A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.

BACKGROUND: Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. RESULTS: 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. CONCLUSION: Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.

Safety and efficacy of riluzole in patients undergoing decompressive surgery for degenerative cervical myelopathy (CSM-Protect): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.

BACKGROUND: Degenerative cervical myelopathy represents the most common form of non-traumatic spinal cord injury. This trial investigated whether riluzole enhances outcomes in patients undergoing decompression surgery for degenerative cervical myelopathy. METHODS: This multicentre, double-blind, placebo-controlled, randomised, phase 3 trial was done at 16 university-affiliated centres in Canada and the USA. Patients with moderate-to-severe degenerative cervical myelopathy aged 18-80 years, who had a modified Japanese Orthopaedic Association (mJOA) score of 8-14, were eligible. Patients were randomly assigned (1:1) to receive either oral riluzole (50 mg twice a day for 14 days before surgery and then for 28 days after surgery) or placebo. Randomisation was done using permuted blocks stratified by study site. Patients, physicians, and outcome assessors remained masked to treatment group allocation. The primary endpoint was change in mJOA score from baseline to 6 months in the intention-to-treat (ITT) population, defined as all individuals who underwent randomisation and surgical decompression. Adverse events were analysed in the modified intention-to-treat (mITT) population, defined as all patients who underwent randomisation, including those who did not ultimately undergo surgical decompression. This study is registered with ClinicalTrials.gov, NCT01257828. FINDINGS: From Jan 31, 2012, to May 16, 2017, 408 patients were screened. Of those screened, 300 were eligible (mITT population); 290 patients underwent decompression surgery (ITT population) and received either riluzole (n=141) or placebo (n=149). There was no difference between the riluzole and placebo groups in the primary endpoint of change in mJOA score at 6-month follow-up: 2·45 points (95% CI 2·08 to 2·82 points) versus 2·83 points (2·47 to 3·19), difference -0·38 points (-0·90 to 0·13; p=0·14). The most common adverse events were neck or arm or shoulder pain, arm paraesthesia, dysphagia, and worsening of myelopathy. There were 43 serious adverse events in 33 (22%) of 147 patients in the riluzole group and 34 serious adverse events in 29 (19%) of 153 patients in the placebo group. The most frequent severe adverse events were osteoarthrosis of non-spinal joints, worsening of myelopathy, and wound complications. INTERPRETATION: In this trial, adjuvant treatment for 6 weeks perioperatively with riluzole did not improve functional recovery beyond decompressive surgery in patients with moderate-to-severe degenerative cervical myelopathy. Whether riluzole has other benefits in this patient population merits further study. FUNDING: AOSpine North America.

[Liver Injury Risk Factors in Amyotrophic Lateral Sclerosis Patients Treated with Riluzole].

Riluzole, a drug used in the management of amyotrophic lateral sclerosis (ALS), is associated with a high incidence of liver failure. It is imperative to determine risk factors and severity of liver injury in patients taking riluzole to devise an appropriate treatment regimen. We, therefore, studied risk factors for liver injury in ALS patients who were prescribed riluzole at Kitasato University East Hospital from 1999 to 2015. Of the 222 patients enrolled in this study, 113 and 109 patients were diagnosed with mild to moderate (grade 1 or 2) and without (grade 0) liver injury, respectively. Prediction of risk factors was determined using binary logistical regression analyses. The results showed that 50.9% (n=113) of ALS patients developed mild to moderate liver injury; 71.7% and 53.1% of patients were concurrently using CYP1A2 inhibitors (p=0.005) and diclofenac (p=0.032), respectively; 55.8% of patients with liver injury had a history of smoking (p=0.011). Multivariate analyses revealed that the concurrent use of CYP1A2 inhibitors [odds ratio (OR) 2.152, 95% confidence interval (CI) 1.225-3.780, p=0.008] and history of smoking (OR 1.938, 95% CI 1.125-3.340, p=0.017) were independent risk factors for liver injury in patients receiving riluzole. In conclusion, treatment of ALS patients with riluzole, smoking habits, and concurrent use of CYP1A2 inhibitors are independent liver injury risk factors. Further studies on liver injury are warranted in ALS patients treated with riluzole to comprehensively understand the underlying mechanisms of riluzole-associated liver toxicity.

