A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours.

BACKGROUND: ARQ 087 is an orally administered pan-FGFR inhibitor with multi-kinase activity. This Phase 1 study evaluated safety, pharmacokinetics, and pharmacodynamics of ARQ 087 and defined the recommended Phase 2 dose (RP2D). METHODS: Patients with advanced solid tumours received ARQ 087 administered initially at 25 mg every other day and dose-escalated from 25 to 425 mg daily (QD) continuous dosing. FGF19, 21, 23, and serum phosphate were assessed as potential biomarkers of target engagement. RESULTS: 80 patients were enrolled, 61 in dose-escalation/food-effect cohorts and 19 with pre-defined tumour types in the expansion cohort. The most common ARQ 087-related adverse events were fatigue (49%), nausea (46%), aspartate aminotransferase (AST) increase (30%), and diarrhoea (23%). Four patients (5%) experienced grade 1 treatment-related hyperphosphataemia. Dose-limiting toxicity was reversible grade 3 AST increase. The RP2D was 300 mg QD. Pharmacokinetics were linear and dose-proportional from 25 to 325 mg QD, and were unaffected by food. Statistically significant changes (P-value<0.05) suggest phosphate and FGF19 levels as markers of target engagement. In 18 evaluable patients with FGFR genetic alterations, 3 confirmed partial responses (two intrahepatic cholangiocarcinomas (iCCA) with FGFR2 fusions and one urothelial cancer with FGFR2 and FGF19 amplification) and two durable stable disease at ⩾16 weeks with tumour reduction (FGFR2 fusion-positive iCCA and adrenocortical carcinoma with FGFR1 amplification) were observed. CONCLUSIONS: ARQ 087 had manageable toxicity at the RP2D of 300 mg QD, showed pharmacodynamics effects, and achieved objective responses, notably in patients with FGFR2 genetic alterations.

First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas.

BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1-1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially. RESULTS: Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years. CONCLUSION: Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL. CLINICALTRIALSGOV: NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.

Carcinoma base of tongue: single institution 15 year experiences.

AIMS: To report the outcome with radiotherapy and concomitant chemoradiotherapy in patients with locally advanced squamous cell carcinoma base of tongue treated and followed up at single institution over a period of 15 years. MATERIALS AND METHODS: This study was carried out by auditing the medical records of 103 patients treated at our institution between 1991 and 2006. Mean age with standard deviation of patients in the Radiotherapy only (group I) and chemoradiotherapy (group II) was 55.26 ± 14.16 and 49.81 ± 12.16 years. 46 patients were treated with radiotherapy alone and 57 patients were treated with concurrent chemo radiotherapy using infusion cisplatinum 3 weekly and 5 fluorouracil twice weekly. Mean follow up was 13.35 months. All the patients characteristic and treatment characteristics were recorded. RESULTS: There were 81 men and 22 women in the study. Group I contains 15 and 31 cases of stage III and IV tumors while group II contains 19 and 38 cases of stage III and IV respectively. Group II has shown improved loco regional control rate for the T3 and T4 tumors as compared to group I. Disease free survival and overall survival in the group II is 25.51 months and 22.53 months while group I has 8.67 months and 6.74 months respectively. Grade III mucosal toxicity incidence was higher in group II as compared to group I. CONCLUSIONS: In locally advanced squamous cell carcinoma of base of tongue tumors concomitant chemoradiotherapy with infusional cisplatinum and 5 fluorouracil results in higher disease free and overall survival as compared to radiotherapy as single modality. This better tumor response with chemoradiotherapy comes at cost of higher incidence of mucosal toxicity.

Effects of carbamazepine on the hypothalamic-pituitary-thyroid axis.

