HTX-019 via 2-min injection or 30-min infusion in healthy subjects.

Aim: HTX-019 (CINVANTI [aprepitant injectable emulsion]) is a neurokinin 1 receptor antagonist approved for preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV). HTX-019 is free of polysorbate 80 and other synthetic surfactants and showed bioequivalence to and a more favorable safety profile than fosaprepitant when administered as a 30-min infusion in healthy subjects. The shortage of small-volume parenteral solutions led to a recommendation to administer HTX-019 by intravenous push.

Hypersensitivity and infusion-site adverse events with intravenous fosaprepitant after anthracycline-containing chemotherapy: a retrospective study.

Aim: Fosaprepitant, an intravenous neurokinin-1 receptor antagonist for chemotherapy-induced nausea and vomiting, contains polysorbate 80, which is associated with infusion-site adverse events (ISAEs) and hypersensitivity systemic reactions (HSRs). This study investigated ISAEs/HSRs following fosaprepitant with anthracycline-containing chemotherapy.

Patients & Methods: This retrospective chart review noted ISAEs/HSRs following the anthracycline doxorubicin+cyclophosphamide and a three-drug fosaprepitant regimen, via peripheral line.

Safety of HTX-019 (intravenous aprepitant) and fosaprepitant in healthy subjects.

Aim: Evaluate safety of HTX-019, a novel polysorbate 80- and synthetic surfactant-free intravenous formulation of neurokinin 1 receptor antagonist aprepitant for chemotherapy-induced nausea and vomiting.

Methods: Two open-label, randomized, two-way crossover studies evaluated treatment-emergent adverse events (TEAEs) in 200 healthy subjects. Subjects received HTX-019 130 mg (30-min infusion) and fosaprepitant 150 mg (20- or 30-min infusion), with ≥7-day washout between doses.

Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects: a Phase I, open-label, randomized, two-way crossover evaluation.

Introduction: Fosaprepitant, an intravenous (IV) aprepitant prodrug for chemotherapy-induced nausea and vomiting prophylaxis, is associated with systemic and infusion-site reactions attributed in part to its surfactant, polysorbate 80. HTX-019 is an IV aprepitant formulation free of polysorbate 80 and other synthetic surfactants.

Materials And Methods: This open-label, single-dose, randomized, two-way crossover bioequivalence study compared pharmacokinetics and safety of HTX-019 and fosaprepitant.

A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer.

Purpose: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies.

Experimental Design: This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg.

Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancer.

Purpose: To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors.

Experimental Design: BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD.

Phase II trial of nolatrexed dihydrochloride [Thymitaq, AG 337] in patients with advanced hepatocellular carcinoma.

Background: To evaluate the tolerability and efficacy of nolatrexed in patients with advanced hepatocellular carcinoma.

Patients And Methods: Forty-eight patients were entered onto this study. Nolatrexed was administered every 3 weeks as a 24-h continuous intravenous infusion of 725 mg/m(2)/day for 5 days.

Phase I and pharmacokinetic study of prinomastat, a matrix metalloprotease inhibitor.

Purpose: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate the acute and chronic toxicities of various doses of prinomastat and to determine prinomastat pharmacokinetics.

Result of two randomized trials comparing nolatrexed (Thymitaq) versus methotrexate in patients with recurrent head and neck cancer.

We report on two randomized trials performed in the USA and Europe, which compared methotrexate and nolatrexed as treatment for patients with recurrent head and neck cancer. Eligibility criteria included: histologically confirmed squamous-cell carcinoma, measurable disease, adequate hematological, renal and hepatic functions, failure of a first-line chemotherapy, and informed consent. Methotrexate 40 mg/m2 was weekly given by short infusion, and nolatrexed 725 mg/m2 per day was administered as a five-day continuous infusion, every three weeks.

Randomized, double-blind comparison of two nelfinavir doses plus nucleosides in HIV-infected patients (Agouron study 511).

Objective: To evaluate the safety and antiretroviral activity of nelfinavir mesylate at two doses as part of a combination regimen in HIV-infected, antiretroviral-naive patients.

Design: Phase III, multicenter, double-blind, placebo-controlled trial.

