scholarly journals Lyra: A Phase 2 Study of Daratumumab (Dara) Plus Cyclophosphamide, Bortezomib, and Dexamethasone (Cybord) in Newly Diagnosed and Relapsed Patients (Pts) with Multiple Myeloma (MM)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 152-152 ◽  
Author(s):  
Habte Yimer ◽  
Jason Melear ◽  
Edward Faber ◽  
William Bensinger ◽  
John M Burke ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Split Dose ◽  
Phase 2 Study ◽  
Equity Ownership ◽  
Grade 3 ◽  
Line Of Therapy

Abstract Background: Dara, a human IgGκ monoclonal antibody that targets CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of newly diagnosed (ND) MM. CyBorD is another commonly used immunomodulatory drug-sparing regimen for MM. We evaluated the safety and efficacy of dara-CyBorD and administered the first dara infusion as a split dose over 2 days in pts with NDMM or relapsed MM (RMM) after 1 prior line of therapy. Methods: This is an ongoing, multicenter, single-arm, open-label, phase 2 study conducted at US community oncology centers in pts aged ≥18 years with documented MM per IMWG criteria; measurable disease; ECOG performance score (PS) of 0-2; and ≤1 prior line of therapy. Pts received 4-8 cycles (C) of dara-CyBorD (oral cyclophosphamide 300 mg/m2 on Days 1, 8, 15, and 22; subcutaneous bortezomib 1.5 mg/m2 on Days 1, 8, and 15; and oral or IV dexamethasone 40 mg weekly) every 28 days. Dara was administered at 8 mg/kg IV in 500 ml on Days 1 and 2 of C1, 16 mg/kg weekly from C1D8 through C2, 16 mg/kg every 2 weeks (q2w) for C3-6, and 16 mg/kg q4w for C7-8. After induction, pts could undergo autologous stem cell transplantation (ASCT). All pts receive 12 cycles of maintenance dara 16 mg/kg IV q4w. The primary endpoint was the proportion of pts achieving very good partial response or better (VGPR+) after 4 induction cycles using a computer algorithm based upon IMWG response criteria. Results: A total of 101 (87 ND, 14 RMM) pts were enrolled; 100 (86 ND, 14 RMM) pts received at least 1 dose of study treatment. Median age was 63 years (63 ND, 68 RMM); most pts were white (81%), male (64%), had ECOG PS 0-1 (94%), and had IgG (57%) or IgA (17%) MM; 35% of pts had high-risk cytogenetics defined as del(17p), t(4:14), or t(14;16). Eighty-two ND pts completed at least 4 induction cycles, 55 at least 6 cycles, and 26 the maximum of 8 cycles; 28 ND pts underwent ASCT by the data cutoff date. After 4 induction cycles, 44% of ND pts achieved VGPR+ (5% CR) with an overall response rate (ORR) of 79%. The VGPR+ rate (57%), CR rate (14%), and ORR (71%) were similar in RMM pts. At the end of induction (median 6 cycles), the VGPR+ rate, CR rate, and ORR in ND pts were 56%, 9%, and 81%, respectively. With a median follow up of 7.9 months, median PFS and OS were not reached; the 12-month PFS and OS rates were 87% and 99%, respectively, in ND pts. All 100 evaluable pts experienced ≥1 treatment-emergent adverse event (AE). AEs with incidence ≥20% included fatigue, nausea, diarrhea, cough, insomnia, vomiting, constipation, upper respiratory tract infection, dyspnea, headache, and back pain. Grade ≥3 AEs were reported for 56% of pts; the most common (≥10%) was neutropenia. Serious AEs (SAEs) occurred in 21% of pts; the most common (≥2%) were atrial fibrillation, bacteremia, pulmonary embolism, and mental status changes. AEs led to permanent treatment discontinuation in 3% of pts. Infusion reactions (IRs) occurred in 54% of pts, including 49% at C1D1 and 4% at C1D2; 2 Grade 3 IRs (hypertension, anaphylactic reaction) occurred at C1D1; no Grade ≥4 IRs occurred. The most common (≥5%) IRs were chills, cough, dyspnea, nausea, pruritus, and flushing. Median infusion time was 4.5 hours for C1D1, 3.8 hours for C1D2, and 3.5 hours for subsequent doses. Conclusion: Dara-CyBorD was active and well tolerated in pts with ND and RMM, including pts with high-risk cytogenetics. ORR, VGPR+, and CR rates improved with cycles 5-8 of induction, indicating that longer therapy with dara results in deeper response. Preliminary PFS and OS data in ND pts in the first year are comparable to dara-VMP. The safety profile was consistent with that previously reported for dara, with no new safety signals observed. Split first daratumumab dosing was feasible, reduced Day 1 infusion time, and resulted in a similar IR rate as previously described for single-dose administration. These findings indicate that dara-CyBorD, using a split-dose first infusion, can be safely administered in the community setting and may be an effective treatment option for pts with MM. www.clinicaltrials.gov identifier: NCT02951819 Figure 1. Kaplan-Meier estimate of progression-free survival (PFS) among patients with newly diagnosed multiple myeloma. Disclosures Yimer: AstraZeneca: Speakers Bureau; Puma Biotechnology: Equity Ownership; Clovis Oncology: Equity Ownership; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Equity Ownership; Janssen: Speakers Bureau. Melear:Janssen: Speakers Bureau. Faber:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Burke:Gilead: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Tempus Labs: Consultancy. Narang:Janssen: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Stevens:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gunawardena:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Lutska:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Qi:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Ukropec:Janssen Scientific Affairs, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. Lin:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Rifkin:Amgen: Consultancy; McKesson: Equity Ownership; Boehringer Ingelheim: Consultancy; Celgene: Consultancy; EMD Serono: Consultancy; Takeda: Consultancy; Sandoz: Consultancy.

