Pharmacokinetic and Safety of CT-P10, a Biosimilar Candidate to the Rituximab Reference Product, in Patients with Newly Diagnosed Advanced Stage Follicular Lymphoma (AFL)

Abstract Background: CT-P10 is a biosimilar candidate to the reference rituximab product, EU-approved MabThera® and US-licensed Rituxan®. CT-P10 has an identical amino acid sequence and highly similar physicochemical and in vitro functional properties to its reference drug. In patients with rheumatoid arthritis, CT-P10 has demonstrated compelling similarity in pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety and immunogenicity (Yoo DH, et al. Arthritis Rheum. 2013;65(10):1736). Objective: The goal of this study was to demonstrate PK similarity of CT-P10 to rituximab, each administered in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed Advanced Follicular Lymphoma (AFL) (NCT02162771) (Kim WS et al. Blood. 2015;126(23): 5111). The results of PK, PD, safety and immunogenicity up to Core Cycle 4 (12 weeks) are presented here from this ongoing study. Methods: Patients with AFL were randomized 1:1 to receive infusion (375mg/m2) of either CT-P10 or rituximab, at a 3-week interval, in combination with CVP. PK analysis was conducted in terms of AUCtau and Cmax at steady state, Core Cycle 4, as primary PK endpoints. PK parameter values considered as outliers determined by robust regression outlier testing were excluded from the pharmacokinetic primary analysis. Results: In total, 121 patients were randomly assigned to receive either CT-P10 (n=59) or rituximab (n=62) in combination with CVP. Result of CT-P10 PK at Core Cycle 4 was similar to that of rituximab. The ratios (90% CI) of geometric least square means (CT-P10 to rituximab treatment group) were 102.3% (94.1%-111.2%) for AUCtau and 100.7% (93.8%-108.0%) for CmaxSS at Core Cycle 4. The 90% CIs of ratio of geometric LS means for both AUCtau and CmaxSS were entirely contained within the equivalence margin of 80% to 125% (Table 1 and Figure 1). Mean serum concentrations of the study drug were highly similar for the 2 treatment groups at each time point (Core Cycle 1 to 4). The B-cell kinetics was similar up to Core Cycle 4 in the 2 treatment groups. Median number of B-cells decreased to below the lower limit of quantification (LLoQ) (20 cells/μL) 1 hour after the end of infusion at Core Cycle 1 and remained below the LLoQ at each subsequent cycle, up to and including Core Cycle 4. The proportion of patients with a positive anti-drug antibody up to Core Cycle 4 at post-treatment visits was similar between the 2 treatment groups; 3/59 (5.1%) patients and 2/62 (3.2%) patients in the CT-P10 and rituximab groups, respectively. In addition, CT-P10 was well tolerated and the safety profile of CT-P10 up to Core Cycle 4 was similar to that of rituximab. The number of patients who experienced at least 1 treatment emergent adverse event (TEAE) was 43 (72.9%) patients and 41 (66.1%) patients in CT-P10 and rituximab treatment groups, respectively. The proportion of patients who experienced at least 1 treatment emergent serious adverse event considered by the investigator to be related to the study treatment was similar between the 2 treatment groups; 2/59 (3.4%) patients and 2/62 (3.2%) patients in the CT-P10 and rituximab groups, respectively. The frequencies of adverse events special interest (AESI) were similar between the 2 treatment groups (Table 2). Conclusion: This study demonstrated similarity of PK in terms of AUCtau and CmaxSS between CT-P10 and rituximab in AFL patients. The B-cell kinetics and immunogenicity were comparable between the two treatment groups. CT-P10 was well tolerated with a safety profile comparable to that of rituximab up to and including Core Cycle 4 (12 weeks). Table 1 Statistical Analysis of Rituximab Pharmacokinetic Primary Endpoints for Core Cycle 4 at Steady State: Pharmacokinetic Population Table 1. Statistical Analysis of Rituximab Pharmacokinetic Primary Endpoints for Core Cycle 4 at Steady State: Pharmacokinetic Population Figure 1 Mean (±SD) Serum Concentration of Rituximab Versus Time for Cycle 4 at Steady State (Linear Scale): Pharmacokinetic Population Figure 1. Mean (±SD) Serum Concentration of Rituximab Versus Time for Cycle 4 at Steady State (Linear Scale): Pharmacokinetic Population Table 2 The Incidence Rates of Adverse Events Special Interest: Safety Population Table 2. The Incidence Rates of Adverse Events Special Interest: Safety Population Disclosures Coiffier: Celltrion, Inc.: Consultancy, Honoraria. Sancho:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jurczak:Celltrion, Inc: Research Funding; Gilead Sciences: Research Funding; Acerta: Research Funding; Bayer: Research Funding; Janssen: Research Funding. Kim:Celltrion, Inc.: Research Funding. Nagarkar:Celltrion, Inc.: Research Funding. Zhavrid:Celltrion, Inc.: Research Funding. Hernandez Rivas:Celltrion, Inc.: Research Funding. Prokharau:Celltrion, Inc.: Research Funding. Zodelava:Celltrion, Inc.: Research Funding. Osmanov:Celltrion, Inc.: Research Funding. Ogura:SymBio Pharmaceuticals: Consultancy, Honoraria; Celltrion, Inc.: Consultancy, Honoraria. Buske:Celltrion, Inc.: Consultancy, Honoraria. Kwak:Celltrion, Inc.: Consultancy. Kim:Celltrion, Inc.: Consultancy, Honoraria.

