Randomized, double-blind, phase two study of ruxolitinib plus regorafenib in patients with relapsed/refractory metastatic colorectal cancer.

BACKGROUND: The Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a key role in the systemic inflammatory response in many cancers, including colorectal cancer (CRC). This study evaluated the addition of ruxolitinib, a potent JAK1/2 inhibitor, to regorafenib in patients with relapsed/refractory metastatic CRC. METHODS: In this two-part, multicenter, phase 2 study, eligible adult patients had metastatic adenocarcinoma of the colon or rectum; an Eastern Cooperative Oncology Group performance status of 0-2; received fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor therapy (if no contraindication); and if KRAS wild-type (and no contraindication), an anti-epidermal growth factor receptor therapy; and progressed following the last administration of approved therapy. Patients who received previous treatment with regorafenib, had an established cardiac or gastrointestinal disease, or had an active infection requiring treatment were excluded. The study was conducted in 95 sites in North America, European Union, Asia Pacific, and Israel. After an open-label, safety run-in phase (part 1; ruxolitinib 20 mg twice daily [BID] plus regorafenib 160 mg once daily [QD]), the double-blind, randomized phase (part 2) was conducted wherein patients were randomized 1:1 to receive ruxolitinib 15 mg BID plus regorafenib 160 mg QD [ruxolitinib group] or placebo plus regorafenib 160 mg QD [placebo group]. Part 2 included substudy 1 (patients with high systemic inflammation, ie, C-reactive protein [CRP] >10 mg/L) and substudy 2 (patients with low systemic inflammation, ie, CRP ≤10 mg/L); the primary endpoint was overall survival (OS). RESULTS: The study was terminated early; substudy 1 was terminated for futility at interim analysis and substudy 2 was terminated per sponsor decision. Ruxolitinib 20 mg BID was well tolerated in the safety run-in (n = 11). Overall, 396 patients were randomized (substudy 1: n = 175 [ruxolitinib group, n = 87; placebo group, n = 88]; substudy 2: n = 221 [ruxolitinib group, n = 110; placebo group, n = 111]). There was no significant difference in OS or progression-free survival (PFS) between treatments in substudy 1 (OS: hazard ratio [HR] = 1.040 [95% confidence interval: 0.725-1.492]; PFS: HR = 1.004 [0.724-1.391]) and substudy 2 (OS: HR = 0.767 [0.478-1.231]; PFS: HR = 0.787 [0.576-1.074]). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib were identified. CONCLUSIONS: Although addition of ruxolitinib to regorafenib did not show increased safety concerns in patients with relapsed/refractory metastatic CRC, this combination did not improve OS/PFS vs. regorafenib plus placebo.

Erythrocytes from patients with myeloproliferative neoplasms and splanchnic venous thrombosis show greater expression of Lu/BCAM.

INTRODUCTION: Lutheran/BCAM protein (Lu) on the surface of erythrocytes is key for their adhesion to the endothelium, and erythrocytes from individuals with JAK2V617F-mutated myeloproliferative neoplasms (MPN) have increased endothelial adhesion. Splanchnic vein thrombosis (SVT) is a devastating thrombotic complication of MPN, and frequently, the only diagnostic feature is the JAK2V617F mutation. We sought to examine whether erythrocytes from patients with JAK2V617F mutated SVT (MPN-SVT) exhibited increased Lu expression, thereby supporting a mechanistic contribution to the development of thrombosis. METHODS: We report the validation of a novel flow cytometry assay for Lu expression on erythrocytes. We examined the expression of Lu on erythrocytes from a cohort of MPN patients with and without SVT, and healthy controls. Samples were obtained from 20 normal individuals, 22 with MPN (both JAK2V617F-mutated and wild-type) and 8 with JAK2V617F-mutated MPN-SVT. RESULTS: Lu expression by erythrocytes from patients with MPN and MPN-SVT is significantly increased compared to erythrocytes from healthy individuals (P < .05), but there was no significant difference between patients with MPN-SVT and MPN. CONCLUSIONS: Patients with MPN have increased expression of the red cell Lu/BCAM adhesion molecule. Further work is required to determine the role of the increased Lu/BCAM adhesion to the endothelium in the development of thrombosis in MPN of all genotypes.

Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies.

Background Ruxolitinib, a Janus kinase 1 (JAK1)/JAK2 inhibitor, plus capecitabine improved overall survival (OS) vs capecitabine in a subgroup analysis of patients with metastatic pancreatic cancer and systemic inflammation (C-reactive protein [CRP] >13 mg/dL) in the randomized phase II RECAP study. We report results from two randomized phase III studies, JANUS 1 (NCT02117479) and JANUS 2 (NCT02119663). Patients and Methods Adults with advanced/metastatic pancreatic cancer, one prior chemotherapy regimen and CRP >10 mg/L were randomized 1:1 (stratified by modified Glasgow Prognostic Score [1 vs 2] and Eastern Cooperative Oncology Group performance status [0/1 vs 2]) to 21-day cycles of ruxolitinib 15 mg twice daily plus capecitabine 2000 mg/m2/day (Days 1-14) or placebo plus capecitabine. The primary endpoint was OS. Results Both studies were terminated following a planned interim futility/efficacy analysis of JANUS 1. Overall, 321 and 86 patients were randomized in JANUS 1 (ruxolitinib: n = 161; placebo: n = 160) and JANUS 2 (ruxolitinib: n = 43; placebo: n = 43). There was no significant difference in OS or progression-free survival (PFS) between treatments in JANUS 1 (OS: hazard ratio [HR], 0.969, 95% confidence interval [CI], 0.747-1.256; PFS: HR, 1.056; 95% CI, 0.827-1.348) or JANUS 2 (OS: HR, 1.584; 95% CI, 0.886-2.830; PFS: HR, 1.166; 95% CI, 0.687-1.978). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib or capecitabine were identified. Conclusions Ruxolitinib plus capecitabine was well tolerated in refractory pancreatic cancer patients; this combination did not improve survival.

JAK2V617F and calreticulin mutations in recurrent venous thromboembolism: results from the EDITH prospective cohort.

Cancer incidence in patients with recurrent unprovoked venous thromboembolism (VTE) is much higher than after a first event, but the incidence of myeloproliferative neoplasms (MPN) in this situation is still unknown. We tested for JAK2V617F and calreticulin mutants, 372 DNA samples of patients treated for (VTR). Among these patients, 10 (2.7%) were carrying JAK2V617F mutation and none of them any of the calreticulin (CALR) mutations. Among the 19 patients who had VTE recurrence under vitamin K antagonists, 4 patients (21.0%) were positive for JAK2V617F. Despite the identification of JAK2V617F mutation, only three patients were diagnosed for MPN despite a median follow-up of 4 years. We showed that the screening for JAK2V617F not CALR mutations should be helpful in this indication especially if recurrence happened under VKA therapy.

Frequency and Clinicohematologic Characteristics of MPL W515 Mutations in Patients with Myeloproliferative Neoplasms

BACKGROUND: Recently, myeloproliferative leukemia (MPL) W515 mutations have been reported to be molecular markers for myeloproliferative neoplasms (MPNs). We studied the association between MPL W515 mutations and the clinico-hematological features of patients with MPNs. METHODS: Our study included 154 consecutive patients diagnosed with MPNs (31 had polycythemia vera [PV]; 106, essential thrombocythemia [ET]; and 17, primary myelofibrosis [PMF]). MPL W515 mutations were detected by real-time PCR and direct sequencing methods. RESULTS: The MPL W515L mutation was found in 4 patients and the MPL W515A mutation was detected in 1 patient. These 5 patients were diagnosed with JAK2 V617F-negative ET, and they accounted for 12.5% of patients with JAK2 V617F-negative ET. The patients with MPL W515-positive ET showed significantly lower hemoglobin levels and WBC counts than did patients with MPL W515-negative ET or JAK2 V617F-positive ET. CONCLUSIONS: MPL W515 mutation is a useful diagnostic marker for JAK2 V617F-negative MPNs and it is associated with specific hematologic characteristics such as lower hemoglobin levels and WBC counts.