The Ultra-Low-Molecular-Weight Heparin Semuloparin for Prevention of Venous Thromboembolism In Patients Undergoing Major Abdominal Surgery

Abstract Abstract 188 Background/Aim: Venous thromboembolism (VTE) remains a common and potentially fatal complication of major abdominal surgery. Semuloparin is a novel ultra-low-molecular-weight heparin (ULMWH) with high anti-factor Xa and residual anti-factor IIa activities currently under development for prevention of VTE. We have conducted a study to assess the efficacy and safety of semuloparin compared to enoxaparin for the prevention of VTE in patients undergoing major abdominal surgery. Material and methods: SAVE-ABDO is a multinational, randomized, double-blind phase III study of patients undergoing major abdominal or pelvic operation. Patients were randomized to receive either once-daily enoxaparin 40 mg commenced pre-operatively or semuloparin 20 mg commenced post-operatively, both agents continued for 7–10 days. Patients were eligible for inclusion if they were aged > 60 years, had undergone major surgery in the peritoneal or the retroperitoneal space, and/or pelvis under general anesthesia lasting more than 45 minutes. For patients under the age of 60 years old, an additional risk factor (history of VTE, body mass index ≥ 30 kg/m2, chronic heart failure, chronic respiratory failure, inflammatory bowel disease, or operation for malignancy) was required. For patients with severe renal impairment, defined as a creatinine clearance < 30 mL/min, the dose of semuloparin was reduced to 10 mg once-daily, and that of enoxaparin to 20 mg once-daily. Randomization was stratified by indication for operation (cancer versus non-cancer), renal function (creatinine clearance ≥ or < 30 mL/min), and geographic region. Mandatory bilateral venography was performed between day 7 and 11. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. Secondary efficacy endpoints included the composite of any VTE and VTE-related mortality, and the composite of any proximal DVT, symptomatic distal DVT, non-fatal pulmonary embolism, and all-cause mortality. The main safety endpoint was major bleeding, with main secondary safety endpoints of clinically-relevant non-major (CRNM) bleeding, and the composite of major and CRNM bleeding. All study endpoints were independently and blinded adjudicated. The non-inferiority will be reached if the upper limit of the confidence interval of the odds ratio for the primary analysis is < 1.25. If the non-inferiority is demonstrated the superiority will be tested using a stratified exact test on the primary efficacy endpoint. Results: 4414 patients were randomized between May 2008 and June 2010. The mean age was 61 years (±13 years) and 57% of subjects were male. 81% of patients underwent an operation for malignant disease. The majority of patients underwent gastro-intestinal procedures, with 59% having colon or colo-rectal surgery, and 20% gastric surgery. Final data will be available for presentation at the meeting. Disclosures: Kakkar: Bayer Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; sanofi-aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Agnelli:sanofi-aventis: Research Funding. Fisher:sanofi-aventis: Honoraria, Research Funding; Bayer Healthcare: Honoraria, Research Funding; Takeda Pharmaceuticals: Honoraria, Research Funding; Pfizer: 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; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees. George:sanofi-aventis: Honoraria. Mouret:Bayer Healthcare: Consultancy, Honoraria; sanofi-aventis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Lassen:Astellas Pharma Europe: Consultancy; Bayer Healthcare: Consultancy; Bristol-Myers Squibb: Consultancy; GlaxoSmithKline: Consultancy; Merck Serono: Consultancy; Pfizer: Consultancy; sanofi-aventis: Consultancy. Mismetti:sanofi-aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Honoraria; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria. Murphy:sanofi-aventis: Employment. Turpie:Astellas Pharma Europe: Consultancy; Bayer Healthcare: Consultancy; Portola Pharma: Consultancy; sanofi-aventis: Consultancy.

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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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Treatment Of Serious Bleeds With a B-Domain Deleted Recombinant Porcine Sequence Factor VIII (OBI-1) In Patients With Acquired Hemophilia A: A Prospective Clinical Trial

Blood ◽

10.1182/blood.v122.21.206.206 ◽

2013 ◽

Vol 122 (21) ◽

pp. 206-206 ◽

Cited By ~ 1

Author(s):

Rebecca Kruse-Jarres ◽

Jean St. Louis ◽

Anne Greist ◽

Amy D. Shapiro ◽

Hedy Smith ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Positive Response ◽

