A Phase 2a Study of the LSD1 Inhibitor Img-7289 (bomedemstat) for the Treatment of Myelofibrosis

Ruxolitinib (Jakafi®) is the one approved therapy for myelofibrosis (MF) based on reduction of splenomegaly and symptoms but JAK inhibition has not proven to significantly modify disease progression. There remains the need for novel therapies with distinct modes of action that can improve the patient experience of MF and impact progression. Lysine-specific demethylase, LSD1, is an epigenetic enzyme critical for self-renewal of malignant myeloid cells and differentiation of myeloid progenitors. LSD1 bound to GFI1b permits maturation of progenitors to megakaryocytes and enables their normal function. IMG-7289 (bomedemstat) is an orally available LSD1 inhibitor. In mouse models of myeloproliferative neoplasms (MPN), IMG-7289 reduced elevated peripheral cell counts, spleen size, inflammatory cytokines, mutant allele frequencies, and marrow fibrosis (Jutzi et al. 2018) supporting its clinical development. IMG-7289-CTP-102 is an ongoing, multi-center, open-label study that recently transitioned from a Phase 1/2a dose-range finding study to a Phase 2b study of IMG-7289 administered orally once-daily in adult patients with intermediate-2 or high-risk MF resistant to or intolerant of ruxolitinib. The key objectives are safety, PD, changes in spleen volume (MRI/CT) and total symptoms scores (TSS) using the MPN-SAF instrument. Inclusion criteria included a platelet count ≥100K/μL. Bone marrow (BM) biopsies and imaging studies (both centrally-read) were conducted at baseline and during washout (post-Day 84). The MPN-SAF was self-administered weekly. Phase 1/2a patients were treated for 84 days followed by a washout of up to 28 days. Patients demonstrating clinical benefit could resume treatment for additional 12 week cycles. Dosing was individually tailored using platelet count as a biomarker of effective thrombopoiesis. Patients were started at a presumed sub-therapeutic dose of 0.25 mg/kg/d and up-titrated weekly until the platelet count rested between 50 and 100K/μL. This preliminary analysis includes 20 patients; 18 enrolled in the Phase 1/2a study, 2 in the Phase 2b portion. 50% had PMF, 35% Post-ET-MF, 15% Post-PV-MF. The median age was 65 (48-89) with 70% males. The median baseline platelet count was 197 k/μL (102-1309k/μL). 12 patients (56%) were transfusion-dependent at baseline. Sixty percent were IPSS-classified as high risk, the remainder, intermediate risk-2. 71% had more than 1 mutation of the 261 AML/MPN genes sequenced of which 63% were high molecular risk (ASXL1, U2AF1, SRSF2) mutations; 31% had abnormal karyotypes. Sixteen patients completed the first 12 weeks; 4 patients withdrew, one due to fatigue (Day 33), one for progressive disease (Day 39), one due to physician decision (Day 76), one for an unrelated SAE of cellulitis (Day 83). All patients were up-titrated from the starting dose 0.25 mg/kg to an average daily dose of 0.89 mg/kg ± 0.20 mg/kg, the dose needed to achieve the target platelet count range; 17 achieved the target platelet range in a mean time of 45 days. Of patients evaluable for response after cycle 1 in Phase1/2a (N=14), 50% had a reduction in spleen volume from baseline (median SVR: -14%; -2% to -30%). Further, 79% (N=11) recorded a reduction in TSS (mean change -28%; -13% to -69%); for 21% of patients (N=3), the change was >-50%. Improved BM fibrosis scores at Day 84 were observed in 2/13 patients. Two patients had improvement in transfusion requirements. Plasma IL-8 levels were significantly elevated in 6/14 patients at baseline and dropped in a dose-dependent manner over 21 days in 5/6 patients. The mean duration of treatment is 166 days (14-539) at the census point in this ongoing study. Nineteen patients (95%) reported 358 AEs of which 22 were SAEs. Of the SAEs, 2 were deemed by investigators as possibly related: painful splenomegaly and heart failure. There have been no safety signals, DLTs, progression to AML, or deaths. This is the first clinical study of an LSD1 inhibitor in patients with MPNs. Once-daily IMG-7289 was well-tolerated in a heterogeneous population of patients with advanced MF and limited therapeutic options. Despite under-dosing and slow dose escalation, IMG-7289 improved symptom burdens in most patients and modestly reduced spleen volumes in a subset of patients. The Phase 2b 24-week expansion study with more aggressive dosing aimed at preserving safety and enhancing efficacy is open for enrollment in the US, UK and EU. Figure Disclosures Pettit: Samus Therapeutics: Research Funding. Gerds:Imago Biosciences: Research Funding; Celgene Corporation: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Roche: Research Funding; Sierra Oncology: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy. Yacoub:Hylapharm: Equity Ownership; Agios: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Equity Ownership; Cara: Equity Ownership; Dynavax: Equity Ownership. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bradley:AbbVie: Other: Advisory Board. Shortt:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astex: Research Funding; Amgen: Research Funding; Gilead: Speakers Bureau; Takeda: Speakers Bureau. Natsoulis:Imago BioSciences: Consultancy, Equity Ownership. Jones:Imago BioSciences: Employment, Equity Ownership. Talpaz:Samus Therapeutics: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Constellation: Research Funding; Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding. Peppe:Imago BioSciences: Employment, Equity Ownership. Ross:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rienhoff:Imago Biosciences: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

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A Pooled Overall Survival (OS) Analysis of 5-Year Data from the COMFORT-I and COMFORT-II Trials of Ruxolitinib for the Treatment of Myelofibrosis (MF)

Blood ◽

10.1182/blood.v128.22.3110.3110 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3110-3110 ◽

Cited By ~ 6

Author(s):

Srdan Verstovsek ◽

Vikas Gupta ◽

Jason R. Gotlib ◽

Ruben A. Mesa ◽

Alessandro M. Vannucchi ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Spleen Volume ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Safety And Efficacy ◽

