Sanaa Tahiri

A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma

Purpose: On the basis of preclinical evidence of synergistic activity between MEK and EGFR inhibitors in pancreatic ductal adenocarcinoma (PDAC), we evaluated the safety and efficacy of selumetinib, a MEK1/2 inhibitor, plus erlotinib in patients with previously treated advanced PDAC. Experimental Design: In this single-arm phase II trial, eligible patients received the combination of erlotinib 100 mg plus selumetinib 100 mg daily in 3-week cycles. Study assessments included measurement of clinical outcomes, with a primary endpoint of overall survival, and exploration of potential molecular predictors of treatment benefit. Results: Forty-six patients were enrolled and received a median of two cycles (range, 1–7). Although no objective responses were observed, 19 patients (41%) showed evidence of stable disease for ≥6 weeks, and 13 of 34 patients (38%) had a CA19-9 decline ≥50%. Median progression-free survival was 1.9 months [95% confidence interval (CI), 1.4–3.3 months], with a median overall survival of 7.3 months (95% CI, 5.2–8.0 months). Common adverse events included rash, diarrhea, and nausea/vomiting. Patients with tumors exhibiting an epithelial phenotype (demonstrated by a high level of E-cadherin expression) were more likely to be sensitive to study treatment. Tumor-derived DNA was detectable in plasma from the majority of patients using next-generation digital DNA sequencing, and its relative abundance correlated with tumor burden. Conclusions: A therapeutic strategy of dual targeted inhibition of the MEK and EGFR pathways shows modest antitumor activity in pancreatic cancer. Specific molecular subtypes may derive greatest benefit from this combination. Further exploration, both with more potent MEK inhibitors and in molecularly enriched patient subsets, is warranted. Clin Cancer Res; 22(1); 61–68. ©2015 AACR.

Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma

Pelareorep causes oncolysis in tumor cells with activated Ras. We hypothesized that pelareorep would have efficacy and immunomodulatory activity in metastatic pancreatic adenocarcinoma (MPA) when combined with carboplatin and paclitaxel. A randomized phase 2 study (NCT01280058) was conducted in treatment-naive patients with MPA randomized to two treatment arms: paclitaxel/carboplatin + pelareorep (Arm A, n = 36 evaluable patients) versus paclitaxel/carboplatin (Arm B, n = 37 evaluable patients). There was no difference in progression-free survival (PFS) between the arms (Arm A PFS = 4.9 months, Arm B PFS = 5.2 months, P = 0.6), and Kirsten rat sarcoma viral oncogene (KRAS) status did not impact outcome. Quality-adjusted Time without Symptoms or Toxicity analysis revealed that the majority of PFS time was without toxicity or progression (4.3 months). Patient immunophenotype appeared important, as soluble immune biomarkers were associated with treatment outcome (fractalkine, interleukin (IL)-6, IL-8, regulated on activation, normal T cell expressed and secreted (RANTES), and vascular endothelial growth factor (VEGF)). Increased circulating T and natural killer (NK)-cell subsets were also significantly associated with treatment outcome. Addition of pelareorep was associated with higher levels of 14 proinflammatory plasma cytokines/chemokines and cells with an immunosuppressive phenotype (Tregs, cytotoxic T lymphocyte associated protein 4 (CTLA4)(+) T cells). Overall, pelareorep was safe but does not improve PFS when administered with carboplatin/paclitaxel, regardless of KRAS mutational status. Immunologic studies suggest that chemotherapy backbone improves immune reconstitution and that targeting remaining immunosuppressive mediators may improve oncolytic virotherapy.

