A Phase 2a randomized, single-center, double-blind, placebo-controlled study to evaluate the safety and preliminary efficacy of oral iOWH032 against cholera diarrhea in a controlled human infection model.

Cholera remains a major cause of infectious diarrhea globally. Despite the increased availability of cholera vaccines, there is still an urgent need for other effective interventions to reduce morbidity and mortality. Furthermore, increased prevalence of antibiotic-resistant Vibrio cholerae threatens the use of many drugs commonly used to treat cholera. We developed iOWH032, a synthetic small molecule inhibitor of the cystic fibrosis transmembrane conductance regulator chloride channel, as an antisecretory, host-directed therapeutic for cholera. In the study reported here, we tested iOWH032 in a Phase 2a cholera controlled human infection model. Forty-seven subjects were experimentally infected with V. cholerae El Tor Inaba strain N16961 in an inpatient setting and randomized to receive 500 mg iOWH032 or placebo by mouth every 8 hours for 3 days to determine the safety and efficacy of the compound as a potential treatment for cholera. We found that iOWH032 was generally safe and achieved a mean (± standard deviation) plasma level of 4,270 ng/mL (±2,170) after 3 days of oral dosing. However, the median (95% confidence interval) diarrheal stool output rate for the iOWH032 group was 25.4 mL/hour (8.9, 58.3), compared to 32.6 mL/hour (15.8, 48.2) for the placebo group, a reduction of 23%, which was not statistically significant. There was also no significant decrease in diarrhea severity and number or frequency of stools associated with iOWH032 treatment. We conclude that iOWH032 does not merit future development for treatment of cholera and offer lessons learned for others developing antisecretory therapeutic candidates that seek to demonstrate proof of principle in a cholera controlled human infection model study. Trial registration: This study is registered with ClinicalTrials.gov as NCT04150250.

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein.

AIMS: To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). METHODS: The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10). RESULTS: In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h. CONCLUSIONS: BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated.

The long and winding road for the development of tasquinimod as an oral second-generation quinoline-3-carboxamide antiangiogenic drug for the treatment of prostate cancer.

IMPORTANCE OF THE FIELD: Prostate cancer is the mostly commonly diagnosed non-skin cancer in males. The culmination of the last 70 years of clinical drug development has documented that androgen ablation plus taxane-based systemic chemotherapy enhances survival, but is not curative, in metastatic prostate cancer. To effect curative therapy, additional drugs must be developed that enhance the response when combined with androgen ablation/taxane therapy. AREAS COVERED IN THIS REVIEW: The history of the discovery and development of tasquinimod as a second-generation oral quinoline-3-carboxamide analogue for prostate cancer will be presented. WHAT THE READER WILL GAIN: The mechanism for such anticancer efficacy is via tasquinimod's ability to inhibit the 'angiogenic switch' within cancer sites required for their continuous lethal growth. TAKE HOME MESSAGE: Tasquinimod is a novel inhibitor of tumor angiogenesis that enhances the therapeutic anticancer response when combined with other standard-of-care modalities (radiation, androgen ablation, and/or taxane-based chemotherapies) in experimental animal models, but does not inhibit normal wound healing. It has successfully completed clinical Phase II testing in humans and will shortly enter registration Phase III evaluation for the treatment of metastatic prostate cancer.

Dermatologic changes associated with roquinimex immunotherapy after autologous bone marrow transplant.

