Prabhu Rajagopalan

Hypertension and Rarefaction during Treatment with Telatinib, a Small Molecule Angiogenesis Inhibitor

Purpose: Hypertension is a commonly reported side effect in antiangiogenic therapy. We investigated the hypothesis that telatinib, a small molecule angiogenesis inhibitor, impairs vascular function, induces rarefaction, and causes hypertension. Experimental Design: A side-study was done in a phase I trial of telatinib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptors 2 and 3, platelet-derived growth factor receptor, and c-KIT in patients with advanced solid tumors. Measurements of blood pressure, flow-mediated dilation, nitroglycerin-mediated dilation, aortic pulse wave velocity, skin blood flux with laser Doppler flow, and capillary density with sidestream dark field imaging were done at baseline and after 5 weeks of treatment. Blood pressure and proteinuria were measured weekly. Results: Mean systolic and diastolic blood pressure values increased significantly at +6.6 mm Hg (P = 0.009) and +4.7 mm Hg (P = 0.016), respectively. Mean flow-mediated dilation and mean nitroglycerin-mediated dilation values significantly decreased by −2.1% (P = 0.003) and −5.1% (P = 0.001), respectively. After 5 weeks of treatment, mean pulse wave velocity significantly increased by 1.2 m/s (P = 0.001). A statistically significant reduction of mean skin blood flux of 532.8% arbitrary units was seen (P = 0.015). Capillary density statistically significantly decreased from 20.8 to 16.7 capillary loops (P = 0.015). Proteinuria developed or increased in six patients during telatinib treatment. Conclusion: The increase in blood pressure observed in the treatment with telatinib, an angiogenesis inhibitor, may be caused by functional or structural rarefaction.

Effect of High‐Fat Breakfast and Moderate‐Fat Evening Meal on the Pharmacokinetics of Vardenafil, an Oral Phosphodiesterase‐5 Inhibitor for the Treatment of Erectile Dysfunction

The effects of food on the pharmacokinetics of vardenafil were examined in 25 healthy adult males. Single‐dose vardenafil 20 mg was administered in a randomized four‐way crossover design after an overnight fast (at 8 a.m.), after consumption of a high‐fat breakfast (at 8 a.m.), on an empty stomach (at 6 p.m.), and after a typical moderate‐fat evening meal (at 6 p.m.). Serial blood samples were analyzed for vardenafil and metabolite (M1) levels. When administered after an overnight fast and after a high‐fat breakfast, vardenafil geometric mean Cmax was 17.14 and 14.0 μg/L, respectively, and AUC was 66.78 and 67.09 μg•h/L, respectively; the median tmax was 1 hour under fasting conditions and 2 hours with consumption of high‐fat breakfast. When administered in the evening on an empty stomach and after a moderate‐fat meal, vardenafil geometric mean Cmax was 14.22 and 13.04 μg/L, respectively, and AUC was 51.97 and 59.12 μg•h/L, respectively. The median tmax was 1 hour after fasting or a moderate‐fat meal in the evening. All treatments were well tolerated. Thus, while a high‐fat meal may alter Cmax slightly and delay the absorption up to 1 hour, a moderate‐fat meal has no clinically relevant effect on vardenafil pharmacokinetics. Dosage changes are not warranted based on the wide therapeutic index and the efficacy observed with vardenafil in Phase III studies that were not restricted with respect to food.

Population pharmacokinetics of ciprofloxacin in pediatric patients

The objective of this study was to characterize ciprofloxacin population pharmacokinetics in pediatric patients. A total of 150 pediatric patients (including 28 patients with cystic fibrosis [CF], ages 0.27–16.9 years) received ciprofloxacin by the oral and/or intravenous routes. Population pharmacokinetic analyses were performed with NONMEM software. Exponential error models were used to describe the interindividual variance in pharmacokinetic parameters, and the residual error model included both proportional and additive components. Based on principles of allometry, the patients body weight was used as a covariate, along with appropriate allometric exponents, in the construction of the base model. Model building was accomplished by a stepwise forward inclusion procedure, and the final model was evaluated by multiple techniques, including bootstrap, leverage analysis, and cross‐validation. With body weight included in the model (two compartments with first‐order absorption), ciprofloxacin clearance was influenced by age, and the absorption rate constant was altered in CF patients. The final model is summarized as follows: CL (L/h) = 30.3 × (WT/70)0.75 × (1 + 0.045 [AGE −2.5]), VC (L) = 56.7 × (WT/70)1.0, VP (L) = 89.8 × (WT/70)1.0, Q (L/h) = 37.5 × (WT/70)0.75, Ka (1/h) = 1.27 × (1 + [−0.611 × CF]), absorption lag time = 0.35 hours, and bioavailability fraction = 61.1%, where WT and AGE are the patients body weight (kg) and age (years), respectively, and the variable CF equals 1 for CF patients and 0 for non‐CF patients. The interpatient variability in pharmacokinetic parameters (percentage coefficient of variation [%CV]) ranged from 22.5% to 49.8%. The residual variabilities (%CV) for the oral and intravenous data were 40% and 27%, respectively. The shared additive residual variance component was small (SD = 0.04 mg/L). Model evaluation by the different methods indicated that the final model was robust and parameter estimates were precise. A small difference (< 6%) was noted when the patients age was not used in dose calculation. Therefore, in routine clinical use, for pediatric patients older than 3 months, ciprofloxacin dose may be calculated solely based on body weight.

