ALBERT

Beschreibung: BACKGROUND: Polycythemia vera (PV) is characterized by increased red cell mass often associated with elevated leukocyte and platelet counts, splenomegaly and significant symptom burden. In the RESPONSE study, which only enrolled PV patients with splenomegaly, ruxolitinib (Rux) demonstrated superior improvements in hematocrit (HCT) control and reductions in spleen volume compared with best available therapy (BAT) in pts who were resistant to or intolerant of HU. Supportive data included clinically meaningful improvements in PV-related symptom burden and quality of life (QOL) measures. Here, we describe the baseline (BL) characteristics and symptom burden of PV pts resistant to or intolerant of HU enrolled in the RESPONSE-2 study, which unlike RESPONSE, enrolled PV patients with a nonpalpable spleen. METHODS: RESPONSE-2 is an open-label, randomized (1:1), multicenter, phase 3 study evaluating the efficacy and safety of Rux vs BAT in PV pts who are HU-resistant/-intolerant, require phlebotomy (PBT), and have no palpable spleen. Pts' BL symptom burden, BL QOL and BL pt-reported outcomes (PRO) were assessed by using 10-items modified Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), the Pruritus Symptom Impact Scale (PSIS), European QOL Questionnaire (EQ-5D-5L), and Work Productivity and Activity Impairment: Polycythemia Vera V2.0 (WPAI: PV). RESULTS: A total of 149 pts were enrolled. BL demographic data from both arms combined are summarized in the Table. Forty percent of the patients were resistant whereas 60% were intolerant of HU treatment. Other than HU, prior treatments included interferons (15.4%), alkylating agents (8.1%), alkyl sulfonates (2.7%), pyrimidine analogs (0.7%), and other antineoplastic agents (1.0%). Ninety-seven percent of pts had at least 1 PBT within 16 weeks (wks) prior to screening and 72% had ≥ 2 PBT within 24 wks prior to screening. Past medical histories included hypertension (49%), pruritus (23%) and fatigue (9%). BL demographics of pts in RESPONSE-2 were generally comparable with previous PV studies (Table). Despite using frequent phlebotomy and cytoreductive agents during the screening period prior to randomization, 55% and 52% of pts had WBC counts greater than 10 × 109/L and platelet counts greater than 400 × 109/L, respectively, suggesting inadequately controlled disease even while receiving therapy. Additionally, pts had significant symptom burden at BL as measured by the MPN-SAF with fatigue (3.6) and pruritus (3.4) (Table). As measured by EQ-5D-5L scale, 26% and 19% of pts reported moderate to extreme pain/discomfort and depression, respectively. In WPAI outcomes, 40 of 149 pts reported missing work due to PV accounting for 14.3% of their working time. SUMMARY/CONCLUSION: Demographic and BL data from the RESPONSE-2 study highlight the significant unmet medical need in this inadequately controlled HU-resistant/-intolerant PV population. As expected, pts in RESPONSE-2 reported lower scores for symptoms associated with splenomegaly (early satiety, 1.8 vs 2.0; abdominal discomfort, 1.7 vs 2.0) as compared with RESPONSE population. In comparison to PV pts with splenomegaly in the RESPONSE trial, pts without splenomegaly in the RESPONSE-2 trial have a distinct but comparable disease burden with marked fatigue and pruritus. Table 1. Baseline demographics and symptoms (n = 149) Age, median (range), years 66.0 (26.0, 87.0) Time since diagnosis of PV, median, months 80.7 Male, % 57.7 Female, % 42.3 ECOG performance status, % 0 1 72.5 26.8 Hematocrit (%), median,(n=149) 43.0 n (%) 〈 40 ≥ 40 to ≤ 45 〉 45 2 (1.3) 146 (98.0) 1 (0.7) WBC count (x 109/L), median (n=149) 10.6 n (%) ≤ 10 〉 10 and ≤ 15 〉 15 67 (45.0) 43 (28.9) 39 (26.2) PLT count (x 109/L), median (n=148) 420.0 n (%) 〈 100 ≥ 100 and 〈 400 ≥ 400 to 〈 600 ≥ 600 2 (1.3) 68 (45.6) 38 (25.5) 40 (26.8) JAK2 mutation, n (%) (n=149) Positive Negative Unknown 143 (96.0) 4 (2.7) 2 (1.3) MPN-SAF Symptom (n) Mean (SD) Total score (n=145) 2.0 (1.67) Fatigue (n=146) 3.6 (2.72) Early satiety (n=145) 1.8 (2.47) Abdominal discomfort (n=143) 1.7 (2.44) Inactivity (n=142) 2.1 (2.77) Concentration problem (n=146) 2.3 (2.75) Night sweats (n=145) 2.2 (3.07) Pruritus (n=145) 3.4 (3.37) Bone pain (n=144) 2.1 (2.89) Fever (n=144) 0.2 (0.92) Weight loss (n=142) 0.7 (1.72) Disclosures Passamonti: Novartis: Consultancy. Cavo:JANSSEN, CELGENE, AMGEN: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Bensasson:Novartis: Employment. Khan:Novartis: Employment. Mounedji:Novartis: Employment.