BACKGROUND: Roquinimex (Linomide) is an immunotherapeutic agent used in conjunction with autologous bone marrow transplantation (ABMT) for treatment of acute and chronic myelogenous leukemia (AML and CML). This agent may induce graft-versus-host reactions (GVHR) as well as graft-versus-leukemia (GVL) effects. OBJECTIVE: We documented the incidence of acute cutaneous GVHR associated with roquinimex immunotherapy. The presence or absence of autologous GVHR was also correlated with a potential GVL effect in patients with CML treated with ABMT and subsequent roquinimex immunotherapy in the period after the transplant. METHODS: Fifteen patients undergoing bone marrow transplantation and roquinimex immunotherapy for CML were followed up, and clinicopathologic data were analyzed. RESULTS: Acute cutaneous GVHRs were observed in 6 of 15 patients (40%) treated with roquinimex. Ten of 11 evaluable patients receiving roquinimex exhibited eccrine sweat gland necrosis (ESGN) (90.9%), which was independent of the acute GVHR. Neither bone marrow engraftment status nor the survival rates of patients with and without GVHR was significantly different. CONCLUSION: Roquinimex immunotherapy enhances the incidence of GVHR and was associated with a high rate of ESGN in patients with CML who were undergoing ABMT. There was no significant association between ESGN and acute GVHR. Acute autologous GVHR caused by roquinimex did not correlate with a GVL effect in our study of 15 patients with CML.

Roquinimex (Linomide) vs placebo in AML after autologous bone marrow transplantation.

Roquinimex, Linomide, a quinoline derivative with pleiotropic immunomodulatory activity, has previously been shown to enhance natural killer (NK) cell number and activity after ABMT in patients with AML. In this study 278 AML patients in remission were randomized to receive Roquinimex 0.2 mg/kg body weight or placebo twice weekly for 2 years following ABMT. Out of 139 patients in each group, 109 Roquinimex patients and 108 placebo patients were in their first CR. Median age at inclusion was 41 years for Roquinimex patients and 39 years for placebo patients. Twelve patients in each group had their marrow purged prior to reinfusion. Relapse and death were study endpoints. Surviving patients were followed for 2.6 to 6. 9 years. The total number of relapses was 60 in the Roquinimex group and 63 in the placebo group (not significant). Leukemia-free and overall survivals were similar in the two groups. Recovery of platelet counts was significantly delayed in the Roquinimex group as compared to placebo. No other significant differences regarding toxicity parameters were recorded. In conclusion, previous findings on NK cells could not be confirmed and the study showed no benefit for Roquinimex over placebo regarding relapse or survival following ABMT for AML in remission.

Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results. North American Linomide Investigators.

OBJECTIVE: To determine whether linomide (roquinimex) is better than placebo in slowing the time to confirmed clinical worsening in patients with relapsing-remitting (RR) and secondary progressive (SP) MS. METHODS: In this 27-center, randomized, double-blind, placebo-controlled, multiple-dose, phase III trial, 715 patients with active RRMS (n = 90) or SPMS (n = 625) were randomized to receive either linomide (1.0, 2.5, or 7.5 mg orally daily) or placebo. Patients were evaluated at 3-month intervals clinically and with MRI. The planned primary outcome was the time to the development of "confirmed" clinical worsening (increase of >/= 1.0 Expanded Disability Status Scale [EDSS] score for an enrollment EDSS score /= 0.5 point for an enrollment EDSS score of >/= 5.5) not associated with an acute relapse. RESULTS: The trial was terminated 1 month after it became fully enrolled due to unanticipated serious cardiopulmonary toxicities (pericarditis, pleural effusion, myocardial infarction, and possible pulmonary embolism), pancreatitis, and death. Notable arthralgia, myalgia, bursitis, and facial and peripheral edema were common adverse events. The high dose of linomide (7.5 mg) was not well tolerated. The trial was too brief to determine unequivocal clinical benefits. Trends suggested an unconfirmed early effect on change in EDSS score at 6 months for the medium dose (2.5 mg daily). CONCLUSION: MS patients may be more prone to develop important linomide treatment-related adverse events than other previously studied patients. However, linomide may be a potentially more toxic drug than was suspected from observations made in smaller studies for other indications. Phase III trials may identify infrequent and important toxicities that may not be anticipated by phase I and II trials.

Linomide in relapsing and secondary progressive MS: part II: MRI results. MRI Analysis Center of the University of Texas-Houston, Health Science Center, and the North American Linomide Investigators.

