Long-term survival and biomarker correlates of tasquinimod efficacy in a multicenter randomized study of men with minimally symptomatic metastatic castration-resistant prostate cancer.

PURPOSE: Tasquinimod (Active Biotech) is an oral immunomodulatory, anti-angiogenic, and anti-metastatic agent that delayed metastatic disease progression in a randomized placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). Here, we report long-term survival with biomarker correlates from this trial. EXPERIMENTAL DESIGN: Two hundred and one (134 tasquinimod and 67 placebo) men with mCRPC were evaluated. Forty-one men randomized to placebo crossed over to tasquinimod. Survival data were collected with a median follow-up time of 37 months. Exploratory biomarker studies at baseline and over time were collected to evaluate potential mechanism-based correlates with tasquinimod efficacy including progression-free survival (PFS) and overall survival (OS). RESULTS: With 111 mortality events, median OS was 33.4 months for tasquinimod versus 30.4 months for placebo overall, and 34.2 versus 27.1 months in men with bone metastases (n = 136), respectively. Multivariable analysis demonstrated an adjusted HR of 0.52 [95% confidence interval (CI), 0.35-0.78; P = 0.001] for PFS and 0.64 (95% CI, 0.42-0.97; P = 0.034) for OS, favoring tasquinimod. Time-to-symptomatic progression was improved with tasquinimod (P = 0.039, HR = 0.42). Toxicities tended to be mild in nature and improved over time. Biomarker analyses suggested a favorable impact on bone alkaline phosphatase and lactate dehydrogenase (LDH) over time and a transient induction of inflammatory biomarkers, VEGF-A, and thrombospondin-1 levels with tasquinimod. Baseline levels of thrombospondin-1 less than the median were predictive of treatment benefit. CONCLUSIONS: The survival observed in this trial of men with minimally symptomatic mCRPC suggests that the prolongation in PFS with tasquinimod may lead to a survival advantage in this setting, particularly among men with skeletal metastases, and has a favorable risk:benefit ratio.

Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer.

BACKGROUND: Tasquinimod is a quinoline-3-carboxamide derivative with anti-angiogenic activity. Two open-label phase I clinical trials in patients were conducted to evaluate the safety and tolerability of tasquinimod, with additional pharmacokinetic and efficacy assessments. METHODS: Patients with castration-resistant prostate cancer with no previous chemotherapy were enrolled in this study. The patients received tasquinimod up to 1 year either at fixed doses of 0.5 or 1.0 mg per day or at an initial dose of 0.25 mg per day that escalated to 1.0 mg per day. RESULTS: A total of 32 patients were enrolled; 21 patients were maintained for >or=4 months. The maximum tolerated dose was determined to be 0.5 mg per day; but when using stepwise intra-patient dose escalation, a dose of 1.0 mg per day was well tolerated. The dose-limiting toxicity was sinus tachycardia and asymptomatic elevation in amylase. Common treatment-emergent adverse events included transient laboratory abnormalities, anaemia, nausea, fatigue, myalgia and pain. A serum prostate-specific antigen (PSA) decline of >or=50% was noted in two patients. The median time to PSA progression (>25%) was 19 weeks. Only 3 out of 15 patients (median time on study: 34 weeks) developed new bone lesions. CONCLUSION: Long-term continuous oral administration of tasquinimod seems to be safe, and the overall efficacy results indicate that tasquinimod might delay disease progression.

A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma.

In a phase II study, 43 renal cell carcinoma patients were treated with individualised doses of ABR-214936; a fusion of a Fab recognising the antigen 5T4, and Staphylococcal enterotoxin A. Drug was given intravenously on 4 consecutive days, treatment was repeated 1 month later. Treatment was associated with moderate fever and nausea, but well tolerated. Of 40 evaluable patients, 28 had disease control at 2 months, and at 4 months, one patient showed partial response (PR) and 16 patients stable disease. Median survival, with minimum follow-up of 26 months was 19.7 months with 13 patients alive to date. Stratification by the Motzer's prognostic criteria highlights prolonged survival compared to published expectation. Patients receiving higher drug exposure had greater disease control and lived almost twice as long as expected, whereas the low-exposure patients survived as expected. Sustained interleukin-2 (IL-2) production after a repeated injection appears to be a biomarker for clinical effect, as the induced-IL-2 level on the day 2 of treatment correlated with survival. The high degree of disease control and the prolonged survival suggest that this treatment can be effective. These findings will be used in the trial design for the next generation of drug, with reduced antigenicity and toxicity.

