Prospective, randomized, double-blind, vehicle controlled, multicenter phase IIb clinical trial of the pore forming protein PRX302 for targeted treatment of symptomatic benign prostatic hyperplasia.

PURPOSE: We conducted a safety and efficacy evaluation of intraprostatic injection of PRX302, a modified pore forming protein (proaerolysin) activated by prostate specific antigen, as a highly targeted, localized approach to treat lower urinary tract symptoms due to benign prostatic hyperplasia. MATERIALS AND METHODS: A total of 92 patients with I-PSS (International Prostate Symptom Score) 15 or greater, peak urine flow 12 ml or less per second and prostate volume 30 to 100 ml were randomized 2:1 to a single ultrasound guided intraprostatic injection of PRX302 vs vehicle (placebo) in this phase IIb double-blind study. Injection was 20% of prostate volume and 0.6 µg PRX302 per gm prostate. Peak urine flow was determined by a blinded reviewer. Benign prostatic hyperplasia medications were prohibited. The primary data set of efficacy evaluable patients (73) was analyzed using last observation carried forward. RESULTS: PRX302 treatment resulted in an approximate 9-point reduction in I-PSS and 3 ml per second increase in peak urine flow that were statistically significant changes from baseline compared to vehicle. Efficacy was sustained for 12 months. Early withdrawal for other benign prostatic hyperplasia treatment was more common for patients in the vehicle group. Relative to vehicle, PRX302 apparent toxicity was mild, transient, and limited to local discomfort/pain and irritative urinary symptoms occurring in the first few days, with no effect on erectile function. CONCLUSIONS: A single administration of PRX302 as a short, outpatient based procedure was well tolerated in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. PRX302 produced clinically meaningful and statistically significant improvement in patient subjective (I-PSS) and quantitative objective (peak urine flow) measures sustained for 12 months. The side effect profile is favorable with most effects attributed to the injection itself and not related to drug toxicity.

Accelerated pharmacokinetics and glucodynamics of prandial insulins injected with recombinant human hyaluronidase.

BACKGROUND: This phase 1 study investigated the pharmacokinetics (PK) and glucodynamics of insulin lispro (Humalog; Eli Lilly and Co., Indianapolis, IN) or regular human insulin (Humulin R; Eli Lilly and Co.) administered with or without (+/-) recombinant human hyaluronidase (rHuPH20). METHODS: Healthy male volunteers (n = 26), 18-55 years old with body mass index 18-28 kg/m(2), weight >70 kg, and normal fasting glucose, were randomized to a crossover sequence of two subcutaneous injections, each followed by a 6-h euglycemic clamp targeting glucose 90-110 mg/dL: Cohort 1 received 20 U of Humalog +/- 300 U of rHuPH20 (11.3 microg/mL), whereas Cohort 2 received 20 U of Humulin R +/- 240 U of rHuPH20 (10 microg/mL). Pharmacokinetic parameters included peak serum insulin concentration (C(max)), time to C(max) (t(max)), and area under the curve (AUC) of serum concentration versus time. Glucodynamic parameters included time to maximal glucose infusion rate (tGIR(max)) and area under the GIR-versus-time curve (G). RESULTS: For Humalog and Humulin R, respectively, rHuPH20 co-administration reduced t(max) by 51% (P = 0.0006) and 58% (P = 0.0002), increased C(max) by 90% (P = 0.0003) and 142% (P < 0.0001), increased early exposure (AUC(0-2h)) by 85% (P < 0.0001) and 211% (P < 0.0001), and reduced late exposure (AUC(4-6h)) by 41% (P < 0.0001) and 48% (P < 0.0001). Similarly, rHuPH20 reduced tGIR(max) by 41% (P = 0.006) and 35% (P = 0.01), increased early metabolism (G(0-2h)) by 52% (P = 0.001) and 127% (P < 0.0001), and reduced late metabolism (G(4-6h)) by 29% (P = 0.002) and 26% (P = 0.03) for Humalog and Humulin R, respectively. Injections were well tolerated. CONCLUSIONS: Co-administration of rHuPH20 accelerated the PK and glucodynamics of both insulin formulations. Additional studies are necessary to evaluate the clinical relevance of these findings in patients with diabetes.

Comparison of the tolerability of recombinant human hyaluronidase + normal saline and recombinant human hyaluronidase + lactated ringer's solution administered subcutaneously: A phase IV, double-blind, randomized pilot study in healthy volunteers.

