AOP2014, a Novel Peg-Proline-Interferon Alpha-2b with Improved Pharmacokinetic Properties, Is Safe and Well Tolerated and Shows Promising Efficacy in Patients with Polycythemia Vera (PV)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 175-175 ◽  
Author(s):  
Heinz Gisslinger ◽  
Robert Kralovics ◽  
Bettina Gisslinger ◽  
Daniel Lechner ◽  
Veronika Buxhofer-Ausch ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Iii ◽  
Molecular Response ◽  
Overall Response ◽  
Long Term Treatment

Abstract Abstract 175 AOP2014 is a next generation long-acting pegylated IFNa-2b, consisting predominantly of only one isoform, as opposed to other commercially available pegylated interferons. AOP2014 has a distinct pharmacokinetic and pharmacodynamic profile which may potentially allow reduced dosing frequencies compared to other pegylated IFNs. This is being expected to result in improved tolerability, better compliance, and, finally, favorable long-term treatment outcomes. AOP2014 is a designated Orphan Drug in EU for treatment of patients with PV. The maximum tolerated dose (MTD), long term safety and efficacy of AOP2014, administered subcutaneously every 14 days, are the main objectives of the study. Patients with confirmed PV diagnosis, age equal or older 18 years, both naïve and cytoreduction pre-treated are eligible. After establishing the MTD, an extended cohort of 25 additional patients was planned to be recruited. European LeukemiaNet criteria were used for response assessment. 34 patients, treated by March 31, 2012 were included into this analysis: 25 in Phase I (dose-finding) and 9 in the Phase II (cohort extension). Median time from diagnosis was 24 months (range 0–180). 12 patients (35%) were HU pre-treated (mean past duration of HU pre-treatment 39 months, mean daily HU dose 950 mg). Median number of phlebotomies in the past 3 months prior to inclusion was 1 (range 0–8), a total of 21 patients (62%) were regularly phlebotomized at least once in three months prior to study entry. 11 patients (32%) had a history of thrombotic complications. Median Hct at baseline was 42% (range 36–51). Median WBC and platelet counts were 10.6*109/l (range 3.9–20.4) and 452*109/l (range 141–1019), respectively. 17 patients (50%) had splenomegaly at baseline. The median reported treatment duration was 41 weeks (range: 1 day – 80 weeks), 11 patients completed 1 year on treatment. Doses from 50 to 540 ug every two weeks were tested, 540 ug has been concluded as MTD as the highest tested dose, since no DLTs occurred in the study. The mean administered dose (both Phase I and II patients) was 287 ug. After 28 weeks of treatment (21 evaluable patients), 71% of patients had hematological response (7 CR, 33%; 8 PR, 38%), at week 36 (19 evaluable patients) 8 patients (42%) achieved a CR and 8 patients (42%) a PR, overall response rate (ORR, CR+PR) was 84%. At week 52 (1 year; 11 evaluable patients), 5 patients (46%) had CR and 5 (46%) PR, ORR was 91%; 8 (73%) patients presented with completely normalized blood values, all evaluable patients were phlebotomy free at this timepoint. 4 patients (of 12 evaluable for this measurement, 33%) had still enlarged spleen at week 52. At week 76, 2 evaluable patients were complete responders. At week 52, 1 patient (of 9 evaluable, 11%) developed partial molecular response, at week 68 3 patients (of 7 evaluable, 43%) had partial molecular response. One patient with allelic burden of 22% at baseline developed complete molecular response at week 36 (still ongoing). Mainly grade 1 and 2 adverse events were reported. A total of 358 adverse events occurred. 27 patients (79%) suffered from drug-related adverse events. 9 patients (26%) developed serious adverse events; 4 SAEs were considered to be treatment related. 5 patients (15%) discontinued their study participation prematurely, 3 of them due to adverse events (deterioration of underlying disease and two cases of depression). Acceptable tolerability and durable clinical benefits have been demonstrated in PV patients measured as overall response rate of above 90% with CRs of 46% at one year after treatment start. Phlebotomy independence and normalization of hematological parameters could be seen in most of the patients. The study continues to recruit and collect long term follow up information. Presented data support further development of AOP2014 in PV, a Phase III study is planned to start early 2013. Disclosures: Gisslinger: AOP Orphan Pharmaceuticals AG: Research Funding; Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau. Kralovics:AOP Orphan Pharmaceuticals AG: Research Funding. Gisslinger:AOP Orphan Pharmaceuticals AG: Research Funding. Lechner:AOP Orphan Pharmaceuticals AG: Research Funding. Buxhofer-Ausch:AOP Orphan Pharmaceuticals AG: Research Funding. Strecker:AOP Orphan Pharmaceuticals AG: Research Funding. Gastl:AOP Orphan Pharmaceuticals AG: Research Funding. Willenbacher:AOP Orphan Pharmaceuticals AG: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Melchardt:AOP Orphan Pharmaceuticals AG: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals AG: Research Funding. Schloegl:AOP Orphan Pharmaceuticals AG: Research Funding. Tarmann:AOP Orphan Pharmaceuticals AG: Employment. Zoerer:AOP Orphan Pharmaceuticals AG: Employment. Klade:AOP Orphan Pharmaceuticals AG: Employment. Zahriychuk:AOP Orphan Pharmaceuticals AG: Employment. Thaler:AOP Orphan Pharmaceuticals AG: Research Funding.