Treatment with laquinimod reduces development of active MRI lesions in relapsing MS.

BACKGROUND: Laquinimod is a novel immunomodulatory substance developed as an orally available disease modifying treatment in multiple sclerosis (MS). The purpose of this study was to evaluate safety, tolerability, and efficacy on MRI lesions of two different doses of laquinimod compared with placebo in patients with relapsing MS. METHODS: In this multicenter, double-blind, randomized trial, patients with relapsing MS received 0.1 mg or 0.3 mg laquinimod or placebo as three daily tablets for 24 weeks. Gadolinium-enhanced brain MRI scans were performed at screening, every eighth week during treatment, and 8 weeks after end of treatment. The primary efficacy variable was the cumulative number of active lesions over 24 weeks. Safety measures included adverse events, physical examination, and laboratory variables. RESULTS: Of 256 screened patients, 209 were randomized (67 to 74 patients per group) in 20 centers. There was a significant difference between laquinimod 0.3 mg and placebo for the primary outcome measure (mean cumulative number of active lesions reduced by 44%). In the subgroup of patients with at least one active lesion at baseline the reduction was slightly more pronounced (52%). No differences with respect to clinical variables (relapses, disability) were found. The safety profile was favorable; there were no clinical signs of undesired inflammatory manifestations. CONCLUSION: Oral laquinimod in a dosage of 0.3 mg daily was well tolerated and effective in suppressing development of active lesions in relapsing multiple sclerosis.

Metabolism of roquinimex in mouse and rat: an in vitro/in vivo comparison.

1. In vitro studies with roquinimex, an immuno-modulator, in liver microsomes from mouse and rat were conducted to evaluate the primary metabolism and compare the metabolite pattern as well as the rate of metabolism with the in vivo pharmacokinetics of the compound in these two species. 2. In the presence of NADPH, roquinimex was metabolized to six primary metabolites (R1-6) by liver microsomes from mouse and rat. The formation of these metabolites was qualitatively similar in both species, and was greatly enhanced by pretreatment with PCN, an inducer of cytochrome P4503A. 3. The identification of the R1-6 demonstrated that roquinimex had been hydroxylated and demethylated. Hydroxylation at different sites of the quinoline moiety was the dominating reaction in both species. 4. Comparison of the resulting microsomal intrinsic clearance of 0.3 micromol mg(-1) protein min(-1) in mouse liver microsomes, versus 0.03 micromol mg(-1) protein min(-1) in rat liver microsomes demonstrated that the mouse possesses about a 10-fold greater metabolic capacity for roquinimex than the rat. 5. The in vivo pharmacokinetics of roquinimex demonstrated a 7-fold higher clearance in mouse than in the rat (82 ml h(-1) kg(-1) in mouse, 10.6 ml h(-1) kg(-1) in rat), which is in concordance with the in vitro findings.

Time for revival of estrogens in the treatment of advanced prostatic carcinoma? Pharmacokinetics, and endocrine and clinical effects, of a parenteral estrogen regimen.

BACKGROUND: The present pilot study tested the clinical performance of a new pharmacokinetically guided dosing regimen of parenteral estrogen in patients with advanced prostatic carcinoma. The aim was to accelerate endocrine effects and to avoid cardiovascular side effects. METHODS: Seventeen patients were randomized to intramuscular injections of 240 mg polyestradiol phosphate (PEP) every second week for the first 8 weeks (five doses), followed by a maintenance dose of 240 mg every month; and 16 patients were randomized to bilateral orchidectomy. The estrogen dosing was calculated by pharmacokinetic modelling to achieve a rapid increase in serum estradiol and thereby a fast decrease in testosterone. RESULTS: The predicted increment in serum estrogen was achieved, together with a subsequent decrease in testosterone in the PEP group. In addition, there were no signs of an increased cardiovascular morbidity. This was probably due to a minimal estrogenic influence on the liver and was reflected by unchanged levels of coagulation factor VII. Clinical effects, during the first 2 years of treatment, were similar in the two treatment arms, with 12 patients in the orchidectomy group and 14 patients in the PEP group responding to treatment. CONCLUSIONS: The present parenteral regimen is an efficient and time-saving estrogen regimen with a favorable side-effect profile. PEP seems to offer a potential for revival of the most cost-effective endocrine treatment of cancer of the prostate, i.e., estrogen.

Dissolution rate-limited absorption and complete bioavailability of roquinimex in man.