Acquired Hemophilia A ◽

Advisory Committees ◽

Baxter Healthcare ◽

Bayer Healthcare ◽

Travel Grant

Abstract Introduction Acquired hemophilia A (AHA) is a rare bleeding disorder, resulting from auto-antibodies to human factor VIII (hFVIII). The challenges created by the management of AHA and the co-morbidities present in this typically elderly population, can be managed by a recombinant, highly pure, B-domain deleted, porcine sequence FVIII (OBI-1) that is not generally susceptible to the inhibitory activity of anti-human FVIII antibodies. Treatment with OBI-1 allows for monitoring of FVIII levels which provides a reproducible and objective surrogate predictor of hemostasis. Eradication of hFVIII inhibitors with immunosuppressive therapy is critical for disease management. During immunosuppression, the patient transitions from a bleeding state at initial presentation to a relative hypercoagulable state which can be an issue in patients who are susceptible to thromboembolic events due to their comorbidities. This transition period is of most concern especially when using traditionally utilized bypassing agents that cannot be monitored. OBI-1 enables measurement of FVIII levels, guiding dosing and enhancing treatment safety during this critical period. Methods This global, prospective, multi-center phase 2/3 open label clinical trial investigates the efficacy and safety of OBI-1 in the treatment of serious bleeds in adults with AHA conducted under ICH guidelines and local IRB/Ethics Committee oversight. Primary efficacy endpoint was assessed at 24 hours (eg. effective, partially effective). All subjects (N= 18) presented with a serious bleed and were treated with an initial dose of OBI-1 (200 U/kg), followed by additional doses based on the subject's target factor VIII levels, anti-OBI-1 titer, and clinical factors. Results In all 18 subjects, a positive response (14 effective/4 partially effective) to treatment was observed at 24 hours. This positive response to OBI-1 treatment was seen by 8 hours in 14/18 of the subjects and at 16 hours in 16/18 of the subjects. Median total exposure to OBI-1 per subject was 1782.5 U/kg. The median total first dose was 14,000 U. For subjects who received additional doses of OBI-1, the median dose was reduced from the initial dose, but did not differ considerably over subsequent doses (9180 to 13561 U; median 11000 U). The majority of subjects (17/18) received concomitant immunosuppressive therapies. No related serious adverse reactions occurred. Non-serious adverse events related to treatment were noted in 5/18 (27.8%) subjects. One subject had mild tachycardia, hypotension and constipation. One subject had 2 instances of mild PICC line occlusion. One subject had a mild hypofibrogenemia. All of these adverse effects completely resolved. Three subjects developed anti-porcine inhibitors after infusion of study drug (range 8-108 BU) and two were discontinued from treatment. Anti-porcine inhibitors were detected prior to infusion in 6/18 patients (range 0.8-29 BU). All of these subjects had a favorable clinical response at 24 hours post-OB-1 infusions. Conclusions Data from this prospective study demonstrate OBI-1 as a safe and effective treatment of bleeding episodes in patients with AHA, with the added advantage over other bypass therapies of allowing FVIII monitoring throughout treatment and healing phase. Disclosures: Kruse-Jarres: Baxter Healthcare: Consultancy; Bayer HealthCare: Consultancy; Biogen IDEC: Consultancy; Grifols: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy. St. Louis:CSL Behring: Research Funding; Octapharma: Consultancy, Research Funding; Baxter: Consultancy; Novo Nordisk: Honoraria. Shapiro:Kedrion Biopharma: Consultancy; Chugai Pharma USA: Consultancy; Biogen IDEC: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Baxter Healthcare: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Chowdary:Baxter Healthcare: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Travel grant Other; Novo Nordisk: Honoraria, Research Funding, Travel grant, Travel grant Other; Bayer HealthCare: Honoraria, Travel grant, Travel grant Other; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel grant, Travel grant Other; CSL Behring: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel grant Other; Biogen IDEC: Honoraria, Travel, Travel Other. Drebes:Octapharma: Travel grant Other; CSL Behring: Travel grant, Travel grant Other; Leo-pharma: Travel grant, Travel grant Other; Bayer Healthcare: Consultancy, Honoraria. Gomperts:Baxter Healthcare: Consultancy; Asklepios Biopharmaceutoicals Inc: Consultancy; Cangene Inc: Consultancy. Chapman:Baxter Healthcare: Employment. Mo:Baxter Healthcare: Employment. Novack:Baxter Healthcare: Employment. Farin:Baxter Healthcare: Employment.

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Low Molecular Weight Heparin for Prevention of Placenta-Mediated Pregnancy Complications: An Individual Patient Data Meta-Analysis

Blood ◽

10.1182/blood.v126.23.890.890 ◽

2015 ◽

Vol 126 (23) ◽

pp. 890-890

Author(s):

Marc Rodger ◽

Johanna IP de Vries ◽

Evelyne Rey ◽

Jean-Christophe JCG Gris ◽

Ida Martinelli ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Molecular Weight Heparin ◽

Individual Patient Data ◽

Meta Analysis ◽

Risk Difference ◽

Patient Data ◽

Low Molecular Weight ◽

Single Center ◽

Advisory Committees

Abstract Introduction Placenta-mediated pregnancy complications (PMPC) include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age (SGA) newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality. Affected women are at an elevated risk of recurrence in subsequent pregnancies. We completed a pooled summary-based (i.e. study level) meta-analysis that strongly suggests that low-molecular-weight heparin (LMWH) reduces the risk of recurrent PMPCs. However, our study-level meta-analysis was limited by high clinical and statistical heterogeneity likely due to the inclusion of women with heterogeneous prior PMPCs and trial designs (e.g. single vs multi-center trials). To address these limitations, the trialists agreed to conduct an individual patient data meta-analysis to identify sources of heterogeneity including exploring which patients benefit from LMWH and which outcomes are prevented. Methods We conducted a systematic review to identify randomised controlled trials that were eligible to contribute individual patient data to a meta-analysis to evaluate the effectiveness of LMWH for reducing the risk of PMPC in women with prior PMPCs. The primary outcome was a composite of early-onset or severe pre-eclampsia, birth of an SGA newborn < 5th percentile, late pregnancy loss (> 20 weeks), or placental abruption leading to delivery. Individual patient data from eligible women were re-coded in a prescribed format and combined in a common dataset for analysis. All studies were assessed for risk of bias. Results Data from 1049 women in nine trials were analysed; Participants were mostly Caucasian (88%) with a mean age of 31.518 had thrombophilia. 525 women were randomised to LMWH and 524 to no LMWH. In our primary outcome analysis, LMWH did not significantly reduce the risk of recurrent PMPCs (LMWH 60/459 (13.1%) vs. no LMWH 92/449 (20.5%) p=0.1). Significant heterogeneity was noted between single center and multi-center trials. In multi-center trials, LMWH reduced HELLP (p=0.03) but none of the other secondary outcomes, whereas in single center trials LMWH reduced all of the secondary outcomes. In sub-group analysis, in multi-center trials LMWH reduced the primary outcome in women with prior abruption (p<0.01) but none of the other sub-groups, whereas in single center trials LMWH was beneficial in all the sub-groups (prior pre-eclampsia, prior severe pre-eclampsia, prior early onset pre-eclampsia, prior SGA <10th, prior SGA < 5th and prior abruption). Conclusions In this individual patient data meta-analysis, LMWH does not appear to reduce the risk of recurrent PMPC in women with prior PMPC. Promising results suggest that women with prior abruption may benefit from LMWH but this should be replicated in future multi-center trials. PROSPERO registration:CRD42013006249 Table. Primary Analysis All Studies Multi-Center Studies Single Center Studies Composite outcome Risk difference (95% CI) N=908 -0.07 (-0.16, 0.01)p = 0.10 N=524 -0.01 (-0.11, 0.09) p = 0.89 N=384 -0.17 (-0.21, -0.13) p < .0001 Secondary Outcome Analyses Severe or Early Preeclampsia Risk difference (95% CI) N=946 -0.04 (-0.10, 0.02) p = 0.20 N=562 0.01 (-0.06, 0.07) p = 0.81 N=384 -0.11 (-0.16, -0.07) p <.0001 HELLP Risk difference (95% CI) N=813 -0.02 (-0.04, -0.004) p = 0.01 N=429 -0.01 (-0.02, -0.001) p = 0.03 N=384 -0.04 (-0.07, -0.01) p = 0.02 SGA <10 Risk difference (95% CI) N=913 -0.08 (-0.14, -0.02) p = 0.01 N=529 -0.03 (-0.10, 0.03) p = 0.32 N=384 -0.14 (-0.18, -0.10) p <0.0001 Abruption leading to delivery Risk difference (95% CI) N=945 -0.01 (-0.02, 0.003) p = 0.14 N=561 -0.01 (-0.03, 0.01) p = 0.53 N=384 -0.016 (-0.027, -0.005) p = 0.005 Subgroup Analyses Prior preeclampsia Risk difference (95% CI) N=583 -0.12 (-0.19, -0.04) p = 0.002 N=288 -0.06 (-0.19, 0.06) p = 0.34 N=295 -0.17 (-0.24, -0.11) p <.0001 Prior severe or early onset Preeclampsia Risk difference (95% CI) N=487 -0.10 (-0.19, -0.02) p = 0.02 N=236 -0.04 (-0.19, 0.12) p = 0.65 N=251 -0.17 (-0.23, -0.11) p <.0001 Any prior late loss (2 >12 weeks or 1 >16 weeks) Risk difference (95% CI) N=245 0.001 (-0.11, 0.12) p = 0.98 N=0 Prior SGA < 10 Risk difference (95% CI) N=305 -0.12 (-0.25, 0.01) p = 0.08 N=203 -0.03 (-0.17, 0.10) p = 0.64 N=102 -0.29 (-0.38, -0.20) p <.0001 Prior abruption Risk difference (95% CI) N=281 -0.16 (-0.22, -0.11) p <.0001 N=95 -0.13 (-0.22, -0.04) p = 0.01 N=186 -0.18 (-0.22, -0.14) p <.0001 Disclosures Rodger: Biomerieux: Honoraria, Research Funding. Off Label Use: Low Molecular Weight Heparin to prevent pregnancy complications. de Vries:Pfizer: Research Funding. Rey:Leo Pharma: Other: Travel Grant. Gris:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stago: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Leo Pharma: Consultancy, Speakers Bureau; LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxter: Research Funding; BI: Speakers Bureau; Bayer: Speakers Bureau; BMS: Speakers Bureau. Schleussner:Bayer: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Merck: Research Funding, Speakers Bureau. Middeldorp:GSK/Aspen: Research Funding; Bayer: Consultancy, Speakers Bureau; BI: Consultancy, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Daiichi-Sankyo: Consultancy, Speakers Bureau. Bates:Eli Lilly Canada: Other: I hold the Eli Lilly Canada/May Cohen Chair in Women's Health. Eli Lilly Canada provides unrestricted funding for partial salary support through this Chair. Eli Lilly Canada does not manufacture/distribute drugs relevant to the topic to be discussed..

