Tracy Curley

Phase I Study of an Oral Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid, in Patients With Advanced Cancer

PURPOSE To determine the safety, dosing schedules, pharmacokinetic profile, and biologic effect of orally administered histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with advanced cancer. PATIENTS AND METHODS Patients with solid and hematologic malignancies were treated with oral SAHA administered once or twice a day on a continuous basis or twice daily for 3 consecutive days per week. Pharmacokinetic profile and bioavailibity of oral SAHA were determined. Western blots and enzyme-linked immunosorbent assays of histones isolated from peripheral-blood mononuclear cells (PBMNCs) pre and post-therapy were performed to evaluate target inhibition. RESULTS Seventy-three patients were treated with oral SAHA and major dose-limiting toxicities were anorexia, dehydration, diarrhea, and fatigue. The maximum tolerated dose was 400 mg qd and 200 mg bid for continuous daily dosing and 300 mg bid for 3 consecutive days per week dosing. Oral SAHA had linear pharmacokinetics from 200 to 600 mg, with an apparent half-life ranging from 91 to 127 minutes and 43% oral bioavailability. Histones isolated from PBMNCs showed consistent accumulation of acetylated histones post-therapy, and enzyme-linked immunosorbent assay demonstrated a trend towards a dose-dependent accumulation of acetylated histones from 200 to 600 mg of oral SAHA. There was one complete response, three partial responses, two unconfirmed partial responses, and 22 (30%) patients remained on study for 4 to 37+ months. CONCLUSIONS Oral SAHA has linear pharmacokinetics and good bioavailability, inhibits histone deacetylase activity in PBMNCs, can be safely administered chronically, and has a broad range of antitumor activity.

Multi-Institutional Randomized Phase II Trial of the Epothilone B Analog Ixabepilone (BMS-247550) With or Without Estramustine Phosphate in Patients With Progressive Castrate Metastatic Prostate Cancer

PURPOSE To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer. PATIENTS AND METHODS Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5. RESULTS Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm. CONCLUSION Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

Estramustine and vinblastine: use of prostate specific antigen as a clinical trial end point for hormone refractory prostatic cancer.

The combination of estramustine phosphate and vinblastine sulfate, 2 agents with separate and unique antimicrotubular effects, has demonstrated additive cytotoxicity against the DU145 human prostate derived cell line in vitro. We evaluated this combination in 25 patients with progressive hormone refractory prostate cancer. Of 24 patients with an elevated prostate specific antigen (PSA) level at the start of treatment 13 (54%, 95% confidence limits 34 to 74%) had a greater than 50% decrease in PSA levels on at least 3 consecutive biweekly determinations. The median decrease in PSA in responding patients was 64% (mean 71.7%) and the median duration of response was 7 months. In 5 patients with bidimensionally measurable disease 2 partial responses were observed. Treatment was well tolerated, with mild and manageable toxicity. This is a well tolerated outpatient treatment regimen for patients with hormone-refractory prostatic cancer which deserves further investigation.

Paclitaxel, Estramustine Phosphate, and Carboplatin in Patients With Advanced Prostate Cancer

PURPOSE To determine the safety and activity of weekly paclitaxel in combination with estramustine and carboplatin (TEC) in patients with advanced prostate cancer. PATIENTS AND METHODS In a dose-escalation study, patients with advanced prostate cancer were administered paclitaxel (weekly 1-hour infusions of 60 to 100 mg/m(2)), oral estramustine (10 mg/kg), and carboplatin (area under the curve, 6 mg/mL-min every 4 weeks). Paclitaxel levels were determined 0, 30, 60, 90, and 120 minutes and 18 hours after infusion, and a concentration-time curve was estimated. Once a safe dose was established, a multi-institutional phase II trial was conducted in patients with progressive androgen-independent disease. RESULTS Fifty-six patients with progressive androgen-independent disease were treated for a median of four cycles. The dose of paclitaxel was escalated from 60 to 100 mg/m(2) without the occurrence of DLT. Posttherapy decreases in serum prostate-specific antigen levels of 50%, 80%, and 90% were seen in 67%, 48%, and 39% (95% confidence interval, 55% to 79%, 35% to 61%, 26% to 52%) of the patients, respectively. Of the 33 patients with measurable disease, two (6%) had a complete response and 13 (39%) had a partial response. The overall median time to progression was 21 weeks, and the median survival time for all patients was 19.9 months. Major grade 3 or 4 adverse effects were thromboembolic disease (in 25% of patients), hyperglycemia (in 38%), and hypophosphatemia (in 42%). Significant leukopenia, thrombocytopenia, and peripheral neuropathy were not observed. CONCLUSION TEC has significant antitumor activity and is well tolerated in patients with progressive androgen-independent prostate cancer.

