Poplin, Elizabeth

Abstract Purpose: Patients with metastatic colorectal cancer refractory to chemotherapy have limited treatment options. Ensituximab (NEO-102) is a novel chimeric mAb targeting a variant of MUC5AC with specificity to colorectal cancer. Patients and Methods: Single-arm, phase II trial assessed the efficacy and safety of ensituximab in patients with advanced, refractory cancer who expressed MUC5AC antigen in tumor tissue. Ensituximab was administered intravenously every 2 weeks with 3 mg/kg as recommended phase II dose (RP2D). A minimum sample size of 43 patients was required on the basis of the assumption that ensituximab would improve median overall survival (OS) by 7 months using a one-sided significance level of 10% and 80% power. Written informed consent was obtained from all patients. Results: Sixty-three patients with advanced, refractory colorectal cancer were enrolled and 53 subjects were treated in phase II arm. Median age was 58 years and 46% of the patients were female. Among 57 evaluable patients, median OS was 6.8 months. No responses were observed, and stable disease was achieved in 21% of the patients. The most common treatment-related adverse events (AE) at RP2D included fatigue (38%), anemia (30%), nausea (15%), vomiting (11%), increased bilirubin (9%), constipation (8%), decreased appetite (6%), and diarrhea (6%). Serious AEs at least possibly related to ensituximab occurred in 4 patients and included anemia, nausea, increased bilirubin, and hypoxia. No patients discontinued treatment due to drug-related AEs. Conclusions: Ensituximab was well tolerated and demonstrated modest antitumor activity in patients with heavily pretreated refractory colorectal cancer.

LBA4004 Background: Gemcitabine (GEM) is the cornerstone of treatment of metastatic pancreatic cancer (PANCA). FDR GEM or GEMOX are promising, but have yet to convincingly demonstrate a survival advantage over GEM alone. E6201 compares overall survival (OS) of standard GEM 1000 mg/m2/30 min wkly ×7 over 56 days then wkly ×3 q28 d (ARM A) vs. FDR GEM 1500 mg/m2/150 min wkly ×3 q28 days (ARM B) or GEM 1000 mg/m2/100-min/d1 + oxaliplatin 100 mg/m2/d2 q14d (ARM C). Secondary endpoints are the comparison of the experimental regimens, toxicity, response, patterns of failure, progression-free survival and quality-of-life. Methods: This multi-institutional trial included patients (pts) with measurable and non-measurable advanced, unresectable PAN CA, normal organ function and PS 0–2. Pts were chemonaive, although prior adjuvant radiosensitizing 5FU was permitted. Pts were stratified by PS 0–1 vs 2 and locally advanced vs metastatic disease The study was designed to detect a 33% difference in median survival (hazard ratio 1.33) with 81% power while maintaining a significance level of 2.5% in a two-sided test for each of the two primary comparisons, assuming exponential failure and median survival of 6 mo for Arm A and 8 mo for Arm B and C (N = 750 eligible). Results: Accrual started in 3/03 and completed in 3/05. Median follow up is 5.8 mo. 833 pts (53% men; 88% PS 0–1; 88% metastatic), were randomized with 280, 277 and 276 pts in Arms A, B and C. The third interim analysis was conducted with 89.5% information on 3/2006. The predominant toxicity, available for 758 pts, was grade 3/4 myelosuppression and fatigue. Two deaths from ARDS and infection occurred. Median OS for ARMS A, B, and C are 4.96, 6.01 and 6.47 months, respectively. Hazard ratio A vs B is 1.21 with stratified log rank of 0.053 and for A vs C is 1.22 with stratified log rank of 0.045, neither statistically significant. Conclusion: E6201 final OS results will be available in June, 2006. [Table: see text] [Table: see text]

341 Background: Genomes of metastatic pancreatic cancers frequently contain intrachromosomal aberrations indicating DNA repair abnormalities associated with sensitivity to DNA damaging agents such as the platinums. Cisplatin was added to a nab-paclitaxel + gemcitabine regimen, which has been determined to improve survival over gemcitabine alone (NEJM 2013; 369:1691-1703). The objectives are to determine the efficacy and safety of nab-paclitaxel and gemcitabine plus cisplatin in patients with Stage IV pancreatic cancer. Methods: Eligibility criteria included Stage IV adenocarcinoma of the pancreas, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. Doses are nab-paclitaxel 125 mg/m2 undiluted, gemcitabine 1000 mg/m2 in 500 ml of normal saline (NS), each infused over 30 minutes on days 1 and 8 of a 21 day cycle, along with 3 different dose levels of cisplatin (25, 37.5 or 50 mg/m2) in 500 ml of NS infused over 60 minutes, after the nab-paclitaxel infusion. Pre and post cisplatin hydration was given. The maximum tolerated dose and phase II dose of cisplatin is 25 mg/m2. Results: 25 pts were treated; 24 were evaluable (baseline and ≥ 1 follow up CT scan). The most common drug related grade (gr) 3 - 4 adverse events (AEs), n = 25, were thrombocytopenia 76% (gr 3 = 36%, gr 4 = 40%) with no serious bleeding events, anemia 32% (gr 3 = 32%, gr 4 = 0%), neutropenia 24% (gr 3 = 20%, gr 4 = 4%), infection 20% (gr 3 = 16%, gr 4 = 4%), and diarrhea 16% (gr 3 = 16%, gr 4 = 0%). Peripheral neuropathy ≥ gr 3 was seen in only 1 pt (gr 3 = 4%). Grade 5 AEs were infection (1), cardiac arrest (1), and stroke (1). Median time on therapy was 5.5 months, range (1 – 9.5). By RECIST 1.1 criteria, 2 pts had complete response (8.3%), 15 partial response (62.5%), 4 stable disease (16.7%), and 3 progressive disease (12.5%). Median overall survival to date as of 11/10/16 is 16.5 months. Conclusions: Although a small study, the high response rate and landmark evolving median survival are very encouraging. This regimen is being expanded in patients with stage IV pancreatic cancer, neoadjuvant and adjuvant settings. Clinical trial information: NCT01893801.

