Carlos Becerra

Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: Results of a Phase II, randomized, noncomparative study

SummaryPurpose Gemcitabine (G) is standard therapy for pancreatic cancer. Enzastaurin (E) inhibits PKCβ and PI3K/AKT signaling pathways with a dose-dependent effect on growth of pancreatic carcinoma xenografts. Data suggest that the GE combination may improve clinical outcomes. Methods Primary objective was overall survival (OS); secondary objectives assessed progression-free survival (PFS), response rate (RR), quality of life (QOL), toxicity, and relationships between biomarker expression and clinical outcomes. Patients were randomly assigned (2:1) to GE or G treatment; GE arm: E 500xa0mg PO daily; loading-dose (1200xa0mg; Day 1 Cycle 1 only) and G 1000xa0mg/m2 IV Days 1, 8, and 15 in 28-day cycles; G arm: G as in GE. Biomarker expression was assessed by immunohistochemistry. Results Randomization totaled 130 patients (GEu2009=u200986, Gu2009=u200944); 121 patients were treated (GEu2009=u200982, Gu2009=u200939). GE/G median OS was 5.6/5.1xa0months; median PFS was 3.4/3.0xa0months. GE responses: 1 complete response (CR, 1.2%), 6 partial response (PR, 7.4%), and 33 stable disease (SD, 40.7%); disease control rate (DCR=CR+PR+SD, 49.4%). G responses: 2 PR (5.3%) and 16 SD (42.1%); DCR (47.4%). No QOL differences were noted between arms. GE/G Grade 3–4 toxicities included: neutropenia (18.3%/28.2%); thrombocytopenia (14.6%/25.6%); and fatigue (11.0%/7.7%). No statistically significant relationships between biomarker expression and outcomes were observed. However, patients with low expression of cytoplasmic pGSK-3β trended toward greater OS with GE treatment. Conclusions OS, PFS, QOL, and RR were comparable between arms. Adding E to G did not increase hematologic toxicities. GE does not warrant further investigation in unselected pancreatic cancer patients.

A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers

SummaryPurpose ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, a novel cell surface target expressed on most pancreatic and gastric cancers. This first-in-human study of ASG-5ME evaluated safety, pharmacokinetics, and preliminary activity of ASG-5ME in advanced pancreatic and gastric cancer patients. Experimental Design This phase 1, dose-escalation, multicenter study determined the maximum tolerated dose (MTD) and assessed safety and antitumor activity. The dose-escalation portion enrolled metastatic pancreatic adenocarcinoma patients; gastric adenocarcinoma patients were included in the dose-expansion portion. Patients received ASG-5ME intravenously on Days 1, 8, and 15 of 28-dayxa0cycles. Results Thirty-five pancreatic cancer patients (median age 63xa0years; performance status 0 [40xa0%] or 1 [60xa0%]) were treated at doses of 0.3 to 1.5xa0mg/kg (median duration 8.1xa0weeks). The MTD was exceeded at 1.5xa0mg/kg (nxa0=xa07) with 1 dose-limiting toxicity (DLT) of Grade 4 gastrointestinal hemorrhage. Four patients experienced non-DLT Grade 3 or 4 neutropenia. Fifteen gastric cancer patients (median age 59xa0years; performance status 0 [33xa0%] or 1 [67xa0%]) were treated at the identified MTD of 1.2xa0mg/kg (median duration 8.7xa0weeks). Common drug-related adverse events included fatigue (29xa0%), nausea (23xa0%), and vomiting (23xa0%) for pancreatic cancer patients and fatigue (33xa0%) and decreased appetite (33xa0%) for gastric cancer patients. Best clinical response was 1 partial response in each cohort. Disease-control rates of 33xa0% (pancreatic) and 47xa0% (gastric) were observed at the MTD. All patient biopsies (23 pancreatic, 15 gastric) expressed the SLC44A4 antigen. Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity.

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.

Abstract 4640: Randomized, phase 1 crossover study assessing the bioequivalence of tablet and capsule formulations of dovitinib (TKI258)