Patients And Methods: Two-hundred and ninety-seven patients were randomized to one of three treatment groups: nelfinavir 750 mg three times daily (tid), nelfinavir 500 mg tid, or matching placebo, each in combination with open-label zidovudine (ZDV) 200 mg tid and lamivudine (3TC) 150 mg twice daily (bid).

Short-term measures of relative efficacy predict longer-term reductions in human immunodeficiency virus type 1 RNA levels following nelfinavir monotherapy.

We calculated the relative efficacy of treatment, defined as the rate of decline of virus levels in plasma during treatment relative to the rate of decline during highly potent combination therapy, in human immunodeficiency virus type 1 (HIV-1) patients treated for 56 days with different doses of the protease inhibitor nelfinavir. Relative efficacies based on the rate of decline of HIV-1 RNA levels in plasma over the first 14 to 21 days correlated with drug dose and viral load reduction by day 56. Calculation of relative treatment efficacies over the first 2 to 3 weeks of treatment can allow rapid assessment of new antiretroviral agents and dosing regimens, reducing the need to keep subjects in clinical trials on monotherapy for prolonged periods of time.

A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation.

A phase I study of nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m(2)24 h(-1). 8 patients were evaluable for toxicity.

Phase I study of AG2034, a targeted GARFT inhibitor, administered once every 3 weeks.

Purpose: To identify a recommended phase II dose for the second generation glycinamide ribonucleotide transformylase (GARFT) inhibitor, AG2034, administered by intravenous bolus every 3 weeks without folate supplementation and to describe AG2034 pharmacokinetics.

Methods: Adults with advanced malignancies were enrolled in cohorts of three per dose level with expansion to six upon observation of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was defined as the dose at which two of up to six patients experienced DLT.

Predictors of optimal virological response to potent antiretroviral therapy.

Background: Current potent antiretroviral therapy (using a protease inhibitor and two nucleoside reverse transcriptase inhibitors) produces a durable suppression of HIV replication in less than 75% of treated patients. Identification of predictors of successful therapy might allow the development of improved strategies to increase response rates.

Methods: We analyzed retrospectively the results from a multicenter, randomized, double-blind Phase III study of combination anti-HIV therapy with nelfinavir, zidovudine, and lamivudine to evaluate the relationship between virological response over 48 weeks of treatment to variables which could potentially serve as early predictors of long-term response.

A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq (nolatrexed dihydrochloride) given by 10-day oral administration.

2-Amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (nolatrexed dihydrochloride, Thymitaq, AG337), a specific inhibitor of thymidylate synthase, was developed using protein structure-based drug design. Intravenously administered nolatrexed is active clinically. As oral bioavailability is high (70-100%), nolatrexed was administered orally, 6 hourly for 10 days, at 3-week intervals, and dose escalated from 80 to 572 mg m(-2) day(-1) in 23 patients.

Phase I studies with the nonclassical antifolate nolatrexed dihydrochloride (AG337, THYMITAQ) administered orally for 5 days.

Phase I studies of p.o. administered nolatrexed dihydrochloride (AG337, THYMITAQ), a nonclassical thymidylate synthase inhibitor, were performed to establish the maximum tolerated dose and a recommended dose for Phase II studies.

Safety, pharmacokinetics, and antiretroviral activity of the potent, specific human immunodeficiency virus protease inhibitor nelfinavir: results of a phase I/II trial and extended follow-up in patients infected with human immunodeficiency virus.

The safety, antiretroviral activity, and pharmacokinetic profile of nelfinavir, a potent and specific inhibitor of human immunodeficiency virus (HIV) protease, were assessed in a small open-label phase I/II dose-ranging study in protease inhibitor-naive HIV-positive men. A total of 22 patients with baseline plasma HIV RNA > or = 20,000 copies/mL and CD4+ counts between 200 and 500 cells/mm3 were enrolled in the study. Of the 22 patients, 20 were evaluated for activity; 10 patients assigned to 771 mg/day base equivalent (300 mg three times daily) and 10 patients assigned to 1,026 mg/day base equivalent (600 mg twice daily) given monotherapy.

A preliminary evaluation of nelfinavir mesylate, an inhibitor of human immunodeficiency virus (HIV)-1 protease, to treat HIV infection.