Decitabine Is Effective and Safe In Patients with Chronic Myelomonocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4032-4032
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
A. Megan Cornelison ◽  
Tapan Kadia ◽  
...  
Keyword(s):  
Median Survival ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Chronic Myelomonocytic Leukemia ◽  
Phase Iii ◽  
White Blood Count ◽  
Survival Duration ◽  
Overall Response ◽  
Myelomonocytic Leukemia

Abstract Abstract 4032 Background: Chronic myelomonocytic leukemia (CMML) is a rare yet indolent disease. The median survival duration in CMML is 12 to 18 months and patients with poor prognostic features do even worse, with median survival time ranging 3 to 6 months. Activity with decitabine in CMML has been previously reported. We sought to analyze the clinical experience of 17 adults with a diagnosis of CMML treated on two decitabine studies. Methods: A subset of patients with CMML from a pivotal phase III 3-day dosing and an open-label trial of 5-day dosing were identified and reviewed to determine the overall response rate (ORR, based on IWG 2006 criteria), duration of response, time to response, and overall survival (OS). Results: A total of 17 patients with CMML were included in this review. Mean age at diagnosis was 71 years (range, 47 to 81 years) with a mean time from diagnosis of 406.4 days. The majority of CMML patients had de novo (94.1%), good risk cytogenetics (58.8%) with an IPSS classification of Intermediate-1 (64.7%). Baseline mean white blood count (WBC), hemoglobin (HGB), and platelets (plts) were 7.5 × 103/μ L, 14.6 g/dL and 81.9 × 103/μ L, respectively. A larger proportion of CMML patients at baseline were plt and RBC transfusion independent. Objective response rate (ORR) was 41% [17.6% complete response (CR) and 23.5% marrowCR (mCR)]; Hematologic improvement (HI) was observed in 11.7% and stable disease in 29.4% of patients. Median survival was 391 (95% CI 239, 678) days and 2 (11.7%) patients progressed to AML. The adverse event profile was similar to observations in previous trials with myelosuppression and infectious complications. Conclusions: This retrospective review of responses in CMML patients supports previous findings of decitabine experience in this population. In this analysis an overall response rate of 41.4% was achieved. Decitabine provided anti-CMML activity with an acceptable safety profile. Disclosures: Jabbour: Eisai Inc.: Editorial and statistical support from Eisai Inc., Honoraria. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy. Ravandi:Eisai Inc.: Research Funding; Eisai Inc.: Honoraria. Borthakur:Eisai Inc.: Research Funding. Cortes:Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding.

Switch from Every Two Weeks to Every Four Weeks Administration Schedule of AOP2014, an Innovative Pegylated Interferon Alpha, in Polycythemia Very Patients Allows Maintaining of Efficacy with Improved Toxicity Profile in Phase I/II Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3177-3177
Author(s):  
Heinz Gisslinger ◽  
Veronika Buxhofer-Ausch ◽  
Josef Thaler ◽  
Ernst Schloegl ◽  
Guenther A. Gastl ◽  
...  
Keyword(s):  
Phase I ◽  
Interferon Alpha ◽  
Exposure Duration ◽  
Research Funding ◽  
Blood Parameters ◽  
Phase Iii ◽  
Long Term Treatment ◽  
One Year ◽  
Monthly Dose

Abstract Background AOP2014 is a next generation long-acting pegylated IFN-alpha-2b, consisting predominantly of only one isoform, as opposed to other commercially available pegylated interferons. Due to this property, reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with Polycythemia Vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development. Study design This phase I/II single arm dose escalation study with cohort extension included 51 patients with PV who could be either cytoreduction therapy naive or pre-treated. AOP2014 was administered subcutaneously in a dose range of 50-540 mcg every two weeks. Main objectives were to define the maximum tolerated dose as well as observe the long term safety and efficacy in terms of normalization of blood parameters and molecular abnormalities (results were already presented at the ASH 2013 annual meeting by Gisslinger et al). The option to switch to an "once every four weeks" schedule has been implemented by the amended protocol for patients who responded well to the treatment and participated in the study for longer than one year. The dose of the study drug had to remain unchanged after the switch, resulting in a decrease (by approx. the half) of the overall exposure to the drug. Outcomes of this switch are presented here. Results Patients (period A, median exposure duration 34 weeks, mean monthly dose 484 mcg) were dosed every two weeks based on the Phase II dosing rules prior having switch option. 33 patients (period B, median exposure duration 12 weeks, mean monthly dose 413 mcg) were dosed every two weeks beyond the first year and, showing benefit from treatment, have been assessed as eligible for switch. 28 patients (period C, median exposure duration 42 weeks) were then switched to once every four weeks schedule (mean monthly dose 221 mcg). Blood parameters were normalized and remained stable following one year of treatment and could be maintained after the switch (hematocrit, median,% - period A: 43, period B: 43, period C: 42; WBC, median, G/l - period A: 6.1, period B: 5.9, period C: 5.7; platelets, median, G/l - period A: 246, period B: 211, period C: 204). Spleen length stayed stable within the normal range following the switch in the majority of patients either (mean, in cm – period A: 11.4, period B: 8.3, period C: 10.3). Complete response as best individual response could be maintained in 42% from the period A, 55% in the period B and 67% of the period C patients, while for the partial hematological responders the results were 60%, 71% and 67%, respectively. Molecular response improved continuously over time, being maintained at the best individual level in 31% of period A patients, compared to 42% of period B and 75% of period C patients. Decrease of application frequency and total dose exposure led to decrease of the occurrence of all/drug related AEs (measured as mean count of adverse events [AE] per patient week exposure) to 0.17/0.09 (arm A) from 0.3/0.09 (arm B) and 0.08/0.03 (arm C). Conclusions This explorative data from endpoints pre-defined in the prospective study demonstrate the feasibility to further reduce the frequency of AOP2014 administration to once every four weeks in responding patients, previously treated every two weeks. Reduced injection frequency is not associated with a lack of- response, but clearly improves tolerability. Finally, continuous reduction of the JAK2 allelic burden indicates that duration of interferon exposure rather than dose of interferon is an important variable inducing molecular responses. The here presented findings support the idea that interferon alpha effects in PV are pleiotropic, such as induction of immune-surveillance, which is continuously maintained at lower AOP2014 levels. Disclosures Gisslinger: AOP Orphan Pharmaceuticals AG: Research Funding. Buxhofer-Ausch:AOP Orphan Pharmaceuticals AG: Research Funding. Thaler:AOP Orphan Pharmaceuticals AG: Research Funding. Schloegl:AOP Orphan Pharmaceuticals AG: Research Funding. Gastl:AOP Orphan Pharmaceuticals AG: Research Funding. Wolf:AOP Orphan Pharmaceuticals AG: Research Funding. Kralovics:AOP Orphan Pharmaceuticals AG: Research Funding. Gisslinger:AOP Orphan Pharmaceuticals AG: Research Funding. Strecker:AOP Orphan Pharmaceuticals AG: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Melchardt:AOP Orphan Pharmaceuticals AG: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals AG: Research Funding. Willenbacher:AOP Orphan Pharmaceuticals AG: Research Funding. Zoerer:AOP Orphan Pharmaceuticals AG: Employment. Kadlecova:AOP Orphan Pharmaceuticals AG: Consultancy. Zagrijtschuk:AOP Orphan Pharmaceuticals AG: Employment. Klade:AOP Orphan Pharmaceuticals AG: Employment. Greil:AOP Orphan Pharmaceuticals AG: Research Funding.

