Franklin Chu

A Clinical Study Of 22.5 mg. La-2550: A New Subcutaneous Depot Delivery System For Leuprolide Acetate For The Treatment Of Prostate Cancer

PURPOSEnThe safety, efficacy and pharmacokinetics of a unique 3-month subcutaneous depot of leuprolide acetate were investigated in patients with prostate cancer.nnnMATERIALS AND METHODSnThis open label, noncomparative, 6-month multicenter study enrolled 117 patients diagnosed with adenocarcinoma of the prostate. LA-2550 (22.5 mg. depot) (Atrix Laboratories, Fort Collins, Colorado) was administered subcutaneously once every 3 months. The primary efficacy parameter was serum testosterone 50 ng./dl. or less. Pharmacokinetics were analyzed in a subset of 22 patients.nnnRESULTSnOf the 117 enrolled patients 111 (98%) completed the 6-month study. Five patients withdrew for nontreatment related events and 1 was withdrawn because he received less than a full dose of the study drug. By day 28, 98% of patients had serum testosterone 50 ng./dl. or less and 84% had achieved 20 ng./dl. or less. By day 35 all patients had 50 ng./dl. or less testosterone. A patient with a breakthrough response after testosterone suppression on day 49 (112 ng./dl.) regained suppression (27 ng./dl.) 14 days after the second injection (day 98). At study completion all patients had 50 ng./dl. or less testosterone (mean plus or minus standard error of mean 10.1 +/- 0.07) and 104 of the 111 (94%) had 20 ng./dl. or less. From baseline to month 6 mean luteinizing hormone decreased from 9.2 +/- 1.1 to 0.08 +/- 0.01 mIU/ml. and mean prostate specific antigen decreased more than 98%. No flare reactions were observed and patient assessments of bone pain and urinary symptoms were unchanged. The most common treatment related adverse event was hot flashes, which were mild in 57% of cases, moderate in 12% and severe in 0%.nnnCONCLUSIONSnLA-2550 (22.5 mg. depot) produced and maintained safe and effective suppression of serum testosterone to well below the medical castrate level of 50 ng./dl. or less.

An eight-month clinical study of LA-2575 30.0 mg: a new 4-month, subcutaneous delivery system for leuprolide acetate in the treatment of prostate cancer

PURPOSEnThe safety, efficacy and pharmacokinetics of LA-2585, a new 6-month subcutaneous depot of leuprolide acetate (Atrix Laboratories, Fort Collins, Colorado) were investigated in patients with prostate cancer.nnnMATERIALS AND METHODSnIn this 12-month, open label, multicenter study 111 patients with adenocarcinoma of the prostate were administered 45.0 mg LA-2585 subcutaneously once every 6 months. The primary efficacy parameter was serum testosterone 50 ng/dl or less. Leuprolide acetate pharmacokinetics were analyzed in a subset of 28 patients.nnnRESULTSnOf the 111 enrolled patients 103 (93%) completed the 12-month study. Eight patients withdrew due to nonmedical reasons in 1, disease progression in 5 and cardiovascular disease in 2. By day 28, 108 of the 109 remaining patients (99%) achieved testosterone suppression, while 1 who never attained suppression was withdrawn at day 85. Mean time to castrate suppression was 21.2 days (median 21). At study completion 102 of 103 patients (99%) were below medical castrate testosterone levels of 50 ng/dl (mean +/- SE 12.3 +/- 2.1 ng/dl) with 91 of 103 (88%) at less than 20 ng/dl. Mean luteinizing hormone decreased from 6.98 +/- 0.48 mIU/ml at baseline to 0.23 +/- 0.14 mIU/ml at month 12. Luteinizing hormone was consistently below 1 mIU/ml. Mean prostate specific antigen decreased 97% from 39.8 +/- 21.5 ng/ml at baseline to 1.2 +/- 0.3 ng/ml at 12 months. No clinically significant flare reactions were observed. The most common treatment related adverse event was mild to moderate hot flashes.nnnCONCLUSIONSnLA-2585 (45.0 mg depot) consistently produced and maintained safe and effective serum testosterone suppression with total serum testosterone well below the medical castrate level of less than 50 ng/dl.