Bortezomib, Thalidomide, and Dexamethasone (VTD) Versus VTD Plus Cyclophosphamide as Induction Therapy in Previously Untreated Multiple Myeloma Patients Eligible for HDT-ASCT: A Randomized Phase 2 Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2312-2312 ◽  
Author(s):  
Heinz Ludwig ◽  
Luisa Viterbo ◽  
Richard Greil ◽  
Tamas Masszi ◽  
Ivan Spicka ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rates ◽  
Phase 2 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2312 Poster Board II-289 Bortezomib (Velcade®) has shown substantial activity and manageable toxicity in newly diagnosed multiple myeloma (MM) in combination with thalidomide (Thalomid®) and dexamethasone (VTD) in a phase 3 study (Cavo et al, ASH 2008), and with cyclophosphamide and dexamethasone (VCD) in a phase 2 study (Knop et al, ASCO 2009). Four-drug combinations may be more effective than 3-drug regimens, but may also be associated with increased toxicity. This randomized, non-comparative, open-label, multicenter, phase 2 study was designed to evaluate the efficacy and safety of VTD and VTD plus cyclophosphamide (VTDC) as induction therapy prior to high-dose therapy plus autologous stem cell transplant (HDT-ASCT). A total of 98 previously untreated MM patients with measurable disease who were candidates for HDT-ASCT were enrolled. Additional eligibility criteria included: age 18–70 years, Karnofsky Performance Status (KPS) ≥60%, adequate hematologic, hepatic, and renal function, and no grade ≥2 peripheral neuropathy (PN)/neuropathic pain. Patients were randomized (1:1), stratified by International Staging System (ISS) disease stage (I / II / III), to receive four 21-day cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, thalidomide 100 mg daily, and dexamethasone 40 mg on days 1–4 and 9–12 (VTD), or VTD plus cyclophosphamide 400 mg/m2 IV on days 1 and 8, as induction therapy prior to HDT-ASCT. All patients received antithrombotic prophylaxis. Patients who became ineligible for HDT-ASCT or had a complete response (CR) after induction therapy could receive an additional 4 cycles of treatment. Responses were categorized using modified IMWG Uniform Response Criteria (stringent CR [sCR] were unconfirmed by immunohistochemistry) through blinded review by the principal investigator and medical monitor, using central laboratory M-protein data and local bone marrow data. The primary efficacy endpoint was combined CR rate (sCR + CR + near-CR) following induction therapy. Secondary objectives included combined CR rate post-HDT-ASCT, overall response rate (ORR: ≥partial response) post-induction and post-HDT-ASCT, time to progression (TTP), overall survival (OS), and safety. Adverse events (AEs) were graded using NCI CTCAE v3.0. Forty nine patients were randomized to each arm; median age was 57 and 58 years in the VTD and VTDC arms, respectively, 53% and 51% of patients were male, 49% and 43% had KPS ≤80%, and 24 / 45 / 31% and 18 / 47 / 35% had ISS stage I / II / III MM. All but 7 patients completed induction; these patients discontinued due to AEs (3 [6%] each arm) and disease progression (1 [2%] VTDC). Four VTDC patients received additional cycles of treatment. One patient (VTDC arm) was not evaluable for response. Response rates following induction are shown in the table. Median CD34+ stem cell yields were 8.16 (VTD; n=48) and 8.13 (VTDC; n=40) x 106/kg. At data cut-off (April 10, 2009), 47 VTD and 35 VTDC patients had undergone HDT-ASCT; response rates post-HDT-ASCT in 38 and 27 evaluable patients are shown in the table. Time-to-event data are not mature (median follow-up: 9.8 months). The 1-year survival rate was estimated to be 94% in each arm. At least one AE was reported in 98% and 96% of patients on the VTD and VTDC arms, with at least one grade ≥3 AE reported in 47% and 59%, respectively. The most common non-hematologic grade 3/4 AEs included fatigue (2% and 8%) and constipation (6% and 2%); analyses of hematology laboratory values indicated grade 3/4 AEs of lymphopenia (39% and 77%), anemia (8% and 18%), neutropenia (14% and 18%), and thrombocytopenia (6% each). PN was reported in 35% (VTD) and 29% (VTDC) of patients, including 8% grade 3 in each arm and 2% grade 4 in the VTD arm. Two patients (1 [2%] each arm) had deep vein thrombosis; one (VTDC arm) was a grade 3 SAE. At least one serious AE (SAE) was reported in 22% (VTD) and 41% (VTDC) of patients, including 6% and 14% with SAEs of infections (MedDRA SOC), and 2% and 14% with musculoskeletal-related pain. In conclusion, both VTD and VTDC are highly active induction regimens, with CR rates and ORRs among the highest reported; the efficacy profiles were similar between the arms, but there were higher rates of toxicity in the VTDC arm compared with the VTD arm. Table. Response rates following induction and post-HDT-ASCT. Post-induction n=49 n=48 Combined CR*, % 51 44 sCR†, % 27 27 ORR, % 100 96 Post-HDT-ASCT n=38 n=27 Combined CR*, % 76 78 sCR, % 39 33 ORR, % 100 100 * sCR + CR + near-CR † unconfirmed Disclosures: Ludwig: Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria. Masszi:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees. Shpilberg:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen-Cilag: Honoraria. Dmoszynska:Milllennium: Research Funding. Cakana:Janssen Cilag: Employment, Equity Ownership. Enny:Johnson & Johnson: Employment, Equity Ownership. Feng:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership.