BACKGROUND: Recombinant human hyaluronidase (rHuPH20) (150 U) is approved by the US Food and Drug Administration to facilitate subcutaneous fluid administration in adults and children. OBJECTIVE: This Phase IV, double-blind, randomized pilot study was designed to compare the tolerability, flow rate, and safety profile of subcutaneous infusions of normal saline (NS) and lactated Ringer's (LR) solutions following subcutaneous administration of rHuPH20. METHODS: Healthy volunteers received 1 mL rHuPH20 (150 U) in each thigh, followed by simultaneous gravity-driven subcutaneous infusions of 500 mL of LR solution into 1 thigh and NS solution into the contralateral thigh. Subjects rated infusion-site discomfort in each thigh using a 100-mm (0 = no pain to 100 = most severe pain) visual analog scale (VAS) at baseline (ie, after catheter placement/ rHuPH20 injection and just prior to the start of the infusions) and at the following times: after infusion of 250 mL, after infusion of 500 mL (end of infusion), and when thigh circumference returned to within 5% of baseline. Adverse events (AEs) were recorded throughout the study. The primary tolerability end point was the maximal increase from baseline in infusion-site discomfort on the VAS. Secondary end points included infusion flow rate, change in thigh circumference, subject preference for leftversus right-thigh infusion, and safety profile measures. RESULTS: Fifteen subjects (14 women, 1 man; mean age, 41 years [range, 20-60 years]) were included in the study. Mean (SD) maximal increase from baseline VAS pain score was significantly greater with NS solution than with LR solution (20.0 [19.4] vs 9.4 [18.3] mm, respectively; P = 0.005). Mean infusion flow rate was not significantly different between the NS and LR solutions (384.1 [118.1] vs 395.8 [132.8] mL/h). No significant differences between solutions were observed in mean maximal change in thigh circumference (5.2% [1.6%] vs 5.3% [1.5%]). All subjects expressed global preference for LR infusion over NS infusion. All subjects experienced ≥1 AE; the majority of AEs were mild, localized infusion-site reactions. Of all AEs (regardless of their relationship to study drug or procedure), 81% were mild injectionsite reactions that were similar in nature for the NS and LR solutions. Although the types of mild local AEs were similar for the 2 infusions, they were numerically more common with NS infusions (15 subjects [100%]) than with LR infusions (9 subjects [60%]). For the NS and LR solutions, the most frequent infusion-site AEs were pain (67% vs 40%, respectively), erythema (47% vs 13%), and irritation (27% vs 20%). CONCLUSIONS: This small pilot study found that the mean maximal increase from baseline in self-assessed pain VAS scores was statistically significantly higher with NS solution than LR solution. In addition, all subjects preferred LR solution to NS solution, and the incidence of some infusion-site AEs was numerically greater with NS solution. Although the VAS score indicated a statistically significant difference in tolerability favoring LR, the modest changes from baseline suggest both solutions were generally well tolerated and support the use of both NS and LR, as appropriate, for rHuPH20-facilitated subcutaneous isotonic fluid infusion in healthy adults. These results need to be confirmed in larger, controlled clinical studies.

Assessing the role of human recombinant hyaluronidase in gravity-driven subcutaneous hydration: the INFUSE-LR study.

BACKGROUND: Subcutaneous hydration has potential advantages over intravenous. Despite studies supporting the efficacy and safety of subcutaneous hydration it has not been studied extensively to date either with or without hyaluronidase. OBJECTIVES: To compare flow rate, tolerability, and safety of gravity-driven subcutaneous fluid administration with and without recombinant human hyaluronidase (rHuPH20) in healthy volunteers. DESIGN: Randomized, double-blind, placebo-controlled, within-subject trial. SETTING: Contract research organization. PARTICIPANTS: Fifty-four volunteers. INTERVENTION: 24-gauge angiocatheters were placed subcutaneously in both upper arms. Each arm received rHuPH20 (150 U, 750 U, or 1500 U) or equal volume saline placebo. Immediately, 400 mL Lactated Ringer's (LR) solution was gravity-infused from a 100 cm height. In the pilot stage, 5 subjects also received a similar intravenous infusion. MEASUREMENTS: Primary outcome was time to infuse 400 mL LR. Secondary outcomes included discomfort assessments, edema, arm circumference, time to recover to baseline arm circumference, subject and investigator global preference, and adverse events. RESULTS: rHuPH20 150 U, 750 U, and 1500 U yielded mean flow rates of 383 +/- 119 mL/hr, 518 +/- 154 mL/hr, and 494 +/- 136 mL/hr, respectively, compared to their respective placebo rates of 82 +/- 30 mL/hr, 148 +/- 57 mL/hr, and 124 +/- 50 mL/hr. rHuPH20 was well tolerated. CONCLUSIONS: In volunteers, clinically relevant fluid volumes can be rapidly delivered subcutaneously with rHuPH20 in a well-tolerated manner without a pump. These findings suggest that this method of hydration could potentially replace intravenous infusions in many clinical settings; further studies with rHuPH20, in patients, are warranted.