In order to investigate the bioavailability and the rate-limiting step of the absorption of roquinimex, an oral solution and a tablet formulation (Linomide(R)) were given to healthy volunteers. The study was conducted as a randomized three-period crossover study in seven male and seven female healthy volunteers. The subjects received an intravenous infusion, an oral solution and an oral tablet formulation, each of 5 mg (about 0.07 mg kg(-1)), as single doses after an overnight fast on three occasions, with a wash-out period of 3 weeks in between. Venous blood samples were taken over 7 days and the plasma concentrations of roquinimex were determined by high-performance liquid chromatography (HPLC) with ultraviolet (UV)-detection. The pharmacokinetics of roquinimex was characterized by a low plasma clearance, 4.9 mL h(-1) kg(-1) and a small volume of distribution, 0.22 L kg(-1). The oral bioavailability of the drug was complete for both the solution and the tablet formulation. The absorption rate was faster for the solution than for the tablet. The disposition of roquinimex was biphasic, with a terminal disposition half-life of 32 h. Between 4 and 8 hours after dosing, a secondary plasma peak was observed, indicating enterohepatic circulation of the drug. No major sex differences were shown in the pharmacokinetics of roquinimex. In conclusion, dissolution rate-limited absorption of roquinimex was shown, which demonstrates that disintegration and dissolution of the tablet play a major role in the absorption process of roquinimex. Despite the delayed absorption after administration of the tablet, the extent of absorption was complete.

Treatment of high-grade, high-stage prostate cancer with estramustine phosphate or diethylstilbestrol. A double-blind study. The SPCG-1 Study Group. Scandinavian Prostate Cancer Group.

Between 1984 and 1989, 197 patients with T1-4, NX, M1, G2-3 or G3 prostate cancer were randomized to treatment with 560 mg estramustine phosphate (EMP, Estracyt, Emcyt) or 3 mg diethylstilbestrol (DES) per day in a double blind study with stratification on presence or absence of cancer pain at start. A total of 194 patients were evaluated for efficacy of therapy. Time to progression (p = 0.054), to treatment failure (p = 0.036), cancer-specific survival (p = 0.068) as well as overall survival (p = 0.021) were longer in the DES group. There were more patients with prognostic parameters indicating bad prognosis in the EMP group. This trial was designed to study whether EMP had better effect than DES as the primary treatment of high-grade, disseminated prostate cancer. The results did not confirm this hypothesis. On the contrary, treatment with DES had relatively good effect on this very aggressive form of prostate cancer.

Immediate estrogen or estramustine phosphate therapy versus deferred endocrine treatment in nonmetastatic prostate cancer: a randomized multicenter study with 15 years of followup. The South Sweden Prostate Cancer Study Group.

From November 1978 to July 1984, 285 men with previously untreated, localized prostate cancer were consecutively randomized in an open multicenter study. The main objective was to determine if early endocrine treatment prolongs the interval to metastasis and/or cancer related or overall survival. Patients were randomized to receive either 80 mg. polyestradiol phosphate by intramuscular injection every 4 weeks plus 50 micrograms ethinylestradiol 3 times daily or 280 mg. estramustine phosphate 2 times daily, or for surveillance only but with deferred endocrine treatment at progression to metastatic disease. From 1983 further inclusion into the polyestradiol phosphate plus ethinylestradiol group was closed because of a high frequency of cardiovascular complications and thereafter 13 patients were instead randomized to a new treatment group with 80 mg. polyestradiol phosphate only by intramuscular injection every 4 weeks. Mean age was 70 years for 228 evaluable patients: 66 in the polyestradiol phosphate plus ethinylestradiol group, 74 in the estramustine phosphate group and 88 in the deferred treatment group, respectively. Mean followup for 100 patients alive on August 31, 1993 was 144 months (range 111 to 180). During the observation period 51 patients had metastasis. There was no difference in interval to metastasis (p = 0.07) among the 3 groups, although there was a tendency for a higher probability of metastases in the deferred treatment group. A total of 128 patients (56%) died during the observation period and prostatic cancer was considered to be the cause of death in 46 (20%). There was a significant difference (p = 0.03) among the 3 groups in the probability of dying of prostatic cancer, with the highest risk in the surveillance group but we found no significant difference in overall survival. The relevance of different prognostic factors and their interaction with treatment was also evaluated. These analyses were applied to the entire patient group as well as to the different subgroups. We found that patients with moderately well differentiated cancer (stage greater than T0a) who received early treatment with estramustine phosphate had the lowest risk of metastases or death from prostatic cancer, while those with well differentiated cancer (stage greater than T0a) did best on early polyestradiol phosphate plus ethinylestradiol treatment.