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Early Prophylaxis Provides Continued Joint Protection in Severe Hemophilia A: Results of the Joint Outcome Continuation Study

Blood ◽

10.1182/blood-2018-99-117413 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 382-382 ◽

Cited By ~ 3

Author(s):

Beth Boulden Warren ◽

Dianne Thornhill ◽

Jill Stein ◽

Michael Fadell ◽

Sharon Funk ◽

...

Keyword(s):

Soft Tissue ◽

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Joint Damage ◽

Severe Hemophilia ◽

Advisory Committees ◽

Episodic Treatment ◽

Bayer Healthcare

Abstract Background: The Joint Outcome Study (JOS) was a randomized controlled trial showing that, in severe hemophilia A, prophylactic factor VIII every other day starting prior to age 30 months leads to better joint outcomes at age 6 years than enhanced episodic treatment with factor VIII for bleeding1. After conclusion of the JOS, all participants were encouraged to continue on, or to transition to, prophylaxis. Here we describe the results of the Joint Outcome Continuation Study (JOS-C), which followed the participants of the JOS to age 18 years. Methods: All participants of the JOS were eligible for the JOS-C. MRIs of 6 index joints (right and left ankles, knees, and elbows), index joint physical exam scores using the Colorado Haemophilia Paediatric Joint Physical Examination Scale2 , estimates of joint bleeding episodes, and surgery information were collected. The primary endpoint, as in the initial JOS analysis, was evidence of hemophilia-related osteochondral joint damage on MRI, scored using the extended MRI scale3. Results: Of the 65 previous participants of the JOS, 37 gave informed consent for the JOS-C study, including 18 initially randomized to prophylaxis prior to age 30 months ("early prophylaxis"), and 19 initially randomized to enhanced episodic treatment who started prophylaxis at a mean age of 7.5 years (median 6.1, range 2.7-17.1, "delayed prophylaxis"). All initially on prophylaxis in the JOS continued on prophylaxis through the JOS-C. One participant (early prophylaxis arm) failed to complete an MRI, and four others (2 early and 2 delayed prophylaxis) had their MRIs excluded for technical reasons. Four participants (3 early prophylaxis and 1 delayed prophylaxis) developed high titer inhibitors during or shortly after the JOS and were analyzed separately. Osteochondral joint damage was defined as evidence of osteochondral damage on MRI or a need for joint surgery. The relative risk of osteochondral damage in those on delayed prophylaxis as compared to those on early prophylaxis was 6.5 (95% CI 1.3, 33.6; p=0.029). At age 18, 67% of those on early prophylaxis, and only 24% of those on delayed prophylaxis had zero index joints with osteochondral damage (Figure 1). Twenty-five percent of early prophylaxis and 47% of delayed prophylaxis participants had osteochondral damage to more than one joint. Most participants had some soft tissue changes on MRI, defined as effusion, synovial hypertrophy, or hemosiderin deposition. There was no difference in risk of soft tissue damage between initial treatment groups (p=0.48). Osteochondral damage scores were available for 3 patients with inhibitors: two with refractory inhibitors had osteochondral changes on at least one joint, and one with an inhibitor that tolerized within 3 months had no osteochondral damage. Total physical exam scores were also higher in the delayed prophylaxis arm (mean 22.6, standard deviation (SD) 15.5) than in the early prophylaxis arm (mean 16.2, SD 10.5), but this difference was not statistically significant (p=0.19). Conclusion: The JOS-C demonstrates that, in severe hemophilia A, initiation of prophylaxis prior to age 30 months provides continued protection against joint damage throughout childhood. Those who started on prophylaxis later in childhood had higher risk of joint damage at age 18. Initiation of factor VIII prophylaxis in the toddler years is critical to preventing osteochondral joint damage and should not be delayed. ReferencesManco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-544.Hacker MR, Funk SM, Manco-Johnson MJ. The Colorado Haemophilia Paediatric Joint Physical Examination Scale: normal values and interrater reliability. Haemophilia. 2007;13(1):71-78.Hong W, Raunig D, Lundin B. SPINART study: validation of the extended magnetic resonance imaging scale for evaluation of joint status in adult patients with severe haemophilia A using baseline data. Haemophilia. 2016;22(6):e519-e526. Figure 1: Percentage of participants with zero joints with osteochondral damage at JOS exit (age 6 years) and JOS-C exit (age 18 years), excluding participants with inhibitors. Disclosures Warren: Bayer Healthcare: Research Funding; HTRS/Novo Nordisk: Research Funding; Bayer Hemophilia Awards Program Fellowship Project Award: Research Funding; CSL Behring Heimburger Award: Research Funding. Shapiro:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Prometic Life Sciences: Consultancy, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Bio Products Laboratory: Consultancy; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Sangamo Biosciences: Consultancy; Octapharma: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; OPKO: Research Funding; BioMarin: Research Funding. Recht:Shire: Research Funding; Biogen: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees. Manco-Johnson:Bayer AG: Honoraria, Research Funding; Novo Nordisk: Honoraria; Biogentek: Honoraria; CSL Behring: Honoraria; Baxalta, now part of Shire: Honoraria.