Phase 1/1b Study of the Efficacy and Safety of the Combination of Panobinostat + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4081-4081 ◽  
Author(s):  
Jatin J. Shah ◽  
Sheeba K. Thomas ◽  
Donna M. Weber ◽  
Michael Wang ◽  
Raymond Alexanian ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Advisory Committees ◽  
Overall Response ◽  
Elevated Creatinine

Abstract Abstract 4081 Background: Carfilzomib, a novel irreversible proteasome inhibitor (PI), has demonstrated single agent activity in, and was recently FDA approved for relapsed and refractory myeloma. Panobinostat, a potent histone deacetylase inhibitor (HDACi), has been studied as a single agent and in combination with bortezomib, demonstrating promising response rates and a favorable safety profile in bortezomib-refractory patients. Our hypothesis proposed that the combination of carfilzomib and panobinostat (Car-Pan) would also be highly active, and we therefore aimed to combine these two agents for the first time. We report the initial findings from the phase I dose-escalation and expansion portions of our phase I/II trial of this novel combination regimen. Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of Car-Pan in patients with relapsed or refractory multiple myeloma. Secondary objectives included determination of the overall response rate, time to progression, progression free survival, and time to next therapy. Panobinostat was administered orally on days 1, 3, 5, 8, 10, 12 of every 28-day cycle, while carfilzomib was given intravenously over 30 minutes on days 1, 2, 8, 9, 15, and 16. Dose level 1 started carfilzomib at 20 mg/m2 with 15 mg of panobinostat, and escalated from there using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. An amendment was later introduced to allow carfilzomib to be given at 20 mg/m2for days 1 and 2 of cycle 1, followed by an increase to the full dose level for that cohort. Adverse events (AEs) were graded using the NCI-CTCAE v4, and responses were assessed with the modified International Uniform Response Criteria. Results: To date, 20 patients have been enrolled, 3 of whom are still in their first cycle, leaving 17 evaluable patients who are described herein, who have received a median of 4 cycles (range 1–8). The median age was 62 years (range 46–73), 11/17 (70%) were male, and the median number of prior regimens was 5 (range 2–15). Patients were very heavily pretreated, with 16/17 (94%) having undergone stem cell transplantation, 16/17 (94%) having prior bortezomib, including 8/17 (47%) who were bortezomib-refractory, and 17/17 (100%) having prior lenalidomide, including 12/17 (70%) who were lenalidomide-refractory. Cytogenetic abnormalities were common, including: 4 with del(17p), 4 with t(4;14), 2 with t(11;14), 9 with del(13), of whom 7 had additional mutations. Grade 1–4 AEs regardless of causality occurring in >20% of patients included anemia (14/17), thrombocytopenia (17/17), neutropenia (8/17), diarrhea (9/17), nausea/emesis (7/17), fatigue (10/17), elevated creatinine (8/17), and pneumonia (5/17). Grade ≥3 AEs regardless of causality included anemia (7/17), thrombocytopenia (10/17), neutropenia (6/17), diarrhea (2/17), nausea/emesis (1/17), fatigue (4/17), elevated creatinine (2/17), and pneumonia (4/17). An MTD has not been established, and dosing is ongoing in cohort 4, with Carfilzomib at 45mg/m2and 20 mg of Panobinostat. Of the 17 evaluable patients, the overall response rate was 35% (6/17) who achieved at least a partial response (PR); including 2 with very good PR (VGPR). In addition, one patient had a minor response, and 65% overall achieved stable disease or better. Conclusions: The combination of Carfilzomib + Panobinostat is well tolerated with a manageable side effect profile. Importantly, the combination achieves a promising response rate in a very heavily pre-treated, lenalidomide/bortezomib/high dose melphalan-refractory population, with an overall response (≥PR) rate of 35%. Updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about panobinostat, which is not yet approved for use in patients with multiple myeloma. Thomas:Celgene: Research Funding; Millenium: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Johnson & Johnson: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees. Wang:Onyx Pharmaceuticals: Honoraria, Research Funding. Orlowski:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Phase I/II Study of Vosaroxin and Decitabine in Newly Diagnosed Older Patients (pts) with Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 385-385 ◽  
Author(s):  
Daver Naval ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Naveen Pemmaraju ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Advisory Board ◽  
Standard Chemotherapy ◽  
Overall Response ◽  
Board Membership