Riluzole for treatment of men with methamphetamine dependence: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Riluzole is a glutamate regulator and effective in treatment of neuropsychiatric conditions. AIMS: We assessed riluzole for treatment of methamphetamine dependence. METHODS: In this randomized, double-blind, placebo-controlled clinical trial, male outpatients with methamphetamine dependence who were 18-65 years old received either 50 mg riluzole ( n=34) or placebo ( n=54) twice daily for 12 weeks. Patients were excluded in case of comorbid serious medical conditions or neurologic disorders, comorbid psychiatric disorders other than methamphetamine dependence requiring specific treatment interventions, simultaneous positive urine test result for substances of abuse other than methamphetamine, smoking >3 days per week, simultaneous consumption of medications which are contraindicated or have interaction with riluzole. RESULTS: Concerning primary outcomes, the cumulative mean number of attended weekly visits was higher in the riluzole arm compared with the placebo arm approaching a statistically significant difference (riluzole, median (range)=13.00 (2.00-13.00); placebo=4.00 (2.00-13.00); Mann-Whitney U=505.00, p-value=0.073), and the weekly measured rate of positive methamphetamine urine test results was significantly lower in the riluzole arm by the end of the study (riluzole=1 (5.00%), placebo=9 (45.00%), p-value=0.004). Patients in the riluzole arm experienced significantly greater improvement on all the craving, withdrawal, and depression measures regarding mean score changes from baseline to endpoint. No significant difference was detected between the two arms in terms of incidence of adverse events. CONCLUSION: Future randomized clinical trials are needed to investigate proper dosing strategy in a more inclusive sample.

Multidisciplinary management of motor neurone disease.

BACKGROUND: Motor neurone disease (MND) is the term for a group of progressive, debilitating, neurodegenerative disorders that affect various aspects of a patient's life, including speech, swallowing, breathing and limb function. OBJECTIVE: This review outlines the common symptoms and issues in MND and the latest available treatment options. A multidisciplinary approach to MND, involving the general practitioner (GP) and rehabilitation, palliative care and allied health services, is discussed. DISCUSSION: The complexity of care for patients with MND and their families is best managed using a multidisciplinary team approach, with the GP as an important member of that team. The biopsychosocial care model discussed can improve the quality of life for patients and carers, as well as the life expectancy of patients with MND.

A phase II trial of riluzole, an antagonist of metabotropic glutamate receptor 1 (GRM1) signaling, in patients with advanced melanoma.

Studies demonstrate that GRM, expressed by >60% of human melanomas, may be a therapeutic target. We performed a phase II trial of 100 mg PO bid of riluzole, an inhibitor of GRM1 signaling, in patients with advanced melanoma with the primary endpoint of response rate. Thirteen patients with GRM1-positive tumors were enrolled. No objective responses were observed, and accrual was stopped. Stable disease was noted in six (46%) patients, with one patient on study for 42 weeks. Riluzole was well tolerated, with fatigue (62%) as the most common adverse event. Downregulation of MAPK and PI3K/AKT was noted in 33% of paired tumor biopsies. Hypothesis-generating correlative studies suggested that downregulation of angiogenic markers and increased leukocytes at the active edge of tumor correlate with clinical benefit. Pharmacokinetic analysis showed interpatient variability consistent with prior riluzole studies. Future investigations should interrogate mechanisms of biologic activity and advance the development of agents with improved bioavailability.

[Amyotrophic lateral sclerosis--diagnosis and treatment]. / Amyotrophe Lateralsklerose--Abklärung und Therapie.

Amyotrophic lateral sclerosis (ALS) represents the most common motoneuron disorder in adulthood. It is characterized by selective degeneration of the motoneurons. About 10% of patients have a genetically determined ALS. Clinically, ALS is characterized by coexistence of signs of the first motoneuron, such as spasticity and hyperreflexia, as well as the second motoneuron, such as muscular atrophy and fasciculations. If such signs are present in at least three regions and if other possible causes have been excluded, a definite diagnosis of ALS can be made based on the revised El-Escorial criteria. Initial manifestations are often focalized and generalization develops during the course. The glutamate antagonist riluzole is worldwide the only approved ALS treatment. However, symptomatic treatments to ameliorate spasticity, drooling, speech and swallowing problems, and assisted ventilation to treat respiratory failure are essential.