Beschreibung: Abstract 2844 Background: Myeloproliferative neoplasms, including PMF, PET-MF, and PPV-MF, are a group of clonal stem cell–derived diseases characterized by bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms. Ruxolitinib (rux), a potent oral JAK1 & 2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life in 2 phase 3 studies (COMFORT-I and -II). Due to unmet medical need, rux has been made available through an individual patient supply program (IPSP) outside the US. Methods: Patients (pts) with PMF, PPV-MF, or PET-MF requiring treatment (as determined by their physician) and classified as high-, intermediate (int)-2–, or int-1–risk with an enlarged spleen were evaluated for eligibility on an individual basis by the sponsor, irrespective of JAK2 mutation status. The starting dose of rux was determined on the basis of baseline platelet count (15 or 20 mg twice daily for pts with platelet counts of 100–200 × 109/L and 〉 200 × 109/L, respectively) and can be adjusted for efficacy and safety. Dose changes during treatment, adverse events (AEs), and serious AEs (SAEs) are registered throughout the program. Results: To date, 1339 requests have been received from 〉 800 physicians in 48 countries, including locations in Europe, Latin America, the Middle East, and Asia. The baseline characteristics are shown in the Table for pts whose requests for access were approved (n = 1240). Drug resupply requests are received every ≈ 3 months. Follow-up information, based on the first resupply request, was available for 381/639 (60%) of the pts who were enrolled in the program prior to February 2012; 303 (80%) remain on rux therapy, 37 (10%) have discontinued, 11 (3%) died, and 30 (8%) did not initiate therapy. Spleen response was available for 247 pts (decreased, n = 201; unchanged, n = 39; increased, n = 7). Changes in constitutional symptoms were available for 203 pts (decreased, n = 151; unchanged, n = 49; increased, n = 3). In pts enrolled in the IPSP undergoing rux treatment, most pts who had a decrease in spleen length also had a decrease in symptoms. Dose-modification information was available for 259 pts, of whom 44 had dose increases and 89 had dose decreases. Reasons for dose modifications included efficacy (n = 28), safety (n = 69), and other reasons (n = 36). Safety information was available for 266 pts; 75 reported significant AEs or SAEs as determined by investigators. Enrolled pt characteristics are generally similar to those expected in the overall MF pt population. Thus far, the proportion of pts enrolled in the IPSP with the JAK2 V617F mutation (73%) is higher than that for the general MF population (50%-60%). This may reflect a misconception that JAK inhibition is primarily effective in pts who have the JAK2 V617F mutation, when in fact rux has demonstrated similar efficacy in both pt types in the phase 1/2 251 study and the two phase 3 COMFORT trials. This may also be reflected in the higher proportion of PPV-MF pts in the IPSP than in the general MF population (28% vs 10%-15%), of whom 95% are JAK2 V617 F–positive. Conclusions: Considerable requests for access to rux have been received through the IPSP, highlighting the need for an effective treatment in pts with a range of IPSS risk-assessment scores. The demographics of the IPSP pts are similar to those expected in the overall MF population. Responses and safety patterns observed in the IPSP appear to be comparable to those from the COMFORT trials. Disclosures: Off Label Use: Jakafi™ (ruxolitinib) is indicated in the United States for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. In Canada, JAKAVI ® is indicated for the treatment of splenomegaly and/or its associated symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. This abstract reports on a clinical study conducted outside the US including patients of all risk categories. All patients have provided written informed consent. Zweegman:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Willenbacher:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Raymakers:Novartis: Consultancy. Cantoni:CSL Behring Switzerland: Research Funding; Robapharm/Pierre Fabre Oncology Switzerland: Research Funding; Janssen-Cilag Switzerland: Consultancy; Novartis Oncology Switzerland: Consultancy, Research Funding. Modi:Novartis Pharmaceuticals Corporation: Employment. Khan:Novartis: Employment. Perez:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Gisslinger:AOP Orphan Pharmaceuticals AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Lavie:Novartis: Membership on an entity's Board of Directors or advisory committees. Harrison:Sanofi Aventis: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Research Funding.

Beschreibung: Key PointsPanobinostat + bortezomib + dexamethasone recaptures responses in heavily pretreated, bortezomib-refractory multiple myeloma patients.