OBJECTIVE: To determine the safety and efficacy of roquinimex (linomide) in the management of relapsing-remitting and secondary progressive MS as monitored by MRI. BACKGROUND: Preclinical studies and several short term randomized trials of linomide suggested clinical and MRI-measured benefits with acceptable risk for closely followed MS patients. METHODS: The North American Linomide Trial formally screened 853 individuals for relapsing or secondary progressive, clinically definite MS; recent disease activity or progression; and an Expanded Disability Status Scale score at entry of 3.0 to 6.5 inclusive. MRI was obtained on 811 subjects at pre-enrollment, 718 cases at enrollment, and then at three monthly intervals until the trial was prematurely terminated for unacceptable toxicity. RESULTS: Enhancement was found on 40.2% of 718 entry scans. Statistically robust correlations were found between clinical demographic data and several entry MRI measures including CSF volume, a reflection of brain atrophy. Assessment of the effect of treatment on MRI-measured disease was limited by early trial termination. However, active treatment for 3 months reduced the proportion of patients with one or more enhancements. An exploratory analysis suggested that 2.5 mg was the most active of three doses tested in limiting the total volume of enhanced tissue, the proportion of MRI-defined lesions designated as "black holes," and by a novel MRI composite disease measure. CONCLUSIONS: The short term signature of the effect of linomide on MRI-measured aspects of the disease suggests that safer drugs of this class might be useful in the management of MS. The use of a composite index of the heterogeneous nature of the pathology of MS as captured by MRI may have merit as an outcome measure in clinical trials.

Linomide in the treatment of multiple sclerosis: MRI results from prematurely terminated phase-III trials.

Due to an unexpected increase in serious cardiovascular events in MS patients treated with Linomide, a synthetic immunomodulator, two phase-III multinational relapsing remitting (RR) and secondary progressive (SP) MS trials had to be discontinued. MRI results of 413 patients who participated for at least 3 months were analysed. Patients received placebo, 2.5 or 5 mg Linomide. Scans were performed at pre-enrolment, month 3 and termination. The number and volume of enhancing lesions (ELV), and the number of active scans were evaluated. At month 3, the decrease in the number of enhancing lesions in the placebo group was 11%, compared with 15% in the 2.5 mg group (P=0.027) and 23% in the 5 mg group (P=0.057). Using the percentage of active scans as outcome parameter, the odds ratio for improvement between placebo and 2.5 mg group was 1.62 (P=0.14); between placebo and 5 mg Linomide group 3.58 (P=0.003). At termination, a rebound effect was noted in the 2.5 mg group (P=0.01). Analysis of the ELV showed no significant difference between placebo and treatment groups. Although Linomide has unacceptable side effects, it seems to have a modest effect on MS disease activity, as measured by MRI. Multiple Sclerosis (2000) 6, 99 - 104

Treatment of chronic myelogenous leukemia with autologous bone marrow transplantation followed by roquinimex.

Unmanipulated autologous bone marrow transplant (ABMT) offers patients with chronic myelogenous leukemia (CML) a long-term survival of 10%, at best. Immunotherapy has a role in the myeloid leukemias, and there is increasing evidence that of all hematopoietic neoplasms, CML may be the most susceptible to immune regulation. Roquinimex is known to enhance T cell, NK cell and macrophage activity. A phase II study was initiated in March 1992 to evaluate the role of roquinimex in Ph chromosome-positive CML post ABMT. Patients were conditioned with busulfan/ cyclophosphamide followed by reinfusion of unmanipulated Ph-positive bone marrow stem cells (>1 x 108 NBC/kg). When engraftment of neutrophils (ANC) reached 100/microl, patients received oral roquinimex twice weekly, escalating to a maximal dose of 0.2 mg/kg in 2 weeks. Seventeen patients have entered the study; 11 in first chronic phase (CP1); two in second chronic phase (CP2) and four in accelerated phase (AP). All required significant myelosuppressive therapy prior to ABMT to maintain stable blood counts and most had also received prior interferon therapy. All patients survived the transplant. Subsequent toxicity consisted mainly of musculoskeletal aches and peripheral edema. Additionally, specific skin changes were observed including graft-versus-host-like disease and eccrine sweat gland necrosis. Eight out of 17 patients are alive 28-60 months post ABMT. Of the nine patients who died, two were in CP2 and three in AP. All patients in CP1 went into a complete hematological remission post ABMT and seven of the 11 patients had at least a major cytogenetic response (greater than 65% Ph-negative metaphases) at 1 year or beyond and four of the 11 patients had a complete cytogenetic response at 2 years or beyond. Cytogenetic response post transplant often developed over time and did not simply represent post ABMT engraftment with Ph-negative cells. The clinical and cytogenetic data in these patients are encouraging and suggest that roquinimex may have significant activity when given post ABMT to patients with Ph-positive CML.