Riluzole-induced lung injury in two patients with amyotrophic lateral sclerosis.

Riluzole has recently been proven as the first effective drug for the treatment of amyotrophic lateral sclerosis (ALS). We report two rare cases of lung injury caused by riluzole therapy in patients with ALS. Chest radiographs showed bilateral lower lobe, dorsal-dominant ground glass opacity, and/or consolidation. A drug lymphocyte stimulation test (DLST) of peripheral blood or bronchoalveolar lavage cells was positive for riluzole. Histopathological examination of lung biopsy specimens revealed lung injury without fungoid granuloma, vasculitis, or diffuse alveolar damage. To the best of our knowledge, this is the first report of riluzole-induced lung injury with positive DLST results.

Riluzole improves motor deficits and attenuates loss of striatal neurons in a sequential double lesion rat model of striatonigral degeneration (parkinson variant of multiple system atrophy).

We investigated neuroprotective effects of riluzole, an anti-glutamatergic agent that is FDA approved for disease-modifying therapy in amyotrophic lateral sclerosis (ALS), in an established double lesion rat model of striatonigral degeneration (SND), the neuropathological substrate of parkinsonism associated with MSA (MSA-P). Riluzole was administered prior to and consecutively for ten days following double lesion placement in the left-sided medial forebrain bundle and ipsilateral striatum. Assessment of motor behaviour using a flex field system showed a significant reduction of motor disturbance in animals with striatonigral lesions treated with riluzole compared to lesioned but untreated animals (P<0.001). DARPP-32 immunohistochemistry revealed a significant reduction of absolute striatal lesion volume in riluzole treated animals compared to lesioned but untreated animals (P<0.01). No significant difference in counts of nigral dopaminergic neurons was found in treated versus untreated double-lesioned animals. The results of our study indicate that riluzole mediates neuroprotective effects in the double lesion rat model of MSA-P. Whether riluzole also protects autonomic and cerebellar pathways that are frequently affected in MSA remains to be determined. Nonetheless, our study is the first to provide an experimental rationale for exploring possible neuroprotective effects of riluzole in MSA.

Riluzole serum concentrations in patients with ALS: associations with side effects and symptoms.

Riluzole exerts a dose-dependent effect on survival of patients with ALS and, although serum levels show a high interindividual variability, is usually prescribed in a fixed dose. In this study, riluzole serum levels and area under the curve per kilogram of body weight (AUC/kg) of 169 patients with ALS showed a high interindividual variability. Patients with high serum levels and AUC/kg more often had diarrhea but less often had fasciculations and muscle stiffness. It may therefore be advantageous to raise the riluzole dose in patients with low riluzole serum concentrations without the risk of serious side effects.

Examining the evidence about treatment in ALS/MND.

The application of evidence-based medicine to the treatment of patients with amyotrophic lateral sclerosis (ALS) is just beginning. A small number of systematic reviews analyzing the pertinent evidence, grading the methodology and formulating recommendations to guide clinical decision-making have begun to appear. The American Academy of Neurology practice parameters for informing the patient and managing nutritional and respiratory issues and palliative care are discussed. In addition, the first systematic review in the field of ALS/MND from the Cochrane collaboration concerns riluzole treatment and this meta-analysis is also described. Some of the most important recommendations that have the potential to significantly prolong survival and enhance quality of life are the early institution of percutaneous endoscopic gastrostomy for patients with significant dysphagia, and the initiation of non-invasive positive pressure ventilation for patients with symptoms of early respiratory insufficiency. Assertive treatment of pain and dyspnea are also strongly recommended for patients with ALS. The North American ALS patient database, ALS C.A.R.E., is also described as a methodology for measuring clinical outcomes, and some early results are presented. The evidence on riluzole indicates effectiveness in prolonging survival with a good safety profile.