Background: Vosaroxin, is a first-in-class anti-cancer quinolone derived (AQD) DNA topoisomerase II inhibitor, which is not a substrate for p53 or P-glycoprotein, has limited toxicity, and is currently under evaluation for the treatment of pts with AML and high-risk MDS. Methods: Pts were eligible if they had AML or high-risk MDS (defined as having ³ 10% blasts in the bone marrow), were 60 years of age or older, and had adequate performance status (ECOG ² 2) and organ function. Pts younger than 60 who were unsuitable for standard chemotherapy were also eligible. In the phase I part of the study the first six pts received vosaroxin 90 mg/m2 daily on days 1 and 4 with decitabine 20 mg/m2 daily for 5 days. This dose was well tolerated with no dose limiting toxicity identified and pts were then enrolled on phase II at this dose and schedule. However, due to mucositis in a few subsequent pts, the induction dose of vosaroxin was reduced to 70 mg /m2, starting with pt #25. The vosaroxin dose could be maintained at 70 mg/m2 or reduced to 50 mg/m2 in consolidation cycles, which were repeated in approximately 4 to 5-week intervals for a total of up to 7 cycles. Dose adjustments and dose delays of one or both agents, were allowed based on toxicity. The primary endpoint was to determine the overall response rate including complete response (CR) + CR without platelet recovery (CRp) + CR with insufficient hematological recovery (CRi). Secondary endpoints were: CR duration, disease-free survival, overall survival, safety, and early mortality. Results: To date, 35 pts (32 AML, 3 high-risk MDS) with a median age of 71 years (range, 41-78) have been enrolled; 34 (97%) pts were older than 60 years. They included 15 (43%) pts with diploid cytogenetics, 12 (34%) with complex cytogenetic abnormalities including chromosome 5 and/or 7 abnormalities, and 8 (23%) with other miscellaneous abnormalities. 13 (37%) pts with AML had antecedent hematological disorders (AHD) including 7 (20%) with MDS, 4 (11%) with myeloproliferative neoplasm and 2 (6%) with MDS/MPN. Three pts with AHD had received prior therapy including 5-azacytidine (n=1), ruxolitinib + 5-azacytidine (n=1), and lenalidomide (n=1). Additionally, 5 (15%) pts had therapy-related disease with prior exposure to chemotherapy or radiation therapy. Median bone marrow blast %, median white blood cell, hemoglobin, & platelet counts were 40% (9-97), 4.1 x 109/L (0.4-57.0), 9.4 g/dL (6.8-11.5), and 40 x 109/L (7-333), respectively. 34 pts were evaluable for response; 17 (50%) achieved CR, 6 (18%) CRp, and 3 (9%) CRi for an overall response rate of 77%. One pt is too early for response assessment. Responses by age, cytogenetic and molecular characteristics are shown in table 1. The median follow-up is 5.1 months (range, 0.9-11.0). Pts have received a median of 2 (1-6) treatment cycles with the median number of cycles to response being 1 (1-4). Three pts have relapsed and the median duration of CR/CRp/CRi has not been reached (0.5-9.9+ months). Four (12%) pts have proceeded to allogeneic stem cell transplant (ASCT). 4-week and 8-week mortality were 0% and 14%, respectively. The regimen is well tolerated with the main grade ³ 3 toxicity being mucositis in 9 (26%) pts and liver enzyme elevation in 3 (9%). Conclusion: Combination of vosaroxin and decitabine is effective and feasible in older pts with AML and high-risk MDS. Enrollment is ongoing. Table 1: Response by baseline characteristics Parameter Category N Overall response Too early to evaluate Age* 60-70 16 14/16 (88%) 0 >70 18 12/17 (71%) 1 Cytogenetics Diploid 15 11/14 (79%) 1 -5/-7/other adverse 12 8/12 (67%) 0 Miscellaneous 8 5/8 (63%) 0 Mutation Status IDH2 7 7/7 (100%) 0 IDH1 5 1/4 (25%) 1 TP53 9 6/9 (67%) 0 RAS 9 4/9 (44%) 0 *1 pt below the age of 60 years was unsuitable for standard chemotherapy and was enrolled on study. Disclosures Naval: Sunesis: Advisory board membership Other, Research Funding. Off Label Use: Vosaroxin (Qinprezo) has not been approved for AML. In this clinical trial we are evaluating the efficacy and safety of vosaroxin (Qinprezo) in combination with decitabine in elderly patients with AML. . Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Kadia:GSK: Research Funding; ARIAD: Honoraria. Borthakur:Tetralogic Pharmaceuticals: Research Funding. Jabbour:Ariad, Novartis, BMS, Pfizer, and Teva: Consultancy. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Craig:Sunesis: Employment. Ravandi:Sunesis: Advisory board membership Other, Research Funding.

scholarly journals A single-arm study evaluating bevacizumab, cisplatin, and paclitaxel followed by single-agent bevacizumab in Japanese patients with advanced cervical cancer

2016 ◽  
Vol 47 (1) ◽  
pp. 39-46 ◽  
Author(s):  
Toru Sugiyama ◽  
Mika Mizuno ◽  
Yoichi Aoki ◽  
Manabu Sakurai ◽  
Tadaaki Nishikawa ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Adverse Events ◽  
Overall Response Rate ◽  
Response Rate ◽  
Japanese Patients ◽  
Primary Objective ◽  
Phase Iii ◽  
Advanced Cervical Cancer ◽  
Recurrent Cervical Cancer ◽  
Overall Response

Background Adding bevacizumab to chemotherapy for recurrent, persistent or metastatic cervical cancer significantly improved overall survival (primary endpoint), progression-free survival and overall response rate in the randomized Phase III GOG-0240 trial. However, data for bevacizumab-containing therapy are scarce in Japanese patients with advanced cervical cancer. Methods The primary objective of the single-arm multicenter Phase II JO29569 study was to evaluate the tolerability of paclitaxel (135 mg/m2 over 24 h or 175 mg/m2 over 3 h), cisplatin (50 mg/m2) and bevacizumab (15 mg/kg), administered every 3 weeks until disease progression or unacceptable toxicity in Japanese patients with stage IVB, persistent or recurrent cervical cancer. Results The seven treated patients received a median of nine (range 7–12) bevacizumab cycles and six (range 4–12) chemotherapy cycles. None of the predefined adverse events occurred during the tolerability evaluation period. The most common all-grade adverse events were alopecia, hypertension, decreased appetite, nausea and peripheral sensory neuropathy. There were no cases of fistula. The most common grade ≥3 adverse events were hypertension, neutrophil count decreased and neutropenia. Only one patient experienced febrile neutropenia. The overall response rate was 86% (95% confidence interval, 42–100%), including a complete response in one patient. At data cutoff, disease had progressed in one patient; bevacizumab therapy was ongoing in the remaining six. Conclusions According to the specified primary objective, a regimen of cisplatin, paclitaxel and bevacizumab was tolerable in Japanese patients and demonstrated encouraging activity in this small single-arm study. Further study is warranted to confirm the safety and effectiveness of bevacizumab in Japanese patients with cervical cancer.