A six-month, open-label study assessing a new formulation of leuprolide 7.5 mg for suppression of testosterone in patients with prostate cancer

OBJECTIVEnThe safety, efficacy, and pharmacokinetics of monthly subcutaneous injections of a new leuprolide acetate (LA) depot formulation were investigated in patients with advanced prostate cancer.nnnMETHODSnThe 2-part, 6-month (168-day), open-label, multicenter study enrolled male patients diagnosed with adenocarcinoma of the prostate (Jewett stage C or D). LA-2500 7.5-mg (a new subcutaneous depot formulation containing 7.5 mg of LA) injections were administered at monthly (28-day) intervals. The primary efficacy parameter was total serum testosterone level. A breakthrough response was defined as a single testosterone measurement > 50 ng/dL after achieving castration testosterone levels. Testosterone was isolated from sera by alumina column chromatography and measured by radioimmunoassay (RIA). LA was purified by solid-phase extraction and high-performance liquid chromatography and was then quantitated by RIA.nnnRESULTSnOne hundred seventeen of the 120 enrolled patients completed the 6-month study. Three patients withdrew for reasons not related to treatment. LA had a mean (SD) maximal concentration of 26.3 (12.6) ng/mL at 4.66 (1.44) hours and was detected for a mean of 37 days (range, 28-49 days). By day 28, 94.1% (112/119) of the patients achieved medical castration (serum testosterone < or = 50 ng/dL). By day 42, 100.0% (118/118) of the patients remaining in the study had serum testosterone levels < or = 50 ng/dL and 97.5% (115/118) had levels < or = 20 ng/dL. At study completion, the mean (SD) serum testosterone level was 6.12 (4.3) ng/dL (range, 3.0-27.0 ng/dL). No breakthrough or acute-on-chronic responses were reported throughout the study. From baseline to month 6, mean (SD) luteinizing hormone level decreased from 8.0 (7.3) mIU/mL to 0.09(0.1) mIU/mL, and mean (SD) prostate-specific antigen level decreased from 32.9 (86.3) ng/mL to 3.2 (12.0) ng/mL. Treatment-related adverse events were reported by 74.2% (89/120) of patients, the most common being hot flashes (56.7%).nnnCONCLUSIONnThis 6-month, open-label, noncontrolled study showed LA-2500 7.5-mg depot was well tolerated and maintained testosterone suppression (< or = 50 ng/dL) in the patients completing the study without any testosterone breakthrough responses.

Abstract CT-07: ARMOR1: Safety of galeterone (TOK-001) in a Phase 1 clinical trial in chemotherapy naive patients with castration resistant prostate cancer (CRPC)

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, ILnnIntroduction: Galeterone is an orally available, semi-synthetic steroid analog for the treatment of castration-resistant prostate cancer (CRPC) that inhibits prostate cancer growth through a triple mechanism-of-action by: a) inhibiting CYP17 lyase activity; b) binding to and inhibiting the androgen receptor; and, c) degrading androgen receptor protein. ARMOR1, a phase I dose escalation study in men with chemotherapy naive CPRC, evaluated the safety of galeterone. Preliminary efficacy was also assessed by measuring changes in prostate-specific antigen (PSA) levels and tumor response. Methods: Forty-nine men with metastatic and non-metastatic chemotherapy-naive CRPC were enrolled in the ARMOR1 study. Patients were enrolled with confirmed adenocarcinoma of the prostate and disease progression during androgen ablation therapy. Patients ranged in age from 48 to 93 years old and had ECOG status of 0 or 1. Patients were randomized to one of eight dose escalation cohorts receiving galeterone capsules in single or split oral doses of 650, 975, 1300, 1950, or 2600mg daily for 12 weeks. After 12 weeks, eligible patients could continue treatment in an extension phase. Results: Maximum tolerated dose was not reached. The frequency of patients with Grade 1 and Grade 2 adverse events (AEs) reported by body system was 58% and 30% respectively. The most commonly reported AEs by patient were fatigue (36.7%), aspartate aminotransferase (AST) increase (32.7%), alanine aminotransferase (ALT) increase (30.6%), nausea (28.6%), diarrhea (26.5%), and pruritus (24.5%). Grade 2 and 3, transient, non-serious, elevations of liver function tests (LFTs) were observed in 15 patients with the majority being completely asymptomatic. Of these patients, 11 underwent drug interruptions, and 6 of 7 patients were successfully rechallenged and returned to treatment with no recurring Grade 3 or higher LFT elevations. Nine SAEs were reported in the study, with all except one unrelated to galeterone. The single, related, grade 4 case involved rhabdomyolysis that occurred in the setting of simvastatin therapy (40 mg qd) and underlying renal insufficiency. No events of adrenal mineralocorticoid excess (AME) were observed in this study. PSA reductions were seen in a majority of patients; 24 (49%) patients had >30% maximal PSA reductions, including 11 patients (22%) with >50% maximal PSA reductions. Conclusion: Galeterone was well tolerated, with all cohorts showing an acceptable safety profile. Galeterone also demonstrated activity in patients with CRPC. Additional long term safety will be further explored in a planned phase II study.nnCitation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr CT-07. doi:1538-7445.AM2012-CT-07

