L. S. Smith

Gemcitabine Plus nab-Paclitaxel Is an Active Regimen in Patients With Advanced Pancreatic Cancer: A Phase I/II Trial

PURPOSEnThe trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake.nnnPATIENTS AND METHODSnPatients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m(2) nab-paclitaxel followed by gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents.nnnRESULTSnA total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m(2), respectively. The MTD was 1,000 mg/m(2) of gemcitabine plus 125 mg/m(2) of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [(18)F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone.nnnCONCLUSIONnThe regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.

Phase I Study of Pembrolizumab (MK-3475; Anti–PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors

Purpose: This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors. Experimental Design: In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005–10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses ≥2 mg/kg every 3 weeks. Conclusions: Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks. Clin Cancer Res; 21(19); 4286–93. ©2015 AACR. See related commentary by van Elsas et al., p. 4251

Phase I and pharmacokinetic study of paclitaxel in combination with biricodar, a novel agent that reverses multidrug resistance conferred by overexpression of both MDR1 and MRP.

PURPOSEnTo evaluate the feasibility of administering biricodar (VX-710; Incel, Vertex Pharmaceuticals Inc, Cambridge, MA), an agent that modulates multidrug resistance (MDR) conferred by overexpression of both the multidrug resistance gene product (MDR1) P-glycoprotein and the MDR-associated protein (MRP) in vitro, in combination with paclitaxel. The study also sought to determine the maximum-tolerated dose (MTD) of paclitaxel that could be administered with biologically relevant concentrations of VX-710 and characterize the toxicologic and pharmacologic profiles of the VX-710/ paclitaxel regimen.nnnPATIENTS AND METHODSnPatients with solid malignancies were initially treated with VX-710 as a 24-hour infusion at doses that ranged from 10 to 120 mg/m2 per hour. After a 2-day washout period, patients were re-treated with VX-710 on an identical dose schedule followed 8 hours later by paclitaxel as a 3-hour infusion at doses that ranged from 20 to 80 mg/m2. The pharmacokinetics of both VX-710 and paclitaxel were studied during treatment with VX-710 alone and VX-710 and paclitaxel. Thereafter, patients received VX-710 and paclitaxel every 3 weeks.nnnRESULTSnVX-710 alone produced minimal toxicity. The toxicologic profile of the VX-710/paclitaxel regimen was similar to that reported with paclitaxel alone; neutropenia that was noncumulative was the principal dose-limiting toxicity (DLT). The MTD levels of VX-710/ paclitaxel were 120 mg/m2 per hour and 60 mg/m2, respectively, in heavily pretreated patients and 120/60 to 80 mg/m2 per hour in less heavily pretreated patients. At these dose levels, VX-710 steady-state plasma concentrations (Css) ranged from 2.68 to 4.89 microg/mL, which exceeded optimal VX-710 concentrations required for MDR reversal in vitro. The pharmacokinetics of VX-710 were dose independent and not influenced by paclitaxel. In contrast, VX-710 reduced paclitaxel clearance. At the two highest dose levels, which consisted of VX-710 120 mg/m2 per hour and paclitaxel 60 and 80 mg/m2, pertinent pharacokinetic determinants of paclitaxel effect were similar to those achieved with paclitaxel as a 3-hour infusion at doses of 135 and 175 mg/m2, respectively.nnnCONCLUSIONnVX-710 alone is associated with minimal toxicity. In combination with paclitaxel, biologically relevant VX-710 plasma concentrations are achieved and sustained for 24 hours, which simulates optimal pharmacologic conditions required for MDR reversal in vitro. The acceptable toxicity profile of the VX-710/ paclitaxel combination and the demonstration that optimal pharmacologic conditions for MDR reversal are achievable support a rationale for further trials of VX710/paclitaxel in patients with malignancies that are associated with de novo or acquired resistance to paclitaxel caused by overexpression of MDR1 and/or MRP.

Phase I and pharmacokinetic studies of topotecan administered as a 72 or 120 h continuous infusion.

Topotecan (SK&F 104864-A, NSC 609699) is a water-soluble, semi-synthetic analog of camptothecln which is an Inhibitor of topolaomerase I. Since topoisomerase I is cell specific for S phase, we undertook a phase I study to determine the maximum tolerated dose and toxicltiea of continuous Infusion (CI) topotecan. This phase I trial first explored a S day CI every 21 day schedule. Doses of topotecan Included 0.17, 0.34 and 0.68 mg/m2/day. Fourteen patients [median age 60; median performance status (PS) of 1] with refractory malignancies received 59 courses of drug. Hematologic toxicities occurred only at the highest dose level; NCI grade 3–4 granulocytopenia and thrombocytopenia occurred in 4/8 and 3/8 patients, respectively. The protocol was amended to a 3 day Infusion in an effort to ameliorate toxicity and obtain greater dose Intensity (Dl). Doses of 0.68, 0.85, 1.05, 1.3 and 1.6mg/m2/day were evaluated. Thirty-two patients (median age 60; median PS of 1) received a total of 115 couraes. The major toxicity seen was hematologic with 9/32 and 5/32 patients demonstrating grade 3–4 granulocytopenia and thrombocytopenia, respectively. Non-hematologic toxicities were mild (grade 1–2) In the two schedules and included nausea, vomiting, fatigue and alopecia. At the maximum tolerated dose (MTD) on the 5 day schedule, patients received 0.87 mg/m2/week, whereas they received 1.08 mg/m2/week at the MTD on the 3 day schedule (24% Increase In relative dose Intensity). A atesdy-stste plasma lactone concentration of 5.5 mg/ml of topotecan was achieved at the phase II recommended dose of 1.6 ng/m2/day as a 3 day continuous Infusion. Minor responses were seen in two patienta with non-small cell lung cancer and three patients with ovarian cancer. In summary, a greater Dl can be achieved with topotecan given on a 3 day schedule than on a 5 day schedule.

Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001)

PurposeVatalanib (PTK 787/ZK22584) is an oral poly-tyrosine kinase inhibitor with strong affinity for platelet-derived growth factor and vascular endothelial growth factor (VEGF) receptors. We conducted an open-label, phase II multicenter therapeutic trial investigating the efficacy and tolerability of vatalanib in patients with metastatic or advanced pancreatic cancer who failed first-line gemcitabine-based therapy.MethodsVatalanib treatment consisted of a twice daily oral dosing using a “ramp-up schedule,” beginning with 250xa0mg bid during week 1,500xa0mg bid during week 2, and 750xa0mg bid on week three and thereafter. The primary objective of this study was to evaluate the 6-month survival rate.ResultsSixty-seven patients were enrolled. The median age was 64, and 66xa0% (Nxa0=xa043) had only one prior regimen. Common grade 3/4 adverse events included hypertension (20xa0%; Nxa0=xa013), fatigue (17xa0%; Nxa0=xa011), abdominal pain (17xa0%; Nxa0=xa011), and elevated alkaline phosphatase (15xa0%; Nxa0=xa010). Among the 65 evaluable patients, the 6-month survival rate was 29xa0% (95xa0% CI 18–41xa0%) and the median progression-free survival was 2xa0months. Fifteen patients survived 6xa0months or more. Two patients had objective partial responses, and 28xa0% of patients had stable disease. Changes in biomarkers including soluble VEGF and vascular endothelial growth factor receptor did not correlate with response to drug.ConclusionVatalanib was well tolerated as a second-line therapy and resulted in favorable 6-month survival rate in patients with metastatic pancreatic cancer, compared with historic controls.

Phase I First-in-Human Study of CUDC-101, a Multitargeted Inhibitor of HDACs, EGFR, and HER2 in Patients with Advanced Solid Tumors

Purpose: This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-hour intravenous (i.v.) infusion for 5 consecutive days every 2 weeks. Experimental Design: Twenty-five patients with advanced solid tumors received escalating doses of CUDC-101 (range, 75–300 mg/m2/day) following a standard 3 + 3 dose escalation design. Results: The MTD was determined to be 275 mg/m2. Common grade 1/2 adverse events included nausea, fatigue, vomiting, dyspnea, pyrexia, and dry skin. DLTs occurred in 1 patient in the 275-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 1) and 3 patients in the 300-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 2; pericarditis, n = 1), all of which were transient and reversible. CUDC-101 exposure increased linearly with the mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vdss), area under curve (AUC), and terminal elimination half-life (t1/2) at the MTD dose of 9.3 mg/L, 51.2 L/h, 39.6 L, 9.95 h·ng/mL and 4.4 hours, respectively. Acetylated histone H3 induction was observed in posttreatment skin samples from 3 patients in the 275-mg/m2 dose cohort, suggesting adequate systemic exposure and target inhibition. One patient with gastric cancer had a partial response and 6 patients had stable disease. Conclusion: CUDC-101 administered by 1-hour i.v. infusion for 5 consecutive days every 2 weeks was generally well tolerated with preliminary evidence of antitumor activity. A dose of 275 mg/m2 is recommended for further clinical testing. Clin Cancer Res; 20(19); 5032–40. ©2014 AACR.

Tesetaxel: Development of a weekly dosing schedule for an oral advanced-generation taxane.

e13045 Background: Tesetaxel, a novel, orally absorbed taxane that is not a substrate for P-glycoprotein, has demonstrated antitumor activity in pts with breast, gastric, and other solid tumors. Neutropenia is the most common dose-limiting effect. To date, tesetaxel has solely been administered using a once every 3 weeks schedule with an MTD of 27 mg/m2. Since other taxanes such as docetaxel and paclitaxel exhibit schedule-dependent effects, we evaluated a weekly dosing regimen of tesetaxel in escalating fixed doses. Threshold models predict taxane pharmacodynamics, and times above a threshold concentration (tC) correlate with both tumor response and toxicity; for paclitaxel, for instance, tC > 0.05 micromol/L was the best predictor of objective response and severe neutropenia (Joerger et al., Clin Cancer Res, 2007).nnnMETHODSnEligible pts had advanced solid tumors, ECOG PS 0-2, and adequate organ function. Tesetaxel was given once weekly for 3 weeks in 28-day cycles, beginning at a flat dose of 25 mg per cycle (e.g., 10 mg in Weeks 1 and 2 and 5 mg in Week 3), with progressive increase in total dose per cycle to 30, 45, 60 mg, and continued escalation in 15-mg increments to the MTD. Serial blood samples were collected, and parent compound was assayed by HPLC.nnnRESULTSnTo date, 12 pts (3 pts/level) have been treated. Weekly dosing has been well tolerated up to 60 mg. No dose-limiting reactions have been observed, and the MTD has not been reached. Tesetaxel has a long T1/2 (~180 hrs), and low plasma concentrations in the range of 0.3-2.5 nmol/mL were detectable prior to the next dose. There was no substantial drug accumulation over multiple cycles.nnnCONCLUSIONSnWeekly oral administration of tesetaxel is feasible and provides long-term, low-level exposure to this taxane. Given threshold effects observed with other taxanes, this finding may similarly predict clinical outcome and toxicity with tesetaxel. The MTD of this weekly regimen has not been reached, but exceeds the MTD of the every-3-week regimen.