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Chemotherapy-Free Combination of Obinutuzumab and Ibrutinib in First LINE Treatment of Follicular Lymphoma. the Alternative Study By the German Low Grade Lymphoma Study Group (GLSG)

Blood ◽

10.1182/blood-2018-99-111692 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 448-448 ◽

Cited By ~ 2

Author(s):

Christian Schmidt ◽

Anna-Katharina Zoellner ◽

Vindi Jurinovic ◽

Martin Sökler ◽

Roswitha Forstpointner ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Tumor Burden ◽

Primary Efficacy ◽

Primary Efficacy Endpoint ◽

Advisory Committees ◽

Low Toxicity ◽

Grade 3 ◽

One Year ◽

Support Research

Abstract Background: The clinical course of follicular lymphoma (FL) is characterized by a slow progression over years with continuous relapses despite good response to initial treatment. The median overall survival is 10 to more than 15 years. Standard therapy for patients requiring treatment consists of an anti-CD 20 antibody combined with chemotherapy followed by antibody maintenance. With this combination a 1-year-PFS of 93% was seen in the GLSG-2000 trial (Hiddemann et al, Blood 2005). Because of the substantial side effects of chemotherapy such as infections, secondary malignancies and impairment of the stem cell reserve novel "chemotherapy-free" treatment approaches could substantially improve the treatment tolerability in FL. The BTK-inhibitor ibrutinib has demonstrated promising activity in patients with iNHL, CLL and MCL. Anticipating the recent reports on a superior activity of obinutuzumab as compared to rituximab in the GALLIUM trial (Marcus et al., NEJM 2017), the GLSG initiated a phase II study combining ibrutinib and obinutuzumab to explore the efficacy and safety of this "chemotherapy-free" alternative. Methods: ALTERNATIVE is a prospective multicenter single-arm phase 2 study of the combination of ibrutinib and obinutuzumab in 98 patients with previously untreated FL and a high tumor burden (defined by modified GELF criteria) in need of treatment. Induction comprises 6 cycles of obinutuzumab at a dose of 1000 mg by intravenous infusion on days 1, 8, 15 of cycle 1 and on day 1 of cycles 2-6 to be given every 21 days. Ibrutinib is administered orally at a dose of 560 mg once daily throughout all 6 cycles. In patients with at least partial response (defined by Cheson Response Criteria 2007) after the end of induction, maintenance with obinutuzumab (1000mg every 8 weeks) plus ibrutinib (560mg daily) is given for an additional 24 months. In patients remaining MRD positive at 30 months ibrutinib is continued for another 12 months in an extended maintenance setting without obinutuzumab. The primary efficacy endpoint is the rate of investigator-assessed PFS one year after registration. Response rates at end of induction, after one year and after end of maintenance, duration of response, percentage of progression during induction and maintenance, time to treatment failure, overall survival, duration of molecular remission in MRD negative patients and safety are key secondary endpoints. Results: 98 patients with advanced stage FL were included, The median age was 59 years (29-81), 60% were male and 40% had a high risk FLIPI, 90% stage III/IV disease and 10% were stage II with a high tumor burden. Response to in induction was 90% (87/97) with 85% (82/97) PR and 5% (5/97) CR. 5 patients (5%) progressed during induction. Of the 82 patients with PR after end of induction, 8 patients achieved a CR during the first 6 months of maintenance treatment. 95 patients were evaluable for the primary endpoint of 1-year-PFS and 76 patients (80%) remained alive and free of progression at this timepoint. 18 patients progressed in the first year, two of whom died due to progressive disease. One additional death was caused by a non-lymphoma related event. An MRD-marker was found in 65 patients. MRD at the end of induction was evaluable for 63 patients. 44 patients (70%) were MRD negative after induction treatment. Of the 42 patients with follow-up MRD peripheral blood or bone marrow samples, 35 (83%) were MRD negative one year after registration. Therapy was generally well tolerated. Most common adverse events were diarrhea in 30% of patients, rash in 25% and fatigue and nasopharyngitis (common cold) in 23% and 20%, respectively. Concerning hematotoxicity grade 3-4 neutropenia and thrombopenia were seen in 8% and 4% of patients, respectively. Severe (>=grade 3) infectious complications were rare (6% pneumonia/bronchitis, 2% sepsis, 7% other infections). Conclusions: The chemotherapy - free combination of ibrutinib and obinutuzumab showed high anti-lymyphoma activity with high overall response rates and a high proportion of MRD negativity at one year. While the combination of ibrutinib and obinutuzumab was associated with a low toxicity profile, the combination was inferior to the published results of conventional immunochemotherapies in terms of the primary efficacy endpoint (1-year-PFS). Further evaluations might demonstrate whether subgroups exist which particularly benefit clinically from this low toxicity regime. Figure Figure. Disclosures Schmidt: Celgene: Honoraria; Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Buske:Bayer: Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Viardot:Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Keller:BMS: Consultancy; Roche: Consultancy; Takeda: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Equity Ownership; MSD: Consultancy; Celgene: Research Funding. Graeven:Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria. Marks:Merck: Honoraria; BMS: Honoraria; Servier: Honoraria. Hänel:Novartis: Honoraria; Roche: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Liersch:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria. Dürig:Celgene: Honoraria; Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria. Hoster:Roche Pharma AG: Other: Travel support, Research Funding; F. Hoffman-La Roche: Other: Travel support, Research Funding. Unterhalt:F. Hoffman-La Roche: Other: Travel support. Hiddemann:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding.