Equity Ownership

Abstract Background:The Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib has been evaluated for patients with MF in the phase 3 COMFORT studies. In both trials, ruxolitinib prolonged OS, reduced splenomegaly, and improved MF-related symptoms and quality of life compared with controls. Here, we report the results of an exploratory pooled analysis of OS in the COMFORT studies at 5 years of follow-up. Methods: The double-blind COMFORT-I trial and the open-label COMFORT-II trial were randomized phase 3 studies that evaluated the safety and efficacy of ruxolitinib in patients with intermediate-2 (int-2) or high-risk primary MF (PMF), post-polycythemia vera MF (PPV-MF), or post-essential thrombocythemia MF (PET-MF). The comparator was placebo in COMFORT-I and best available therapy (BAT) in COMFORT-II. The ruxolitinib starting dose was 15 or 20 mg twice daily based on baseline platelet counts (100-200 and >200 × 109/L, respectively); dose modifications were permitted for safety and efficacy. Patients were allowed to cross over to ruxolitinib from the control arm for progressive splenomegaly, defined as a ≥25% increase in spleen volume from baseline (COMFORT-I) or study nadir (COMFORT-II), or select protocol-defined progression events; crossover was mandatory following treatment unblinding in COMFORT-I. OS was a secondary endpoint in both studies and was evaluated in an intent-to-treat (ITT) analysis using a Cox proportional hazard model that estimated the treatment effect stratified by clinical trial and International Prognostic Scoring System (IPSS) risk. The crossover-corrected treatment effect was estimated using a rank-preserving structural failure time (RPSFT) method. Results: Overall, 528 patients were randomized: 301 to ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 to placebo (n=154) or BAT (n=73). All ongoing patients in the control arms crossed over to ruxolitinib by the 3-year follow-up. Patient populations were similar between the two trials and their details were previously published. In the combined ruxolitinib group, 162 patients (53.8%) had high-risk MF and 139 (46.2%) had int-2 risk MF based on IPSS criteria. At the 5-year ITT analysis, 128 patients (42.5%) died in the ruxolitinib group compared with 117 (51.5%) in the control group. The risk of death was reduced by 30% with ruxolitinib compared with control (median OS: ruxolitinib, 63.5 mo; control, 45.9 mo; HR, 0.70; 95% CI, 0.54-0.91; P=0.0065; Figure A). After correcting for crossover using RPSFT, OS advantage was more pronounced for patients originally randomized to ruxolitinib (median OS: ruxolitinib, 63.5 mo; control, 27 mo; HR, 0.35; 95% CI, 0.23-0.59; Figure B). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged survival compared with control (median OS: ruxolitinib, 63.5 mo; control, 28.3 mo; HR, 0.53; 95% CI, 0.36−0.78; P=0.0013; Figure C). Among all patients treated with ruxolitinib, those with lower-risk disease had longer survival compared with those with high-risk disease (median OS: int-2, not reached [estimated, 102 mo]; high-risk, 50 mo; HR, 2.86; 95% CI, 1.95-4.20; P<0.0001; Figure D). In a subgroup analysis, OS favored ruxolitinib compared with placebo for patients with int-2 or high-risk MF (data not shown). At 5 years, median OS appeared to favor patients with int-2 (n=58) or high-risk (n=89) PMF who were originally randomized to ruxolitinib compared with historical (Cervantes et al; J Clin Oncol 30:2981-2987) controls (int-2 PMF, not reached [estimated, 70 mo] vs 48 mo; high-risk PMF, 34 vs 27 mo); OS was longer among patients with int-2 vs high-risk PMF (P=0.0003). Subgroup analyses showed that ruxolitinib provided an OS advantage regardless of age (>65 or ≤65 y), sex, disease type (PMF, PPV-MF, PET-MF), risk status (int-2 or high), JAK2V617F mutation status, baseline spleen volume (>10 or ≤10 cm), anemia, white blood cell count (>25 or ≤25 × 109L), or platelet count (>200 or ≤200 × 109/L). Conclusion: Long-term treatment with ruxolitinib up to 5 years prolonged survival in patients with MF compared with BAT or placebo. Corrections for patients who crossed over to ruxolitinib suggested that the separation between ruxolitinib and control OS curves was primarily caused by a delay in ruxolitinib treatment. The results suggest that earlier treatment with ruxolitinib may provide a greater survival advantage for patients with MF. Disclosures Gupta: Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mesa:Incyte: Research Funding; Ariad: Consultancy; Novartis: Consultancy; Celgene: Research Funding; CTI: Research Funding; Promedior: Research Funding; Galena: Consultancy; Gilead: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kiladjian:AOP Orphan: Research Funding; Novartis: Research Funding. Cervantes:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sun:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Dong:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Gopalakrishna:Novartis Pharma AG: Employment, Equity Ownership. Harrison:Incyte Corporation: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau.

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Clinical Benefit of Ruxolitinib Treatment after Crossover from Best Available Therapy in Patients with Polycythemia Vera: Analysis of the RESPONSE Trial

Blood ◽

10.1182/blood.v124.21.3181.3181 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3181-3181 ◽

Cited By ~ 1

Author(s):

Jean-Jacques Kiladjian ◽

Alessandro M. Vannucchi ◽

Martin Griesshammer ◽

Tamas Masszi ◽

Simon Durrant ◽

...

Keyword(s):

High Risk ◽

Polycythemia Vera ◽

Board Of Directors ◽

Research Funding ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

To Receive ◽

Response Trial

Abstract Background : Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by erythrocytosis, and in many cases leukocytosis and thrombocytosis. PV is driven by activating mutations in the JAK/STAT pathway, primarily JAK2V617F. For high-risk patients, a commonly used first-line therapy is hydroxyurea (HU); however, a subgroup of patients become intolerant of or resistant to HU. The phase 3 RESPONSE trial compared ruxolitinib (RUX) and best available therapy (BAT) in patients with PV who were intolerant of or resistant to HU (modified European LeukemiaNet criteria). Patients randomized in the BAT arm were permitted to cross over to receive RUX from Week 32 of the study. The results of the primary analysis comparing RUX to BAT prior to crossover have been reported, in which RUX was superior to BAT in achieving hematocrit control, reductions in spleen volume, and improvements in PV-related symptoms. This current analysis was conducted to evaluate the efficacy of RUX treatment in patients who crossed over from BAT relative to their original BAT treatment and relative to those originally randomized to RUX. Methods : Enrollment criteria included PV diagnosis, age ≥18 years, resistance to or intolerance of HU, splenomegaly, and phlebotomy requirement to control hematocrit. Patients were randomized 1:1 to receive open-label RUX 10 mg BID or BAT administered based on investigator judgment. BAT may have included HU, interferon/pegylated interferon, pipobroman, anagrelide, immunomodulators (eg, lenalidomide or thalidomide), or no medication. The protocol allowed for dose modifications (RUX, 5-mg BID increments [25 mg BID max]; BAT was adjusted per investigator judgment). Patients in the BAT group could cross over to RUX from Week 32 if they had not met the primary endpoint, or after Week 32 due to protocol-defined disease progression. The primary study endpoint was a composite of hematocrit control and a ≥35% reduction in spleen size at Week 32. Hematocrit was assessed at screening, every 2 weeks from Day 1 to Week 12, followed by every 4 weeks until Week 32, and 2, 4, 6, 8, 16, 24, and 32 weeks following crossover. Spleen volume was assessed by magnetic resonance imaging at screening and study Weeks 16, 32, 48, 64, 80 and every 32 weeks thereafter. The number of phlebotomy procedures was evaluated over time in each group. Results : A total of 110 patients were randomized to RUX and 112 to BAT; study discontinuation by Week 32 (before crossover was permitted) was 11% in both groups. However, most patients in the BAT arm crossed over to receive RUX treatment immediately after the Week 32 visit (84% between Weeks 32 and 48); only 3% of patients remained in the BAT arm compared with 85% in the RUX arm at the time of the data analysis (median 81-week follow-up). With up to 32 weeks on BAT therapy, 25% of patients in this group did not require a phlebotomy; in contrast, with up to 32 weeks on RUX, 79% of patients after crossover and 74% of patients initially randomized to RUX did not require phlebotomy. The number of phlebotomy procedures adjusted for 100 patient-years during BAT therapy was 196.8 vs 38.5 after crossover to RUX and 34.1 on randomized RUX treatment. Reduction in spleen volume from baseline at any visit occurred in 49% of patients receiving BAT, vs 73% of patients after crossover to RUX and 88% of patients initially randomized to RUX. The proportion of patients achieving at least a 35% reduction in spleen volume (best percentage change) was 1.8% during BAT treatment vs 38.5% after crossover to RUX and 60.0% during randomized RUX treatment. Conclusion : Treatment with RUX after crossover from BAT resulted in improved clinical outcomes compared with original BAT treatment. These findings support the primary RESPONSE results and further validate the efficacy of RUX in this patient population. Disclosures Kiladjian: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Masszi:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Durrant:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals : Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Verstovsek:Incyte Corporation: Research Funding.