A phase I/II dose-ranging open-label 28-day monotherapy study of the safety, pharmacokinetics, and antiviral activity of nelfinavir mesylate (Viracept), an inhibitor of human immunodeficiency virus (HIV)-1 protease, was done in 65 HIV-1-infected subjects. After 28 days, 54 responding subjects entered an open-label extension that allowed for the addition of nucleoside inhibitors of reverse transcriptase and dose escalation to maintain durability. The drug was well-tolerated and demonstrated robust antiviral activity, with demonstrable superiority of the 750 mg and 1000 mg three times daily regimens.

Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors.

Purpose: A phase I, multicenter trial of the thymidylate synthase (TS) inhibitor THYMITAQ (nolatrexed dihydrochloride; Agouron Pharmaceuticals, Inc, San Diego, CA) given by 5-day continuous infusion was performed to establish the maximum-tolerated dose (MTD) and to investigate pharmacokinetics, pharmacodynamics, and antitumor effects.

Methods: In vitro and in vivo preclinical studies demonstrated increased activity with prolonged nolatrexed exposure. In 32 patients, nolatrexed was given as a 5-day infusion at 96 to 1,040 mg/m2/d for 5 days.

Initial clinical trial and pharmacokinetics of Thymitaq (AG337) by 10-day continuous infusion in patients with advanced solid tumors.

Purpose: To establish the maximum tolerated dose (MTD), dose-limiting and other major toxicities and the major pharmacokinetic parameters of a 10-day infusion of the nonclassical antifolate Thymitaq.

Methods: The drug was given by 10-day infusion via a portable pump. The starting dose was 286 mg/m2 per day with escalation to 572 and 716 mg/m2 per day.

Phase II trial of oral piritrexim in advanced, previously treated transitional cell cancer of bladder.

Unlabelled: Oral piritrexim (PTX), a second generation antimetabolite, has been shown to be an active agent against methotrexate refractory transitional cell cancer (TCC) of the bladder in phase I trials. We conducted a phase II trial of this drug in patients with TCC of the bladder who failed a first line chemotherapy regimen.

Methods: Oral PTX was started at the dose of 25 mg three times per day for 5 days weekly for 3 weeks followed by one week of rest.

Phase I trial of the thymidylate synthase inhibitor AG331 as a 5-day continuous infusion.

AG331 (N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2, 6-diaminobenz-[c,d]-indole glucuronate) is a lipophilic thymidylate synthase inhibitor with activity in solid tumor models. On the basis of preclinical data supporting regimens of frequent drug administration, we performed a Phase I trial of AG331 as a 5-day continuous infusion repeated every 3 weeks. Twenty-nine patients were entered at doses ranging from 25 to 1000 mg/m2/day.

Phase II trial of piritrexim and DTIC using an alternating dose schedule in metastatic melanoma.

A Phase II trial was conducted in patients with metastatic malignant melanoma with DTIC 250 mg/m2 intravenously for 5 days alternating monthly with Piritrexim (PTX) using an intermittent, low-dose oral administration schedule. PTX was administered at a starting dose of 25 mg orally three times per day for 5 days weekly for 3 weeks followed by 1 week of rest. Twenty-one patients were entered into the study.

A phase II study of vinblastine in combination with acrivastine in patients with advanced renal cell carcinoma.

Renal cell carcinoma exhibits chemoresistance attributable in part to the P-glycoprotein drug efflux mechanism. Acrivastine is a hydrophylic antihistamine that has been shown in vitro to reverse this form of resistance. After five patients were treated on a dose-finding study, seventeen patients with metastatic or unresectable renal cell carcinoma were entered into a phase II study of vinblastine in combination with acrivastine.

Phase I clinical and pharmacology study of 502U83 given as a 24-h continuous intravenous infusion.

502U83 is an arylmethylaminopropanediol that displays significant antitumor activity in a number of murine and human tumor-model systems. In the present phase I study, a 24-h continuous intravenous infusion of this agent was given every 28 days to patients with advanced or refractory solid tumors. In all, 46 patients received a total of 96 cycles of 502U83 at doses ranging from 25 to 8,000 mg/m2.