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Venous Thromboembolism (VTE) Prevention with Semuloparin in Cancer Patients Initiating Chemotherapy: Benefit-Risk Assessment by VTE Risk in SAVE-ONCO

Blood ◽

10.1182/blood.v118.21.206.206 ◽

2011 ◽

Vol 118 (21) ◽

pp. 206-206 ◽

Cited By ~ 32

Author(s):

Daniel George ◽

Giancarlo Agnelli ◽

William Fisher ◽

Ajay Kakkar ◽

Michael R Lassen ◽

...

Keyword(s):

Risk Assessment ◽

High Risk ◽

Board Of Directors ◽

Cancer Patients ◽

Research Funding ◽

P Value ◽

Advisory Committees ◽

Benefit Risk Assessment ◽

Bayer Healthcare ◽

High Risk Cancer

Abstract Abstract 206 Background: Cancer patients receiving chemotherapy are at increased risk for VTE. Recent oncology guidelines emphasize the need for randomized studies with VTE risk assessment in these patients (Streiff MB, et al. JNCCN. 2011;9:714–777). Semuloparin is a new ultra-low-molecular-weight heparin with high anti-factor Xa and minimal anti-factor IIa activities. The SAVE-ONCO study investigated semuloparin vs placebo for VTE prevention in cancer patients receiving chemotherapy. Methods: Patients with metastatic or locally advanced cancer of lung, pancreas, stomach, colon-rectum, bladder or ovary initiating a chemotherapy course, were randomized to once-daily subcutaneous semuloparin 20 mg or placebo until change of chemotherapy. The primary efficacy outcome was a composite of symptomatic deep-vein thrombosis, any non-fatal pulmonary embolism, or VTE-related death. The main safety outcome was clinically relevant bleeding (major and non major). Baseline VTE risk was assessed by a score specifically developed and validated in chemotherapy-treated cancer patients (Khorana AA, et al. Blood. 2008;111:4902–7). According to this predictive model a score of 2 was assigned to very high-risk cancer sites (pancreatic or gastric), a score of 1 was assigned to high-risk cancer sites (lung, ovarian, or bladder cancer) and 1 is added to the score for each of the following parameters: platelet count ≥350 × 109/L, hemoglobin <10 g/dL and/or use of erythropoietin-stimulating agents, leukocyte count >11 × 109/L, and body mass index ≥35 kg/m2. Results: Among the 3212 patients randomized, the majority had lung (36.6%) or colorectal (28.9%) cancer and approximately two-thirds had metastatic cancer. In total, 550 (17.4%) of patients enrolled were at high risk of VTE, 1998 (63.2%) were at moderate risk, and 614 (19.4%) were at low risk (VTE risk score of ≥ 3, 1–2, or 0 points, respectively). All risk groups were well balanced between the treatment groups. Median treatment duration was approximately 3.5 months. Overall, semuloparin significantly reduced VTE or VTE-related death by 64% (p<0.0001; Table) vs placebo. The treatment effect was consistent across various levels of VTE risk (interaction p-value=0.6048; Table). Clinically relevant bleeding occurred in 2.8% and 2.0% of the patients in the semuloparin and placebo groups, respectively (Table). The incidence of major bleeding was similar: 1.2% and 1.1% patients in the semuloparin and placebo groups, respectively (hazard ratio [HR] 1.05; 95% confidence interval [CI] 0.55–1.99). No increased incidence of clinically relevant bleeding was observed with semuloparin vs placebo across various levels of VTE risk (interaction p-value=0.9409; Table). Conclusions: In cancer patients receiving chemotherapy, thromboprophylaxis with semuloparin was consistently associated with a favorable benefit-risk profile across various levels of VTE risk, but greatest in moderate to high risk patients. Antithrombotic prophylaxis should be considered in patients with cancer receiving chemotherapy, particularly in those who are at moderate to high risk of VTE. Disclosures: George: Viamet: Consultancy, Research Funding; Sanofi: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Medivation: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Ipsen: Consultancy, Research Funding; Genentech/Roche: Consultancy, Speakers Bureau; Dendreon: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy; Astellas: Consultancy; GSK: Research Funding, Speakers Bureau; BMS: Research Funding; Exelixis: Research Funding. Agnelli:GlaxoSmithKline: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; sanofi-aventis: Honoraria. Fisher:Boehringer Ingelheim: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; sanofi-aventis: Honoraria, Research Funding. Kakkar:Bayer HealthCare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; sanofi-aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARYx Therapeutics: Consultancy; Canyon: Consultancy; GlaxoSmithKline: Honoraria. Lassen:Astellas Pharma Europe: Consultancy; Bayer HealthCare AG: Consultancy; Bristol-Myers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; GlaxoSmithKline: Consultancy; Merck Serono: Consultancy; Pfizer: Consultancy; Protola Pharma: Consultancy; sanofi-aventis: Consultancy. Mismetti:sanofi-aventis: served as a member of Steering Committees. Mouret:Bayer HealthCare: Consultancy, Honoraria; sanofi-aventis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Lawson:Sanofi: Employment. Turpie:Astellas Pharma Europe: Consultancy; Bayer HealthCare AG: Consultancy; Portola Pharma: Consultancy; sanofi-aventis: Consultancy.