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A Phase 1 Study of TTI-621, a Novel Immune Checkpoint Inhibitor Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Blood ◽

10.1182/blood.v128.22.1812.1812 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1812-1812 ◽

Cited By ~ 19

Author(s):

Stephen Ansell ◽

Robert W Chen ◽

Ian W. Flinn ◽

Michael B. Maris ◽

Owen A. O'Connor ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Receptor Occupancy ◽

Hematologic Malignancies ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Dose Dependent

Abstract Introduction The phagocytic activity of macrophages is regulated by activating ("eat") and inhibitory ("do not eat") signals. Under normal physiologic conditions, the ubiquitously expressed cell surface antigen CD47 suppresses phagocytosis by binding to signal regulatory protein alpha (SIRPα) on macrophages. It is hypothesized that overexpression of CD47 by cancer cells enables immune evasion. Blockade of CD47 results in phagocytosis of cells bearing "eat" signals and primes effective anti-tumor T cell responses. TTI-621(SIRPαFc)is a soluble recombinant fusion proteinconsisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1designed to both: 1) block the CD47 "do not eat" signal, and 2) engagemacrophage Fcγ receptors with IgG1 Fc to enhance phagocytosis and antitumor activity.In vitro, TTI-621 binds to normal human cells, platelets, a wide range of human primary tumor cells and cell lines, but only minimally to human erythrocytes. TTI-621 selectively promotes macrophage-mediated phagocytosis of hematologic and solid tumors over that observed with normal monocytes, and exhibits antitumor activity in xenograft mouse models. Methods A first-in-human, phase 1, open label, multicenter study (NCT02663518) is ongoing to evaluate the safety and tolerability, and to identify the maximum tolerated dose of TTI-621 in patients (pts) with relapsed/refractory lymphomas using a 3+3 dose-escalation design. Once the optimal dose has been determined in the dose-escalation phase, multiple expansion cohorts will be enrolled comprising pts with various relapsed/refractory hematologic malignancies. Assessments include peripheral receptor occupancy, serum cytokine levels, pharmacokinetics, and immunogenicity. Eligible pts are adults with advanced, measurable, hematologic malignancies, who have progressed on standard anticancer therapy or for whom no other approved therapy exists. Pts are required to have baseline hemoglobin ≥10 g/dL, platelets ≥75 x 109/L, and be transfusion- and growth factor-independent. Pts with cutaneous T-cell lymphoma, high-grade lymphoma, and acute promyelocytic leukemia are excluded. TTI-621 is administered IV once weekly at protocol-defined doses. Treatment may continue until disease progression or unacceptable toxicity. Results Eleven pts (6M/5F, age 21-72 years) have been enrolled as of the data cut-off date of 28 July 2016. Lymphoma diagnoses included Hodgkin (N=4), diffuse large B cell (DLBCL) (N=4), follicular (N=2), and mantle cell (N=1). Treatment has been reasonably well tolerated by pts in the 0.05 mg/kg (N=3), 0.1 mg/kg (N=3), and 0.3 mg/kg (N=5) dose cohorts. The majority of pts experienced mild to moderate infusion-related events. Hemoglobin levels have remained stable or improved with treatment. Transient, dose-dependent decreases in platelets and leukocytes occurred in the hours following infusion in all pts without clinical sequelae. The 0.3 mg/kg dose was associated with reversible, dose-limiting toxicity (DLT) in 2 of 5 pts: one pt with G3 elevated ALT/AST and G4 platelet count, and a second pt with G4 platelet count who was transfused. Dosing at 0.2 mg/kg is now being explored. Aside from the DLTs and 2 non-DLT G3 platelet count (all in 0.3 mg/kg cohort), treatment-related adverse events have been ≤G2. CD47 receptor occupancy increased with each cohort, peaking at the end of infusion and remaining detectable 24 hrs after the 1st infusion in Cohort 3. Macrophage-associated cytokines, including MIP-1α and MIP-1β, increased during the 4 hrs after infusion. Six pts continue to receive weekly infusions of TTI-621; one pt with DLBCL and another with FL have experienced progression-free intervals of 161 and 70 days, respectively. Conclusions TTI-621 has been reasonably well tolerated. Pts retained stable hemoglobin levels consistent with minimal drug binding to erythrocytes. Manageable, dose-dependent thrombocytopenia was likely due to increased phagocytic clearance of platelets. TTI-621 binds to CD47+ cells in a dose-dependent manner, potently yielding increases in cytokines associated with augmented phagocytic activity. Enrollment continues at the 0.2 mg/kg dose level; updated data will be provided at the meeting. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Chen:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. O'Connor:Bristol Myers Squibb: Research Funding; Spectrum: Research Funding; TG Therapeutics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; TG Therapeutics: Research Funding. Johnson:Trillium Therapeutics: Employment. Irwin:Hoffmann La Roche: Employment, Equity Ownership; Trillium Therapeutics: Employment, Equity Ownership. Petrova:Trillium Therapeutics Inc: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Uger:Trillium Therapeutics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Sievers:Seattle Genetics: Employment, Equity Ownership; Trillium Therapeutics: Employment, Equity Ownership; MEI Pharma: Consultancy.