MP57-17 POLYMER DELIVERED, SUBCUTANEOUSLY ADMINISTERED LEUPROLIDE ACETATE PROVIDES STABLE AND LONG-TERM DRUG DELIVERY AND TESTOSTERONE SUPPRESSION ACROSS 4 PIVOTAL TRIALS

INTRODUCTION AND OBJECTIVES: The presence of metabolic syndrome in men with prostate cancer (PCa) undergoing androgen-deprivation therapy (ADT), especially intermittent type, has not been completely evaluated. The aim of this study is to evaluate metabolic syndrome in men with PCa undergoing intermittent ADT. METHODS: In this longitudinal study, we studied the prevalence of metabolic syndrome and its components in 190 patients who were undergoing intermittent ADT. The metabolic syndrome was defined according to the Adult Treatment Panel III criteria. All metabolic parameters, including lipid profile, blood glucose, blood pressures, and waist circumferences of the patients were measured six and 12 months after treatment. RESULTS: Mean age of the patients was 67.5 6.74 years. The incidence of metabolic syndrome after six and 12 months was 6.8% and 14.7%, respectively. Analysis of various components of the metabolic syndrome revealed that patients had significantly higher overall prevalence of hyperglycemia, abdominal obesity, and hypertriglyceridemia in their sixand 12-month follow ups, but blood pressure has not been changed in the same period except for diastolic blood pressure after six months. CONCLUSIONS: Although there was an increased risk of metabolic syndrome in patients receiving intermittent ADT, it was lower than other studies that treated the same patients with continuous ADT. Also it seems that intermittent ADT has less metabolic complications than continuous ADT and could be used as a safe alternative in patients with advanced and metastatic PCa.

Polymer delivered, subcutaneously administered leuprolide acetate provides stable and long-term drug delivery and testosterone suppression in 4 pivotal trials.

e592Background: Prostate cancer patients receive androgen deprivation therapy (ADT) to suppress testosterone (T) to prevent proliferation of cancer cells. T suppression levels achieved by bilateral orchiectomy remain the gold standard for the target of suppression by ADT. Although the historical threshold definition of castration is T ≤ 50 ng/dL, increasing evidence suggests T lower than 20ng/dL may improve clinical outcomes, e.g., an increased cancer specific survival and delayed disease progression. To determine the minimal threshold of serum leuprolide required to maintain castrate level T suppression in prostate cancer patients, data from 4 pivotal trials evaluating long-acting, subcutaneously (SC) administered leuprolide acetate (LA) formulated with a biodegradable polymer were pooled. Methods: 438 eugonadal prostate cancer patients (age 40-86) were treated with SC-LA at 7.5, 22.5, 30, or 45mg delivered with a single dose lasting over 1, 3, 4, or 6 months (n = 120, 117, 90, 111), respectively in 4 op...