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnBackground Dovitinib (TKI258) is an oral receptor tyrosine kinase inhibitor targeting kinases involved in tumor cell proliferation and survival, including FGFR, VEGFR, PDGFR, c-KIT, and FLT3. A phase 3 study in renal cell carcinoma used a capsule (cap) formulation of dovitinib. However, the planned commercial formulation is a tablet (tab). Therefore, this study evaluated the bioequivalence of the tab and cap formulations using a crossover design.nnMethods Patients (pts) ≥ 18 years of age with advanced solid tumors (excluding breast cancer) were randomized to receive caps or tabs (500 mg po once daily, 5 days on/2 days off) for 3 weeks, followed by the same dose and schedule of the other formulation for 1 week. Following the bioequivalence phase, pts could continue to receive dovitinib caps (500 mg once a day, 5 days on/2 days off). Blood samples for dovitinib plasma concentrations were collected before and after the fifth dose in weeks 3 and 4. The pharmacokinetic (PK) analysis set (PAS) comprised pts with ≥ 2 evaluable PK profiles following cap and tab administration, who did not vomit ≤ 4 hours after dosing on blood collection days and received ≥ 7 of the first 10 doses and 4 consecutive days of dosing prior to blood collection. A linear mixed-effects model was fitted to log-transformed parameters (area under the curve [AUClast] and maximal concentration [Cmax]).nnResults A total of 173 pts were randomized to receive the cap/tab sequence (n = 88) or the tab/cap sequence (n = 85). The median age was 60 years, and the most common primary sites of cancer were colon (n = 48), lung (n = 18), and rectum (n = 14). Sixty-nine pts were in the PAS (32 in the cap/tab sequence and 37 in the tab/cap sequence). The most common reason for PAS exclusion was dose interruption due to disease progression or adverse events (AEs). Geometric means of PK parameters were similar for the tab vs cap formulations: AUClast (5379 vs 5705 h·ng/mL), Cmax (247 vs 252 ng/mL), half-life (14.5 vs 15.3 h), oral clearance (89.5 vs 82.5 L/h), and apparent volume of distribution (1876 vs 1823 L). The geometric mean ratios (90% CI) for AUClast and Cmax comparing tab vs cap were 0.95 (0.88-1.01) and 0.98 (0.91-1.05), respectively. In pts who received at least 1 dose of dovitinib throughout the entire study (including the postbioequivalence phase; n = 168), the most common AEs suspected to be related to study drug (any grade) were diarrhea (58.9%), nausea (50.0%), fatigue (42.3%), vomiting (41.7%), and decreased appetite (20.8%). Grade 3/4 AEs were < 5% except for fatigue (11.9%), diarrhea (5.4%), and hypertension (5.4%).nnConclusions The tab and cap formulations were bioequivalent. The safety profile was similar to that observed in other dovitinib studies in pts with advanced solid tumors. The tab formulation is used in selected current studies and will be used in future clinical dovitinib studies.nnCitation Format: John Sarantopoulos, Sanjay Goel, Vincent Chung, Pamela Munster, Shubham Pant, Manish Patel, Jeffrey Infante, Hussein Tawbi, Carlos Becerra, Justine Bruce, Fairooz Kabbinavar, Howard Kaufman, A. Craig Lockhart, Eugene Tan, Shu Yang, Mariama Diallo, Jeffrey Scott, Sunil Sharma. Randomized, phase 1 crossover study assessing the bioequivalence of tablet and capsule formulations of dovitinib (TKI258). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4640. doi:10.1158/1538-7445.AM2014-4640

Abstract A88: Safety, pharmacokinetic, and pharmacodynamic results of BAY 86–9766, an oral MEK inhibitor, in combination with sorafenib, an oral multikinase inhibitor, in advanced cancer patients.

Background: Preclinical data revealed a synergistic interaction between sorafenib (Nexavar®) and BAY 86-9766 (RDEA119). Sorafenib is an oral, small molecule, multikinase inhibitor that is approved for the treatment of unresectable hepatocellular carcinoma (HCC) and advanced renal cell carcinoma. BAY 86-9766 is an investigational, oral, potent, non-ATP competitive, highly selective inhibitor of MEK1/2. In a Phase 1 single-agent trial of BAY 86-9766 in advanced cancer patients, the maximum tolerated dose (MTD) was 100 mg daily, given as 50 mg twice daily (bid) or 100 mg once daily, with rash being the most common treatment-related adverse event (AE) and significant inhibition of tumor phosphorylated ERK (pERK) observed. This Phase 1 trial was conducted to determine the MTD, safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of BAY 86-9766 in combination with sorafenib. Data from the dose escalation cohorts and MTD expansion cohort are reported here. An additional cohort of patients with advanced HCC is ongoing in the MTD expansion phase and is not described here. Materials and Methods: Key eligibility criteria included advanced metastatic or locally recurrent solid tumors, ECOG performance status of 0–1, acceptable organ function, and life expectancy of at least 3 months. Patients initially received BAY 86-9766 alone for up to 3 days to determine PK and then began a 28-day course of combination treatment with BAY 86-9766 and sorafenib. Dose escalation proceeded with increasing doses of BAY 86-9766 from 5 mg to 50 mg bid and either 200 mg or 400 mg bid of sorafenib. At least 3 patients were treated at each of 6 dose escalation levels. Safety was assessed by AEs, clinical laboratory tests, vital signs, ECGs, ECHO/MUGA scans, and physical exams. If benefiting from treatment, patients continued with subsequent 28-day courses and response was assessed every 2 courses. Tumor mutational status and PD effect on pERK in tumor biopsies were evaluated. Results: Forty-three patients have been enrolled (32 in dose escalation and 11 in MTD expansion). Tumor types included 23 colorectal, 6 melanoma, 4 pancreatic, 3 head & neck, 2 esophageal, 2 ovarian, and 1 each of NSCLC, prostate, and small bowel adenocarcinoma. The MTD was determined to be the full doses of both drugs, 50 mg bid for BAY 86-9766 and 400 mg bid for sorafenib. The most common AEs were diarrhea (81%), rash (63%), fatigue (61%), nausea (49%), and vomiting (37%). Following single and multiple doses, mean C max and AUC 0–12 of BAY 86-9766 increased nearly proportionally with dose, ranging between 5 mg bid and 50 mg bid. Plasma exposures of sorafenib at 200 mg bid and 400 mg bid were generally within the range reported from other studies. There was 1 confirmed partial response in a patient with colorectal cancer and 24 patients achieved a best overall response of stable disease. Tumor mutational analysis as well as PD data on tumor pERK suppression will be presented. Conclusions: BAY 86-9766 in combination with sorafenib was well tolerated with diarrhea and rash being the most common AEs. Based on the results of this study, a Phase 2 study with BAY 86-9766 in combination with sorafenib is underway in HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A88.