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Efficacy, Hematologic Effects, and Dose of Ruxolitinib in Myelofibrosis Patients with Low Starting Platelet Counts (50–100 × 109/L): A Comparison to Patients with Normal or High Starting Platelet Counts

Blood ◽

10.1182/blood.v120.21.176.176 ◽

2012 ◽

Vol 120 (21) ◽

pp. 176-176 ◽

Cited By ~ 4

Author(s):

Moshe Talpaz ◽

Ronald Paquette ◽

Lawrence Afrin ◽

Solomon Hamburg ◽

Katarzyna Jamieson ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Platelet Counts ◽

Equity Ownership ◽

Eortc Qlq

Abstract Abstract 176 Background: Ruxolitinib (RUX) has demonstrated clinical benefit for patients with myelofibrosis (MF) with or without the JAK2V617F mutation at starting doses of 15 or 20 mg PO BID by alleviating symptoms, improving quality of life measures, reducing spleen volume and exhibiting an apparent increase in overall survival in the phase III placebo (PBO)-controlled COMFORT-I study. Reversible declines in platelet count and hemoglobin (Hgb) can occur with ruxolitinib but are rarely treatment-limiting. Patients with MF who have low platelet counts represent an important subset of MF patients; given the potential risk of bleeding complications, a dosing strategy for such patients is needed. We assessed an alternative strategy using lower starting doses of ruxolitinib with subsequent dose escalation in patients with MF who have platelet counts of 50–100 × 109/L (Study INCB018424-258; NCT01348490). Methods: RUX dosing started at 5 mg BID. With adequate platelet count, doses could increase by 5 mg once daily every 4 weeks to 10 mg BID. Further increases required evidence of suboptimal efficacy. Assessments include measurement of MF symptoms (MF Symptom Assessment Form v2.0 Total Symptom Score [TSS]); Patient Global Impression of Change (PGIC); EORTC QLQ-C30, measurement of spleen volume by MRI, and safety/tolerability. Results: A total of 50 patients have enrolled, with data available for 41 patients. Nineteen have completed 24 weeks of treatment; >70% of these patients attained a final dose of ≥10 mg BID of RUX. Treatment was generally well tolerated in this study population with no withdrawals for thrombocytopenia or bleeding events. Based on analysis of adverse events, no new safety signals were observed in this population of MF patients with low platelet counts. Data for efficacy parameters, including spleen volume reduction, TSS reduction, and improvement in EORTC-QLQ-C30 subscales and PGIC were consistent with RUX treatment in the COMFORT-I study, and demonstrated clinically meaningful efficacy compared with the COMFORT-I PBO arm (Table). Of 19 patients with platelet count data through Week 24, 5 showed increased platelet count over the duration of the study (range of increase: 20 to 95 x109/L); all 5 patients had optimized dosing to ≥10 mg BID. Compared with the 14 patients showing smaller increases or modest decreases in platelet count, these 5 patients were younger (mean age: 63 years vs. 71 years), had been diagnosed with MF more recently (2.2 years vs. 5.2 years) and had lower DIPSS scores (60% Intermediate-1; 20% Intermediate-2; 20% High vs. 0% Intermediate-1; 79% Intermediate-2; 21% High). Four patients (9.8%) reported adverse events of bleeding (excluding events related to bruising) of any grade (all events were Grade 1 except one Grade 2 hematochezia), consistent with previously reported hemorrhage frequency in the COMFORT-I study (16.8%, RUX; 12.6%, PBO). Conclusions: These preliminary findings suggest that a dosing strategy of a low starting dose of RUX with escalation to 10 mg BID may be appropriate in MF patients who have low platelet counts. Most patients were able to titrate to a dose of ≥10 mg BID of RUX, a dose showing efficacy for both spleen volume and patient-reported outcomes generally consistent with previously reported data from Phase III trials. An increase in platelet counts was observed in approximately one-fourth of patients who completed 24 weeks of RUX treatment. Escalation to, and subsequent maintenance of, a 10 mg BID dose of RUX also preserves both Hgb and platelet count which may be beneficial for MF patients with anemia or thrombocytopenia. Disclosures: Talpaz: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Paquette:Incyte: Consultancy. Jamieson:Sunesis: Membership on an entity's Board of Directors or advisory committees; Blue Distinction Centers for Transplants BlueCross BlueShield Association: Consultancy. Lyons:Amgen: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Novartis: Research Funding. Tiu:Incyte: Honoraria, Speakers Bureau. Winton:Incyte Corporation: Consultancy, Honoraria. Odenike:Incyte: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis:Membership on an entity's Board of Directors or advisory committees. Peng:Incyte: Employment, Equity Ownership. Sandor:Incyte: Employment, Equity Ownership. O'Neill:Incyte: Employment, Equity Ownership. Erickson-Viitanen:Incyte: Employment, Equity Ownership. Leopold:Incyte: Employment, Equity Ownership. Levy:Incyte: Employment, Equity Ownership. Kantarjian:Incyte Corporation: grant support Other. Verstovsek:Incyte Corporation: Research Funding.

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Effect of the Cytochrome P450 3A4 Inducers, Rifampicin and Dexamethasone, on the Pharmacokinetic, Pharmacodynamic and Safety Profile of Bortezomib In Patients with Multiple Myeloma (MM) and Non-Hodgkin's Lymphoma (NHL)

Blood ◽

10.1182/blood.v116.21.3983.3983 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3983-3983

Author(s):

Andrzej Hellmann ◽

Simon A. Rule ◽

Jan Walewski ◽

Ofer Shpilberg ◽

Huaibao Feng ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Proteasome Inhibition ◽