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EBMT Risk Score for Pre Transplant Risk Assessment in Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v120.21.3094.3094 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3094-3094 ◽

Cited By ~ 1

Author(s):

Zartash Gul ◽

Hasan Khan ◽

Qaiser Bashir ◽

Nina Shah ◽

Simrit Parmar ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Board Of Directors ◽

Risk Score ◽

Cumulative Incidence ◽

Research Funding ◽

Advisory Committees ◽

All Cause Mortality ◽

Response Status

Abstract Abstract 3094 Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for patients with multiple myeloma (MM) but its use is limited by high non-relapse mortality (NRM). European Group for Bone Marrow transplant (EBMT) risk score is a validated predictor of outcome for patients undergoing allo-HCT for hematological malignancies. It takes into consideration patient's age, donor's gender and type, disease status and the interval from diagnosis to allo-HCT, with the score ranging from 0 to 7. We assessed the impact of EBMT risk score in MM patients undergoing allo-HCT. Methods: A total of 189 patients with MM who underwent HSCT between November 1985 and June 2010 at MD Anderson Cancer Center were included in the analysis. Results: Patient characteristics are summarized in Table 1. There were 110 males (58%) and 79 females (42%) with a mean age of 50 years (range 28–70). Donors were related in 146 patients (HLA-identical=131, 1 antigen mismatched (AGMM) = 5, 2 AGMM =1, 3AGMM=1, syngeneic=8) and unrelated in 43 patients (HLA identical= 37, 1AGMM=4, 2AGMM=1, unknown=1). One-hundred and twelve patients had prior autologous transplants (auto-HCT). Of these 83 had 1, 28 had 2 and 1 had 3 prior auto-HCT, respectively. Median time from diagnosis to allo-HCT was 24.7 months (range 3.3–232) and median overall follow up was 13 months (0.2–266). Overall 94 patients (49%) had progressed before last follow-up. Incidence of all-cause mortality was 138 (73.4%) with 69 (36%) of all deaths attributed to NRM. KM estimates of 2-year PFS and OS were 25% and 42%, and 5-year PFS and OS were 16% and 27%, respectively. Cumulative incidence (CI) of grade 2–4 and grade 3–4 acute graft versus host disease (aGVHD) was 33% and 13%, respectively. Cumulative incidence of overall and extensive chronic GVHD (cGVHD) was 47% and 17%, respectively. EBMT risk score was, 0–3 for 41 (21.7%), 4 for 72 (38.1%) 4 and 5–7 for 76 (40.2%) patients. EBMT risk score was higher for males, African-Americans and older allo-HCT recipients, patients with higher LDH levels (>618mg/dl), ß2-microglobulin >3.5mg/dl and patients with bone marrow plasmacytosis. Median PFS in patients with EBMT scores 0–3, 4 and 5–7 were 10.1, 8.4 and 6.4 months, respectively (P=0.0036). Median OS in patients with EBMT scores 0–3, 4 and 5–7 were 39, 15.8 and 9.6 months, respectively (p=0.001). Cumulative NRM in patients with EBMT scores 0–3, 4 and 5–7 were 37% (15/41), 36.1% (26/72) and 37.3% (28/75), respectively (p= 0.234). Cumulative incidence of progression in patients with EBMT scores 0–3, 4 and 5–7 were 36.5% (15/41), 50% (36/72) and 56.5% (43/76), p=0.119. Compared to those with EBMT risk score (0–3), individuals with EBMT risk scores >5 had a higher risk of all-cause mortality (HR 2.34, 95% CI 1.44–3.80), and disease progression (HR 3.06, 95% CI 1.67–5.61). Addition of ß2-microglobulin, BM plasma cells or prior response status alone or in combination with EBMT risk score significantly improved the discrimination properties of the model containing EBMT score alone (p<0.05). Conclusions: EBMT risk score is an independent predictor of survival in MM patients undergoing allo-HCT. Addition of myeloma-specific factors predictors (ß2-microglobulin, plasma cell infiltration and prior response status) to EBMT score significantly improves its prognostic impact. Disclosures: Giralt: Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Phase 1 Study Update of the Novel Pan-Pim Kinase Inhibitor LGH447 in Patients with Relapsed/ Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.301.301 ◽

2014 ◽

Vol 124 (21) ◽

pp. 301-301 ◽

Cited By ~ 20

Author(s):

Marc S Raab ◽

Enrique M Ocio ◽

Sheeba K. Thomas ◽

Andreas Günther ◽

Yeow-Tee Goh ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Kinase Inhibitor ◽

Phase 1 ◽

Single Agent ◽

Hematologic Malignancies ◽

Advisory Committees ◽

Once Daily ◽

Grade 3 ◽

Dose Levels

Abstract Background: LGH447 is a novel, specific pan-Pim kinase inhibitor in development for the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. The PIM (Provirus Integration site for Moloney leukemia) kinase gene family encodes 3 serine/threonine protein kinases that have roles in cell cycle progression and survival. In human disease, elevated levels of Pim1 and Pim2 are associated with hematologic malignancies, with MM showing the highest level of Pim2 expression. In preclinical studies, a majority of MM cell lines proved sensitive in vitro to LGH447-mediated Pim inhibition, exhibiting a dose-dependent decrease in cell proliferation. LGH447 demonstrated significant tumor growth inhibition in xenograft mouse models of MM as compared with control animals, supporting the clinical development of LGH447 in MM patients. Methods: Patients with relapsed/refractory MM for whom no effective treatment options exist were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CLGH447X2101). Escalating doses of single-agent LGH447 were administered orally on a continuous daily dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of LGH447 administered as a single agent, orally, once daily. Secondary objectives included assessing the safety, tolerability, preliminary anti-myeloma activity, and pharmacokinetics of LGH447. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to NCI-CTCAE v4.03. Efficacy assessments were made by investigators according to International Myeloma Working Group (IMWG) uniform response criteria with modifications. Results:At the data cutoff, 54 patients have been treated at the following doses: 70 mg (n = 5), 150 mg (n = 6), 200 mg (n = 6), 250 mg (n = 7), 300 mg (n = 4), 350 mg (n=10), 500 mg (n=10), 700 mg (n=6), with the MTD determined to be 500 mg once daily. Median age was 65 years (range, 41-87 years). Most patients (92.6%) presented with baseline Eastern Cooperative Oncology Group performance status 0-1. Patients were heavily pretreated with a median of 4 prior lines of therapy (range, 1-16). 81.5% had received prior proteasome inhibitor therapy, 83.3% had received prior immunomodulatory therapy (70.4% lenalidomide and 48.1% thalidomide), 68.5% were treated with both proteasome inhibitor and immunomodulatory therapies, and 87.0% had received prior stem cell transplant. Seventeen patients are ongoing at doses between 250-700 mg, with a median duration of exposure of 10.6 weeks (range, 0.1-56.1 weeks), and 37 patients discontinued (disease progression [n = 29], AEs [n = 4], withdrawal of consent [n = 4]). There were 8 DLTs, consisting of four grade 3/4 thrombocytopenia (1 each at 200, 250, 350, 500 mg dose levels), two grade 3 fatigue (1 each at 500 and 700 mg dose levels), one grade 3 hypophosphatemia (300 mg), and one episode of vaso-vagal syncope (700 mg). This last event was the only reported unexpected serious AE that was suspected to be due to LGH447 treatment. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were thrombocytopenia (18.5%), anemia (18.5%), neutropenia (13%), and fatigue (11.1%). No deaths have occurred on study. Forty-eight individuals (70-500 mg) were evaluable for disease response assessments. Evidence of single agent activity was noted at doses ≥ 150 mg, including 1 VGPR at 200 mg (exposure duration > 55 weeks) and 4 PRs noted at doses ranging from 150-500 mg (respective exposure durations of 32, 29, 24, and 21 weeks). Five additional patients achieved MR, resulting in a clinical benefit rate (≥ MR) of 20.8%, and 23 patients were noted to have SD, resulting in a remarkable disease control rate (≥ SD) of 68.8%. In addition, of those patients with SD, 8 had exposure durations for > 20 weeks. Conclusions:In heavily treated patients with relapsed/refractory MM, LGH447 was generally well tolerated and exhibited evidence of durable single-agent efficacy in multiple patients, with the best response being a VGPR. These findings validate Pim kinase inhibition as a promising therapeutic rationale in MM patients and support further clinical development in patients. Disclosures Ocio: Novartis: Honoraria. Thomas:Novartis: Research Funding; Celgene: Consultancy, Research Funding; Millennium: Research Funding; Idera Pharmaceuticals: Research Funding; Immunomedics: Research Funding. Günther:Novartis: Consultancy, Research Funding. Goh:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jannsen Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Lebovic:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millennium: Consultancy. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, 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; SkylineDx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Song:Novartis: Employment. Xiang:Novartis: Employment. Patel:Novartis: Employment. Vanasse:Novartis: Employment, Equity Ownership. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Research Funding; Array: Research Funding; Cephalon: Research Funding.

