A Phase 3, Multicenter, Randomized, Double-Blind, Vehicle-Controlled Study Evaluating the Safety and Efficacy of Metronidazole Vaginal Gel 1.3% in the Treatment of Bacterial Vaginosis.

BACKGROUND: Bacterial vaginosis (BV), a prevalent infection in women of reproductive age, is associated with increased risk of upper genital tract and sexually transmitted infections, and complications in pregnancy. Currently approved treatments include metronidazole, which requires once or twice daily intravaginal administration for 5 days or twice daily oral administration for 7 days. This phase 3 study determined the safety and efficacy of single-dose metronidazole vaginal gel (MVG) 1.3%. METHODS: In this double-blind, vehicle-controlled study, 651 women with clinical diagnosis of BV were randomized 1:1 to receive MVG 1.3% or vehicle vaginal gel. Primary efficacy measure was clinical cure (normal discharge, negative "whiff test," and <20% clue cells) at day 21. Secondary measures included therapeutic cure (both clinical and bacteriological; day 21) and bacteriologic cure (Nugent score <4), clinical cure, and time to resolution of symptoms (day 7). RESULTS: A total of 487 participants were included in the primary analysis. Clinical and therapeutic cure rates (day 21) were higher in participants treated with MVG 1.3% compared with vehicle gel (37.2% vs. 26.6% [P = 0.010] and 16.8% vs. 7.2% [P = 0.001], respectively). Clinical and bacteriologic cure rates (day 7) were also higher in the MVG 1.3% group (46.0% vs. 20.0% [P < 0.001] and 32.7% vs. 6.3% [P < 0.001], respectively). The median time to resolution of symptoms was shorter in the MVG 1.3% (day 6) than vehicle group (not reached). No serious adverse events were reported, and incidence was similar across treatment groups. CONCLUSIONS: Single-dose MVG 1.3% was safe and superior to vehicle gel in producing cure among women with BV.

Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects.

AIMS: The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. METHODS: Healthy subjects, 18-55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1-2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days. RESULTS: The coadministration of CQ + TQ had no effect on TQ AUC0-t , AUC0-∞ , Tmax or t1/2 . The 90% confidence intervals of CQ + TQ vs. TQ for AUC0-t , AUC0-∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0-24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated. CONCLUSIONS: No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects.

[18F]FDG and [18F]FES PET/CT Imaging as a Biomarker for Therapy Effect in Patients with Metastatic ER+ Breast Cancer Undergoing Treatment with Rintodestrant.

PURPOSE: PET with 16α-[18F]-fluoro-17ß-estradiol ([18F]FES) allows assessment of whole body estrogen receptor (ER) expression. The aim of this study was to investigate [18F]-fluorodeoxyglucose ([18F]FDG) and [18F]FES PET/CT imaging for response prediction and monitoring of drug activity in patients with metastatic ER-positive breast cancer undergoing treatment with the selective estrogen receptor downregulator (SERD) rintodestrant. EXPERIMENTAL DESIGN: In this trial (NCT03455270), PET/CT imaging was performed at baseline ([18F]FDG and [18F]FES), during treatment and at time of progression (only [18F]FES). Visual, quantitative, and mutational analysis was performed to derive a heterogeneity score (HS) and assess tracer uptake in lesions, in relation to the mutation profile. The primary outcome was progression-free survival (PFS). RESULTS: The HS and PFS in the entire group did not correlate (n = 16, Spearman's rho, P = 0.06), but patients with a low HS (< 25.0%, n = 4) had a PFS of > 5 months whereas patients with no [18F]FES uptake (HS 100.0%, n = 3) had a PFS of < 2 months. [18F]FES uptake was not affected by estrogen receptor 1 (ESR1) mutations. On-treatment [18F]FES PET/CT scans showed no [18F]FES uptake in any of the baseline [18F]FES-positive lesions. At progression, [18F]FES uptake remained blocked in patients scanned ≤ 1-2 half-lives of rintodestrant whereas it restored in patients scanned ≥ 5 days after end of treatment. CONCLUSIONS: Absence of ER expression on [18F]FES PET is a predictor for no response to rintodestrant. [18F]FES uptake during treatment and at time of progression is useful to monitor the (reversible) effect of therapy and continued mode of action of SERDs. See related commentary by Linden and Mankoff, p. 2015.

Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-Mutant Pancreatic Cancer.

Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation of KRAS in promoting the development and malignant growth of pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration of p16INK4A function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown limited clinical efficacy in PDAC. Here, we found that concurrent treatment with both a CDK4/6 inhibitor (CDK4/6i) and an ERK-MAPK inhibitor (ERKi) synergistically suppresses the growth of PDAC cell lines and organoids by cooperatively blocking CDK4/6i-induced compensatory upregulation of ERK, PI3K, antiapoptotic signaling, and MYC expression. On the basis of these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). As inhibition of other proteins might also counter CDK4/6i-mediated signaling changes to increase cellular CDK4/6i sensitivity, a CRISPR-Cas9 loss-of-function screen was conducted that revealed a spectrum of functionally diverse genes whose loss enhanced CDK4/6i growth inhibitory activity. These genes were enriched around diverse signaling nodes, including cell-cycle regulatory proteins centered on CDK2 activation, PI3K-AKT-mTOR signaling, SRC family kinases, HDAC proteins, autophagy-activating pathways, chromosome regulation and maintenance, and DNA damage and repair pathways. Novel therapeutic combinations were validated using siRNA and small-molecule inhibitor-based approaches. In addition, genes whose loss imparts a survival advantage were identified (e.g., RB1, PTEN, FBXW7), suggesting possible resistance mechanisms to CDK4/6 inhibition. In summary, this study has identified novel combinations with CDK4/6i that may have clinical benefit to patients with PDAC. SIGNIFICANCE: CRISPR-Cas9 screening and protein activity mapping reveal combinations that increase potency of CDK4/6 inhibitors and overcome drug-induced compensations in pancreatic cancer.

Phase I trial of verubulin (MPC-6827) plus carboplatin in patients with relapsed glioblastoma multiforme.

Verubulin (MPC-6827) is a microtubule-destabilizing agent that achieves high concentrations in the brain. Verubulin disrupts newly formed blood vessels in xenografts. We determined the safety and tolerability of verubulin administered in combination with carboplatin in patients with relapsed glioblastoma multiforme (GBM). Three pre-selected doses of verubulin were tested: 2.1, 2.7, and 3.3 mg/m(2) in a standard "3+3" design. Verubulin was given every second week of a 6-week cycle in the 2.1 mg/m(2) cohort or weekly for 3 weeks of a 4-week cycle in subsequent cohorts. Carboplatin was administered intravenously at an area under the curve (AUC) dosage 4 every 2 weeks for the 2.1 mg/m(2) cohort or on day 1 of each 4-week cycle in subsequent cohorts. Nineteen patients with GBM in first or second relapse were enrolled. Four patients (21 %) experienced a grade 3 or greater verubulin- or carboplatin-related adverse event, including hypesthesia, cerebral ischemia, anemia, and thrombocytopenia. The mean plasma half life of verubulin was 3.2 h (SD = 0.82). Two patients achieved at least a partial response by Macdonald criteria. One of these patients remains progression free and off treatment more than 24 months beyond his initiation of verubulin. Five patients had stable disease. Median progression-free survival (PFS) across all patients was 8 weeks, and the 6-month PFS rate was 21 %. The combination of verubulin at the previously determined single-agent maximum tolerated dose of 3.3 mg/m(2) with carboplatin in patients with recurrent/refractory GBM is safe and well tolerated. In this patient population with a highly vascularized tumor, no cerebral hemorrhage was observed.

Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial.

CONTEXT: Amyloid-beta peptide (Abeta(42)) has been implicated in the pathogenesis of Alzheimer disease (AD). Tarenflurbil, a selective Abeta(42)-lowering agent, demonstrated encouraging results on cognitive and functional outcomes among mildly affected patients in an earlier phase 2 trial. OBJECTIVE: To determine the efficacy, safety, and tolerability of tarenflurbil. DESIGN, SETTING, AND PATIENTS: A multicenter, randomized, double-blind, placebo-controlled trial enrolling patients with mild AD was conducted at 133 trial sites in the United States between February 21, 2005, and April 30, 2008. Concomitant treatment with cholinesterase inhibitors or memantine was permitted. INTERVENTION: Tarenflurbil, 800 mg, or placebo, administered twice a day. MAIN OUTCOME MEASURES: Co-primary efficacy end points were the change from baseline to month 18 in total score on the subscale of the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog, 80-point version) and Alzheimer Disease Cooperative Studies-activities of daily living (ADCS-ADL) scale. Additional prespecified slope analyses explored the possibility of disease modification. RESULTS: Of the 1684 participants randomized, 1649 were included in the analysis, and 1046 completed the trial. Tarenflurbil had no beneficial effect on the co-primary outcomes (difference in change from baseline to month 18 vs placebo, based on least squares means: 0.1 for ADAS-Cog; 95% CI, -0.9 to 1.1; P = .86 and -0.5 for ADCS-ADL; 95% CI, -1.9 to 0.9; P = .48) using an intent-to-treat analysis. No significant differences occurred in the secondary outcomes. The ADAS-Cog score decreased by 7.1 points over 18 months. The tarenflurbil group had a small increase in frequency of dizziness, anemia, and infections. CONCLUSION: Tarenflurbil did not slow cognitive decline or the loss of activities of daily living in patients with mild AD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00105547.