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Post-Approval Safety Study (PASS) of Lenalidomide Compared with Other Treatments in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.1867.1867 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1867-1867

Author(s):

Michele Cavo ◽

Luciano Masini ◽

Igor W. Blau ◽

Miguel T. Hernandez ◽

Renato Zambello ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Second Primary ◽

Safety Study ◽

Advisory Committees ◽

Treatment Groups ◽

Prior Therapy ◽

Non Invasive ◽

Grade 3

Abstract Abstract 1867 Background: In recent years, there have been major advances in the treatment of multiple myeloma (MM) as patients now have treatment options that greatly improve clinical outcomes. Many publications have described the safety of anti-myeloma drugs in the clinical trial setting. However, very few have addressed the issue of tolerability of these agents in a real-world clinical setting. Lenalidomide is an effective treatment option for MM and is currently approved by the EMA and US FDA for the treatment of MM patients who have received at least 1 prior therapy. Here we analyze the tolerability of 3 common novel agent-based anti-myeloma therapies in daily clinical practice. Methods: This observational post-authorization safety study was designed to characterize the safety profile of lenalidomide and to compare the incidence of adverse events (AE) with those occurring in patients receiving other anti-myeloma treatments. Patients entering the study had previously received at least 1 prior therapy and were commencing a new treatment for their relapsed/refractory MM (RRMM). Patients were enrolled into the Lenalidomide Cohort (lenalidomide plus dexamethasone) or the Background Cohort (all other treatments) based on investigator's discretion. Thromboprophylaxis was allowed, but not required. Results: As of July 2011, 2201 RRMM patients in 265 institutions in 17 European countries were enrolled. 1500 received lenalidomide, 538 bortezomib, 90 thalidomide, and 73 received other therapies or had missing data. 75 patients from the Background Cohort crossed over to receive lenalidomide. Median follow-up was 20.7 weeks (range, 0.1–125.7 weeks). Overall, the median age was 69 years (range, 29–92) and 55% were male. Most patients had a good performance status (ECOG 0–1) but 18% had an ECOG score of 2–4. The median number of previous treatment lines was 2 (1–6), 51.5% had 2 previous lines and 24% had 3 or more. Baseline characteristics across treatment groups were similar. Patients receiving lenalidomide had a median treatment duration of 4.4 months; patients receiving bortezomib and thalidomide had 3.4 months and 3.7 months, respectively. NCI grade 3/4, serious and life threatening AEs are presented in the table. Venous thromboembolism was experienced in 5% of lenalidomide-treated patients (3% had grade 3/4); 0.7% of bortezomib-treated patients (0.6% had grade 3/4); 1 (1%) thalidomide-treated patient had grade 3/4. Peripheral neuropathy was observed in 10% of lenalidomide-treated patients (1% had grade 3/4); 28% of bortezomib-treated patients (4% had grade 3/4); and 21% of thalidomide-treated patients (2% had grade 3/4). Ten (0.5%) invasive second primary malignancies (SPM) were reported across all treatment groups; 5/1500 (0.3%) patients treated with lenalidomide, 4/538 (0.7%) with bortezomib, and 1/90 (1%) with thalidomide. Three cases of second primary hematologic malignancies (lenalidomide, 2; bortezomib, 1; thalidomide, none) and 7 cases of second primary solid tumors (lenalidomide, 3; bortezomib, 3; thalidomide, 1) were observed. Additionally in the lenalidomide group, 1 patient each developed a non-invasive basal cell carcinoma and a non-invasive fibrous histiocytoma. All of these patients were heavily pre-treated and most had received autologous stem cell transplantation to support high-dose melphalan during the course of their disease. 51% of patients in the lenalidomide group discontinued therapy while 65% and 71% discontinued bortezomib and thalidomide treatments, respectively. Primary reasons for discontinuation were adverse events (lenalidomide, 13%; bortezomib, 14%; thalidomide, 18%) and disease progression (lenalidomide, 15%; bortezomib, 13%; thalidomide, 17%). Overall, 1% of patients died due to an adverse event suspected to be related to drug (lenalidomide, 1%; bortezomib, 0%; thalidomide, 1%). Conclusion: Consistent with previous reports, lenalidomide is generally well tolerated. With the exception of peripheral neuropathy, adverse events in this group of patients treated in daily clinical practice appeared similar across treatment groups. Disclosures: Cavo: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Symeonidis:Novartis Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Genzyme: Research Funding; Pfizer: Research Funding; Gilead: Consultancy, Research Funding. Bird:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Genzyme: Membership on an entity's Board of Directors or advisory committees. Bacon:Celgene Corporation: Employment. Rosettani:Celgene Corporation: Employment. Kueenburg:Celgene Corporation: Employment. Minton:Celgene Corporation: Employment, Equity Ownership.