Employment Equity ◽

Advisory Committees ◽

Time Curve ◽

Once Daily ◽

Cyp3a4 Inducer ◽

Equity Ownership ◽

The Mean

Abstract Abstract 3983 Background: Bortezomib is primarily metabolized by cytochrome P450 (CYP) 3A4 and 2C19 enzymes. Effects of co-administration of rifampicin (a potent CYP3A4 inducer) and dexamethasone (weak CYP3A4 inducer) on the pharmacokinetic (PK), pharmacodynamic (PD) and safety profiles of bortezomib were evaluated. Methods: Patients with relapsed or refractory multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) were enrolled in this open-label, 2-stage, parallel-group study. In stage 1, patients were randomized (1:1) to receive 3 cycles of bortezomib (1.3 mg/m2) on d 1, 4, 8, and 11 q3wk either alone or in combination with rifampicin 600 mg once-daily on d 4 to 10 of cycle 3 only. Stage 2 patients received bortezomib at same dose and schedule in combination with dexamethasone 40 mg once-daily on d 1 to 4 and d 9 to 12 of cycle 3 only. Patients could continue with bortezomib monotherapy for up to 10 cycles in case of clinical benefit. For PK/PD, blood samples were collected before and through 72 hours following bortezomib administration on d 11 of cycles 2 and 3. PK was the primary endpoint, secondary endpoints included PD (proteasome inhibition) and safety. Results: 61 patients were enrolled (39 MM, 22 NHL) in the study. 13 were treated with bortezomib + rifampicin, 18 with bortezomib + dexamethasone, and 30 with bortezomib only. Co-administration of rifampicin reduced the mean bortezomib maximum plasma concentration (Cmax) by approximately 23% (118 vs 93 ng/mL) and the mean area under plasma concentration-time curve from 0 to 72 hours (AUC72) by approximately 45% (223 vs 123 ng.h/mL). Co-administration of dexamethasone had no effect on mean AUC72 (179 vs 170 ng.h/mL). The mean bortezomib Cmax was 20% lower after co-administration of dexamethasone (140 vs 119 ng/mL); however this difference in Cmax was within the observed variability in Cmax during cycle 2 (CV=38%) and cycle 3 (CV=45%). Mean (SD) maximum percent proteasome inhibition (Emax) and area under percent proteasome inhibition-time curve from 0 to 72 hours (AUE72h) were comparable for bortezomib alone and in combination with rifampicin (Emax: 61.9 [4.56] vs. 62.3 [3.81] and AUE72h: 836 [323] vs. 777 [358]). Co-administration of dexamethasone did not affect the Emax (66.7 [4.27] vs. 61.8 [6.69]) or AUE72h (1329 [638] vs. 1157 [381]). Safety profiles were consistent with prior bortezomib experience in this population. Drug-related serious adverse events and treatment discontinuations were reported in 7/30 (23%) and 8/30 (27%) in bortezomib-only, in 3/13 (23%) and 3/13 (23%) in bortezomib + rifampicin, and 3/18 (17%) and 5/18 (28%) in bortezomib + dexamethasone subgroups. Investigator-assessed responses (CR+PR) were observed in 13/17 MM and 6/13 NHL patients in bortezomib-only, in 6/9 MM and 3/4 NHL patients in bortezomib + rifampicin, and in 10/13 MM and 2/5 NHL patients in bortezomib + dexamethasone subgroups. Conclusions: Co-administration of dexamethasone did not affect the PK or PD profiles of bortezomib. Co-administration of rifampicin reduced bortezomib exposure (AUC) by approximately 45%. Patients receiving bortezomib concomitantly with strong CYP3A4 inducers, such as rifampicin, should be monitored for reduction in clinical effect, while concomitant administration of weak CYP3A4 inducers, such as dexamethasone, is not expected to affect the bortezomib pharmacologic profile. Disclosures: Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Rule:Johnson & Johson: Consultancy, Speakers Bureau; Roche: Consultancy. Walewski:Johnson & Johnson: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Investigators fee. Shpilberg:Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feng:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Patel:Johnson & Johnson: Employment, Equity Ownership. Skee:Johnson & Johnson: Employment. Girgis:Johnson & Johnson: Employment. Louw:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Key Oncologics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Final Results from an International, Multi-Center, Single-Arm Study Evaluating the Safety and Efficacy of Romiplostim in Adults with Primary Immune Thrombocytopenia (ITP),

Blood ◽

10.1182/blood.v118.21.3279.3279 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3279-3279 ◽

Cited By ~ 6

Author(s):

Ann Janssens ◽

Michael D. Tarantino ◽

Robert Bird ◽

Maria Gabriella Mazzucconi ◽

Ralph Vincent V. Boccia ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Platelet Response ◽

Employment Equity ◽

Advisory Committees ◽

Platelet Production ◽

Platelet Counts ◽

Equity Ownership

Abstract Abstract 3279 Background: ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production. Romiplostim stimulates platelet production via the TPO-receptor, and is recommended for second- and third-line treatment of chronic ITP in adults. We report final data from a large prospective study of romiplostim in adults with ITP of varying duration and severity. Methods: Eligibility criteria were broad: patients ≥18 years of age, who had received prior ITP therapies (final protocol amendment: ≥1, previous amendments: ≥3), with low platelet counts (final amendment: ≤ 30 × 109/L, previous amendments: ≤ 10, ≤ 20 × 109/L) or experiencing uncontrolled bleeding. The only excluded comorbidities were: hematological malignancy, myeloproliferative neoplasms, MDS and bone marrow stem cell disorder. Romiplostim was initiated at 1 (final amendment) or 3 (previous amendments) μg/kg/week, with dose adjustments allowed to maintain platelet counts ≥50 × 109/L. Patients could continue on study until they had access to commercially available romiplostim. Rescue medications were allowed at any time; concurrent ITP therapies could be reduced when platelet counts were > 50 × 109/L. Primary endpoint was incidence of adverse events (AEs) and antibody formation. Secondary endpoint was platelet response, defined as either (1) doubling of baseline count and ≥ 50 × 109/L or (2) ≥20 × 109/L increase from baseline. Results: A total of 407 patients received romiplostim, 60% of whom were female. Median (Q1, Q3) time since ITP diagnosis was 4.25 (1.20, 11.40) years (maximum 57.1 years), with 51% of patients splenectomised and 39% receiving baseline concurrent ITP therapies. Seventy-one percent of patients completed the study, with requirement for alternative therapy and withdrawn consent the most common reasons for discontinuation (5% each). Median (Q1, Q3) on-study treatment duration was 44.29 (20.43, 65.86) weeks (maximum 201 weeks), with a total of 20,201 subject-weeks on study. Incidence and type of AEs were consistent with previous studies. The most common serious treatment-related AEs were cerebrovascular accident, headache, bone marrow reticulin fibrosis (with no evidence of positive trichrome staining for collagen and no evidence suggesting primary idiopathic myelofibrosis), nausea, deep vein thrombosis, hemorrhage and pulmonary embolism, with each reported in 2 of 407 (0.5%) patients. All other serious treatment-related AEs were each reported in one patient. Eighteen patients died; 3 deaths (hemolysis, intestinal ischaema, aplastic anemia) were considered treatment-related. No neutralizing antibodies to romiplostim or TPO were reported. Approximately 90% of patients achieved each of the platelet response definitions, regardless of splenectomy status. Overall, median (Q1, Q3) time to response was 2 (1, 4) weeks for response definition 1, and 1 (1, 3) week for response definition 2. Median (Q1, Q3) baseline platelet count was 14 (8, 21) × 109/L. After 1 week of treatment median (Q1, Q3) platelet count had increased to 42 (18, 101) × 109/L. From week 8 onwards, and excluding counts within 8 weeks of rescue medication use, median platelet counts were consistently above 100 × 109/L (range 101.0–269.5 × 109/L). Median (Q1, Q3) average weekly romiplostim dose was 3.62 (1.99, 6.08) μg/kg. Summary/conclusions: This is the largest prospective study in adult ITP reported to date. The data reported here are similar to those reported for previous romiplostim studies, with romiplostim able to safely induce a rapid platelet response in adult ITP patients with low platelet counts or bleeding symptoms. Romiplostim is an important, well-tolerated, treatment option for adult ITP patients, which significantly increases and maintains platelet counts. Adverse Event Subject Incidence Platelet Response Disclosures: Janssens: Amgen: Consultancy; Roche: Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Tarantino:Cangene corporation: Research Funding; Baxter: Research Funding; Talecris: Honoraria, Speakers Bureau; Up-to-date: Patents & Royalties; The Bleeding and Clotting Disorders Institute: Board Member. Bird:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Boccia:Amgen: Equity Ownership, Honoraria, Speakers Bureau. Lopez-Fernandez:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kozak:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Steurer:Amgen: Honoraria. Dillingham:Amgen Limited: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.