Phase I Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Advanced Cancer

Purpose: To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules. Experimental Design: Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m2 daily for 5 days with cycles repeated every 21 days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily × 3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1 and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies. Results: Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m2 on the daily × 5 schedule; 112 mg/m2 on the daily × 3 schedule; and 220 mg/m2 on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily × 5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1 were observed in biomarker studies. Conclusion: The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies.

Pilot Trial of Unlabeled and Indium-111–Labeled Anti–Prostate-Specific Membrane Antigen Antibody J591 for Castrate Metastatic Prostate Cancer

Background: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591 is an IgG1 monoclonal antibody that targets the external domain of the PSMA. The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591 has not been explored. Patients and Methods: Patients with progressive metastatic prostate cancer despite androgen deprivation were eligible. Each patient received 10, 25, 50, and 100 mg of J591. Two milligrams of antibody, conjugated with the chelate 1,4,7,10-tetraazacyclododecane-N, N′,N″,N‴-tetraacetic acid, were labeled with 5 mCi indium-111 (111In) as a tracer. One group of patients received unlabeled J591 before the labeled antibody; the other received both together. Toxicities, pharmacokinetic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects were assessed. Results: Fourteen patients were treated (seven in each group). Treatment was well tolerated. Biodistribution of 111In-labeled J591 was comparable in both groups. The mean T1/2 was .96, 1.9, 2.75, and 3.47 days for the 10, 25, 50, and 100 mg doses, respectively. Selective targeting of 111In-labeled J591 to tumor was seen. Hepatic saturation occurred by the 25-mg dose. ADCC activity was proportional to dose. One patient showed a >50% prostate-specific antigen decline. Conclusions: J591 is well tolerated in repetitive dose-escalating administrations. The rate of serum clearance decreases with increasing antibody mass. ADCC activation is proportional to antibody mass. The optimal dose is 25 mg for radioimmunotherapy and 100 mg for immunotherapy. Phase II studies using J591 as a radioconjugate are under way.

Prospective evaluation of hydrocortisone and suramin in patients with androgen-independent prostate cancer.

PURPOSE To assess efficacy of intermittent infusion of suramin in patients with androgen-independent prostate cancer who have had disease progression on hydrocortisone. PATIENTS AND METHODS Chemotherapy-naive patients with progressive androgen-independent prostate cancer were given hydrocortisone 40 mg/d and monitored for treatment effect. At the time of disease progression, suramin was administered on a pharmacokinetically derived, 2-week dosing schedule. RESULTS Thirty patients with a median Karnofsky performance status (KPS) of 90% were treated with hydrocortisone. No responses were seen in 12 patients with measurable disease or 29 patients with abnormal bone scans. Thirty patients had an increasing prostate-specific antigen (PSA) level before treatment and six (20%) had a more than 50% decline in PSA from the baseline value for a median of 16 weeks (range, 12 to 52+). Twenty-eight patients had disease progression after a median of 7 weeks (range, 3 to 23), and two patients have continued to receive hydrocortisone for 44 and 52 weeks. Twenty-eight patients received hydrocortisone and suramin, with median suramin concentrations of 97 to 170 micrograms/mL for 4 weeks. No responses in measurable disease and no improvements in bone scans were seen. Five patients (18%) showed a more than 50% decline in PSA levels from baseline, of whom three had previously responded to hydrocortisone. Only two of 24 patients who did not show a posttherapy decline in PSA levels after hydrocortisone had a reduction in PSA levels with the addition of suramin. Toxicity profiles were acceptable with each agent, although a higher proportion of subjects showed hematologic, cardiac, and neurologic events when suramin was added. CONCLUSION Suramin has limited efficacy in patients with androgen-independent prostate cancer who have had disease progression after hydrocortisone.

Dose-intensification of MVAC with recombinant granulocyte colony-stimulating factor as initial therapy in advanced urothelial cancer.