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Phase II Dose-Finding Study with TAK-442, An Oral Factor Xa Inhibitor, in Patients Undergoing Elective Knee Arthroplasty.

Blood ◽

10.1182/blood.v114.22.170.170 ◽

2009 ◽

Vol 114 (22) ◽

pp. 170-170 ◽

Cited By ~ 4

Author(s):

Jeffrey I. Weitz ◽

Charlie Cao ◽

Bengt Eriksson ◽

William D. Fisher ◽

Stuart Kupfer ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Primary Efficacy ◽

Advisory Committees ◽

Treatment Groups ◽

Safety Population ◽

Total Knee ◽

Dose Dependent ◽

Global Research

Abstract Abstract 170 TAK-442 is an oral, selective, direct competitive inhibitor of activated factor X (fXa). This phase 2, multicenter, randomized, parallel-group study compared a range of TAK-442 doses with enoxaparin for thromboprophylaxis after elective unilateral total knee arthroplasty. After surgery, males and females 18 years of age or older were randomly assigned to 1 of 7 treatment groups: TAK-442 at doses of 40 or 80 mg p.o. once daily (QD) or 10, 20, 40, or 80 mg p.o. twice daily (BID), or enoxaparin 30 mg s.c. BID (n=150 per group). Enoxaparin was given unblinded, whereas TAK-442 given double-blinded with regard to dose and regimen. The first dose of TAK-442 was administered 6-8 hours postoperatively and after hemostasis was established, while the first dose of enoxaparin was given 12-24 hours after surgery according to North American guidelines; TAK-442 and enoxaparin were given for 10 days and patients were followed for 30 days after the last dose of study drug. Bilateral ascending venography was performed after the last dose of study drug to screen for deep vein thrombosis (DVT). The primary efficacy endpoint was the composite of all-cause mortality, symptomatic and asymptomatic DVT, and pulmonary embolism (PE). The primary safety endpoint was major bleeding, based on a pre-specified bleeding scale. Independent, blinded committees adjudicated all suspected efficacy outcomes and bleeding events. Of the 1038 patients who received study drug and were included in the full analysis set (FAS) and safety population, 949 completed the study; 730 patients had evaluable venograms. Following the recommendation of the Data Safety Monitoring Board, the TAK-442 10 mg and 20 mg BID groups were discontinued prematurely because of lack of efficacy with respect to asymptomatic DVT. The incidences of the primary efficacy endpoint and its components in the population with evaluable endpoints, and of major bleeding in the safety population, are shown in the table.Values are n (%) unless otherwise specified.* P<0.05 vs enoxaparin. Patients in the FAS exhibited a similar trend in efficacy, with incidences of the composite primary endpoint of 28.8%, 25.8%, 16.7%, 14.8%, 18.8%, and 10.6%, respectively, across the TAK-442 doses, and 14.9% for enoxaparin. The minimum effective dose of TAK-442 was determined to be 40 mg QD, while the maximum dose of 80 mg BID tended to be more effective than enoxaparin in this study. The frequency of major and clinically significant non-major (CSNM) bleeding was not dose-dependent or different from that seen with enoxaparin. Similarly, the frequency of liver function test abnormalities was not dose-dependent or different from that seen with enoxaparin. Treatment-emergent AEs leading to study drug discontinuation occurred in 5.5% of the TAK-442 subjects and 7.5% of the enoxaparin subjects. In addition, the overall incidence of AEs or SAEs in the TAK-442 treatment groups was not dose-dependent or greatly different from that seen with enoxaparin 30 mg BID. These data suggest that, at total daily doses of 40 to 160 mg, the efficacy of TAK-442 is similar to that of enoxaparin 30 mg BID in patients undergoing total knee replacement. The low incidence of major and CSNM bleeding suggests that TAK-442 has a favorable benefit to risk profile in this population. Disclosures: Weitz: Daiichi-Sankyo: Consultancy; Bayer: Consultancy; BMS: Consultancy; Pfizer: Consultancy; Boehringer-Ingelheim: Consultancy; Takeda Global Research & Development, Inc.: Consultancy; Astra-Zeneca: Consultancy; The Medicines Company: Consultancy; Merck: Consultancy. Cao:Takeda Global Research & Development, Inc.: Employment. Eriksson:Takeda Global Research & Development, Inc.: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fisher:Bristol Myers Squibb: Research Funding; Takeda Global Research & Development, Inc.: Honoraria; Bayer: Consultancy, Honoraria, Research Funding; sanofi-aventis: Honoraria, Research Funding, Speakers Bureau; Boeringer-Ingelhiem: Consultancy, Speakers Bureau. Kupfer:Takeda Global Research & Development, Inc.: Employment. Raskob:Takeda Global Research & Development, Inc.: Consultancy; Bayer: Consultancy; BMS: Consultancy; Boehringer –Ingelheim: Consultancy; Daiichi-Sankyo: Consultancy; Johnson and Johnson: Consultancy; Pfizer: Consultancy; sanofi-aventis: Consultancy. Spaeder:Takeda Global Research & Development, Inc.: Employment, Equity Ownership. Turpie:Takeda Global Research & Development, Inc.: Consultancy; Astellas: Consultancy; Portola: Consultancy; Bayer: Consultancy; Johnson & Johnson: Consultancy.