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Phase II Study of the Pan-Deacetylase Inhibitor Panobinostat in Combination with Bortezomib and Dexamethasone in Relapsed and Bortezomib-Refractory Multiple Myeloma (PANORAMA 2)

Blood ◽

10.1182/blood.v118.21.814.814 ◽

2011 ◽

Vol 118 (21) ◽

pp. 814-814 ◽

Cited By ~ 8

Author(s):

Paul G. Richardson ◽

Melissa Alsina ◽

Donna M. Weber ◽

Steven E. Coutre ◽

Sagar Lonial ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Treatment Phase ◽

Employment Equity ◽

Advisory Committees ◽

Overall Response ◽

Equity Ownership ◽

Grade 3 ◽

Stage 1

Abstract Abstract 814FN2 Background: Patients with refractory multiple myeloma (MM) have limited treatment options and an extremely poor prognosis. A recent study of patients who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive an immunomodulatory drug (IMiD, thalidomide or lenalidomide) demonstrated a median event-free survival of only 5 months (Kumar S et al, Leukemia, 2011). Panobinostat is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of proteins involved in multiple oncogenic pathways. Preclinical studies have demonstrated synergistic anti-myeloma activity of the combination of panobinostat and bortezomib through dual inhibition of the aggresome and proteasome pathways. In a phase I study (B2207) of patients with relapsed or relapsed/refractory MM treated with panobinostat + bortezomib, clinical responses (≥ minimal response [MR]) were observed in 65% of patients, including in patients with bortezomib-refractory disease. PANORAMA 2 seeks to expand upon these preliminary results and seeks to determine whether panobinostat can sensitize resistant patients to a bortezomib-containing therapeutic regimen. Methods: PANORAMA 2 is a single arm, phase II study of panobinostat + bortezomib + dexamethasone in patients with bortezomib-refractory MM. Patients with relapsed and bortezomib-refractory MM (≥ 2 prior lines of therapy including an IMiD and who had progressed on or within 60 days of the last bortezomib-based therapy) are treated in 2 phases. Treatment phase 1 consists of 8 three-week cycles of oral panobinostat (20 mg days 1, 3, 5, 8, 10, 12) + intravenous bortezomib (1.3 mg/m2 days 1, 4, 8, 11) + oral dexamethasone (20 mg on day of and after bortezomib). Patients demonstrating clinical benefit (≥ stable disease) can proceed to treatment phase 2, consisting of 4 six-week cycles of panobinostat (20 mg TIW 2 weeks on 1 week off, and repeat) + bortezomib (1.3 mg/m2 days 1, 8, 22, 29) + dexamethasone (20 mg on day of and after bortezomib). The primary endpoint is overall response (≥ partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation 1998 criteria, in the first 8 cycles of treatment phase 1. A Simon 2-stage design is used to test the primary endpoint where ≥ 4 responses (≥ PR) in 24 patients are needed in stage 1 in order to proceed to stage 2, where ≥ 9 responses in all patients (N = 47) are required to reject the null hypothesis (overall response rate ≤ 10%). Results: A sufficient number of responses ≥ PR were observed in stage 1 to allow for enrollment to continue to stage 2. As of 15 July 2011, 53 patients with bortezomib-refractory MM were enrolled. Safety and demographic data were available for 48 patients. The median age was 61 (41–88) years. Patients were heavily pretreated, with a median of 4 (2–14) prior regimens, and most patients (69%) received prior autologous stem cell transplant. Efficacy data were available for 44 patients. At the time of this analysis, 9 patients achieved ≥ PR (2 near CR [nCR] and 7 PR) as best overall response, and an additional 7 patients achieved an MR. Responders exhibited a long duration on therapy, and, to date, 8 patients have proceeded to treatment phase 2. The 2 patients with nCR have received ≥ 10 cycles of treatment (duration of therapy 190 and 253 days). Four patients who achieved PR have received ≥ 9 cycles (duration of therapy 155–225 days). Updated response data will be presented. Common adverse events (AEs) of any grade included, fatigue (52%), diarrhea (41%), thrombocytopenia (38%), nausea (38%), and anemia (21%). Gastrointestinal AEs were generally mild, with a relatively low incidence of grade 3/4 events. Grade 3/4 AEs were generally hematologic in nature, with grade 3/4 thrombocytopenia, anemia, and neutropenia reported in 38%, 12%, and 10% of patients, respectively. Other common nonhematologic grade 3/4 AEs included fatigue (10%) and pneumonia (10%). Of note, to date, a relatively low rate of peripheral neuropathy (17%) has been observed. No grade 3/4 peripheral neuropathy has been observed. Conclusions: The combination of panobinostat and bortezomib is a promising treatment for patients with bortezomib-refractory MM. These data, along with forthcoming data from the phase III study of panobinostat/placebo + bortezomib + dexamethasone in patients with relapsed MM (PANORAMA 1), will further define the potential role of panobinostat in the treatment of patients with MM. Disclosures: Richardson: Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Alsina:Novartis: Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding; Onyx: Research Funding; Millennium: Consultancy, Research Funding. Weber:Millennium: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Merck: Consultancy; Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy. Gasparetto:Millennium: Speakers Bureau. Warsi:Novartis: Employment, Equity Ownership. Ondovik:Novartis: Employment, Equity Ownership. Mukhopadhyay:Novartis: Employment, Equity Ownership. Snodgrass:Novartis: Employment, Equity Ownership.

