mg/m2 on days 1 through 15 for cycles 1, 3, and 5 only).