Beschreibung: Abstract 1852 Background: There are limited treatment options for patients (pts) with multiple myeloma (MM) whose disease is refractory to bortezomib (BTZ) and are relapsed and/or refractory, intolerant or ineligible to receive an immunomodulatory (IMiD) drug. These pts have a poor prognosis with a response rate for subsequent BTZ-containing regimens of 20% and median event-free survival of 5 months (Kumar S, et al. Leukemia. 2011). Panobinostat (PAN) is an oral pan-deacetylase inhibitor (pan-DACi) that has low nanomolar activity against all class I, II, and IV histone deacetylase enzymes, including those implicated as potential targets in MM. PAN synergizes with BTZ to inhibit both the aggresome and proteasome pathways in preclinical studies. Phase 1 results with PAN + BTZ demonstrated clinical responses in pts with BTZ-refractory disease. PANORAMA 2 expands upon these results and evaluates whether PAN can recapture responses in BTZ-refractory MM pts. Methods: Pts with relapsed and BTZ-refractory MM (≥2 prior lines of therapy including an IMiD and who had progressed on or within 60 days of the last BTZ-based therapy) were treated in this single-arm, phase 2 study with PAN + BTZ + dexamethasone (Dex) in 2 phases. Treatment phase 1 (TP1) consisted of 8 three-week cycles of oral PAN (20 mg) + intravenous BTZ (1.3 mg/m2) + oral Dex (20 mg). Pts demonstrating clinical benefit (≥stable disease [SD]) could proceed to treatment phase 2 (TP2), which consisted of 6-week cycles until disease progression. The primary endpoint was overall response rate (≥partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation (EBMT) 1998 criteria, in TP1. Secondary efficacy endpoints included minimal response (MR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Secondary safety endpoints included safety and tolerability. Results: Fifty-five pts with BTZ-refractory MM were enrolled (median age, 61 years [range, 41–88 years]). Pts were heavily pretreated with a median of 4 prior regimens (range, 2–11), and a median of 2 prior BTZ-containing regimens (range, 1–6). All pts (100%) were previously treated with BTZ, Dex, and at least 1 IMiD (lenalidomide [98%], thalidomide [69%]). The majority of pts received prior autologous stem cell transplant (64%). Forty-five pts (82%) received Dex with their last BTZ-containing regimen. In the most recent prior line of therapy, 27 pts (49%) had BTZ. As of the February 20, 2012, cutoff, all pts had completed TP1 or stopped treatment, and 7 of the 18 pts who entered TP2 were ongoing. The overall response rate was 35% (1 near complete response [nCR] and 18 PR or better, with 3 pts [5%] achieving a very good partial response [VGPR; Table]). An additional 10 pts achieved MR, for a clinical benefit rate of 53%. The median duration of exposure was 4.6 months (range, 〈 1–14.8 months). The median PFS and TTP were 4.9 months. The PFS rates for pts whose disease progressed on BTZ (n = 39) and within 60 days of BTZ (n = 16) were 4.2 and 7.6 months, respectively. In pts who achieved a response, the mean TTR was 1.7 months (range, 0.1–3.9), and the median DOR was 6.0 months. With a median follow-up time of 8.1 months, the median OS has not been reached. Common adverse events (AEs) of any grade regardless of study drug relationship included diarrhea (71%), fatigue (69%), thrombocytopenia (65%), nausea (60%), anemia (47%), dyspnea (44%), decreased appetite (42%), and peripheral edema (40%). Common grade 3/4 AEs regardless of study drug relationship included thrombocytopenia (64%), fatigue (20%), diarrhea (20%), anemia (15%), pneumonia (15%), and neutropenia (15%). Only 1 pt (2%) experienced grade 3 peripheral neuropathy. Conclusions: PAN, when combined with BTZ and Dex can recapture responses in heavily pretreated, BTZ- and Dex-refractory MM pts. The regimen was tolerable with manageable toxicities, with 33% of pts on therapy for 〉 8 cycles. The combination of PAN, BTZ and Dex is therefore an important potential therapeutic option for relapsed and refractory MM pts, including those with BTZ, Dex, and IMiD resistance. Disclosures: Richardson: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Alsina:Millenium: Consultancy, Research Funding. Weber:Novartis: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy. Gasparetto:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mukhopadhyay:Novartis: Employment. Ondovik:Novartis: Employment, Equity Ownership. Khan:Novartis: Employment. Paley:Novartis: Employment, Equity Ownership. Schlossman:Celgene: Membership on an entity's Board of Directors or advisory committees.