A Phase II Study of the Efficacy and Safety of the Combination Therapy of the MEK Inhibitor Refametinib (BAY 86-9766) Plus Sorafenib for Asian Patients with Unresectable Hepatocellular Carcinoma

Purpose: There is an unmet need for treatment options in hepatocellular carcinoma (HCC). Sorafenib is currently the only approved systemic treatment for HCC. Refametinib, an oral, allosteric MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in vitro and in vivo. A phase II study evaluated efficacy and safety of refametinib plus sorafenib in Asian patients with HCC (NCT01204177). Experimental Design: Eligible patients received twice-daily refametinib 50 mg plus twice-daily sorafenib 200 mg (morning)/400 mg (evening), with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade ≥2 hand-foot skin reaction, fatigue, or gastrointestinal toxicity occurred. Primary efficacy endpoint: disease control rate. Secondary endpoints: time to progression, overall survival, pharmacokinetic assessment, biomarker analysis, safety, and tolerability. Results: Of 95 enrolled patients, 70 received study treatment. Most patients had liver cirrhosis (82.9%) and hepatitis B viral infection (75.7%). Disease control rate was 44.8% (primary efficacy analysis; n = 58). Median time to progression was 122 days, median overall survival was 290 days (n = 70). Best clinical responders had RAS mutations; majority of poor responders had wild-type RAS. Most frequent drug-related adverse events were diarrhea, rash, aspartate aminotransferase elevation, vomiting, and nausea. Dose modifications due to adverse events were necessary in almost all patients. Conclusions: Refametinib plus sorafenib showed antitumor activity in patients with HCC and was tolerated at reduced doses by most patients. Frequent dose modifications due to grade 3 adverse events may have contributed to limited treatment effect. Patients with RAS mutations appear to benefit from refametinib/sorafenib combination. Clin Cancer Res; 20(23); 5976–85. ©2014 AACR.

Multicenter Phase I Trial of the Mitogen-Activated Protein Kinase 1/2 Inhibitor BAY 86-9766 in Patients with Advanced Cancer

Purpose: To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors. Experimental Design: BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal–regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes. Results: Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ∼12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate–stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy. Conclusion: This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types. Clin Cancer Res; 19(5); 1232–43. ©2012 AACR.

Phase I Dose Escalation Study of Telatinib, a Tyrosine Kinase Inhibitor of Vascular Endothelial Growth Factor Receptor 2 and 3, Platelet-Derived Growth Factor Receptor {beta}, and c-Kit, in Patients With Advanced or Metastatic Solid Tumors

PURPOSE Telatinib (BAY 57-9352) is an orally available tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -2, VEGFR-3, platelet-derived growth factor receptor-beta, and c-Kit. This phase I dose escalation study was conducted to evaluate the safety and tolerability of telatinib, with additional pharmacokinetic, pharmacodynamic, and efficacy assessments. PATIENTS AND METHODS Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Doses of continuously administered telatinib were escalated from 20 mg once daily to 1,500 mg twice daily. RESULTS Fifty-three patients were enrolled. Most frequently observed drug-related adverse events were nausea (26.4%; grade >or= 3, 0%) and hypertension (20.8%; grade 3, 11.3%; grade 4, 0%). Two dose-limiting toxicities were observed: one poorly controlled hypertension (600 mg twice daily), and one grade 2 weight loss, anorexia, and fatigue (1,500 mg twice daily). A formal maximum-tolerated dose was not reached. Telatinib was rapidly absorbed, with median time to peak concentration (t(max)) lower than 3 hours after dose. A nearly dose-proportional increase in exposure was observed with substantial variability. Telatinib half-life averaged 5.5 hours. Biomarker analyses showed dose-dependent increase in VEGF levels and decrease in plasma soluble VEGFR-2 levels, with a plateau at 900 mg twice daily. A decrease in tumor blood flow (K(trans) and IAUC(60)) was observed with dynamic contrast-enhanced magnetic resonance imaging. Best tumor response was stable disease, observed in 50.9% of patients. CONCLUSION Telatinib was safe and well tolerated up to 1,500 mg twice daily. Based on pharmacodynamic and pharmacokinetic end points, telatinib 900 mg twice daily is the recommended dose for subsequent phase II studies.