Assessment and implication of the allergic sensitivity to a single dose of recombinant human hyaluronidase injection: a double-blind, placebo-controlled clinical trial.

Animal-extracted injectable hyaluronidases have been used safely for more than 50 years to increase the dispersion and absorption of coadministered drugs and fluids; however, concern still exists about the allergic and immunological risks of these products. Hylenex recombinant, a novel formulation of recombinant human hyaluronidase, has been developed as an alternative to these animal-derived hyaluronidases. Because recombinant human hyaluronidase is a human (nonforeign) protein manufactured into a purer preparation than the animal extracts, it is expected to convey reduced allergic and immunologic risks. The recombinant human hyaluronidase product was well tolerated in this double-blind, placebo-controlled, single-dose study. No allergic reactions were observed among the 100 volunteer subjects who were injected intradermally. These findings supported the US Food and Drug Administration approval of the recombinant human hyaluronidase product.

Multicenter phase II study of oral bexarotene for patients with metastatic breast cancer.

PURPOSE: Bexarotene is a retinoid X receptor-selective retinoid that has preclinical antitumor activity in breast cancer. We evaluated the efficacy and safety of oral bexarotene in the treatment of patients with metastatic breast cancer. PATIENTS AND METHODS: The following three groups of patients were treated: hormone-refractory, chemotherapy-refractory, and tamoxifen-resistant patients. Patients in the first two groups were treated with bexarotene alone, whereas the tamoxifen-resistant patients received both tamoxifen and bexarotene. Patients in all groups were randomly assigned to receive bexarotene at either 200 or 500 mg/m(2)/d. RESULTS: One hundred forty-eight patients were randomized; 145 patients were treated. Of 48 hormone-refractory patients, there were two partial responses (6%) and 10 patients with stable disease lasting more than 6 months; of 47 chemotherapy-refractory patients, there were two partial responses (6%) and five patients with stable disease; and of 51 tamoxifen-resistant patients, there was one partial response (3%) and 11 patients with stable disease. All partial responses occurred at the 200-mg/m(2)/d dose. The projected median time to progression across all of the arms was 8 to 10 weeks. There were no drug-related deaths, and only two patients had drug-related serious adverse events. The most common drug-related adverse events were hypertriglyceridemia (84%), dry skin (34%), asthenia (30%), and headache (27%). There were no cases of pancreatitis. CONCLUSION: The efficacy of bexarotene in patients with refractory metastatic breast cancer is limited. However, it is an oral agent with minimal toxicity and a unique mechanism of action, which produced clinical benefit in approximately 20% of patients. Future efforts should define populations likely to benefit from this agent.

Treatment of malignancy-associated hypercalcemia and cachexia with humanized anti-parathyroid hormone-related protein antibody.

Parathyroid hormone-related protein (PTHrP) plays a central role in humoral hypercalcemia of malignancy (HHM), which is one of the most frequent paraneoplastic syndromes. PTHrP produced by the tumor acts through a common PTH/PTHrP receptor to promote bone resorption, inhibit calcium excretion from the kidney, and induce hypercalcemia. Patients with HHM often develop cachexia associated with typical symptoms such as anorexia, malaise, nausea, constipation, polyuria, polydipsia, and confusion. The etiology of the cachexia is not fully understood but is thought to be caused by hypercalcemia and various cytokines such as interleukin-6, tumor necrosis factor-alpha, leukemia inhibitory factor, and others. In this study, we investigated the role of PTHrP in hypercalcemia and cachexia in HHM by using humanized anti-PTHrP antibody. A mouse monoclonal antibody that binds to PTHrP amino acid sequence 1-34 and inhibits PTHrP function has been humanized to create a specific and potent agent for the treatment of patients with HHM. The mouse monoclonal antibody has been shown to have antihypercalcemic activity against nude mice bearing human tumors. Because a mouse antibody is highly immunogenic in human patients, the complementarity-determining regions from the mouse antibody were grafted into a human antibody. The resulting humanized antibody specifically recognizes PTHrP(1-34) and neutralizes PTHrP functions in vitro and in vivo. The humanized anti-PTHrP antibody was administered intravenously to HHM model animals bearing tumors such as LC-6 human lung carcinoma. These animals showed symptoms similar to those of patients with HHM (eg, hypercalcemia and cachexia). The humanized anti-PTHrP antibody-treated animals responded with normalization of blood ionized calcium level through an improvement of bone metabolism and calcium excretion. Moreover, the treated animals also showed an improvement in body weight, ultromotivity, metabolic alkalosis, food consumption, water intake, serum phosphorus, and renal function. Consequently, the humanized antibody-treated animals experienced complete resolution of hypercalcemia and cachexia. These results suggest that the humanized antibody would be an effective and beneficial agent for patients with HHM, and that PTHrP is a major pathogenetic factor of hypercalcemia and cachexia in patients with HHM.