Acrodermatitis enteropática: estudio evolutivo sobre los primeros casos venezolanos desde 1958 / Enteropatic acrodermatitis: evolutive study of the first venezuelan cases since 1958

En 1958 el autor describe junto con el Dr. Régulo Pachano el primer caso de acro-dermatitis enteropática en Venezuela en un niño de seis años de edad, quien respondió favorablemente a la diiodohidroxiquinolona. Posteriormente, el autor reúne 13 nuevos casos de la enfermedad, todos procedentes del barrio San Francisco, situado al Sur de la ciudad de Maracaibo, todos los cuales eran hijos de padres consanguíneos. El tratamiento con diiodohidroxiquinolona en estos casos, produjo el mismo efecto favorable constatado en el primer caso. Dos de los pacientes que habían evolucionado favorablemente con el tratamiento, presentaron una recidiva de la enfermedad que no fue posible controlar, aun con altas dosis de la droga y que curaron con la aplicación de una nueva terapéutica de la enfermedad a base de sulfato de zinc. Después de hacer una revisión de los casos observados desde 1958, el autor analiza la etiopatogenia de la enfermedad, su terapéutica y, en particular, el papel del zinc en patología humana, así como la toxicidad de los derivados halogenados de la hidroxiquinolona

EORTC phase II study of daily oral linomide in metastatic renal cell carcinoma patients with good prognostic factors.

Following a previous EORTC GU-Group study, in which linomide showed some activity in poor prognosis patients, this study was initiated to determine the effect of linomide in more favourable patients. 35 patients with metastatic renal cell carcinoma with good prognostic factors, i.e. good performance status, prior nephrectomy, no prior systemic therapy, and no liver, bone or brain metastases, were treated with linomide, a quinoline derivative with immunomodulating properties, at a dose of 10 mg daily, after an initial dose escalation during the first 4 weeks of treatment. In 29 evaluable patients, no responses were observed (95% confidence interval 0-10%). Best overall response was no change in 9 patients, for a median duration of 4 months. Linomide in this schedule was poorly tolerated, with 17% (6 patients) of patients being withdrawn and 23% (8 patients) having dose reductions due to adverse events, mostly influenza-like symptoms of myalgia, arthralgia and fatigue. Several cases of pericarditis and neuropathy were observed. In spite of selection of favourable prognosis patients and an optimal daily dosing schedule, linomide was not an effective treatment in renal cell carcinoma. In view of toxicity and lack of efficacy, there is no rationale in further testing the drug in this disease.

An EORTC phase II study of the efficacy and safety of linomide in the treatment of advanced renal cell carcinoma.