Modulation of cell cycle progression in human tumors: a pharmacokinetic and tumor molecular pharmacodynamic study of cisplatin plus the Chk1 inhibitor UCN-01 (NSC 638850).

BACKGROUND: UCN-01, a Chk1 inhibitor, abrogates S and G(2) arrest and enhances cancer cell killing by DNA-damaging drugs in preclinical models. UCN-01 avidly binds alpha1-acid glycoprotein in plasma; whether sufficient drug concentrations are achieved in human tumors is unknown. A phase I trial tested the hypothesis that UCN-01 abrogates cisplatin-induced cell cycle arrest (in tumors) at tolerable doses. METHODS: Patients with advanced cancer received i.v. cisplatin, followed 22 hours later by UCN-01 (3-day continuous i.v. infusion of a 28-day cycle). Platinum was measured by atomic absorption, UCN-01 by high-performance liquid chromatography, and cell cycle progression in tumor biopsies by geminin immunostaining (biomarker for S/G(2) phases of cell cycle). RESULTS: The first two patients treated with cisplatin (20 mg/m(2) plus UCN-01 45 mg/m(2)/d) experienced dose-limiting toxicities (subarachnoid hemorrhage, hyperglycemia, hypoxia, cardiac ischemia, and atrial fibrillation). Following 25% UCN-01 dose reduction, no toxicities greater than grade 2 were seen. Median plasma UCN-01 half-life (T(1/2)) was 405 hours. Salivary UCN-01 concentrations showed a rapid initial decline (median T(1/2alpha), 29.9 hours), followed by a terminal decay parallel to that in plasma. UCN-01 pharmacokinetics, and the timing of clinical toxicities, suggests that UCN-01 is bioavailable despite alpha1-acid glycoprotein binding. Marked suppression of cells in S/G(2) in tumor biopsies was seen by geminin immunohistochemistry, suggesting that UCN-01 is bioavailable at concentrations sufficient to inhibit Chk1. CONCLUSIONS: Cisplatin (30 mg/m(2)), followed 22 hours later by UCN-01 (34 mg/m(2)/d for 3 days), is well tolerated clinically and yields UCN-01 concentrations sufficient to affect cell cycle progression in tumors.

The effects of lapatinib on CYP3A metabolism of midazolam in patients with advanced cancer.

PURPOSE: The potential inhibition of CYP3A4 by lapatinib was studied using midazolam as a probe substrate in patients with cancer. METHODS: This was a partially randomized, 4-period, 4-sequence, 4-treatment, cross-over study in 24 patients with advanced cancer. Single 1-mg IV and 3-mg oral doses of midazolam were given 2 days apart, in a partially random order, on study days 1, 3, 9, and 11. Lapatinib 1500-mg was administered orally once daily on study days 4 through 11. Midazolam plasma concentrations were measured up to 24-h post dosing, and lapatinib plasma concentrations measured prior to each midazolam dose. RESULTS: Lapatinib increased the geometric mean (95% CIs) midazolam AUC(o-∞) by 45% (31-60%) after the oral dose and by 14% (0-29%) after the IV dose, and prolonged the midazolam elimination half-life by 48% (22-81%) after the oral dose and by 20% (2-40%) after the IV dose. Lapatinib decreased midazolam total clearance by 13% (1-23%), while total bioavailability was increased 23% (4-46%) without changes in apparent volume of distribution or hepatic bioavailability. CONCLUSION: These data show that lapatinib caused weak inhibition of gastrointestinal CYP3A4 in vivo. This suggests that oral CYP3A4 drug substrates with a narrow therapeutic index may need dose reduction if lapatinib is to be co-prescribed.