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Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽

10.1182/blood-2019-127523 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1961-1961

Author(s):

John F. DiPersio ◽

Jonathan Hoggatt ◽

Steven Devine ◽

Lukasz Biernat ◽

Haley Howell ◽

...

Keyword(s):

Single Dose ◽

Adverse Events ◽

Board Of Directors ◽

Preliminary Data ◽

Research Funding ◽

Fold Change ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

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Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-123887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1956-1956

Author(s):

Amy Wang ◽

Justin Kline ◽

Wendy Stock ◽

Satyajit Kosuri ◽

Andrew S. Artz ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Stem Cell ◽

Adverse Events ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Checkpoint Inhibitors ◽

Advisory Committees ◽

Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: 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; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: 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, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

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Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: 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; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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Final Results of Phase 1/1b Study of Tenalisib, Dual PI3K δ/γ Inhibitor in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽

10.1182/blood-2019-123954 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2831-2831 ◽

Cited By ~ 1

Author(s):

Swaminathan P. Iyer ◽

Brad M. Haverkos ◽

Jasmine Zain ◽

Radhakrishnan Ramchandren ◽

Mary Jo Lechowicz ◽

...

Keyword(s):

T Cell ◽

Adverse Events ◽

Board Of Directors ◽

Dose Escalation ◽

Safety Profile ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Clinical Activity ◽

Advisory Committees

Introduction: Tenalisib (RP6530) is a novel, highly specific, dual PI3K δ/γ inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. PI3K plays a critical role in T-cell development and activation and several studies have validated the PI3K-AKT pathway as a potential therapeutic target in T cell lymphomas. Preliminary results of the ongoing Phase 1/1b T-cell lymphoma (TCL) study demonstrated an acceptable safety profile with encouraging clinical activity in relapsed/refractory TCL (Oki, ASCO 2018 and Iyer, ASH 2018). We now present the final results of the study (NCT02567656). Methods: This study comprised of four-dose escalation cohorts, followed by two dose expansion cohorts at MTD enrolling 20 patients each in PTCL and CTCL cohorts. Patients had histologically confirmed TCL, ECOG PS ≤2, and had received ≥1 prior therapy. Patients received Tenalisib [200 mg BID-800 mg BID (fasting), 800 mg (fed only)] orally until progression or unacceptable toxicity. The primary objectives were to determine the MTD and pharmacokinetic profile. The secondary objective was to evaluate overall response rate (ORR) and duration of response. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2007) and mSWAT respectively. Adverse events were graded according to CTCAE v4.03. Results: Fifty-eight patients were enrolled in study, 19 in dose escalation and 39 in dose expansion (28 PTCL and 30 CTCL). Median number of prior therapies was 4 (range, 1-15). Safety assessment of 58 patients receiving at least one dose of Tenalisib demonstrated an acceptable safety profile. Treatment related Grade≥3 AEs were elevated ALT/AST (21%), rash (5%), and hypophosphatemia (3%). These events were reversible and managed by withholding study drug. Additionally, in few patients (N=9), steroids were used to manage elevated ALT/AST. There were six treatment related serious adverse events, none of these led to fatal outcome. At end of the study, four (3 CTCL; 1 PTCL) patients who completed minimum 8 cycles of therapy were rolled over to a compassionate use study (NCT03711604) and were followed up. Efficacy assessments demonstrated an ORR of 46% (3 CR and 13 PR) and clinical benefit rate (CR+PR+SD) of 77%. Subset efficacy analysis showed an ORR in PTCL of 47% (3 CR; 4 PR) and in CTCL of 45% (9 PR). The median time to initial response was 1.8 months and was similar in both sub-types. The overall median DOR was 4.91 months (range 0.9-26.6); in PTCL patients the DOR was 6.53 months, (range: 0.97-21.0) and 3.8 months (range: 1.67-25.67) in CTCL patients. In 3 PTCL patients who achieved CR, the median DOR was 19.5 months (range 7.5-21). Conclusion: Tenalisib demonstrated promising clinical activity and an improved safety profile in patients with relapsed/ refractory TCL. Currently, a phase I/II combination study to further evaluate safety and efficacy with romidepsin is ongoing in this target population. Disclosures Iyer: Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Dermira: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Routhu:Rhizen Pharmaceuticals S.A.: Employment. Barde:Rhizen Pharmaceuticals S.A.: Employment. Nair:Rhizen Pharmaceuticals S.A.: Employment. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding.

