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A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab-Paclitaxel and Gemcitabine in Advanced Solid Tumors

Beatty, Gregory L; Shahda, Safi; Beck, Thaddeus; Uppal, Nikhil; Cohen, Steven J; Donehower, Ross; Gabayan, Afshin Eli; Assad, Albert; Switzky, Julie; Zhen, Huiling; Von Hoff, Daniel D
LESSONS LEARNED/CONCLUSIONS:-paclitaxel plus gemcitabine demonstrated an acceptable safety profile with clinical activity in patients with advanced solid tumors including pancreatic cancer.The results support future studies of itacitinib as a component of combination regimens with other immunologic and targeted small molecule anticancer agents. BACKGROUND:Cytokine-mediated signaling via JAK/STAT is central to tumor growth, survival, and systemic inflammation, which is associated with cancer cachexia, particularly in pancreatic cancer. Because of their centrality in the pathogenesis of cancer cachexia and progression, JAK isozymes have emerged as promising therapeutic targets. Preclinical studies have demonstrated antiproliferative effects of JAK/STAT pathway inhibition in both in vitro and in vivo models of cancer, including pancreatic cancer. METHODS:. RESULTS:was tolerated and expanded in Part 2. Treatment discontinuation and grade 3/4 neutropenia rates prompted itacitinib de-escalation to 200 mg QD in Part 2A. The most common grade 3/4 toxicities were fatigue and neutropenia. Partial responses occurred across all itacitinib doses and several tumor types (overall response rate, 24%). CONCLUSION/CONCLUSIONS:Itacitinib plus chemotherapy demonstrated acceptable safety and clinical activity in patients with advanced solid tumors including pancreatic cancers. This study was terminated early (sponsor's decision) based on negative phase III results for a JAK1/2 inhibitor in previously treated advanced pancreatic cancer.
PMID: 30115734
ISSN: 1549-490x
CID: 3241442

Results from a phase 2 study of ruxolitinib or placebo with capecitabine as second-line therapy in patients with metastatic pancreatic cancer: The recap trial [Meeting Abstract]

Hurwitz, H; Uppal, N; Wagner, S A; Bendell, J; Thaddeus, B J; Wade, S; Nemunaitis, J; Stella, P; Pipas, J M; Wainberg, Z; Manges, R; Garrett, W; Hunter, D; Clark, J; Leopold, L; Levy, R; Sandor, V
Introduction: Local and systemic inflammation are hallmarks of cancer, including pancreatic cancer, that adversely impact prognosis. Given the role of JAK-STAT signaling in cancer inflammation, the efficacy and safety of ruxolitinib, a JAK1/JAK2 inhibitor, given with capecitabine in patients with metastatic pancreatic cancer refractory to initial therapy was explored. Methods: Patients with adequate performance status and organ function who progressed after gemcitabine treatment were included. Ruxolitinib plus capecitabine was well tolerated in a 9 patient safety run-in. Subsequently, 127 patients were randomized to capecitabine 1000 mg/m2 twice daily (BID) on days 1 to 14 with either ruxolitinib 15 mg BID or placebo on days 1 to 21 of a 21-day cycle. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). To detect a hazard ratio (HR) <0.6 with 2-sided alpha = 0.2 and beta < 0.2, the final analysis was planned to occur after 97 deaths. Subgroup analyses were prespecified to explore treatment heterogeneity and a hypothesis that ruxolitinib would preferentially benefit patients with evidence of inflammation. Results: In the randomized population, OS and PFS favored ruxolitinib. The confirmed ORR was 7.8% for ruxolitinib and 0% for placebo. In a prespecified subgroup of patients with inflammation, as measured by serum C-reactive protein (CRP greater than the group median of 13 mg/L), OS significantly favored ruxolitinib over placebo. In this subgroup, 3 and 6 month survival was 48% and 42% with ruxolitinib versus 29% and 11% with placebo, respectively. In patients with CRP <13 mg/L, significant benefits in OS or PFS were not observed (OS, HR = 0.89; PFS, HR = 0.82). OS benefit was also seen in patients classified by modified Glasgow Prognostic Score (mGPS), a measure of inflammation in cancer (mGPS 0, HR = 0.91; mGPS 1, HR = 0.71; mGPS 2, HR = 0.49). Conclusion: Ruxolitinib may improve OS and PFS in patients with metastatic pancreatic cancer with inflammation as characterized by elevated CRP or mGPS of 1 or 2
EMBASE:611979034
ISSN: 1569-8041
CID: 2258902

Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for Whom Therapy With Gemcitabine Has Failed

Hurwitz, Herbert I; Uppal, Nikhil; Wagner, Stephanie A; Bendell, Johanna C; Beck, J Thaddeus; Wade, Seaborn M 3rd; Nemunaitis, John J; Stella, Philip J; Pipas, J Marc; Wainberg, Zev A; Manges, Robert; Garrett, William M; Hunter, Deborah S; Clark, Jason; Leopold, Lance; Sandor, Victor; Levy, Richard S
PURPOSE: Patients with advanced pancreatic adenocarcinoma have a poor prognosis and limited second-line treatment options. Evidence suggests a role for the Janus kinase (JAK)/signal transducer and activator of transcription pathway in the pathogenesis and clinical course of pancreatic cancer. PATIENTS AND METHODS: In this double-blind, phase II study, patients with metastatic pancreatic cancer who had experienced treatment failure with gemcitabine were randomly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus capecitabine (1,000 mg/m(2) twice daily) or placebo plus capecitabine. The primary end point was overall survival (OS); secondary end points included progression-free survival, clinical benefit response, objective response rate, and safety. Prespecified subgroup analyses evaluated treatment heterogeneity and efficacy in patients with evidence of inflammation. RESULTS: In the intent-to-treat population (ruxolitinib, n = 64; placebo, n = 63), the hazard ratio was 0.79 (95% CI, 0.53 to 1.18; P = .25) for OS and was 0.75 (95% CI, 0.52 to 1.10; P = .14) for progression-free survival. In a prespecified subgroup analysis of patients with inflammation, defined by serum C-reactive protein levels greater than the study population median (ie, 13 mg/L), OS was significantly greater with ruxolitinib than with placebo (hazard ratio, 0.47; 95% CI, 0.26 to 0.85; P = .011). Prolonged survival in this subgroup was supported by post hoc analyses of OS that categorized patients by the modified Glasgow Prognostic Score, a systemic inflammation-based prognostic system. Grade 3 or greater adverse events were observed with similar frequency in the ruxolitinib (74.6%) and placebo (81.7%) groups. Grade 3 or greater anemia was more frequent with ruxolitinib (15.3%; placebo, 1.7%). CONCLUSION: Ruxolitinib plus capecitabine was generally well tolerated and may improve survival in patients with metastatic pancreatic cancer and evidence of systemic inflammation.
PMCID:5089161
PMID: 26351344
ISSN: 1527-7755
CID: 1864012

Venous thromboembolism in patients with diffuse large B-cell lymphoma

Komrokji, Rami S; Uppal, Nikhil P; Khorana, Alok A; Lyman, Gary H; Kaplan, Karen L; Fisher, Richard I; Francis, Charles W
We conducted a retrospective record review to determine the frequency of venous thromboembolism (VTE) in patients with diffuse large B-cell lymphoma (DLBCL). All records from 1990 to 2001 of patients with the diagnosis of DLBCL at a tertiary care hospital were reviewed. Those with transformation from low-grade lymphoma, central nervous system lymphoma, HIV-related lymphoma or with incomplete records were excluded. All episodes of symptomatic VTE confirmed by imaging studies that were either present at diagnosis or occurred during initial treatment were identified. VTE occurred in 27 of 211 patients (12.8%). Stage I disease was associated with a low risk, whereas a high international prognostic index score increased risk. Of patients with VTE, thrombosis was present at diagnosis in 37% and occurred during the first chemotherapy cycle in 22% and during the first three cycles in 82%. The median survival of patients with VTE was 1.04 years [95% confidence interval (CI) = 0.75 - 1.33] compared to 5.2 years (95% CI 1.8 - 8.6) for those without VTE (P = 0.038). We conclude that VTE is a frequent complication of DLBCL that occurs particularly at diagnosis and during initial therapy, and it is associated with a worse prognosis.
PMID: 16840193
ISSN: 1042-8194
CID: 162796