Huiling Zhen

Ruxolitinib versus best available therapy in patients with Polycythemia Vera: 80 Week follow up from the RESPONSE trial

RESPONSE is an open-label phase 3 study evaluating the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib versus best available therapy for efficacy/safety in hydroxyurea-resistant or intolerant patients with polycythemia vera. This preplanned analysis occurred when all patients completed the Week 80 visit or discontinued. Objectives included evaluating the durability of the primary response (Week 32 phlebotomy-independent hematocrit control plus ≥35% spleen volume reduction), its components, and that of complete hematologic remission; and long-term safety. Median exposure was 111 weeks; 91/110 (82.7%) patients randomized to ruxolitinib remained on treatment. No patients continued best available therapy (98/112 [87.5%] crossed over to ruxolitinib, most at/soon after Week 32). At Week 32, primary response was achieved by 22.7% vs. 0.9% of patients randomized to ruxolitinib and best available therapy, respectively (hematocrit control, 60.0% vs. 18.8%; spleen response, 40.0% vs. 0.9%). The probability of maintaining primary and hematocrit responses for ≥80 weeks was 92% and 89%, respectively; 43/44 spleen responses were maintained until Week 80. Complete hematologic remission at Week 32 was achieved in 23.6% of ruxolitinib-randomized patients; the probability of maintaining complete hematologic remission for ≥80 weeks was 69%. Among ruxolitinib crossover patients, 79.2% were not phlebotomized, and 18.8% achieved a ≥35% reduction from baseline in spleen volume after 32 weeks of treatment. New or worsening hematologic laboratory abnormalities in ruxolitinib-treated patients were primarily grade 1/2 decreases in hemoglobin, lymphocytes, and platelets. The thromboembolic event rate per 100 patient-years was 1.8 with randomized ruxolitinib treatment vs. 8.2 with best available therapy. These data support ruxolitinib as an effective long-term treatment option for hydroxyurea-resistant or intolerant patients with polycythemia vera. This trial was registered at clinicaltrials.gov identifier: 01243944.

Changes in quality of life and disease-related symptoms in patients with polycythemia vera receiving ruxolitinib or standard therapy

Polycythemia vera (PV)‐related symptoms may not be adequately controlled with conventional therapy. This current analysis of the RESPONSE trial evaluated the effects of ruxolitinib compared with standard therapy on quality of life (QoL) and symptoms in patients with PV who were hydroxyurea resistant/intolerant.

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double-blind, double-dummy, symptom study (RELIEF)

The randomized, double‐blind, double‐dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)‐related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV‐related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm ‐symptom assessment form total symptom score cytokine symptom cluster (TSS‐C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib‐ and hydroxycarbamide‐treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82–4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13–16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening‐to‐baseline TSS‐C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV‐related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.

Ruxolitinib for essential thrombocythemia refractory to or intolerant of hydroxyurea: long-term phase 2 study results

To the editor: Essential thrombocythemia (ET) is a Philadelphia chromosome–negative myeloproliferative neoplasm (MPN) characterized by persistent thrombocytosis, excessive bone marrow megakaryocyte proliferation, and normal erythrocyte mass.[1][1] Symptoms may include bone pain, pruritus, night

Efficacy and safety of ruxolitinib after and versus interferon use in the RESPONSE studies

Ruxolitinib was well tolerated and superior to best available therapy (including interferon [IFN]) in controlling hematocrit without phlebotomy eligibility, normalizing blood counts, and improving polycythemia vera-related symptoms in the Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care (RESPONSE) studies. This ad hoc analysis focuses on ruxolitinib in relation to IFN in the RESPONSE studies, with attention on the following: (1) safety and efficacy of ruxolitinib and best available therapy in patients who received IFN before study randomization, (2) safety and efficacy of IFN during randomized treatment in best available therapy arm, and (3) use of ruxolitinib after crossover from best available therapy in IFN-treated patients. IFN exposure before randomization had little effect on the efficacy or safety of ruxolitinib. In the randomized treatment arms, ruxolitinib was superior to IFN in efficacy [hematocrit control (RESPONSE = 60% of ruxolitinib vs 23% of IFN patients; RESPONSE-2 = 62% of ruxolitinib vs 15% of IFN patients)] and was tolerated better in hydroxyurea-resistant or hydroxyurea-intolerant patients. After crossing over to receive ruxolitinib, patients who had initially received IFN and did not respond had improved hematologic and spleen responses (62% of patients at any time after crossover) and an overall reduction in phlebotomy procedures. Rates and incidences of the most common adverse events decreased after crossover to ruxolitinib, except for infections (primarily grade 1 or 2). These data suggest that ruxolitinib is efficacious and well tolerated in patients who were previously treated with IFN. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies were registered at clinicaltrials.gov.