Systemic immune activity predicts overall survival in treatment naïve patients with metastatic pancreatic cancer

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate <7% and is ultimately refractory to most treatments. To date, an assessment of immunologic factors relevant to disease has not been comprehensively performed for treatment-naïve patients. We hypothesized that systemic immunologic biomarkers could predict overall survival (OS) in treatment-naïve PDAC patients. Experimental Design: Peripheral blood was collected from 73 patients presenting with previously untreated metastatic PDAC. Extensive immunologic profiling was conducted to assess relationships between OS and the level of soluble plasma biomarkers or detailed immune cell phenotypes as measured by flow cytometry. Results: Higher baseline levels of the immunosuppressive cytokines IL6 and IL10 were strongly associated with poorer OS (P = 0.008 and 0.026, respectively; HR = 1.16 and 1.28, respectively), whereas higher levels of the monocyte chemoattractant MCP-1 were associated with significantly longer OS (P = 0.045; HR = 0.69). Patients with a greater proportion of antigen-experienced T cells (CD45RO+) had longer OS (CD4 P = 0.032; CD8 P = 0.036; HR = 0.36 and 0.61, respectively). Although greater expression of the T-cell checkpoint molecule CTLA-4 on CD8+ T cells was associated with significantly shorter OS (P = 0.020; HR = 1.53), the TIM3 molecule had a positive association with survival when expressed on CD4+ T cells (P = 0.046; HR = 0.62). Conclusions: These data support the hypothesis that baseline immune status predicts PDAC disease course and overall patient survival. To our knowledge, this work represents the largest cohort and most comprehensive immune profiling of treatment-naïve metastatic PDAC patients to date. Clin Cancer Res; 22(10); 2565–74. ©2015 AACR.

A phase I study of high-dose interleukin-2 with sorafenib in patients with metastatic renal cell carcinoma and melanoma.

This study was designed to evaluate the safety and feasibility of high-dose interleukin-2 (HD IL-2) followed by sorafenib in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC). Biomarkers relevant to the antitumor effects of IL-2 that may be altered by sorafenib including the percentages of natural T-regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and STAT5 phosphorylation (pSTAT5) in T cells were evaluated. We hypothesized that the proposed treatment schedule is feasible and safe and may lead to enhanced tumor response. A phase I dose escalation trial was conducted in patients with either metastatic RCC or MM. HD IL-2 (600,000 IU/kg IV q8h×8–12 doses) was administered on days 1–5 and 15–19, followed by sorafenib on days 29–82. The sorafenib dose was escalated. The percentage of Tregs, MDSC, and pSTAT5 in T cells were evaluated in peripheral blood by flow cytometry. Twelve of the 18 patients were evaluable for dose-limiting toxicity. No dose-limiting toxicity was observed. The treatment-related toxicity was predictable and did not seem to be additive with this schedule of administration. Partial responses were seen in 3 patients. No significant changes in the percentage of circulating Treg and MDSC were observed, whereas sorafenib did not adversely affect the ability of IL-2 to induce pSTAT5 in T cells. HD IL-2 followed by sorafenib was safe and feasible in patients with MM and RCC and did not adversely affect T-cell signaling through STAT5 in response to IL-2.

Abstract C221: EZN‐2208, a novel anticancer agent, in patients (pts) with advanced malignancies: A phase 1 dose‐escalation study