The aim of this study was to determine the objective tumour response rate and duration of response and toxicity of linomide (Roquinimex) treatment in patients with disseminated renal cell carcinoma, pretreated or not pretreated with immunotherapy. From March 1991 to July 1992, 72 patients with metastatic and progressive renal cell cancer were entered of whom 9 (12%) were not evaluable for response. Linomide was given orally, twice weekly, 5 mg during the first week with dose escalation to 10 mg during the second week and 15 mg thereafter. Treatment was continued until disease progression or unacceptable toxicity. No haematological toxicity but slight anaemia was observed. A significant WBC (white blood cell count) increase (P < 0.0001, paired T-test) was found during treatment. The most often reported non-haematological side-effects were: flu-like syndrome (54%, grade III-IV 7%), nausea/vomiting (41% and 3%, respectively) and neurotoxicity (34% and 2%). Most side-effects were of mild or moderate intensity (WHO grade 1 or 2). The objective overall response rate was 4%: 1 CR and 2 PRs. Stable disease was reported for 28 patients (40%). The duration of response was 17, 22 and 30 (CR) months. Median time to progression was 5 months. Linomide at the given dose and schedule is well tolerated, but has limited antitumour activity in metastatic renal cell carcinoma.

The first clinical pilot study of roquinimex (Linomide) in cancer patients with special focus on immunological effects.

Roquinimex (Linomide) has been demonstrated to suppress tumor growth in animal models. The effect is at least in part related to enhanced numbers and activity of natural killer (NK) cells. In this clinical pilot study, roquinimex was given at increasing doses (0.05 mg/kg to 0.6 mg/kg) to 13 patients (performance status 0-3) with various malignant disorders. Immunology parameters were followed and side effects were observed during the study. The plasma pharmacokinetics of roquinimex was studied at the 0.2 mg/kg dose level. The clinical side effects were dominated by musculoskeletal discomfort, nausea, and pain. No significant hematological or biochemical toxicity was observed. Pharmacokinetic analysis at the 0.2 mg/kg dose level revealed a Cmax of 4.0 mumol/L at tmax of 1.2 hr and an elimination half-life of 42 hr. Increased numbers of phenotypic NK cells, activated T (DR+CD4+) cells, and monocytes were observed after administration of roquinimex compared with pretreatment values. Roquinimex seems to be an active immunomodulator with manageable toxicity. Further exploration of therapeutic efficacy is warranted.

Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis.

The synthetic immunomodulator Linomide, a quinoline-3-carboxamide, has a profound inhibitory influence in several experimental autoimmune diseases, including acute and chronic experimental allergic encephalomyelitis. In a double-blind trial, 31 patients with relapsing-remitting multiple sclerosis were randomized to oral doses of 2.5 mg Linomide or placebo once a day for six months. Fourteen patients receiving Linomide and 14 receiving placebo completed the trial, and the results were based on this population. The mean number of active (new and enlarged T2 weighted) lesions per monthly MRI scan was 1.37 in the patients receiving Linomide and 4.22 in the patients receiving placebo (p = 0.043). The percentage of scans with active MRI lesions was lower in the Linomide-treated group (p = 0.0064). When neurologic deficit was assessed by the Regional Functional Scoring System (RFSS), the Linomide group showed an improvement of 1% of the maximal RFSS range and the placebo group a deterioration of 0.2% (p = 0.14). There were three patients with relapses in the Linomide-treated group and six in the placebo group (p = 0.22). A slightly decreased proportion of natural killer cells in cerebrospinal fluid and peripheral blood was noted in the Linomide group. A severe adverse event of pleuropericarditis occurred in one of the Linomide-treated patients. The most frequent adverse event was musculoskeletal pain, of mild to severe degree, which tended to diminish after three months on Linomide therapy.

Linomide and interleukin-2 in patients with advanced renal cell carcinoma.