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Comparison of Steady-State Imatinib (IM) Trough Levels, Clinical Response, and Safety Between Caucasian and Asian Patients with Chronic Lyeloid Leukemia in Chronic Phase (CML-CP) Treated with 400mg and 800mg Daily Doses of IM in the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) Study.

Blood ◽

10.1182/blood.v114.22.1127.1127 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1127-1127

Author(s):

Dong-Wook Kim ◽

Camille Granvil ◽

Eren Demirhan ◽

John Reynolds ◽

Yu Jin ◽

...

Keyword(s):

Adverse Event ◽

Steady State ◽

Clinical Response ◽

Board Of Directors ◽

Research Funding ◽

Average Dose ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3 ◽

Trough Levels

Abstract Abstract 1127 Poster Board I-149 Background In the TOPS study, IM trough levels (Cmin) were collected from different race groups, mainly Caucasian and Asian, but also Black and others. Inter-ethnic differences in the PK of a drug are known to be important factors accounting for inter-individual variation in drug responsiveness. This analysis reports the comparison between Caucasian and Asian CML patients (pts) treated at doses of 400 mg QD and 400 mg bid (800 mg daily) of IM Cmin on Day 29 of initial treatment, clinical response, safety and tolerability. Methods Steady state IM Cmin on Day 29 and clinical response and safety data obtained during the first 12 months (mos) of treatment were obtained from pts randomized 2:1 to 800 mg or 400 mg daily IM. The steady-state Cmin was defined as predose concentration collected approximately within ±3 hours of the scheduled dosing time on Day 29. The associations of race with the rates of major molecular response (MMR) and complete cytogenetic response (CCyR) were evaluated. Correlation of IM exposure with clinical response (MMR and CCyR) was assessed by grouping pts into quartiles based on their measured IM Cmin levels at Day 29. The safety endpoint for each pt was the presence or absence of an adverse event (AE) of grade 3 or higher in the first 12 mos from the first dose. Results IM Cmin levels were available from 229 pts in TOPS including 54 Caucasians, 18 Asians, and 14 Black and others at 400 mg (total 86) and 103 Caucasians, 29 Asians, and 11 Black and others at 800 mg (total 143). For the first 12 mos, the means of the average dose intensities for Asian (mean [range], 362 [267-400] in 400 mg and 666 [226-800] in 800 mg) were not significantly different from Caucasian (386 [204-597] in 400 mg and 666 [289-800] in 800 mg) (P=0.070 and P=0.995 for the 400 mg and 800 mg arms, respectively). Mean (± SD) of IM Cmin levels (ng/mL) with respect to race are shown in Table 1. IM Cmin was slightly over-proportional to dose and showed large interpatient variability (CV=42-60%) for both dose groups regardless of the race group. In the lower quartile Cmin group (Cmin<1290 ng/mL), the differences in CCyR and MMR rates between Asian and Caucasian pts were significant (P=0.031 and P=0.022 respectively), which was probably due to a higher rate of dose interruptions in the 1st 12 mos in Asian pts. A definitive conclusion cannot be drawn due to the small number of Asian pts. Occurrences of at least one grade 3 or 4 adverse event were found to be significantly higher in Asian pts (69% and 75% in the 1st 6 and 12 mos respectively) compared to Caucasian pts (53% and 57% in the 1st 6 and 12 mos respectively) (P=0.028 and P=0.008 respectively). Conclusion The results of this analysis from TOPS show that IM Cmin levels were similar between Caucasian and Asian CML pts in each treatment arm. There were no major differences in efficacy, as measured by MMR and CCyR rates by 12 mos, between Asian and Caucasian pts. There were no unexpected differences in patterns of AEs between Caucasian and Asian pts; however, occurrences of one or more grade 3 AEs were higher in Asian. Further analysis on a larger group of CML pts will be needed to evaluate the impact of AE rate differences between Caucasian and Asian pts. Disclosures Kim: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Granvil:Novartis: Employment. Demirhan:Novartis: Employment. Reynolds:Novartis: Employment. Jin:Novartis: Employment. Wang:Novartis: Employment, Equity Ownership. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria.

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Phase Ib Study of Oral Panobinostat In Combination with 5-Azacitidine (5-aza) In Patients with Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v116.21.4957.4957 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4957-4957 ◽

Cited By ~ 1

Author(s):

Pierre Fenaux ◽

Daniel J DeAngelo ◽

Guillermo Garcia-Manero ◽

Michael Lübbert ◽

Anand P. Jillella ◽

...