A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plusnab‐Paclitaxel and Gemcitabine in Advanced Solid Tumors

Abstract Lessons Learned. Itacitinib in combination with nab‐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. This phase Ib/II dose‐optimization study assessed itacitinib, a selective JAK1 inhibitor, combined with nab‐paclitaxel plus gemcitabine in adults with treatment‐naïve advanced/metastatic disease (Part 1) or pancreatic adenocarcinoma (Parts 2/2A; NCT01858883). Starting doses (Part 1) were itacitinib 400 mg, nab‐paclitaxel 125 mg/m2, and gemcitabine 1,000 mg/m2. Additional dose levels incorporated were granulocyte colony‐stimulating factor, de‐escalations of itacitinib to 300 mg once daily (QD), nab‐paclitaxel to 100 mg/m2, and gemcitabine to 750 mg/m2. Results. Among 55 patients in Part 1, 6 developed seven hematologic dose‐limiting toxicities (Cycle 1). Itacitinib 300 mg plus nab‐paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 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. Itacitinib plus chemotherapy demonstrated acceptable safety and clinical activity in patients with advanced solid tumors including pancreatic cancers. This study was terminated early (sponsors decision) based on negative phase III results for a JAK1/2 inhibitor in previously treated advanced pancreatic cancer.

Abstract CT063: Phase 2, open-label, multicenter study of the efficacy and safety of INCB054828 in patients (pts) with advanced, metastatic, or surgically unresectable cholangiocarcinoma (CCA) with inadequate response to prior therapy

Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR translocations and activating mutations is implicated in many cancers, including CCA. FGFR2 translocations are the most common FGFR alterations, which occur in ~13% of pts with intrahepatic CCA and involve a variety of fusion partners/breakpoints. INCB054828 is a novel, orally available, selective inhibitor of FGFR1, FGFR2, and FGFR3 tyrosine kinase activities (AACR 2015; Abstract 771). Methods: This phase 2, open-label trial will evaluate INCB054828 monotherapy in pts with advanced/metastatic or surgically unresectable CCA (Table;NCT02924376). Pts will be prescreened centrally for FGF/FGFR status and enrolled in the following cohorts prior to start of treatment: FGFR2 translocations (Cohort A); other FGF/FGFR alterations (Cohort B); no FGF/FGFR alterations (Cohort C; negative control for effects of FGF/FGFR alterations on objective response rate [ORR]). Pts must be aged ≥18 years, with Eastern Cooperative Oncology Group performance status ≤2, disease progression after ≥1 prior systemic therapy, and no prior use of selective FGFR inhibitors. Pts will self-administer INCB054828 orally at a starting dose of 13.5 mg once-daily on a 21-day cycle (2 weeks on; 1 week off); treatment will continue until disease progression or unacceptable toxicity. The primary endpoint will be ORR (complete or partial response per independent radiologic review committee using Response Evaluation Criteria in Solid Tumors v1.1) in pts with FGFR2 translocations (Cohort A). Secondary endpoints will include ORR in pts positive or negative for any FGF/FGFR alterations and duration of response, progression-free survival, overall survival, and safety (all cohorts). The study is currently open for enrollment (estimated primary completion date, April, 2018). Citation Format: Mitesh J. Borad, S. Lindsey Davis, Maeve A. Lowery, Ekaterine Asatiani, Christine F. Lihou, Huiling Zhen, Ghassan K. Abou-Alfa. Phase 2, open-label, multicenter study of the efficacy and safety of INCB054828 in patients (pts) with advanced, metastatic, or surgically unresectable cholangiocarcinoma (CCA) with inadequate response to prior therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT063. doi:10.1158/1538-7445.AM2017-CT063

Abstract CT057: Phase 2, open-label, multicenter study to evaluate the efficacy and safety of INCB054828 in patients with myeloid/lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) rearrangement