PURPOSE This study was undertaken to define an escalated dose schedule of methotrexate, vinblastine, doxorubicin, and cisplatin (E-MVAC) with hematopoietic growth-factor support, to define the ability to deliver E-MVAC with recombinant human granulocyte colony-stimulating factor (rhG-CSF) on 21- and 14-day schedules, and to assess the ability of rhG-CSF to maintain dose-intensity over four cycles of chemotherapy. PATIENTS AND METHODS Twenty-three patients with transitional-cell carcinoma of the urothelium received E-MVAC in a phase I investigation. Patients were treated on an every-21-day (n = 19) or every-14-day schedule of administration (n = 4), with rhG-CSF support. Delivered dose-intensity was calculated at the completion of four cycles of therapy relative to the planned administration of conventional MVAC (relative dose-intensity [RDI]). Peripheral-blood progenitor cell kinetics in these patients were studied prospectively. RESULTS Overall, the delivered RDI was 33% higher than the previously reported delivered dose-intensity of MVAC without hematopoietic support (140% for doxorubicin, 51% for cisplatin). Dose-intensity was well maintained through three cycles of therapy, after which leukopenia and thrombocytopenia became dose-limiting. Sixty-nine percent of patients with measurable disease responded, four (25%) with complete remissions. In five patients treated beyond the maximally tolerated dose (MTD), a 50- to 200-fold increase in G-CSF, granulocyte-macrophage CSF (GM-CSF), and interleukin-3 (IL-3)-responsive peripheral-blood progenitor cells over baseline was observed after 9 days of rhG-CSF administration. CONCLUSION These findings demonstrate the feasibility and limitations of dose intensification of M-VAC with rhG-CSF. While the overall impact of the increased drug administration can only be assessed in randomized comparisons, the results of the present trial suggest that escalations of the components of the four-drug regimen are unlikely to improve significantly the outcome for patients with advanced urothelial tract tumors.

Phase I Study of Samarium-153 Lexidronam With Docetaxel in Castration-Resistant Metastatic Prostate Cancer

PURPOSE Early studies of patients with castration-resistant metastatic prostate cancer (CRMPC) suggest that chemotherapy administered with a dose of a bone-seeking radiopharmaceutical is superior to chemotherapy alone. To build on this strategy and fully integrate a repetitively dosed bone-seeking radiopharmaceutical into a contemporary chemotherapy regimen, we conducted a phase I study of docetaxel and samarium-153 ((153)Sm) lexidronam. PATIENTS AND METHODS Men with progressive CRMPC were eligible. Cohorts of three to six patients were defined by dose escalations as follows: docetaxel 65, 70, 75, 75, 75 mg/m(2) and (153)Sm ethylenediaminetetramethylenephosphonate (EDTMP) 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle lasted a minimum of 6 (cohorts 1 through 5) or 9 (cohort 6) weeks. Docetaxel was administered on days 1 and 22 (and day 43 for cohort 6), and (153)Sm-EDTMP was administered on day -1 to 1 of each cycle. Patients with acceptable hematologic toxicities were eligible to receive additional cycles until progression. RESULTS Twenty-eight men were treated in six cohorts. Maximum-tolerated dose was not reached, because full doses of both agents were well tolerated, even using an every-6-week dosing schedule of (153)Sm-EDTMP. Patients received an average of 5.6 docetaxel doses (range, one to 13 doses) and 2.9 (153)Sm-EDTMP doses (range, one to six doses). Fifteen patients demonstrated a more than 50% decline in prostate-specific antigen. Treatment significantly reduced indices of bone deposition and resorption. CONCLUSION Docetaxel and (153)Sm-EDTMP can be combined safely at full doses over repeated cycles. Responses were seen in the small group of patients with taxane-resistant disease tested. The optimal phase II doses for patients with taxane-naïve disease may differ from those optimal for patients with taxane-resistant disease.

Palliative hemiskeletal irradiation for widespread metastatic prostate cancer: A comparison of single dose and fractionated regimens

Between 1986 and 1987 patients with hormone refractory metastatic adenocarcinoma of the prostate were treated with hemiskeletal irradiation. One group of 15 patients was treated with a fractionated regimen of 2500-3000 cGy in 9 to 10 fractions. A second group of 14 patients received a single dose of 600 cGy or 800 cGy depending upon whether the upper or lower hemiskeleton was irradiated. Both groups were similar with respect to their initial Karnofsky performance status and extent of disease. With the exception of one patient in the single dose group, all patients treated achieved complete or partial relief shortly after completion of their respective courses of therapy. Of the patients treated with single dose therapy, 10 of 14 (71%) ultimately needed retreatment in the region initially irradiated because of recurrent bone pain or spinal cord compression. In contrast, only 2 of 15 (13%) of the patients receiving the fractionated treatment course needed retreatment (p = .001). Although the median survival of both groups from the time of initial treatments was similar (10 and 11 months), the median duration for palliation was greater for those patients receiving the fractionated regimen as compared with single dose therapy (8.5 months vs 2.8 months). The incidence of treatment related toxicity was similar for both groups. We conclude that fractionated hemiskeletal radiation is a more effective means of palliation when compared to single dose therapy.