scholarly journals Phase I/II Study of Vosaroxin and Decitabine in Newly Diagnosed Older Patients (pts) with Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 461-461 ◽  
Author(s):  
Naval Daver ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Early Mortality ◽  
Overall Response ◽  
Induction Dose ◽  
Baseline Characteristics

Abstract Background: Vosaroxin, is a first-in-class anti-cancer quinolone derived (AQD) DNA intercalator and topoisomerase II inhibitor, which is not a substrate for p53 or P-glycoprotein, and is currently under evaluation for the treatment of pts with AML and high-risk MDS. Methods: Pts are eligible if they have AML or high-risk MDS (defined as having >/= 10% blasts), are 60 years of age or older, and have adequate performance status (ECOG </= 2) and organ function. In the phase I part of the study the first six pts received vosaroxin 90 mg/m2 daily on days 1 and 4 with decitabine 20 mg/m2 daily for 5 days repeated in approximately 4 to 5 week intervals for up to 7 cycles. This dose was well tolerated in the 6 patients. However, due to occurrence of 8 episodes of grade 3/4 mucositis in 7 of the subsequent 16 patients the induction dose of vosaroxin was reduced to 70 mg/m2 with the vosaroxin dose maintained at 70 mg/m2 or reduced to 50 mg/m2 in consolidation cycles. 34 patients were treated at this modified dose regimen. The primary endpoint was to determine the overall response rate including complete response (CR) + CR without platelet recovery (CRp) + CR with insufficient hematological recovery (CRi). Secondary endpoints were: CR duration, disease-free survival, overall survival, safety, and early mortality. Results: To date, 56 pts (50 AML, 6 high-risk MDS) with a median age of 69 years (range, 60 - 78) have been enrolled. They included 19 (34%) pts with diploid cytogenetics, 21 (38%) with complex cytogenetic abnormalities including chromosome 5 and/or 7 abnormalities, and 16 (28%) with other miscellaneous abnormalities. Fourteen (25%) pts with AML had antecedent hematological disorders (AHD) including 7 with MDS, 4 with MPN, 2 with MDS/MPN, and 1 with CLL. Four pts with AHD had received prior therapy including 5-azacytidine (n=1), decitabine (n=1), ruxolitinib + 5-azacytidine (n=1), and lenalidomide (n=1). Additionally, 10 (18%) pts had therapy-related disease with prior exposure to chemotherapy or radiation therapy. Median bone marrow blast %, and median white blood cell, hemoglobin, & platelet counts were 40% (range, 11 - 97), 3.4 x 109/L (range, 0.4 - 57), 9.4 g/dL (range, 6.8 - 13.1), and 35 x 109/L (range, 7 - 333), respectively. All 56 pts have completed >/=2 cycles of therapy and were evaluable for response; 30 (54%) achieved CR, 8 (14%) CRp, and 5 (9%) CRi for an overall response rate of 77%. Minimal residual disease (MRD) by 19 color flow-cytometry was evaluable in 35 of the 43 responders. MRD was not detectable in 24 of 35 (66%) evaluable responders. All 56 patients had baseline cytogenetics and clinically validated next generation sequencing-based analysis for the detection of somatic mutations in the coding sequence of 28 genes commonly mutated in myeloid neoplasms. Response by baseline characteristics is shown in table 1. The median number of cycles to response was 1 (1 - 4); 13 pts have required >1 cycle to achieve response. Seven (13%) pts have proceeded to allogeneic stem cell transplant. The median follow-up is 4.7 months (1.3 - 20.8). The regimen was well tolerated with the main therapy related grade >/= 3 toxicities were mucositis in 10 (18%) pts and liver enzyme elevation in 8 (14%). The median overall survival (OS) for all pts is 8.3 months. Four-week and 8-week mortality for all pts were 0 and 14%, respectively. The induction dose of vosaroxin was 90 mg/m2 in 22 pts and 70 mg/m2 in 34 pts. The lower induction dose of vosaroxin was associated with a reduced early mortality and an improved overall response rate and OS (Table 2 and Figure 1). Conclusion: Combination of vosaroxin and decitabine is effective in older pts with AML and high-risk MDS. Reponses were encouraging in the pts with TP53 and complex cytogenetics. The lower dose of vosaroxin 70 mg/m2 on days 1 and 4 is better tolerated and is associated with significantly improved outcomes. Table 1. Response by baseline characteristics Parameter Category N Overall response(CR, CRp, CRi) CR Age 60-74 44 80% 57% >/=75 12 67% 42% Cytogenetics Diploid 19 86% 57% -5/-7/other adverse 21 68% 42% Miscellaneous 16 75% 63% MutationStatus IDH2 11 91% 73% IDH1 14 57% 43% TP53 11 73% 55% RAS 11 64% 28% Table 2. Outcomes by induction dose of vosaroxin Induction dose(vosaroxin) N Med OS 8-week mortality Overall Response CR Need >1 cycle to response 90 mg/m2 22 5.5 mos 25% 73% 41% 23% 70 mg/m2 34 11.5 mos 6% 79% 62% 23% Figure 1. OS by induction dose of vosaroxin Figure 1. OS by induction dose of vosaroxin Disclosures Daver: ImmunoGen: Other: clinical trial, Research Funding. Off Label Use: Vosaroxin in the management of AML. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. DiNardo:Novartis: Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BerGenBio AS: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Craig:Sunesis: Employment, Equity Ownership.

scholarly journals Phase II Study of the Combination of Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone As Salvage Therapy in Relapsed/Refractory Multiple Myeloma: Results of a Safety Run-in Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3117-3117 ◽  
Author(s):  
Caitlin L. Costello ◽  
Michelle Padilla ◽  
Edward D. Ball ◽  
Carolyn Mulroney
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Residual Disease ◽  
Refractory Multiple Myeloma ◽  
Overall Response ◽  
Grade 3 ◽  
Observation Period