Background: Dysregulation of FGFR signaling is strongly implicated in the establishment and progression of many cancers; rearrangements in chromosome 8p11 leading to activation of FGFR1 have been associated with rare but aggressive myeloid and lymphoid neoplasms with eosinophilia. INCB054828 is a novel, selective, orally administered inhibitor of FGFR1, FGFR2, and FGFR3 tyrosine kinase activities (AACR 2015; Abstract 771). Methods: This open-label, single-arm, phase 2 study will evaluate the efficacy and safety of INCB054828 monotherapy in patients with myeloid/lymphoid neoplasms with FGFR1 rearrangement (Table; NCT03011372). Eligible patients are ≥18 years of age, have documented lymphoid or myeloid neoplasm with 8p11 rearrangement known to lead to FGFR1 activation and have an Eastern Cooperative Oncology Group performance status ≤2. In addition, patients must not be candidates for stem cell transplant (or must have relapsed after transplant and delayed lymphocyte infusion); must have progressed on ≥1 prior anticancer treatment; must not be eligible for other disease-modifying therapies. Patients will self-administer INCB054828 orally, once-daily at a starting dose of 13.5 mg on a 21-day cycle (2 wks on; 1 wk off); treatment will continue until disease progression or unacceptable toxicity occurs. The primary endpoint will be overall clinical benefit rate (proportion of patients with complete or partial response, complete hematologic response, cytogenetic response, marrow response [see Table for response criteria], or clinical benefit). Secondary endpoints will include duration of response/clinical benefit, progression-free survival, overall survival, and safety. The study is currently recruiting (planned enrollment, n~46); primary analysis is expected in January 2019. Citation Format: Srdan Verstovsek, Alessandro Rambaldi, Ekaterine Asatiani, Christine F. Lihou, Huiling Zhen, Andreas Hochhaus. Phase 2, open-label, multicenter study to evaluate the efficacy and safety of INCB054828 in patients with myeloid/lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) rearrangement [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT057. doi:10.1158/1538-7445.AM2017-CT057

Abstract CT059: Phase 2, open-label, multicenter study of the efficacy and safety of INCB054828 for metastatic or surgically unresectable urothelial carcinoma harboring fibroblast growth factor (FGF)/FGF receptor (FGFR) alterations

Background: Aberrant FGFR signaling results in tumor cell proliferation, migration, and survival, as well as angiogenesis, and is implicated in the development and progression of many cancers, including urothelial carcinoma (UC). Ten to 15% of patients with advanced UC have FGFR3 mutations and 6% have an FGFR3 translocation. INCB054828 is a novel, selective, orally administered inhibitor of FGFR1, FGFR2, and FGFR3 tyrosine kinase activities (AACR 2015; Abstract 771). Methods: This phase 2, open-label trial will evaluate INCB054828 monotherapy for histologically confirmed metastatic or unresectable UC (NCT02872714; Table). Eligible patients will have known FGF/FGFR alterations, will be ≥18 years of age, have Eastern Cooperative Oncology Group performance status ≤2, adequate liver and renal function, and have life expectancy ≥12 wks. Patients will have inadequate response to ≥1 previous treatment in this setting or will be platinum-ineligible, and must not have received any investigational drugs within 21 days of first dose, including selective FGFR inhibitors. Patients will self-administer INCB054828 orally once daily at a starting dose of 13.5 mg on a 21-day 2-weeks-on and 1-week-off cycle. Patients will receive treatment until disease progression or unacceptable toxicity. The primary endpoint will be objective response rate (complete plus partial responses assessed from CT scans [or MRI per investigator] using Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints will include safety, duration of response, progression-free survival, and overall survival. Exploratory endpoints will include predictive biomarker assessment. The study is currently recruiting; 96 patients are planned for the primary analysis (estimated to occur in March 2018). Citation Format: Neal D. Shore, Ekaterine Asatiani, Christine F. Lihou, Huiling Zhen, Sumati Gupta. Phase 2, open-label, multicenter study of the efficacy and safety of INCB054828 for metastatic or surgically unresectable urothelial carcinoma harboring fibroblast growth factor (FGF)/FGF receptor (FGFR) alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT059. doi:10.1158/1538-7445.AM2017-CT059