Release of 17-beta-oestradiol from a vaginal ring in postmenopausal women: pharmacokinetic evaluation.

Oestrogen-containing vaginal rings of various designs have been utilised in hormone replacement therapy. In contrast to the traditional 'homogeneous' design, rings designed with a steroid-containing core and outer polymer sheath provide a diffusion-controlled release rate which enables the delivery of low doses of drug. The aim of this investigation was to evaluate in vitro oestradiol release from a 'core' designed vaginal ring (Estring) and furthermore, to establish the in vivo concentration-time course of oestradiol, oestrone and total oestrone (unconjugated plus conjugated) in consecutive applications of such an oestradiol-containing vaginal ring in postmenopausal women. Results indicate that the controlled release design of Estring produces stable, low systemic plasma concentrations of oestradiol and has an extended time period of release.

A comparative study of metronidazole and sulfasalazine for active Crohn's disease: the cooperative Crohn's disease study in Sweden. I. Design and methodologic considerations.

The design and execution of the Cooperative Crohn's Disease Study in Sweden are described in this paper. A double-blind, double-dummy, crossover (2 X 4 mo) technique was used to compare the suppressive efficacy of metronidazole (0.4 g b.i.d.) and sulfasalazine (1.5 g b.i.d.). The number of randomized patients (78) presented approximately one-third of the available population. The Crohn's Disease Activity Index and the plasma level of orosomucoid were the main variables for clinical evaluation. Results were analyzed primarily in the first treatment period by ranking the clinical outcome of every patient according to a uniform and detailed scheme and applying Wilcoxon nonparametric statistics. The cross-over data only served as additional information. Thirty-six patients had had earlier and mostly positive experience with sulfasalazine. Repeated plasma drug analysis indicated good compliance. The blindness of the trial was tested and appeared satisfactory. The coordination of the trial proceeded as planned. A lack of full conformity in the electroimmunoassay of orosomucoid was taken care of satisfactorily.

A comparative study of metronidazole and sulfasalazine for active Crohn's disease: the cooperative Crohn's disease study in Sweden. II. Result.

Seventy-eight patients with active Crohn's disease participated in a randomized, double-blind, cross-over trial. The study comprised two 4-mo period. The purpose was to test the efficacy of metronidazole in comparison with that of sulfasalazine. As the main evaluation criteria the Crohn's Disease Activity Index and plasma levels of orosomucoid were chosen. In the first period no difference in efficacy as measured by Crohn's Disease Activity Index was found between the treatment groups. The reduction of the plasma orosomucoid level was significantly more pronounced in the metronidazole group. The hemoglobin concentration increased more in this group than in the sulfasalazine group, possibly due to a toxic effect of sulfasalazine. The erythrocyte sedimentation rate decreased similarly with both drugs. In 15 patients who had active disease throughout the first period, Crohn's Disease Activity Index decreased significantly in the second period for those who switched to metronidazole, but not for those who switched to sulfasalazine. After crossover, no apparent further change in Crohn's Disease Activity Index occurred in either of the treatment groups among patients who had responded favorably in the first period. The plasma concentration of orosomucoid increased significantly among the patients in the sulfasalazine group but not in the metronidazole group. It is therefore concluded that metronidazole is slightly more effective than sulfasalazine in the treatment of crohn's disease. It is worthwhile switching the drug regimen from sulfasalazine, when it fails, to metronidazole, but not from metronidazole to sulfasalazine.

Estramustine versus conventional estrogenic hormones in the initial treatment of highly or moderately differentiated prostatic carcinoma. A randomized study.

In a prospective randomized multicenter trial patients with highly or moderately differentiated prostatic carcinoma, previously untreated, were allotted either to oral Estramustine phosphate or to intramuscular polyestradiol phosphate plus oral ethinyl estradiol. As regards frequency and duration of tumour remission there was no statistical difference between the two groups. Nor did they differ significantly with respect to adverse reactions. This is an interim report and will be followed later on by a final evaluation.

A self-adjusting randomization plan for allocation of patients into two treatment groups.

This paper presents a self-adjusting randomization plan which is thought to be useful in controlled stratified randomized clinical trials. The method assures an optimal balance of treatments within each subgroup of patients. An imbalance caused by a high number of dropouts in one treatment group will be counteracted by the self-adjusting nature of the method. The method has been tested in computer-simulated trials and has been shown to produce better results than conventional plans for stratified randomized clinical trials. The method does not involve any complicated calculations and its use in a running clinical trial has shown that it is easy to handle.