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Dalteparin Thromboprophylaxis in Cancer Patients at High Risk for Venous Thromboembolism: A Randomized Trial

Blood ◽

10.1182/blood.v126.23.427.427 ◽

2015 ◽

Vol 126 (23) ◽

pp. 427-427 ◽

Cited By ~ 7

Author(s):

Alok A. Khorana ◽

Charles W. Francis ◽

Nicole Kuderer ◽

Marc Carrier ◽

Thomas L. Ortel ◽

...

Keyword(s):

Venous Thromboembolism ◽

High Risk ◽

Board Of Directors ◽

Cancer Patients ◽

Research Funding ◽

Primary Efficacy ◽

Advisory Committees ◽

Intention To Treat ◽

Efficacy Outcome ◽

Risk Patients

Abstract Background: Ambulatory cancer patients at high-risk for venous thromboembolism (VTE) can be identified using a validated risk score. We evaluated the benefit of outpatient thromboprophylaxis with dalteparin in such high-risk patients in a multicenter randomized controlled trial. Methods: Cancer patients at high risk for VTE (Khorana score ≥3) and initiating a new systemic chemotherapy regimen were screened for VTE and, if negative, randomized to either dalteparin 5000 units daily subcutaneously or no prophylactic anticoagulation for 12 weeks. Subjects in both arms were screened with lower extremity ultrasounds every 4 weeks on study. Primary efficacy endpoint was any VTE over 12 weeks and primary safety endpoint was clinically relevant bleeding events over 13 weeks. The study was terminated due to poor accrual. Results: Of 117 enrolled patients, 19 were not randomized due to the presence of VTE on initial screening (N=10, 8.5%) or for other reasons (N=9). The mean age was 59 years with 46% female and 54% male, similar in both arms. The most common primary sites of cancer were pancreas, gastro-esophageal junction, lung and lymphoma. Over three-fourths of patients in each arm had an ECOG performance status of 0 or 1.Of 98 patients randomized, VTE occurred in 12% (N=6/50) of patients on the dalteparin arm and 21% (N=10/48) on the control arm (hazard ratio, HR 0.69, 95% CI 0.23-1.89) (absolute risk reduction 9%, relative risk reduction 42%, number needed to treat = 12). Major bleeding was similar (N=1) in each arm but clinically relevant bleeding was higher in the dalteparin arm (N=7 versus 1 in the control arm) (HR = 7.0, 95% CI 1.2-131.6). There was no difference in overall survival. Conclusions: Thromboprophylaxis is associated with a non-significant reduced risk of VTE with no effect on major bleeding or survival but increased risk of clinically relevant bleeding in this underpowered study population. The Khorana score successfully identifies patients with high incidence of VTE both at baseline and during study. The high incidence of baseline VTE suggests that consideration should be given to screening high-risk patients in clinical practice prior to starting systemic therapy. Future studies should continue to focus on risk-adapted approaches to reduce the burden of VTE in cancer. (Funded by NIH/NHLBI R01HL095109; clinicaltrials.gov identifier: NCT00876915). Table 1. Baseline Characteristics of Patients Enrolled in the PHACS trial Dalteparin Observation Total Enrolled (n) Baseline VTE, n (%) DVT PE Other reasons for not randomizing Randomized (n) Age, mean (SD), y --- --- --- --- --- 50 60 (10) --- --- --- --- --- 48 58 (12) 117 10 (9%) 6* (5%) 4 (3%) 9 98 59 (11) Gender, n (%) Female 21 (42%) 24 (50%) 45 (46%) Male 29 (58%) 24 (50%) 53 (54%) Primary Tumor Site, No. (%) Gynecologic 4 (8%) 4 (8%) 8 (8%) Colorectal 1 (2%) 3 (6%) 4 (4%) GE junction 8 (16%) 4 (8%) 12 (25%) Lung 6 (12%) 7(15%) 13 (27%) Genitourinary 2 (4%) 0 (0%) 2 (2%) Lymphoma 5 (10%) 2 (4%) 7 (15%) Breast 1 (2%) 1 (2%) 2 (2%) Pancreatic 19 (38%) 17 (35%) 36 (37%) Gastric 4 (8%) 6 (13%) 10 (10%) Other 0 (0%) 4 (8%) 4 (4%) Previous history of VTE, n (%) 4 (8%) 2 (4%) 6 (6%) *NOTE: 1 subject had both DVT and PE at baseline screening Abbreviations: DVT, deep vein thrombosis; PE pulmonary embolism; VTE, venous thromboembolism; ECOG: Eastern Cooperative Oncology Group Figure 1. Cumulative Incidence Curves for the Primary Efficacy Outcome in the Intention-to-Treat Population, According to Study Arm. Figure 1. Cumulative Incidence Curves for the Primary Efficacy Outcome in the Intention-to-Treat Population, According to Study Arm. Disclosures Khorana: Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; sanofi: Consultancy, Honoraria. Off Label Use: Randomized trial of dalteparin as prophylaxis. The drug is approved for treatment of cancer-associated thrombosis but not for prophylaxis.. Francis:Eisai: Consultancy, Research Funding; Portola: Consultancy, Honoraria; NHLBI: Consultancy; Lilly: Consultancy. Kuderer:Hospira: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy. Carrier:Leo Pharma: Consultancy, Research Funding; BMS: Research Funding; Bayer: Consultancy, Honoraria; Pfizer: Consultancy. Ortel:Instrumentation Laboratory: Consultancy; Instrumentation Laboratory: Research Funding; Eisai: Research Funding; Daiichi Sankyo: Consultancy. Wun:Janssen: Consultancy. Iyer:Ipsen Pharmaceuticals: Consultancy; Genentec: Research Funding; Bristol Myers Squibb: Honoraria. Lyman:Amgen: Research Funding.