Background: Triplet combination strategies have widely been accepted as the standard of care for the management of multiple myeloma due to improved outcomes as compared to doublets. The combination of daratumumab, pomalidomide and dexamethasone (DPd) has previously demonstrated deep and durable responses, including high rates of MRD negativity, in a heavily pretreated patient population. Quadruplet regimens offer an opportunity to further improve upon these results. We report preliminary findings from an ongoing phase 2 multicenter trial of the addition of ixazomib to the combination of DPd in patients with relapsed/refractory multiple myeloma. The primary objective is to determine overall response rate and the safety and tolerability of this novel regimen. Key secondary endpoints include PFS, OS and MRD negativity rates. Methods: Eligible patients may have received ≥1 and ≤3 prior lines of therapy, have had no prior exposure to daratumumab or ixazomib, and may have not progressed on prior pomalidomide. Patients receive daratumumab 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, pomalidomide 4mg PO days 1-21/28, ixazomib 4mg PO days 1,8,15 every 28 days, and dexamethasone 40mg PO weekly. Patients continue on therapy until disease progression, intolerability or preference. Dose-limiting toxicities (DLT) were defined as grade 3-4 hematologic adverse events (AE) or any AE that required a dose modification of pomalidomide or ixazomib at the lowest dose levels on a dose de-escalation plan. An interim safety review was performed after the first 6 patients were enrolled and completed the DLT observation period, which is the first cycle (28 days) since the start of a new dose level of pomalidomide and/or ixazomib. Results: At the time of this analysis, six patients have been enrolled and treated, and completed the DLT observation period. Patients had a median age of 62 (range 52-65) and median number of 2 prior lines of therapy (range 1-2). All patients were refractory to lenalidomide and pomalidomide-naïve. Common adverse events (AEs) included neutropenia, thrombocytopenia, GI upset, and upper respiratory infection. Grade 3-4 AEs were predominantly hematologic including neutropenia and thrombocytopenia, but also included grade 3 hypertension in 1 patient, and grade 3 hypophosphatemia, grade 4 hypokalemia, and grade 3 small bowel infection in 1 patient. No IRR > grade 2 occurred with daratumumab administration. No DLTs occurred in the first six patients in the safety run-in. The overall response rate of the cohort is 100% with 3 patients achieving a stringent complete response (CR), and 3 patients achieving a very good partial response (VGPR) after a median of 7 cycles of treatment. One patient discontinued therapy due to influenza A, the other five remain on therapy. Minimal residual disease assessments are being performed by EuroFlow for patients in VGPR or better due to concern for daratumumab interference. Pharmacodynamic changes in patients' tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Conclusion: The quadruplet regimen DIPd in patients with relapsed/refractory myeloma is a well-tolerated combination and has shown early safety in an initial safety run-in analysis. Enrollment continues in an expansion cohort to assess efficacy at multiple sites with the University of California Hematologic Malignancies Consortium. Figure Disclosures Costello: Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Clofarabine, Idarubicin, and Cytarabine (CIA) As Frontline Therapy for Patients <= 60 Years with Newly Diagnosed Acute Myeloid Leukemia (AML)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 43-43
Author(s):  
Aziz Nazha ◽  
Farhad Ravandi ◽  
Hagop M. Kantarjian ◽  
Xuelin Huang ◽  
Sangbum Choi ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Hepatic Function ◽  
Phase Iii ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Overall Response

Abstract Abstract 43 Background Clofarabine is a second generation nucleoside analogue with activity in adults with AML. A recent randomized phase III study in relapsed AML showed higher response rates and better event-free survival (EFS) with the combination of clofarabine and cytarabine (CA) compared to cytarabine alone. A phase I/II trial of CIA in patients with relapsed/refractory AML had shown an overall response rate (ORR) of 38% (21% CR; 11% CRp). To explore this combination further, we conducted a phase II study of CIA in patients </= 60 years with previously untreated AML. Patients and Methods Eligible were patients >18–60 years with newly diagnosed AML and adequate renal and hepatic function. Patients were excluded for ECOG PS > 2, cardiac ejection fraction < 45%, or active and uncontrolled infection. For the first 30 patients, induction therapy consisted of Clofarabine (C) 22.5 mg/m2 iv daily (days 1–5), Idarubicin (I) 6 mg/m2 daily (days 1–3), and Cytarabine (A) 0.75 g/m2 daily (days 1–5). From patients 31 onward, induction doses were amended to C 20 mg/m2 × 5, I 10 mg/m2 × 3, and A 1 g/m2 × 5. Patients who did not achieve CR following induction could receive one re-induction course. Patients in CR/CRp/CRi continued with up to 6 consolidation cycles (C 22.5 mg/m2 × 3, I 6 mg/m2 × 2, and A 0.75 g/m2 × 3, subsequently amended to C 15 mg/m2 × 3, I 8 mg/m2 × 2, and A 0.75 g/m2 × 3). Results From April 2010 until February 2012, 59 patients were enrolled (Table 1). Fifty-seven patients were evaluable. Forty-two patients (74%) achieved CR and 3 (5%) CRp for an overall response rate of 79%. Ten patients required a re-induction {4/10 (40%) patients achieved CR, 2/10 (20%) achieved CRp). All patients received a median of 2 cycles (1–8 cycles), 24 (42 %) patients proceeded with an allogeneic stem cell transplant in first remission. With a median follow up of 10.9 months (1.6 - 23.1), the median OS was not reached, the median EFS was 13.5 months, and the median relapse free survival was not reached. Most toxicities were < grade 2. Toxicities > grade 2 included nausea (47%), rash (39 %), diarrhea (25%), elevated transaminases (23%), and elevated bilirubin (12%). Myelosuppression was ubiquitous but prolonged myelosuppression > 42 days was infrequent. Four week mortality was 2%. The response rate and toxicity were similar in both dose schedules. In subgroup analysis, patients < 40 years had better OS (HR 0.12, 95%CI, 0.02–0.90, P = 0.04) and EFS (HR 0.12, 95%CI, 0.02–0.93, P = 0.04) compared to patients > 40 years old. Compared to a historical group of patients who were treated with IA combination (I 12 mg/m2 IV daily × 3 plus A 1.5 g/m2 IV daily × 4) and after controlling for age, cytogenetics and other important clinical factors, the OS and EFS were significantly higher (P = 0.005, 0.0001, respectively) for CIA treated patients. Furthermore, in multivariate analysis, CIA retained its superior impact on OS (HR 0.53, 95% CI, 0.29 to 0.97, P =0.03) and EFS (HR 0.40, 95% CI, 0.22 to 0.73, P =0.003) compared to IA. Conclusion CIA is an active combination for patients </= 60 years with newly diagnosed AML. Patients < 40 years had significantly better OS and EFS. Compared to IA alone, CIA achieved significantly longer OS and EFS. A randomized comparison with standard induction therapy will be needed to further assess the role of CIA in frontline AML therapy of younger patients. Disclosures: Off Label Use: Clofarabine in AML. Ravandi:Genzyme: Research Funding. Kantarjian:Genzyme: Research Funding. Faderl:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Long-Term Use of Ropeginterferon Alpha-2b in Polycythemia Vera: 5-Year Results from a Randomized Controlled Study and Its Extension