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Subset Analysis of Response to Treatment of Chronic Phase CML in a Phase 1 Study of Ponatinib in Refractory Hematologic Malignancies

Blood ◽

10.1182/blood.v118.21.602.602 ◽

2011 ◽

Vol 118 (21) ◽

pp. 602-602 ◽

Cited By ~ 3

Author(s):

Jorge E. Cortes ◽

Hagop M. Kantarjian ◽

Neil Shah ◽

Dale Bixby ◽

Michael J. Mauro ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Phase 1 ◽

Chronic Phase ◽

Hematologic Malignancies ◽

Employment Equity ◽

Advisory Committees ◽

Mutation Status ◽

Equity Ownership

Abstract Abstract 602 Background: Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Initial findings of a phase 1 trial in patients (pts) with refractory hematologic malignancies have been reported. The effect of duration of treatment, prior treatment, and mutation status on response to treatment was examined in CML chronic phase (CP) pts who responded to ponatinib. Methods: An open-label, dose escalation, phase 1 trial of ponatinib in pts with hematologic malignancies is ongoing. The primary aim is to assess the safety; anti-leukemic activity is also being investigated. Pts resistant to prior treatments or who had no standard treatment available were enrolled to receive a single daily oral dose of ponatinib (2 mg to 60 mg). Subset analyses of factors impacting cytogenetic and molecular response endpoints (MCyR and MMR) were performed for pts with CP-CML. Data are presented through April 15, 2011. Results: In total, 81 pts (54% male) received ponatinib. Overall, 43 pts had CP with 34 ongoing at analysis. MCyR was observed as best response in 31/43 (72%), 27 (63%) CCyR. The median time to MCyR was 12 (3 to 104) wks. Response rates were assessed by duration of treatment (1 pt in CCyR at entry was excluded; 6 pts in PCyR had to achieve CCyR). At the 3 month assessment, 22/42 (52%) CP pts achieved MCyR; at 6 months, 24/42 (57%); at 12 months, 29/42 (69%) had MCyR. The impact of prior treatment on response and time to response was assessed. 42 pts (98%) had >2 prior TKIs and 28 (65%) ≥3 prior TKIs, including investigational agents. Of approved TKIs, all pts were previously treated with imatinib, 19 dasatinib or nilotinib after imatinib, and 21 both dasatinib and nilotinib after imatinib. MCyR rate decreased with number of prior TKIs (2 prior TKIs 13/14 [93%], ≥3 prior TKIs 17/28 [61%]) and number of approved TKIs (imatinib followed by dasatinib or nilotinib 17/19 [90%], or by both dasatinib and nilotinib 12/21 [57%]). Time to response was prolonged in pts more heavily treated with prior TKIs. Median time to MCyR increased with the number of prior TKIs and approved TKIs (2 TKIs 12 wks, ≥3 TKIs 32 wks). The effect of mutation status on response and time to response was also evaluated. At entry, 12 pts had the T315I mutation, 15 had other BCR-ABL kinase domain mutations, 12 had no mutations detected, 4 did not allow sequencing. MCyR response rate for CP pts with T315I was 11/12 (92%); for other mutations, 10/15 (67%); and no mutation, 7/12 (58%). Similarly, mutation status had an impact on time to response: median time to MCyR was 12 wks for those with T315I or other mutations and 32 wks in resistant pts with no mutation. All CP patients were evaluable for MMR. At analysis, MMR was 17/43 (40%). MMR rate was inversely related to number of prior TKIs (2 TKIs 10/14 [71%], ≥3 TKIs 6/28 [21%]), approved TKIs (imatinib followed by dasatinib or nilotinib 12/19 [63%], or by both dasatinib and nilotinib 4/21 [19%]), and was higher for T315I pts (7/12, 58%) and those with other mutations (7/15, 47%) compared with no mutation (2/12, 17%). Median time to MMR for CP pts was 97 wks; median time to MMR was shorter for pts who were less heavily treated (2 prior TKIs 24 wks) and those with T315I or other mutations (63 wks). Conclusion: In this subset analysis of the phase 1 data, ponatinib had substantial activity in all subgroups analyzed. Time on treatment, less prior therapy and kinase domain mutations were associated with higher response rates and early responses in CP pts. Cytogenetic responses improved over the first 12 months of treatment and were higher in less heavily treated pts. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding. Shah:Ariad: Consultancy, Research Funding. Bixby:Novartis: Speakers Bureau; BMS: Speakers Bureau; GSK: Speakers Bureau. Mauro:ARIAD: Research Funding. Flinn:ARIAD: Research Funding. Hu:ARIAD: Employment. Clackson:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Druker:MolecularMD: OHSU and Dr. Druker have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and t. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Talpaz:ARIAD: Research Funding.

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Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Blood ◽

10.1182/blood.v120.21.801.801 ◽

2012 ◽

Vol 120 (21) ◽

pp. 801-801 ◽

Cited By ~ 21

Author(s):