OBJECTIVE: To evaluate the effects of treatment with carbamazepine on the hypothalamic-pituitary-thyroid axis and thyroid hormone concentrations in patients with epilepsy. METHODS: We undertook a prospective study in seven subjects in whom the diagnosis of epilepsy had been established and a regimen of carbamazepine (200 mg three times a day) was initiated. All participants underwent 24-hour 123 I thyroid uptake studies, as well as assessment of the basal thyrotropin concentration and the thyrotropin response to intravenous administration of thyrotropin-releasing hormone. In addition, thyroxine (T(4)), free T(4) index, triiodothyronine (T(3)), free T(3) index, reverse T(3), and T(3) resin uptake were determined before initiation of carbamazepine treatment and again after 3 to 4 months of carbamazepine therapy. RESULTS: Serum T(4), T(3), and free T(4) index decreased significantly (P<0.05) after therapy with carbamazepine, whereas no significant alterations were noted in T(3) resin uptake, free T(3) index, and reverse T(3) concentrations. A significant increase occurred in basal serum thyrotropin level (P<0.05). Moreover, the peak thyrotropin concentration, the absolute change from the basal thyrotropin level, and an integrated thyrotropin response expressed as cumulative response to thyrotropin-releasing hormone stimulation were all significantly increased after carbamazepine therapy in comparison with values documented before initiation of therapy (P<0.05 for all comparisons). Finally, 24-hour 123 I uptake by the thyroid gland increased slightly after carbamazepine therapy, but the change was not statistically significant. All values determined both before and after carbamazepine therapy remained within normal ranges. CONCLUSION: Carbamazepine therapy induces significant alterations in serum thyroid hormone concentrations as well as in the hypothalamic-pituitary-thyroid axis. Nevertheless, patients receiving carbamazepine treatment continue to remain euthyroid despite these significant changes.

Sixty years of psychosurgery: its present status and its future.

After its introduction 60 years ago, psychosurgery witnessed a remarkable rise followed by a decline. In the 1990s, it is a marginal treatment practised by a few psychiatrists in some specialised centres around the world. The psychiatric profession, however, continues to support it, and there is some evidence for a recent renewal of interest in the procedure. In this paper, the reasons for this reluctant acceptance of psychosurgery are examined, and the factors that are likely to determine its future are identified. The profession is urged to keep the interest in psychosurgery alive until further theoretical and empirical developments can either announce its death or lead to a resurgence of psychiatric neurosurgery in its present or modified form.

Neuropathic bladder in ankylosing spondylitis with spinal diverticula.

Cauda equina type of syndrome with neuropathic bladder is a rare but known complication of long-standing ankylosing spondylitis. From 1968 until now, diverticula from the subarachnoid space eroding into the bodies of the lumbosacral vertebrae have been reported in 46 cases of ankylosing spondylitis with cauda equina syndrome and neuropathic bladder. We report 3 cases of neuropathic bladder and ankylosing spondylitis with cauda equina symptoms. In 1 of the 3 patients, these rarely encountered spinal diverticula were demonstrated by computerized tomography (CT) scan. The etiology of these diverticula and their treatment are reviewed.

Duane's retraction syndrome associated with cerebral arteriovenous malformation.

We have described a case of Duane's retraction syndrome in association with well documented cerebral arteriovenous malformation. This syndrome has been previously reported in association with anomalies of other parts of the body, but perusal of pertinent literature did not disclose reports of such a combination as seen in our patient.

Lower cranial nerve palsies due to Pseudomonas osteomyelitis of the skull base.

A patient with pseudomonas osteomyelitis of the base of the left posterior fossa is reported. His clinical course was one of progressive paresis of the left 8th, 10th, and 11th cranial nerves. There have been three prior reports of osteomyelitis of the base of the skull not in contiguity with an infected paranasal sinus. Our patient subsequently developed osteomyelitis in the 3rd to 5th cervical vertebrae.

A clinical and follow up study of atypical psychoses.

Twenty-two cases who fulfilled the criteria of having atypical manifestation at any stage of illness and had minimum follow up of three years were studied in detail. Their family history and follow up was analysed. The findings of the present study suggest that the cases showing admixture of schizophrenic and affective symptoms are probably a variant of affective disorders although a possibility of their being a third independent psychosis cannot be ruled out.