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-33
Author(s):  
Heinz Gisslinger ◽  
Christoph Klade ◽  
Pencho Georgiev ◽  
Dorota Krochmalczyk ◽  
Liana Gercheva-Kyuchukova ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Extension Study ◽  
Molecular Response ◽  
Thromboembolic Events ◽  
Advisory Committees ◽  
Allele Burden ◽  
Long Term Treatment

Introduction: Patients with polycythemia vera (PV) require life-long treatment to prevent thromboembolic events and minimize the risk of progression. Ropeginterferon alpha-2b (BESREMi®; hereafter ropeg) may ultimately modify the natural history of PV by selectively targeting the malignant clone. In the PROUD-PV/CONTINUATION-PV studies, long-term treatment with ropeg was compared with standard cytoreductive therapy regarding thromboembolic and other adverse events as well as evolution of hematologic and molecular parameters over five years. Methods: Patients aged ≥18 years and diagnosed with PV according to WHO 2008 criteria who were either cytoreduction-naïve or hydroxyurea (HU)-pre-treated for &lt; 3 years were enrolled. A total of 257 patients were randomized 1:1 (stratified by age &gt; 60 years, prior thromboembolic events, and HU pre-treatment) to receive ropeg or HU at individualized doses for 12 months in the initial study (PROUD-PV). In the extension study (CONTINUATION-PV), patients in the HU arm were permitted to switch to best available treatment. Efficacy assessments included hematologic parameters, phlebotomy need, JAK2V617F allele burden, and molecular response defined by modified ELN criteria. An interim analysis was conducted once all patients reached 5 years of treatment; efficacy data for patients enrolled in the extension study and all available safety data were analyzed. Results: Ninety-five patients in the ropeg arm and 76 in the control arm entered the extension study. Most patients in the control arm continued to receive HU (88% at month 60). At the time of this 5-year analysis, 70 patients in the ropeg arm and 57 in the control arm remained on study; discontinuation rates were balanced between the treatment arms (ropeg: 26.3%; control: 25.0%). Hematocrit &lt;45% was maintained without the need for phlebotomy in 81.8% patients in the ropeg arm in the fifth year of treatment, which was significantly higher than the rate of 63.2% observed in the control group (p=0.01). Very few patients experienced a major thromboembolic adverse event (4.2% [1.2%-patient year] of patients in the ropeg arm and 6.6% [1.2%-patient-year] of patients in the control arm during the entire treatment period). With respect to the causative JAK2V617F mutation, the median allele burden declined from 37.3% at baseline to 7.3% over 5 years of treatment in the ropeg arm, whereas in the control arm the median allele burden increased from 38.1% to 42.6% in the same period (p&lt;0.0001). The rate of molecular response at 5 years was also significantly higher among ropeg-treated patients than in the control arm (69.1% versus 21.6%; RR: 3.2 [95% CI: 2.1 to 4.9; p&lt;0.0001]). The sustained molecular response observed in ropeg-treated patients was accompanied by a low risk of disease progression; only 1 case of progression to myelofibrosis (0.20%-patient year) was reported during the entire study period and no leukemic transformation occurred. In contrast, 2 cases of progression to myelofibrosis and 2 cases of transformation to acute leukemia (1.0%-patient year in total) were reported in the control arm. A further analysis of combined hematologic and molecular parameters was performed, these being known to influence the risk of thrombosis and of progression in PV. At the 5 year visit, 58.5% of patients receiving ropeg had well-controlled hematocrit (&lt;45%) without requiring phlebotomy, as well as achieving a molecular response, compared to 17.3% on standard treatment (RR: 3.52 [2.13 to 5.81]; p&lt;0.0001). Regarding safety and tolerability, no new signals were detected in the fifth year. Treatment related adverse events were reported in 25.6% and 24.2% of patients in the ropeg and control arms, respectively, and one patient in each arm withdrew due to drug-related toxicity. Three patients (3.8%) in the ropeg arm reported grade ≥3 treatment-related adverse events in the fifth year; over the entire treatment period, the rate of grade ≥3 drug-related adverse events was the same in each study arm (16.5%). Conclusions: In a randomized controlled setting, ropeg treatment effectively controlled hematocrit and minimized the occurrence of thromboembolic events in patients with PV. Disease progression was very rare during long-term treatment with ropeg and this possible change in the disease natural history appears to be related to deep and durable molecular responses selectively achieved with ropeg. Disclosures Gisslinger: AOP Orphan Pharmaceuticals AG: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; PharmaEssentia: Honoraria; MyeloPro Diagnostics and Research: Honoraria; Janssen-Cilag: Honoraria; Roche: Honoraria; Celgene: Honoraria. Klade:AOP Orphan Pharmaceuticals AG: Current Employment. Illés:Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria; Takeda, Seattle Genetics: Research Funding; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy. Mayer:Celgene: Research Funding. Krejcy:AOP Orphan Pharmaceuticals AG: Current Employment. Empson:AOP Orphan Pharmaceuticals AG: Current Employment. Hasselbalch:Novartis: Research Funding; AOP Orphan Pharmaceuticals AG: Honoraria. Kralovics:AOP Orphan Pharmaceuticals AG: Honoraria; Qiagen: Honoraria; Novartis: Honoraria; MyeloPro Diagnostics and Research: Current equity holder in private company; PharmaEssentia: Honoraria. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Thromboembolic Risk Reduction and High Rate of Complete Molecular Response with Long-Term Use of Ropeginterferon Alpha-2b in Polycythemia Vera: Results from a Randomized Controlled Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 553-553 ◽  
Author(s):  
Jean-Jacques Kiladjian ◽  
Christoph Klade ◽  
Pencho Georgiev ◽  
Dorota Krochmalczyk ◽  
Liana Gercheva-Kyuchukova ◽  
...  
Keyword(s):  
Adverse Events ◽  
Research Funding ◽  
Term Treatment ◽  
Control Group ◽  
Molecular Response ◽  
Allele Burden ◽  
Long Term Treatment ◽  
Jak2v617f Allele Burden ◽  
Complete Molecular Response