Francisco Cervantes ◽

Jean-Jacques Kiladjian ◽

Dietger Niederwieser ◽

Andres Sirulnik ◽

Viktoriya Stalbovskaya ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Extension Phase ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 801 Background: Ruxolitinib is a potent JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 COMFORT studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. COMFORT-II is a randomized, open-label study evaluating ruxolitinib versus BAT in patients (pts) with MF. The primary and key secondary endpoints were both met: the proportion of pts achieving a response (defined as a ≥ 35% reduction in spleen volume) at wk 48 (ruxolitinib, 28.5%; BAT, 0%; P < .0001) and 24 (31.9% and 0%; P < .0001), respectively. The present analyses update the efficacy and safety findings of COMFORT-II (median follow-up, 112 wk). Methods: In COMFORT-II, 219 pts with intermediate-2 or high-risk MF and splenomegaly were randomized (2:1) to receive ruxolitinib (15 or 20 mg bid, based on baseline platelet count [100-200 × 109/L or > 200 × 109/L, respectively]) or BAT. Efficacy results are based on an intention-to-treat analysis; a loss of spleen response was defined as a > 25% increase in spleen volume over on-study nadir that is no longer a ≥ 35% reduction from baseline. Overall survival was estimated using the Kaplan-Meier method. Results: The median follow-up was 112 wk (ruxolitinib, 113; BAT, 108), and the median duration of exposure 83.3 wk (ruxolitinib, 111.4 [randomized and extension phases]; BAT, 45.1 [randomized treatment only]). Because the core study has completed, all pts have either entered the extension phase or discontinued from the study. The primary reasons for discontinuation were adverse events (AEs; ruxolitinib, 11.6%; BAT, 6.8%), consent withdrawal (4.1% and 12.3%), and disease progression (2.7% and 5.5%). Overall, 72.6% of pts (106/146) in the ruxolitinib arm and 61.6% (45/73) in the BAT arm entered the extension phase to receive ruxolitinib, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis. The primary reasons for discontinuation from the extension phase were progressive disease (8.2%), AEs (2.1%), and other (4.1%). Overall, 70 pts (48.3%) treated with ruxolitinib achieved a ≥ 35% reduction from baseline in spleen volume at any time during the study, and 97.1% of pts (132/136) with postbaseline assessments experienced a clinical benefit with some degree of reduction in spleen volume. Spleen reductions of ≥ 35% were sustained with continued ruxolitinib therapy (median duration not yet reached); the probabilities of maintaining the spleen response at wk 48 and 84 are 75% (95% CI, 61%-84%) and 58% (95% CI, 35%-76%), respectively (Figure). Since the last report (median 61.1 wk), an additional 9 and 12 deaths were reported in the ruxolitinib and BAT arms, respectively, resulting in a total of 20 (14%) and 16 (22%) deaths overall. Although there was no inferential statistical testing at this unplanned analysis, pts randomized to ruxolitinib showed longer survival than those randomized to BAT (HR = 0.52; 95% CI, 0.27–1.00). As expected, given the mechanism of action of ruxolitinib as a JAK1 & 2 inhibitor, the most common new or worsened grade 3/4 hematologic abnormalities during randomized treatment were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%). In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 wk of treatment and then recovered to levels similar to BAT from wk 24 onward; there was no difference in the mean monthly red blood cell transfusion rate among the ruxolitinib and BAT groups (0.834 vs 0.956 units, respectively). Nonhematologic AEs were primarily grade 1/2. Including the extension phase, there were no new nonhematologic AEs in the ruxolitinib group that were not observed previously (in ≥ 10% of pts), and only 1 pt had a new grade 3/4 AE (epistaxis). Conclusion: In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly; this analysis demonstrates that these reductions are sustained over 2 years of treatment in the majority of pts. Ruxolitinib-treated pts showed longer survival than those receiving BAT, consistent with the survival advantage observed in previous (Verstovsek et al. NEJM. 2012) and current analyses of COMFORT-I, as well as with the comparison of pts of the phase 1/2 study with matched historical controls (Verstovsek et al. Blood. 2012). Disclosures: Cervantes: Sanofi-Aventis: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Speakers Bureau; Novartis: AdvisoryBoard Other, Speakers Bureau. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Hunter:Incyte: Employment. Levy:Incyte: Employment, stock options Other. Passamonti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barbui:Novartis: Honoraria. Gisslinger:AOP Orphan Pharma AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

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Efficacy of Ruxolitinib By Baseline Spleen Volume in Patients with Polycythemia Vera Resistant to or Intolerant of Hydroxyurea

Blood ◽

10.1182/blood.v124.21.1840.1840 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1840-1840 ◽

Cited By ~ 1

Author(s):

Alessandro M. Vannucchi ◽

Srdan Verstovsek ◽

Mark M Jones ◽

Shui He ◽

Jingjin Li ◽

...

Keyword(s):

Logistic Regression ◽

Linear Regression ◽

Polycythemia Vera ◽

Board Of Directors ◽

Research Funding ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Response Trial

Abstract Background : Polycythemia vera (PV) is a myeloproliferative neoplasm defined by erythrocytosis; patients may also have increased platelets and white blood cells as well as splenomegaly and disease-related symptoms. JAK/STAT activation is the primary driver of PV pathogenesis, in most cases resulting from the JAK2V617F mutation. The RESPONSE trial compared ruxolitinib (RUX) and best available therapy (BAT) in patients with PV and splenomegaly who were intolerant of or resistant to hydroxyurea (HU) according to modified European LeukemiaNet criteria. At the time of the primary analysis, RUX demonstrated superior improvements in hematocrit (HCT) control, symptom burden, and spleen volume compared with BAT. This post hoc analysis of RESPONSE was conducted to determine if treatment outcomes were influenced by baseline spleen volume. Methods : Patients with PV ≥18 years of age who were resistant to or intolerant of HU with palpable spleen (confirmed by MRI/CT to be ≥450 cm3) and phlebotomy requirement were randomized 1:1 to receive open-label RUX 10 mg BID or BAT. The primary endpoint was a composite that required a ≥35% reduction in spleen volume at Week 32 and hematocrit (HCT) control. HCT control was defined as lack of phlebotomy eligibility (based on HCT values) between Weeks 8–32 with no more than 1 phlebotomy eligibility between randomization and Week 8. A linear regression was conducted to determine the effect of baseline spleen volume on the percent change in spleen volume at Week 32. A logistic regression was conducted to determine the effect of baseline spleen volume on HCT control through Week 32. Spleen volume was measured by MRI at screening and Weeks 16 and 32. Hematocrit was assessed at screening, prerandomization, and every 2 weeks from Day 1 to Week 12, followed by every 4 weeks until Week 32. Results :The RESPONSE trial enrolled 222 patients (RUX, 110; BAT, 112). Median (range) spleen volume at baseline was 1195 cm3 (396–4631 cm3) in the RUX arm and 1322 cm3 (254–5147 cm3) in the BAT arm. Baseline median (range) spleen length by palpation was 7.0 cm (0.0–24.0 cm) in the RUX arm and 7.0 cm (0.0–25.0 cm) in the BAT arm. In the 24 weeks prior to screening, most patients in both arms had ≥2 phlebotomy procedures (RUX, 87%; BAT, 80%). There was no correlation between the percentage change in spleen volume at Week 32 and baseline spleen volume; linear regression showed no significant effect of baseline spleen volume on the percentage change in spleen volume at Week 32 (P=0.40). No significant effect of baseline spleen volume on HCT control through Week 32 was identified based on logistic regression analysis (P=0.37). Conclusion : In PV patients with inadequate response to or intolerant of HU, the degree of splenomegaly at baseline did not influence achievement of HCT control or reduction in spleen volume with RUX therapy. Disclosures Vannucchi: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Verstovsek:Incyte Corporation: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Kiladjian:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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