Background: SN38 is a potent topoisomerase I inhibitor and the active moiety of irinotecan. SN38 has poor solubility in any pharmaceutically acceptable excipient. The poor solubility of SN38 can be vastly improved by PEGylation. EZN‐2208 (PEG‐SN38) is a water‐soluble, polyethylene glycol (PEG) drug conjugate of SN38 that enables increased solubility, parenteral delivery of SN38, longer circulating half‐life, higher exposure of the active drug (SN38) in tumors, and greater preservation of the closed lactone ring (active form) in SN38 compared with SN38 derived from irinotecan. EZN‐2208 is active in a broad spectrum of preclinical models of solid tumors and hematologic cancers, including an in vivo tumor model of CPT‐11 resistance. EZN‐2208 accumulates in tumors, where it releases SN38. EZN‐2208 also down‐modulates mRNA of hypoxia‐inducible factor‐1 α (HIF‐1α) target genes. Methods: Pts with advanced solid tumors were enrolled to determine the safety, tolerability, pharmacokinetics (PK), maximum tolerated dose (MTD), and evidence of preliminary antitumor activity of EZN‐2208 administered as a 1‐hour IV infusion, weekly × 3 per 4‐week cycle, in a 3+3 escalating‐dose design. Dose escalation was based on drug‐related toxicities during Cycle 1. PK samples were obtained after the first and third doses. Plasma concentrations of EZN‐2208, SN38, and SN38G were determined by HPLC using fluorescence detection. PK parameters were estimated using a noncompartmental model analysis. Results: 41 pts (51% women; median age = 60 y [35‐85]) were treated with EZN‐2208 doses of 1 mg/m 2 (n=3), 2 mg/m 2 (n=5, including 2 pts homozygous for UGT1A1*28), 3.3 mg/m 2 (n=3), 5 mg/m 2 (n=6), 7 mg/m 2 (n=8), 9 mg/m 2 (n=10), and 12 mg/m 2 (n=6). All pts had received prior therapies (median number of prior regimens = 2; range = 1–11). Tumor types included colorectal cancer (CRC) (n=24); breast and pancreatic cancers (n=3 each); esophageal cancer and NSCLC (n=2 each); anal, carcinoid, gallbladder, gastric, ovarian, and prostate cancers (n=1 each); and soft tissue sarcoma (n=1). Pts received 1 to 15 cycles. Dose‐limiting toxicities (DLTs) were Grade 3 febrile neutropenia (1 pt, 9 mg/m 2 ) and the inability to deliver the third week of therapy due to Grade 4 neutropenia (1 pt, 12 mg/m 2 ). Most adverse events (AEs) were Grade 1 or 2. The most common AEs (in >20% pts) considered likely related to study drug were nausea (49%), diarrhea and fatigue (44% each), alopecia (30%), and neutropenia and vomiting (28% each). Prolonged stable disease (SD) (>90 days), sometimes associated with tumor shrinkage (), was observed as best response (duration on study) for 13 pts with CRC (485 , 240, 168, 162+, 113, 107, 92 days), NSCLC (127 days), breast (135, 118 days), esophageal (170, 120 days), and pancreatic (253 days) cancers. Five of the 7 pts with mCRC had received prior irinotecan. Conclusions: EZN‐2208, a novel agent, was well tolerated in previously treated pts with advanced malignancies. DLT was neutropenia ± fever, in distinction to the DLT of irinotecan. The MTD and recommended EZN‐2208 dose for this regimen is 9 mg/m 2 . Prolonged periods of SD were observed. For some pts, the duration of EZN‐2208 was longer than for their prior therapy. Enrollment is complete; final data, including PK, will be presented at the meeting. EZN‐2208 is being evaluated in a Phase 2 clinical study in pts with CRC. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C221.

Immunological predictors of overall survival in treatment naïve metastatic pancreatic cancer patients

Meeting abstracts Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has a 5-year survival rate of less than 7% and is ultimately refractory to most treatments. An assessment of immunologic factors relevant to disease has not been performed in a comprehensive manner for treatment

A mechanistic radiographic and biologic phase 2 study of sunitinib in relapsed/refractory esophageal (E) and gastroesophageal (GE) cancers.

149 Background: Patients (pts) with relapsed or treatment-refractory E and GE cancers carry a poor prognosis. Inhibition of the vascular endothelial growth factor (VEGF) pathway may be a potential treatment approach. We conducted a phase II trial to assess the efficacy of sunitinib, a tyrosine kinase inhibitor that inhibits VEGFR 1 and 2. Methods: Pts received sunitinib 37.5 mg orally, daily. Primary endpoint was progression free survival (PFS) at 24 weeks. Secondary endpoints included overall response rate (ORR), overall survival (OS), PFS, and toxicity. Pts underwent serial functional imaging with DCE-MRI and measurements of serum VEGF, PIGF, VEGFR 2 and 3. Gene expression profiling and somatic mutational analysis using next-generation sequencing were also performed on tumor specimens (results to be presented at the symposium). Results: Clinical results are in the table. The PFS in the group that had clinical benefit [partial response (PR) + stable disease (SD)] with sunitinib was 99 days (95% CI: 74-16...

A mechanistic radiographic and biologic phase II single-agent study of sunitinib in relapsed/refractory esophageal (E) and gastroesophageal (GE) cancers.

e14650 Background: There is no established standard for patients (pts) with advanced refractory E or GE cancer. Given the scientific evidence supporting the development of strategies targeting angi...