Quinoline-3-carboxamide (Linomide) is a novel, synthetic immunomodulator acting via immunologic and non-immunologic mechanisms. It has shown efficacy against various malignancies, experimental autoimmune encephalomyelitis, and septic shock in animal models and has been investigated for clinical use in minimal residual myeloid leukemia with promising results. Interleukin-2 has shown considerable efficacy in palliative anti-tumor-treatment of advanced renal cell cancer, revealing remission rates of up to 40% in combination therapy regimens. Linomide is reported to exhibit synergistic effects with interleukin-2. Here we report on a clinical phase I/II study examining tolerance and efficacy of a combination therapy schedule of SQ interleukin-2 and PO Linomide in advanced renal cell cancer. Seventeen patients received 10 IU/m2 interleukin-2 per week for 8 weeks, resting interleukin-2 for another 8 weeks. In week 5 they started 5 mg Linomide daily, continued with 10 mg from week 7 to 16. No objective remissions were observed. Among 15 patients evaluable for response, 10 (66.7%) were progredient during the study. Three patients died during the observation period, including two not evaluable for response. Median survival was 4.0 months, median progression-free survival 2.5 months with a Kaplan-Meier estimate of 3.63 months. Fever, reduced general condition, nausea/vomiting, dyspnea, anorexia, chills and hypotension were the most common side effects, reaching WHO grade 3 in 6 and grade 4 in 2 cases. In summary, Linomide in combination with interleukin-2 provides no advantages in efficacy or toxicity over other therapy regimens employing interleukin-2.

Treatment of secondary progressive multiple sclerosis with the immunomodulator linomide: a double-blind, placebo-controlled pilot study with monthly magnetic resonance imaging evaluation.

Linomide (quinoline-3-carboxamide) is a synthetic immunomodulator that increases the natural killer cell activity. We previously demonstrated that linomide effectively inhibited the clinical and histopathologic signs of acute and chronic relapsing experimental autoimmune encephalomyelitis. We report a double-blind, placebo-controlled study to evaluate tolerability and to obtain preliminary indications of the clinical efficacy of linomide on secondary progressive MS. Thirty patients suffering from clinically definite and laboratory-supported secondary progressive MS, with an expanded disability status scale (EDSS) of 3.0 to 7.0, were included in this study. Patients were treated daily with linomide (2.5 mg) or placebo orally and were followed up for side effects and changes in their neurologic status; monthly MRI scans were taken throughout the treatment period. Twenty-four patients completed at least 6 months of treatment. Mild to moderate side effects, including muscle pains, arthralgia, and edema, were present in 11 of the 15 patients receiving placebo and in 13 of the 15 patients treated with linomide. At 24 weeks, the mean shift in EDSS was +0.272 +/- 0.156 in the placebo group versus -0.166 +/- 0.167 in the linomide group (p = 0.0451). The percentage of patients with evidence of "activity" on their MRI (new, enlarging, or new gadolinium diethylenetriaminepentaacetic acid [Gd-DTPA]-enhancing lesions) throughout the treatment period was 75% in the placebo group and 33% in the linomide group (p = 0.0205). The mean total number of new Gd-DTPA-enhancing lesions per MRI scan for the same period was 0.42 +/- 0.143 in the placebo group and 0.19 +/- 0.114 in the linomide group (p = 0.0387). In this study, linomide proved to be safe and well tolerated in patients with secondary progressive MS. In addition, our results indicate that linomide tends to inhibit the progression of the disease, especially preventing the appearance of new active lesions in the MRI scans. Based on these results, two multicenter phase III trials are currently under way in the United States and in Europe and Australia.

Roquinimex-induced graft-versus-host reaction after autologous bone marrow transplantation.

BACKGROUND: Roquinimex is being used for posttransplantation immunotherapy of autologous bone marrow transplantation for acute and chronic myelogenous leukemia. This immunotherapeutic agent is a cytokine inducer and may induce an autologous graft-versus-host (GVH) and graft-versus-tumor reactions. OBJECTIVE: Our purpose was to examine patients undergoing this immunotherapy for clinical signs and symptoms of acute GVH reactions and to correlate these symptoms with their clinical outcome. METHODS: We studied eight patients receiving requinimex therapy. RESULTS: We found autologous GVH reactions in three of eight patients (38%) treated with this immunotherapy. Their disease was manifested by localized or widespread violaceous papules that on histologic evaluation were compatible with a grade II GVH reaction. The acute cutaneous GVH reaction was associated with eccrine sweat gland necrosis, a dermatologic toxicity usually associated with chemotherapy. CONCLUSION: Long-term studies of larger numbers of patients treated with this immunotherapy will determine whether these GVH reactions confer significant, sustained, antitumor effects.