9-cis-retinoic acid capsules in the treatment of AIDS-related Kaposi sarcoma: results of a phase 2 multicenter clinical trial.

OBJECTIVE: To evaluate the safety, dose tolerance, and anti-tumor effects of 9-cis-retinoic acid in the treatment of Kaposi sarcoma (KS) related to acquired immunodeficiency syndrome (AIDS). DESIGN: Phase 2, open-label clinical trial of oral doses of 9-cis-retinoic acid increasing in 40-mg increments every 2 weeks from 60 mg/m(2) per day to a maximum of 140 mg/m( 2) per day. SETTING: Five hospital or health maintenance organization outpatient clinics. PATIENTS: Fifty-seven adult male patients with human immunodeficiency virus and biopsy-proven KS. MAIN OUTCOMES MEASURES: Safety was evaluated by adverse events, physical examination, laboratory test abnormalities, treatment-limiting toxic effects, and reasons for early withdrawal. Response (>/=50% improvement) was evaluated by an overall KS response and by the area and height from 6 index lesions selected at baseline. RESULTS: Patients tolerated 60 and 100 mg/m(2) per day. Most patients found 140 mg/m(2) per day intolerable owing to headache. Common treatment-related adverse events were headache, xerosis, rash, alopecia, and hyperlipemia. The patient response rate for the overall KS disease was 19% (11/57), including 1 patient with clinically complete response. The response rate assessed by measuring 6 index lesions during treatment was 39% (22/57). Sixteen responding patients (73%) were refractory to at least 1 previous anti-KS therapy. Patients with CD4( +) counts of 150 cells/ micro L or lower were as likely to respond as patients with counts of higher than 150 cells/ micro L. The median time to response was 8.5 weeks (range, 4.0-21.1 weeks). The median duration of treatment was 15.1 weeks (range, 0.14 to >/=62 weeks). CONCLUSION: 9-cis-retinoic acid capsules have moderate activity and provide durable responses, but substantial toxic effects at higher doses limit its suitability as an anti-KS therapy.

A phase II multicenter clinical trial of systemic bexarotene in psoriasis.

BACKGROUND: Bexarotene, a novel and unique synthetic P, RXR-selective retinoid, is available as a treatment for cutaneous T-cell lymphoma. In psoriasis, a common retinoid-sensitive disease, no data are available on bexarotene treatment. OBJECTIVE: In this phase II study we investigated the safety, tolerability, and effectiveness of bexarotene in psoriasis at doses of 0.5 to 3.0 mg/kg/day. METHODS: Fifty patients with moderate to severe plaque-type psoriasis were treated with bexarotene in 4 sequential dose-defined panels of 12-13 patients at doses of 1.0, 2.0, 0.5, and 3.0 mg/kg/day for 12-24 weeks. Patients were monitored for safety and clinical efficacy. RESULTS: No serious adverse events related to the drug occurred. Bexarotene was well tolerated in most patients. Most frequently observed adverse events related to bexarotene were hypertriglyceridaemia (56%) and a decrease in free T4 serum levels (54%). Significant improvement of psoriasis after bexarotene at all doses was confirmed by a modified psoriasis area and severity index (mPASI), plaque elevation (PEL), and physician's global assessment (PGA). Overall response rates (> or =50% improvement) for mPASI, PEL, and PGA were 22%, 52%, and 36%, respectively. No significant dose-response effect was established for these parameters. CONCLUSION: The present study indicates an anti-psoriatic effect of bexarotene. Further studies are necessary to assess the optimal dose and the potential for bexarotene as a new therapy for psoriasis.

The INFUSE-Morphine IIB study: use of recombinant human hyaluronidase (rHuPH20) to enhance the absorption of subcutaneous morphine in healthy volunteers.