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Phase 1, Multicenter, Open-Label, Combination Study (NPI-0052-107; NCT02103335) of Pomalidomide (POM), Marizomib (MRZ, NPI-0052), and Low-Dose Dexamethasone (LD-DEX) in Patients with Relapsed and Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.4220.4220 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4220-4220 ◽

Cited By ~ 4

Author(s):

Andrew Spencer ◽

Jacob P. Laubach ◽

Jeffrey A Zonder ◽

Ashraf Z Badros ◽

Simon Harrison ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Advisory Committees ◽

In Vivo Models ◽

Once Daily ◽

Refractory Multiple Myeloma ◽

Equity Ownership

Abstract Introduction: MRZ is a novel, irreversible, proteasome inhibitor (PI) under clinical development for the treatment of relapsed and refractory multiple myeloma (RRMM). MRZ potently inhibits the 3 proteolytic activities of the 20S proteasome with specificity and activity distinct from that of bortezomib (BZ) and carfilzomib (CFZ). The combination of MRZ and POM has demonstrated promising synergy in in vitro and in vivo models of MM. Methods: As of July 22, 2015, 22 of 36 planned patients (pts) were enrolled with 14 pts in the 3+3 dose-escalation stage and 8 pts into the Recommended Phase 2 Dose (RP2D) stage. All pts received ≥2 prior therapies that must have included both lenalidomide (LEN) and BZ, and have been refractory to their last therapy. Intravenous MRZ (0.3 to 0.5 mg/m2) was administered over 120 minutes on Days (D) 1, 4, 8, and 11; POM (3 or 4 mg) once daily on D1 through 21; and Lo-DEX (5 or 10 mg) once daily on D1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, and 23 of every 28-D cycle. Safety, pharmacokinetics (PK), cytogenetics, proteasome inhibition, and clinical response were assessed. Results: Pts were 68% male, median (range) age 62 yrs (31 - 76), and with a median of 5 (2 - 15) prior lines of therapy. All pts received prior BZ and LEN; 41% and 55% had also received prior CFZ and thalidomide (THAL), respectively. There were no DLTs during dose-escalation and the most common (>10% incidence) adverse events (AEs) related to any study treatment in the 22 pts included fatigue (41%), neutropenia (41%), anemia (27%), thrombocytopenia (23%), nausea (18%), diarrhea, dyspnea, insomnia, edema peripheral, and white blood cell count decreased (14%). The grade 3 AEs related to any study treatment in more than one pt included neutropenia (27%) and anemia (9%), pneumonia (9%), and thrombocytopenia (9%). The only grade 4 AE related to any study treatment was neutropenia in one pt. Tumor lysis syndrome (grade 2) related to study treatment was observed in 1 pt; 2 pts had grade 1 peripheral neuropathy (1 considered related to POM alone and 1 related to possibly MRZ and POM); 2 pts came off study and subsequently died from progressive disease (61 and 102 days after last dose); and 1 pt died suddenly during Cycle 1 due to cardiopulmonary arrest, considered possibly related to POM. Since no DLTs were observed the maximum tolerated dose was not exceeded, the highest dose cohort studied, MRZ 0.5 mg/m2, POM 4 mg, and Lo-DEX 10 mg, was determined to be the RP2D. All 17 pts with pre and post dose measurements demonstrated a rapid decrease in their myeloma proteins by C2D1. Preliminary IMWG response assessments provided for the 14 pts with response data through C3D1 included 9 (64%) with partial response (PR); 2 (14%) with minimal response (MR); and 3 (21%) with stable disease (SD). The overall response rate (PR) was 64% and the clinical benefit rate (MR + PR) was 79%. Subset analyses of these 14 pts included high risk cytogenetics (17p deletion and/or 4:14 chromosome translocation) and prior CFZ treatment. In the high risk cytogenetics there were 4/5 PRs and 1/5 MR. Of the 7 pts with prior CFZ treatment there were 5 with PR and 2 with SD, and all 4 pts who had CFZ in their last regimen achieved PR. There was ~100% inhibition of the chymotrypsin-like subunit as early as C1D11, with robust inhibition of the trypsin-like and caspase-like subunits evolving over time in whole blood assays. MRZ, POM, and Lo-DEX PK are in process and will be presented. Conclusions: MRZ in combination with POM and Lo-DEX was generally well tolerated and demonstrated promising activity in heavily pre-treated pts with RRMM including those with high risk cytogenetics and who were refractory to prior treatment with CFZ. The trial will enroll up to 22 pts at the RP2D (36 pts total) to provide additional safety and efficacy data. Disclosures Off Label Use: marizomib for relapsed multiple myeloma. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Zonder:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support. Harrison:Celgene: Honoraria, Research Funding. Khot:Amgen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Janssen: Honoraria. Chauhan:Triphase: Consultancy. Anderson:Celgene: Consultancy; Millennium: Consultancy; BMS: Consultancy; Gilead: Consultancy; Oncopep: Equity Ownership; Acetylon: Equity Ownership. Reich:Triphase Accelerator Corporation: Consultancy. Trikha:Triphase Accelerator Corporation: Employment. Richardson:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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