Hemolytic Potential of Tafenoquine in Female Volunteers Heterozygous for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (G6PD Mahidol Variant) versus G6PD-Normal Volunteers.

Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40-60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose-response was evident in G6PD-heterozygous subjects (N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (-2.65 to -2.95 g/dL [N = 3]) and primaquine (-1.25 to -3.0 g/dL [N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61-80% (N = 2) and > 80% (N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days.

The pharmacokinetics of the bispecific antibody MDX-H210 when combined with interferon gamma-1b in a multiple-dose phase I study in patients with advanced cancer.

INTRODUCTION: MDX-H210 is a Fab'xFab' bispecific antibody (BsAb) constructed chemically by crosslinking Fab' mAb 520C9 (anti-HER-2/neu) and humanized Fab' mAbH22 (anti-CD64). STUDY DESIGN AND OBJECTIVES: This was a phase I dose-escalation study of intravenous MDX-H210 (1-70 mg/m(2)) combined with subcutaneous IFN-gamma, 50 microg/m(2) given 24 h before the BsAb, both drugs being given three times a week for 3 weeks. The major objectives of the study were to define the safety, tolerability and pharmacokinetics of MDX-H210 when given with IFN-gamma on this schedule. RESULTS: The study group comprised 23 patients (19 female, 4 male; median age 51.5 years, range 25-72 years) with advanced HER-2/neu-positive cancers (19 breast, 3 prostate and 1 lung). Inspection of the log plasma MDX-H210 concentrations-time data for both days 1 and 17 of treatment revealed monoexponential decay in the majority of patients with adequate concentration-time data points. The MDX-H210 T(1/2) ranged from 2.9 to 21.9 h. The MDX-H210 C(max) on day 1 (means+/-SD) increased from 0.30+/-0.22 microg/ml at the 1-mg/m(2) dose tier to 86.91+/-6.46 microg/ml at 70 mg/m(2). Equivalent day-17 values were 0.27+/-0.30 microg/ml increasing to 147.85+/-40.23 microg/ml. The MDX-H210 T(max) occurred at or after the end of the infusion for all treatments. The mean MDX-H210 total body clearance (Cl) was in the range 0.01-0.34 ml/min per kg and the mean MDX-H210 apparent volume of distribution at steady-state (Vd(ss)) in the range 20-170 ml/kg, compatible with distribution primarily limited to the intravascular space. MDX-H210 T(1/2) increased with dose (ANOVA P=0.001) and Cl decreased with dose (ANOVA P=0.006). There were no significant changes in MDX-H210 C(max), AUC, Cl or Vd(ss) between day 1 and day 17. CONCLUSIONS: MDX-H210 pharmacokinetics appeared saturable over the dose range 1-70 mg/m(2), and there was no significant change in MDXH210 pharmacokinetics over the course of the study, or evidence of excessive accumulation of MDX-H210 on this multiple dosing schedule. When MDX-H210 was combined with IFN-gamma, the estimated MDX-H210 pharmacokinetic parameters were similar to the published data for single-agent MDX-H210.

A phase I, dose-escalation study of cyclical weekly oral temozolomide and weekly PEG-interferon alpha-2b in patients with refractory or advanced solid tumours.

BACKGROUND: Temozolomide (TMZ) is an oral alkylating agent used in the treatment of central nervous system neoplasms and metastatic melanoma. Preclinical and clinical data suggested that combining TMZ with interferon alpha-2b (IFN-alpha-2b) may result in increased anti-tumour efficacy. METHODS: This was a phase I, dose-escalation study to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of cyclical oral TMZ (days 1-7 and 15-21) in combination with pegylated IFN-alpha-2b (PEG-IFN-alpha-2b) in patients with advanced solid tumours. RESULTS: We treated 19 patients (10 female and nine male), median age 58 years (range: 41-79 years). Ten patients tolerated TMZ at 100 mg/m² on days 1-7 and 15-21 plus PEG-IFN-alpha-2b at 1.5 mcg/kg/week on 28-day cycles which was the MTD of the combination. The pharmacokinetic parameters of PEG-IFN-alpha-2b were not altered by TMZ, at the MTD. CONCLUSION: The MTD of cyclical oral TMZ was 100 mg/m² on days 1-7 and 15-21 when combined with weekly subcutaneous PEG-IFNα-2b at 1.5 mcg/kg/week on 28 days cycles. The PK of PEG-IFN-alpha-2b appeared consistent with those when it is used as monotherapy.