Keyword(s):

Febrile Neutropenia ◽

Adverse Events ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Myelomonocytic Leukemia ◽

Advisory Committees ◽

Dose Cohort ◽

Phase Ib ◽

Myelomonocytic Leukemia

Abstract Abstract 4957 Background: Panobinostat is a potent pan-deacetylase inhibitor (pan-DACi) that causes increased acetylation of target proteins such as HSP90, p53, α-tubulin and HIF-1α which are involved in cell cycle regulation, gene transcription, angiogenesis, and tumor cell survival. Preliminary evidence from phase I trials has demonstrated anti-tumor activity in patients with hematologic malignancies including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The advent of hypomethylating agents, such as 5-aza, represent a significant advancement in the treatment of MDS, chronic myelomonocytic leukemia (CMML), and AML. Although an improvement in clinical outcomes has been observed, including increased overall survival in patients with MDS, a substantial number of patients do not benefit from the therapies currently available. Preclinical studies suggest that the combination of a demethylating agent and a pan-DACi represents a rational strategy to reverse silencing of tumor suppressor genes, which contributes to the malignant phenotype, and improve outcomes in patients with MDS and AML. In this study, the combination of the pan-DACi, panobinostat, and the hypomethylating agent, 5-aza, was evaluated in patients with MDS, CMML and AML. Methods: This phase Ib, open-label, multicenter, dose-finding study is comprised of 2 stages: a dose-escalation stage to determine the maximum tolerated dose (MTD) of panobinostat in combination with standard dose 5-aza, and a subsequent expansion stage to evaluate safety, tolerability, and preliminary activity at the MTD dose level. The primary endpoint is incidence of dose-limiting toxicity (DLT) and secondary endpoints include type, duration, frequency, and relationship of adverse events (AEs) to the combination. Exploratory endpoints include clinical response and hematologic improvement according to IWG response criteria, and biomarker analysis of methylation status and expression of disease-associated genes in peripheral blood cells prior to and during therapy. Adult patients with IPSS INT-2 or high-risk MDS, CMML, or AML with multi-lineage dysplasia and ≤ 30% marrow blasts who are candidates for therapy with 5-aza and have not received a prior hypomethylating agent or pan-DACi are eligible for enrollment on the trial. Oral panobinostat was administered on Days (D) 3, 5, 8, 10, 12, and 15, starting at 20 mg, in combination with 5-aza (75 mg/m2 sc D 1–7) during a 28-D cycle. Patients received treatment for ≤ 6 cycles or until progression of disease, incidence of unacceptable toxicity, or withdrawal of consent. Results: To date, 11 patients have been enrolled including 9 patients with MDS, 1 patient with AML and 1 patient with CMML. The median age of patients enrolled on the trial was 69.0 (60-80). Patients have been evaluated at 2 panobinostat dose cohorts; 6 (20 mg) and 5 (30 mg). The AE analysis is based on 9 patients (6 from 20 mg cohort and 3 from 30 mg cohort) and the nature and incidence of AEs observed in the two cohorts were similar. Adverse events regardless of study drug relationship included nausea (4 [44%]), vomiting, fatigue (5 [55%] each) and asthenia (3 [33%]). Grade 3/4 AEs suspected to be treatment related included thrombocytopenia (2 [22%], febrile neutropenia and arthritis (1 [11%] each). Serious adverse events observed included febrile neutropenia, asthenia (2 [22%] each), atrial fibrillation and septic shock (1 [11%] each). One DLT has been observed (grade 4 febrile neutropenia) in the 20 mg panobinostat dose cohort. Conclusions: Panobinostat has been well tolerated up to a dose of 30 mg in combination with 5-aza (75 mg/m2) with dose escalation ongoing. Patients are currently being enrolled at the 40mg dose cohort. The most common AEs observed included febrile neutropenia, thrombocytopenia with one DLT observed (grade 4 febrile neutropenia) in the 20mg panobinostat dose cohort. The current data show that the addition of panobinostat to 5-aza is safe with no unexpected toxicities. Updated data, including safety and preliminary efficacy data will be presented at the meeting. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Off Label Use: Panobinostat is an investigational agent currently being evaluated for the treatment of hematologic and solid malignancies. DeAngelo: Novartis: Membership on an entity's Board of Directors or advisory committees. Sekeres: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Winiger: Novartis Pharma AG: Employment. Squier: Novartis: Employment. Li: Novartis: Employment. Ottmann: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A Multicenter, Phase IV Observational Study Of Ofatumumab In Chronic Lymphocytic Leukemia (CLL): A European Research Initiative On CLL (ERIC) Study

Blood ◽

10.1182/blood.v122.21.1645.1645 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1645-1645 ◽

Cited By ~ 1

Author(s):

Carol Moreno ◽

Marco Montillo ◽

Panayiotidis Panayiotis ◽

Adrian Bloor ◽

Jehan Dupuis ◽

...