Abstract LB-291: First-in-human phase I dose escalation study of a novel anti-mesothelin antibody drug conjugate (ADC), BAY 94-9343, in patients with advanced solid tumors.

Background: BAY 94-9343 (BAY, Mesothelin-ADC) is a novel ADC consisting of a fully human monoclonal antibody directed against mesothelin, conjugated to a maytansine derivative DM4. Mesothelin is an internalizing antigen overexpressed by a number of solid tumors, including a majority of mesotheliomas and pancreatic and ovarian adenocarcinomas. BAY demonstrates mesothelin-specific antitumor activity in relevant xenografts. Objectives of this study were evaluation of safety, PK, immunogenicity, biomarkers, antitumor activity, and determination of Maximum Tolerated Dose (MTD) of BAY in patients (pts) with advanced solid tumors. Methods: BAY doses ranged from 0.15 to 5.5 mg/kg IV every 21 days. PK samples were collected in Cycles (C) 1 and 3; biomarker and immunogenicity samples were also collected. Tumor assessments were planned every 6 weeks. Results: 32 pts (16 mesothelioma, 9 pancreatic, 3 ovarian and 4 other) received BAY. No dose limiting toxicities (DLT) have been observed up to 5.5 mg/kg. One pt had possibly study drug related SAE of Grade 3 chest pain in C2. There were no other related Grade 3/4 AEs. One pt had a Grade 2 infusion reaction and one pt had possibly related Grade 2 pericardial effusion (PE). Two other pts had PE not related to BAY but to underlying cancer. The most common possibly related Grade 1/2 AEs were fatigue (10 pts), nausea (7), anorexia (4), vomiting (4), and weakness (3). PK of ADC and Total Antibody increased in a generally dose proportional manner; half-life was 4 to 5 days. DM4 Cmax increased in a dose proportional manner and DM4 metabolite exposure increased in a more than dose proportional manner; half-lives were approx. 2 and 6 days, respectively. Anti-BAY antibodies were observed in 3 pts at dose levels ≤ 2.4 mg/kg which was associated with decreased ADC exposure in C3. Exploratory analysis of cytokeratins (CK18 M30 and M65) and serum mesothelin as biomarkers will be discussed. One mesothelioma pt in 5.5 mg/kg cohort has confirmed partial response and is currently ongoing. Durable stable disease has been observed in 2 mesothelioma pts (6 and 10 cycles, respectively). Conclusions: BAY has been tolerated at doses of up to 5.5 mg/kg and dose escalation continues. There are no prohibitive findings with regards to PK and antidrug antibodies at higher dose levels. Initial signals of clinical activity are seen. Updated results will be presented. Citation Format: Johanna Bendell, George Blumenschein, Ralph Zinner, David Hong, Suzanne Jones, Jeffrey Infante, Howard Burris, Prabhu Rajagopalan, Martin Kornacker, David Henderson, Andrea Kelly, Raffit Hassan. First-in-human phase I dose escalation study of a novel anti-mesothelin antibody drug conjugate (ADC), BAY 94-9343, in patients with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-291. doi:10.1158/1538-7445.AM2013-LB-291

Phase i dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies

Background:To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D).Methods:Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway.Results:Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6).Conclusions:Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.

Safety, tolerability, pharmacokinetics, and efficacy of an interleukin-2 agonist among HIV-infected patients receiving highly active antiretroviral therapy.

We sought to determine the safety, maximum tolerated dose, optimal dose, and preliminary dose efficacy of intermittent subcutaneously (s.c.) administered BAY 50-4798 among patients with HIV infection receiving highly active antiretroviral therapy (HAART) compared with patients receiving HAART alone. A phase I/II randomized, double-blind, dose-escalation study was conducted of the safety, tolerability, pharmacokinetics, and efficacy of s.c. BAY 50-4798 administered to HIV-infected patients already receiving stable HAART. There were no unexpected safety findings in a population of HIV-infected patients receiving HAART plus SC BAY 50-4798 as adjunctive therapy. BAY 50-4798 exhibited nearly dose-proportional pharmacokinetics, and accumulation was minimal during multiple-dose treatment. Limited efficacy data indicated that treatment with BAY 50-4798 caused at least a transient increase in CD4(+) T cell counts in some recipients, particularly at the early time points. In general, this effect appeared to increase with increasing dose. Bay 50-4798 was generally well tolerated across the dose range tested, but a lack of potent, sustained immunologic activity suggests that further optimization of dose and schedule will be necessary.

A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer.

Purpose: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies. Experimental Design: This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation. Results: Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg twice daily plus sorafenib 400 mg twice daily. The most common treatment-related toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of ∼16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year. Conclusions: In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types. Clin Cancer Res; 22(10); 2368–76. ©2015 AACR.