Effects of food on the relative bioavailability of lapatinib in cancer patients.

PURPOSE: This study was conducted to characterize the effect of food on the relative bioavailability of lapatinib. PATIENTS AND METHODS: A single 1,500-mg, oral dose of lapatinib was administered to 27 patients with advanced solid tumors on each of three occasions that were 1 week apart, in random order: after an overnight fast, with a low-fat breakfast, and with a high-fat breakfast. RESULTS: The low-fat breakfast produced mean increases in lapatinib area under the concentration-time curve (AUC) of 167% (2.67-fold) and maximum concentration (C(max)) of 142% (2.42-fold). The high-fat breakfast produced mean increases in lapatinib AUC of 325% (4.25-fold) and C(max) of 203% (3.03-fold) compared with the fasted state. Increased bioavailability in the fed state did not significantly decrease relative variability. Therefore, absolute variability in systemic exposure was increased. CONCLUSION: These large increases in lapatinib bioavailability and absolute variability support the recommendation for dosing in the fasted state to achieve consistent therapeutic exposure. Prescribers and patients should consider the potential consequences of toxicity or diminished efficacy that might result from dosing without regard to variations in diet.

Increased recognition of Powassan encephalitis in the United States, 1999-2005.

Powassan virus (POWV) disease is a rare human disease caused by a tick-borne encephalitis group flavivirus maintained in a transmission cycle between Ixodes cookei and other ixodid ticks and small and medium-sized mammals. During 1958-1998, only 27 POWV disease cases (mostly Powassan encephalitis) were reported from eastern Canada and the northeastern United States (average, 0.7 cases per year). During 1999-2005, nine cases (described herein) of serologically confirmed POWV disease were reported in the United States (average, 1.3 cases per year): four from Maine, two from New York, and one each from Michigan, Vermont, and Wisconsin. The Michigan and Wisconsin cases are the first ever reported from the north-central United States. Of these nine patients, 5 (56%) were men, the median age was 69 years (range: 25-91 years), and 6 (67%) had onset during May-July. All but one patient developed encephalitis with acute onset of profound muscle weakness, confusion, and other severe neurologic signs. In one case, no neurologic symptoms were present but the presence of pleocytosis, an elevated cerebrospinal fluid (CSF) protein concentration, and POWV-specific immunoglobulin M in CSF suggested neuroinvasion. All patients recovered from their acute disease, but most had long-term neurologic sequelae. Periresidential ecologic investigations were performed in three cases, including tests of local mammals and ticks for evidence of POWV infection. Woodchucks (Marmota monax), striped skunks (Mephitis mephitis), and a raccoon (Procyon lotor) collected at two of the Maine case-patients' residences had neutralizing antibody titers to POWV. I. cookei were found on woodchucks and skunks and questing in grassy areas of one of these residences; all were negative for POWV. Although POWV disease is rare, it is probably under-recognized, and it causes significant morbidity, and thus is an additional tick-borne emerging infectious disease entity. Because no vaccine or specific therapy is available, the basis of prevention is personal protection from ticks (or "tick hygiene") and reduced exposure to peridomestic wild mammals.

Ethylene glycol toxicity associated with ischemia, perforation, and colonic oxalate crystal deposition.

Severe ethylene glycol toxicity can cause profound morbidity and is almost universally fatal if untreated. Central nervous system depression with intoxication, pulmonary edema, and acute oliguric renal failure with crystalluria are among the most commonly encountered complications of ingestion. The previously reported gastrointestinal side effects of ethylene glycol toxicity are mostly nonspecific, including nausea, abdominal pain, and cramping. In addition, hepatic damage due to calcium oxalate deposition has been reported. We describe a patient who developed acute colonic ischemia following ethylene glycol intoxication. Three months after the ingestion, the patient presented with severe abdominal pain secondary to a colonic stricture and perforation, necessitating emergent colectomy. Histology of the resected colon revealed polarizable polyhedral crystals suggestive of oxalate deposition. The pathophysiology underlying ethylene glycol intoxication, treatment strategies, and gastrointestinal toxicity are discussed.