Beschreibung: Background Multiple myeloma (MM) remains an incurable disease, with a high unmet need for patients (pts) in the relapsed and refractory setting. The prognosis is especially worse for pts with MM refractory to both bortezomib (BTZ) and immunomodulatory drugs (IMiDs), who have a median progression-free survival (PFS) and median overall survival (OS) of 5 and 9 months, respectively (Kumar, Leukemia 2012). Panobinostat is an oral pan-deacetylase inhibitor (pan-DACi) that has low nanomolar activity against histone deacetylase enzymes that are implicated as potential targets in MM. In preclinical studies, panobinostat and BTZ synergistically inhibit both the aggresome and proteasome pathways. In an interim analysis of PANORAMA 2, panobinostat, in combination with BTZ and dexamethasone (Dex), demonstrated the ability to recapture responses in pts with relapsed and BTZ-refractory MM. At the time of the interim analysis, multiple pts were still receiving treatment, and median OS had not been reached. Here, we present an updated analysis of PANORAMA 2, including an evaluation of PFS and OS. Methods This multicenter, single-arm, phase 2 study enrolled pts with relapsed and BTZ-refractory MM (who had received ≥ 2 prior lines of therapy, including an IMiD, and had progressed on or within 60 days of the last BTZ-based therapy). Pts received oral panobinostat, intravenous BTZ, and oral Dex. The primary endpoint was overall response rate (defined as ≥ partial response [PR]) as defined by the modified European Group of Blood and Marrow Transplantation criteria. Secondary objectives included evaluation of minimal response (MR), time to response, duration of response, PFS, OS, and safety and tolerability of the combination. Results The median age of the 55 enrolled pts was 61 years (range, 41-88), and pts were heavily pretreated with a median of 4 prior regimens (range, 2-11) including a median of 2 prior BTZ-containing regimens (range, 1-6). All pts had received at least 1 IMiD, all were BTZ refractory, and nearly half (n = 27) had BTZ in their most recent prior line of therapy. Most pts (75%) were International Staging System stage 1 or 2, and 14 pts presented with high-risk cytogenetics (del[17p], t[4;14], or t[14;16]). All but 2 pts had discontinued from the study as of the December 4, 2012, data cutoff due to disease progression (n = 36), adverse events (n = 10), or withdrawal of consent (n = 5); 1 pt had died, and 1 pt started new therapy. One pt (2%) had a near complete response and 18 pts (33%) had a PR for an overall response rate of 35%, which met the study's primary objective of response rate 〉 10% (95% CI, 22-47; P 〈 .0001). An additional 10 pts (18%) had an MR, for a clinical benefit rate of 53% (95% CI, 39-66). The median exposure was 4.6 months (range, 〈 1-24.1). The median PFS was 5.4 months (95% CI, 3.5-6.7). The median OS was 17.5 months (95% CI, 10.8-25.2). In a post hoc analysis, the 19 pts who achieved ≥ PR had a median PFS of 7.6 months (95% CI, 5.8-9.7) and a median OS of 25.2 months (95% CI, 17.5-25.2), while the 36 pts with 〈 PR had a median PFS of 2.6 months (95% CI, 2.1-4.9) and a median OS of 9.9 months (95% CI, 5.4-17.4). Similarly, the 29 pts with ≥ MR had a median PFS of 6.9 months (95% CI, 4.9-8.6) and a median OS of 22.2 months (95% CI, 17.5-25.2), and the 26 pts with 〈 MR had a median PFS of 2.1 months (95% CI, 1.4-3.0) and a median OS of 7.9 months (95% CI, 4.1-12.2). No new safety signals were observed. Common grade 3/4 adverse events regardless of study drug relationship included thrombocytopenia (64%), diarrhea (20%), fatigue (20%), anemia (15%), neutropenia (15%), and pneumonia (15%). Peripheral neuropathy was observed in 27% of pts overall, with only 1 (2%) grade 3/4 event. Conclusions The combination of panobinostat, BTZ, and Dex in heavily pretreated relapsed and BTZ-refractory pts demonstrated a median PFS of 5.4 months and a median OS of 17.5 months, which relates favorably to historical controls and other active combinations in this setting (eg, pomalidomide/Dex and carfilzomib/Dex). As expected, pts who achieved ≥ PR or ≥ MR appeared to have a longer median PFS and OS than pts who did not, which is supportive of a clinical benefit for this combination in this vulnerable population with otherwise limited treatment options. The large, randomized, phase 3 study, PANORAMA 1, will further define the role of panobinostat combined with BTZ and Dex in pts with relapsed and relapsed/refractory MM. Disclosures: Richardson: Millennium: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Schlossman:Celgene: Consultancy; Millennium: Consultancy. Alsina:Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Weber:Novartis: Research Funding. Coutre:Novartis: Consultancy, Research Funding. Gasparetto:Millennium: Honoraria, Speakers Bureau. Mukhopadhyay:Novartis: Employment. Ondovik:Novartis: Employment, Equity Ownership. Khan:Novartis: Employment. Paley:Novartis: Employment, Stock options Other. Lonial:Sanofi: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Onyx: Consultancy.