Keyword(s):

Clinical Trials ◽

Adverse Events ◽

Board Of Directors ◽

Safety Profile ◽

Research Funding ◽

Response Rate ◽

Lymphocytic Leukemia ◽

Hematologic Toxicity ◽

Phase Ii Trials ◽

Advisory Committees

Abstract Background Ofatumumab was given a conditional approval in the EU on April 2010 for the treatment of CLL refractory to fludarabine (F-ref) and alemtuzumab (A-ref), encouraging the retrieval of further data in patients treated in a “daily life” setting and to investigate treatment safety. Aims The main objective of this study was to obtain information on the safety profile of ofatumumab given outside clinical trials in patients with previously treated CLL. The secondary endpoints were efficacy, progression-free-survival (PFS), and overall survival (OS). Methods This was an observational, retrospective study. Patients were eligible regardless of prior treatments or disease status and provided they had not been included in ofatumumab clinical trials. Data on patients’ characteristics at diagnosis, prior treatment, adverse events response rate, PFS and OS were recorded. Results One-hundred and twenty patients were screened of which 103 from 25 centers in 10 European countries were eventually eligible for the study. There were 71 males; median age at initiation of ofatumumab was 64 years (range, 38-84); 66% patients were in advanced clinical stage (Rai III-IV/Binet C) and 33 patients presented bulky lymphadenopathy. Number of prior lines of therapy was 4 (range, 1-13). 94% had received prior F-based therapy, 54% received A-based therapy and 51% received both. Eighty-one percent had been previously exposed to rituximab-combination regimens. Fifty-four percent were F-ref, 70% A-ref and 41% were both F- and A-refractory. Cytogenetics within 3 months prior therapy was available in 52 patients of which 34 presented abnormalities (11 patients: 17p-; 9 patients: 11q-; 2 patients: 13q-; 1 patient: trisomy 12; 11 patients: two or more abnormalities including 17p- or 11q-). Forty-two of 50 patients showed unmutated IGHV genes. The median number of cycles of ofatumumab given was 9 (range, 0-16) and the median percentage of given/planned cycles was 83.3% (range, 0-133). In most patients the treatment dose and schedule were as follows: 300 mg 1st infusion followed by 2000 mg for subsequent infusions (8 weekly followed by 4 doses monthly). One hundred and sixty-one adverse events were reported in 68 patients, with 28 (17%) of them being considered as ofatumumab-related. Infusion related-reactions occurred in 19 (28%) patients (III-IV: 6%). Neutropenia was reported in 26% (III-IV: 19%), thrombocytopenia in 15% (III-IV: 12%) and anemia in 15% (III-IV: 7%). The non-hematological adverse events, included infection 44% (III-IV: 36%), fatigue 10% (III-IV: 4%), fever 10% (III-IV: 6%), rash 10% (III-IV: 3%), cough 7% (III-IV: 1%), diarrhea 6% (grade III-IV: 0%) and nausea 1% (III-IV: 0%). Hematologic toxicity correlated with the number of prior lines of therapy. Autoimmune hemolytic anemia and Richter syndrome were reported in one patient each. Two heavily pre-treated patients (5 and 6 prior lines of therapy, respectively) developed progressive multifocal leukoencephalopathy. The overall response rate (ORR) was 23% and the median PFS and OS were 5 and 12 months, respectively. The main causes of death were disease progression (61%) and infection (28%). Conclusions The safety profile of ofatumumab given outside clinical trials to patients with poor-prognosis and heavily pre-treated CLL was consistent with that observed in clinical trials. Although not unexpectedly the ORR was lower in this study, PFS and OS were in line with those reported in phase II trials. Disclosures: Montillo: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Bloor:GSK: Consultancy, Honoraria, Paid speaker Other. Schuh:GSK: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Geisler:Roche: Consultancy; GSK: Consultancy. Hillmen:GlaxoSmithKline: Honoraria, Research Funding. Stilgenbauer:GSK: Honoraria, support Other. Smolej:GSK: Consultancy, Honoraria, travel grants Other. Jaeger:GSK: Honoraria, Research Funding. Leblond:Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kimby:Roche: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding; Emergent BioSolutions: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding; Jansen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding.

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a Phase 1b/2 Study of TAK-659, an Investigational Dual SYK and FLT-3 Inhibitor, in Patients (Pts) with Relapsed or Refractory Acute Myelogenous Leukemia (R/R AML)

Blood ◽

10.1182/blood.v128.22.2834.2834 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2834-2834 ◽

Cited By ~ 9

Author(s):

Jason B Kaplan ◽

Dale L. Bixby ◽

John C Morris ◽

Olga Frankfurt ◽

Jessica Altman ◽

...