Abstract Background: The genomes of metastatic pancreatic cancers contain a myriad of intrachromosomal aberrations indicating a likely high prevalence of DNA repair deficiencies indicating sensitivity to DNA damaging agents such as the platinum’s. Because of this, the drug cisplatin was added to an albumin-bound paclitaxel + gemcitabine regimen, which has already been determined to improve survival over gemcitabine alone in a randomized phase III trial (NEJM 2013; 369:1691-1703). Objectives: To determine the efficacy and safety of albumin-bound paclitaxel and gemcitabine plus cisplatin for patients with advanced pancreatic cancer Methods: Eligibility criteria included Stage IV pancreatic cancer, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. The doses were albumin-bound paclitaxel 125 mg/m2 undiluted, gemcitabine 1000 mg/m2 in 500 ml of normal saline (NS), each infused over 30 minutes on days 1 and 8 of a 21 day cycle, along with 3 different dose levels of cisplatin (25, 37.5 or 50 mg/m2) in 500 ml of NS infused over 60 minutes, after the nab-paclitaxel infusion. Pre and post cisplatin hydration was given. Results: To date, 10 patients have been entered on study with all patients being evaluable, (baseline and at least one follow up CT scans completed). There have been 2 complete responses (20%), 6 partial responses (PR), (60%), 1 stable disease (10%), and 1 patient with progressive disease (10%), by RECIST 1.1 criteria. An exponential decrease in CA19-9 correlating with the t1/2 of the marker was noted. Response was seen rapidly with PR observed at the first staging evaluation at 9 weeks in 7 of 10 patients. The 8th patient achieved a PR at 18 weeks. Serious adverse events occurred in 4 patients: non-neutropenic sepsis/pneumonia (n = 1), and non-neutropenic bacteremia (n = 1) in the cisplatin 25 mg/m2 cohort; clostridium difficile colitis (n = 1) with cisplatin 37.5 mg/m2; and neutropenic fever/pneumonia (n = 1) with cisplatin 50mg/m2. Discussion: The study has completed phase Ib and will be expanded at the phase II dose of cisplatin 25 mg/m2 for a total of 25 patients. If this favorable response rate is confirmed, this 3 drug regimen could be further developed both for patients with advanced disease as well as in neoadjuvant and adjuvant settings. Supported by grants from the Seena Magowitz Foundation and the SU2C Dream Team Citation Format: Gayle S. Jameson, Erkut Borazanci, Elizabeth Poplin, Michael T. Barrett, John Crowley, Adam Rosenthal, Amy Stoll-D'Astice, Karen L. Ansaldo, Steven Boone, Leticia Lebron, Ramesh K. Ramanathan, Ronald L. Korn, Daniel D. Von Hoff. High complete and partial response rate in a phase Ib pilot trial with cisplatin plus albumin-bound paclitaxel and gemcitabine in patients with advanced pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-003. doi:10.1158/1538-7445.AM2015-LB-003

PurposeSingle-agent gemcitabine (GEM) is standard treatment of metastatic pancreatic cancer. Fixed-dose rate (FDR) GEM and GEM plus oxaliplatin have shown promise in early clinical trials. E6201 was designed to compare overall survival (OS) of standard weekly GEM 1,000 mg/m2/30 minutes versus GEM FDR 1,500 mg/m2/150 minutes or GEM 1,000 mg/m2/100 minutes/day 1 plus oxaliplatin 100 mg/m2/day 2 every 14 days (GEMOX).MethodsThis trial included patients with metastatic or locally advanced pancreatic cancer, normal organ function, and performance status of 0 to 2. The study was designed to detect a 33% difference in median survival (hazard ratio [HR] ≤ 0.75 for either of the experimental arms) with 81% power while maintaining a significance level of 2.5% in a two-sided test for each of the two primary comparisons.ResultsEight hundred thirty-two patients were enrolled. The median survival and 1-year survival were 4.9 months (95% CI, 4.5 to 5.6) and 16% for GEM, 6.2 months (95% CI, 5.4 to 6.9), and 21% for GEM FDR (HR, 0.83; stratified log-rank P = .04), and 5.7 months (95% CI, 4.9 to 6.5) and 21% for GEMOX (HR, 0.88; stratified log-rank P = .22). Neither of these differences met the prespecified criteria for significance. Survival was 9.2 months for patients with locally advanced disease, and 5.4 months for those with metastatic disease. Grade 3/4 neutropenia and thrombocytopenia were greatest with GEM FDR. GEMOX caused higher rates of nausea, vomiting, and neuropathy.ConclusionNeither GEM FDR nor GEMOX resulted in substantially improved survival or symptom benefit over standard GEM in patients with advanced pancreatic cancer.