Introduction: The key treatment goals for polycythemia vera (PV) are to prevent thromboembolic events and minimize the risk of progression, ultimately modifying the natural history of the disease by selectively targeting the malignant clone. In the PROUD-PV/CONTINUATION-PV study, long-term treatment with ropeginterferon alpha-2b (BESREMi®; hereafter ropeg) was compared with standard cytoreductive therapy regarding thromboembolic and other adverse events as well as hematological and molecular parameters over a four-year period. Methods: Cytoreduction-naïve or HU-pre-treated patients aged ≥18 years diagnosed with PV according to WHO 2008 criteria were eligible. A total of 257 patients were randomly allocated to ropeg or hydroxyurea at individualized doses for 12 months in the initial study phase (PROUD-PV). In the ongoing extension phase (CONTINUATION-PV), patients in the hydroxyurea arm were permitted to switch to best available treatment. Efficacy assessments included a longitudinal analysis of complete hematological response (CHR) and complete molecular response (CMR; JAK2V617F was determined using real-time PCR [ipsogen® JAK2 MutaQuant® kit; QIAGEN GmbH]), defined by modified ELN criteria. Discontinued patients were considered non-responders. A data snapshot was performed once all patients reached 48 months of treatment; all available safety data were included. Results: Ninety-five patients in the ropeg arm and 76 in the control arm entered the extension phase. At the time of analysis 139 patients remained on study: 74/95 in the ropeg arm and 65/76 in the control arm. Almost all patients in the control arm (&gt;97% at the last available assessment) continued on HU. The rate of patients in CHR was significantly higher in the ropeg arm than in the control arm in the 4th year (60.6% versus 43.4%; p=0.02), as seen after 2 and 3 years of treatment. In line with this effective control of hematologic parameters by ropeg, a very low rate of major thromboembolic adverse events was observed in the ropeg arm: 0.0%, 0.0% and 1.1% of patients in the 2nd, 3rd and 4th years, respectively. In the control arm, rates of major thromboembolic adverse events in the 2nd, 3rd and 4th year were 0.9%, 1.4% and 0.0%, respectively. The median JAK2V617F allele burden declined from 37.3% at baseline to 9.8% over 4 years in the ropeg arm, whereas in the control group, the median allele burden increased from 38.1% to 43.1% in the same period (p&lt;0.0001). The rate of molecular response (partial or complete) at 48 months was significantly higher among ropeg-treated patients than in the control arm (67.0% versus 25.7%; RR: 2.5 [95% CI: 1.7 to 3.7; p&lt;0.0001]). No patients achieved CMR in the control arm. In the ropeg arm, 13 patients had a JAK2V617F allele burden below the threshold of 1% at month 48, 11 of whom also had a CHR at this time point. An additional 34 patients in the ropeg arm achieved an allele burden &lt;10% at 48 months, suggesting that further patients may reach the &lt;1% threshold with ongoing treatment. In terms of safety, no new signals were detected in the 4th year. Rates of patients with treatment-related adverse events remained similar in the ropeg and control arms in the 4th year (ropeg: 28.7% of patients; control: 22.9%). Disease or treatment-related secondary malignancies reported in the entire study period comprised 2 cases of acute leukemia, 2 cases of basal cell carcinoma and 1 case of malignant melanoma, all in the control group; 1 case of disease-related transformation to myelofibrosis occurred in each treatment arm. Conclusions: Ropeg minimizes the occurrence of thromboembolic events in patients with PV over long-term treatment, without leukemogenic risk. In addition, we show for the first time in a randomized study that, in contrast to hydroxyurea, long-term ropeg treatment is capable of inducing deep molecular responses including CMR, which underscores its disease modifying potential. These results also suggest that selected patients could achieve operational cure (with both CHR and CMR) with ropeg, opening the way for treatment discontinuation. Disclosures Kiladjian: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy. Klade:AOP Orphan Pharmaceuticals AG: Employment. Illés:Takeda, Seattle: Research Funding; Janssen, Celgene, Novartis, Takeda, Roche, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Krejcy:AOP Orphan Pharmaceuticals AG: Employment. Hasselbalch:Novartis: Research Funding; AOP Orphan Pharmaceuticals: Other: Data monitoring board. Kralovics:Pharma Essentia: Honoraria; MyeloPro Diagnostics and Research: Equity Ownership; AOP Orphan Pharmaceuticals AG: Honoraria, Other: Advisory board; Qiagen: Honoraria; Novartis: Honoraria. Gisslinger:Celgene GmbH: Honoraria; Pharma Essentia: Other: Personal fees; Roche Austria GmbH: Consultancy; Janssen-Cilag: Honoraria; Novartis Pharma GmbH: Consultancy, Honoraria, Research Funding; AOP Orphan Pharmaceuticals: Consultancy, Honoraria, Research Funding; Myelopro GmbH: Consultancy.

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