Keyword(s):

Tyrosine Kinase ◽

Pharmaceutical Company ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Advisory Committees ◽

Company Limited ◽

Safety Population ◽

Wholly Owned Subsidiary ◽

Phase 1B

Abstract Background Spleen tyrosine kinase (SYK) is a nonreceptor cytoplasmic protein kinase and a key mediator of immunoreceptor signaling that has been shown to play an important role in the pathogenesis of both B-cell and myeloid malignancies. SYK has also been shown to directly bind and activate FMS-like tyrosine kinase 3 (FLT-3), a Class III receptor tyrosine kinase that is commonly mutated in approximately 30% of pts with AML (Puissant et al. Cancer Cell 2014;25:226-42). TAK-659 is an investigational, reversible, and potent dual inhibitor of SYK and FLT-3. Preclinical studies with TAK-659 have demonstrated growth inhibition of cell lines and xenograft tumor models of B-cell lymphoma or AML origin. Moreover, TAK-659 has exhibited antitumor activity in lymphoma pts in an ongoing clinical trial (Petrich et al. Blood 2015;126:2693). The primary objectives of the phase 1b dose-finding portion of this study are to evaluate the safety, tolerability, and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of TAK-659, as well as preliminary efficacy in the phase 2 expansion study. Secondary objectives include evaluation of TAK-659 pharmacokinetics (PK) in this pt population. Methods During dose escalation using a 3x3 schema, adult pts with R/R AML received oral TAK-659 daily (QD) in 28-d cycles (C) starting with a dose of 60 mg. Adverse events (AEs) were assessed per NCI-CTCAE v4.03. Response per IWG criteria for AML was assessed between d22 and d28 of C1, C2, and C4. Blood samples for plasma pharmacokinetic (PK) assessments were collected pre-dose and at multiple times post-dose on d1 and d15 of C1. The pharmacodynamic effect of TAK-659 was assessed at multiple time points by measuring the phosphorylation of ribosomal protein S6 (pS6) in peripheral AML blasts using flow cytometry. FLT-3 mutation status (wild type [FLT-3-WT], FLT-3-ITD, or point mutation [FLT-3-D835Y]) was assessed using a PCR-based assay at a central laboratory. The effect of TAK-659 treatment on FLT-3-ITD phosphorylation was evaluated using a plasma inhibitory assay (PIA) as previously described (Levis et al. Blood 2006;108:3477-83). Results At data cut-off (June 9, 2016), 15 pts had been enrolled at TAK-659 QD 60 mg (n=4), 100 mg (n=7), or 120 mg (n=4). No dose-limiting toxicity per protocol has been observed. Dose escalation is currently ongoing at 160 mg QD. In the safety population (n=13), median age was 67 yrs (range 25-86), 69% of pts were male, and 38% had received ≥4 prior lines of therapy. Baseline mutation data was available for 12 pts: 6 pts were FLT-3-WT, 3 pts had FLT-3-ITD, 1 pt had FLT-3-D835Y, and 2 pts had concurrent FLT-3-ITD/D835Y mutations. In the safety population, all-grade drug-related AEs occurred in 12 (92%) pts overall; the most common were elevated AST (31%), ALT (23%), and amylase levels (23%). Grade ≥3 drug-related AEs occurred in 7 (54%) pts including: increased ALT, AST, and amylase levels, cataract, positive fungal test, macular fibrosis, pancreatitis, pneumocystis jirovecii pneumonia, rash, and fungal sinusitis (each 1pt). Blood LDH levels were increased in almost all pts (significance unknown). Three pts discontinued TAK-659 due to AEs and 3 pts died on study; none of these events were considered related to the study drug. Preliminary plasma PK of TAK-659 (n=11, 60-100 mg) was characterized by rapid absorption (median Tmax of 2 hours), moderate variability in steady-state exposures (42% coefficient of variation for C1 d15 dose-normalized AUCtau), and mean accumulation of 2.1-fold after repeated QD dosing for 15 days. Of 9 pts evaluated to date, pS6 was detected at baseline and reduced after dosing in 4 pts (2 FLT-3-ITD; 2 FLT-3-WT). At 60 mg and 100 mg TAK-659, up to 70% inhibition of FLT-3-ITD phosphorylation was observed as assessed by PIA. Early signs of clinical activity were observed, with decreases in peripheral blood myeloblasts observed in some pts. Assessment is ongoing and preliminary efficacy data will be presented. Conclusions TAK-659 has a unique mechanism of action with dual inhibition of SYK and FLT-3. Dose escalation to determine the MTD/RP2D is ongoing. TAK-659 exhibits an acceptable PK profile in R/R AML pts, supporting continuous oral QD dosing. Disclosures Kaplan: Seattle Genetics: Research Funding; Janssen: Research Funding. Morris:Boehringer-Ingelheim: Speakers Bureau. Altman:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syros: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wise-Draper:Merck: Research Funding. Collins:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Kannan:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Wang:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faucette:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Lee:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shou:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Levis:Millennium: Consultancy, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria.

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