Morphine is usually given intravenously (IV) for the treatment of moderate-to-severe pain, but subcutaneous (SC) administration is a viable alternative for parenteral delivery. The pharmacokinetics of SC morphine may be enhanced by coadministration with a hyaluronidase product. In this Phase IV, double-blind, randomized, crossover study, 18 healthy adults received a single dose of 2mg morphine SC with 150U of recombinant human hyaluronidase (rHuPH20), SC with 0.9% normal saline, or IV on three consecutive days. The primary endpoint was time to maximum plasma morphine concentration (T(max)) for SC injection with rHuPH20 vs. SC injection without rHuPH20. Safety and tolerability were assessed each study day, the day after the last injection, and 28 days after the last injection. After SC dosing, morphine mean T(max) was significantly shorter with rHuPH20 than without it. Mean maximum plasma morphine concentration (C(max)) after SC dosing was 29% greater with rHuPH20 than without rHuPH20 (P=0.023), although the extent of exposure of morphine was similar. T(max) was shortest and C(max) was highest with IV administration. For the major active metabolite of morphine, morphine-6-glucuronide, mean T(max) after SC morphine was significantly shorter with rHuPH20 than without rHuPH20 (a difference of approximately 17.5 minutes; P=0.0169). Coadministration of morphine with rHuPH20 appeared safe and well tolerated. Compared with SC morphine alone, rHuPH20 shortens morphine T(max) and raises C(max) in healthy adults, without changing the extent of exposure.

The INFUSE-Morphine study: use of recombinant human hyaluronidase (rHuPH20) to enhance the absorption of subcutaneously administered morphine in patients with advanced illness.

Morphine is often administered by the subcutaneous (SC) route when venous access is difficult to achieve. Hyaluronidase temporarily increases the permeability of SC connective tissues by degrading hyaluronan and has been shown to increase the dispersion and absorption of coadministered molecules. Therefore, hyaluronidase could enhance the pharmacokinetics of subcutaneous morphine. This Phase IIIB, double-blind, randomized, placebo-controlled crossover study compared the pharmacokinetics, safety, and tolerability of morphine administered SC with and without 150U of recombinant human hyaluronidase (rHuPH20) with those of intravenous (IV) morphine administration in 13 patients in a hospice or palliative care setting. Each patient received morphine 5mg parenterally daily for three days by a different method each day: IV, SC plus rHuPH20, and SC plus placebo (normal saline). The primary endpoint was the time to maximum plasma concentration (T(max)) for morphine. Concomitant SC administration of rHuPH20 enhanced the absorption rate of morphine compared with SC morphine with placebo, significantly reducing the mean T(max) from 13.8 to 9.2 minutes, a 33% decrease (P=0.026). The respective values for geometric mean maximum plasma concentration were 94.9 and 107.5nmol/L, a 13% increase (P=0.024), and the area under the plasma concentration vs. time curve values were 7.7 and 7.2micromol x min/L (P=0.23). Morphine plus rHuPH20 appeared to be safe and well tolerated. In patients requiring opioid analgesia, SC morphine plus rHuPH20 provides pharmacokinetic characteristics that are superior to those of SC morphine alone. These positive results warrant further studies on analgesic efficacy of morphine delivered with rHuPH20.

Topical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III clinical trial.

OBJECTIVES: We sought to determine the safety and efficacy of topical bexarotene (Targretin; Ligand Pharmaceuticals, La Jolla, Calif) gel 1% in patients with refractory or persistent early-stage cutaneous T-cell lymphoma. METHODS: We conducted a multinational, open-label, phase III study of 50 patients with stage IA to IIA cutaneous T-cell lymphoma. The primary end point classification was the overall complete and partial response rate by the higher of 2 measures: the Physician's Global Assessment of Clinical Condition or the Composite Assessment of Index Lesion Disease Severity. RESULTS: The overall response rates for the Physician's Global Assessment of Clinical Condition, Composite Assessment of Index Lesion Disease Severity, and primary end point classification were 44%, 46%, and 54%, respectively. The most common adverse events possibly related to study medication were mild to moderate irritant dermatitis, pruritus, pain (ie, primarily burning at application site), and skin disorder (eg, skin inflammation, excoriation, and new lesions). There were no serious treatment-related adverse events. CONCLUSIONS: Topical bexarotene gel was generally well tolerated and demonstrated substantial efficacy in patients with refractory or persistent early-stage cutaneous T-cell lymphoma.