scholarly journals Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma with the Bispecific T-Cell Engager (BiTE®) Antibody Construct Blinatumomab: Primary Analysis Results from an Open-Label, Phase 2 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4460-4460 ◽  
Author(s):  
Andreas Viardot ◽  
Mariele Goebeler ◽  
Georg Hess ◽  
Svenja Neumann ◽  
Michael Pfreundschuh ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
Board Of Directors ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
Primary Analysis ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Treatment of relapsed or refractory DLBCL can be challenging and little progress has been made in recent years. Blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct, engages CD3+ cytotoxic T cells, resulting in T-cell expansion and lysis of CD19+ B cells. In a prior phase 1 study, blinatumomab treatment resulted in an overall response rate (ORR) of 55% in a subset of patients with diffuse large B-cell lymphoma (DLBCL). In the present phase 2 study, we compared stepwise versus flat dosing of blinatumomab, and evaluated its efficacy in patients with relapsed/refractory (r/r) DLBCL. Methods: Eligible patients were ≥18 years of age, had an Eastern Cooperative Oncology Group performance status ≤2 and had DLBCL; patients were refractory to treatment, had relapsed following autologous HSCT, or had relapsed and were ineligible for autologous hematopoietic stem cell transplantation (HSCT). Blinatumomab was administered over 8 weeks by continuous intravenous infusion. In stage 1, stepwise dosing (cohort I: 9, 28, and 112 μg/day after weeks 1, 2, respectively) was compared to constant dosing of 112 μg/day (cohort II). Based on the benefit/risk assessment from stage 1, stepwise dosing (9, 28, and 112 μg/day) was chosen for cohort III in stage 2. Patients achieving response after 8 weeks of treatment could receive a 4-week consolidation cycle after a 4-week treatment-free period. All patients received prophylactic dexamethasone (2 × 20 mg before infusion start and at infusion start; 3 × 8 mg/day for the first 2 days after infusion start and at dose step). The primary endpoint was ORR by Cheson revised response criteria for malignant lymphomas. Response was evaluated by independent radiologic assessment. Results: As of the primary analysis, 25 patients have been enrolled and treated: 9, 2, and 14 in cohorts I, II, and III, respectively. Fifty-six percent of patients were men, and the median age was 66 years (range, 34–85). Seven (28%) patients had received prior autologous HSCT. Blinatumomab was received as a fourth-line systemic therapy following a median (range) of 3 (1-7) prior treatments. Median (interquartile range) duration of exposure for stepwise dosing (cohorts I and III) was 46.8 (22.1−76.9) days. Twenty-one patients were evaluable for response (cohort I, n=7; cohort II, n=1; cohort III, n=13). Four patients were not evaluable for ORR per protocol definition due to early treatment discontinuation (<1 week on target dose in absence of disease progression): 1 discontinued due to investigator’s decision and 3 discontinued due to AEs. Fourteen patients have died (cohort I, n=5; cohort II, n= 1; cohort II, n=8). Eleven deaths were due to disease progression, one patient died of cardiogenic shock and one from organ failure following transplantation; no cause of death was reported for one patient. Among the evaluable 21 patients, 9 patients responded (4 CRs, 5 PRs) resulting in an ORR of 43%. All patients who responded did so within the first 8-week cycle. Among responders (n=9), median duration of response was 11.6 months. All patients experienced ≥1 adverse event (AE). Regardless of causality and grade, the most common AEs were tremor (52%), pyrexia (44%), diarrhea (24%), fatigue (24%), edema (24%), and pneumonia (24%). Twenty-four (96%) and 5 (20%) patients had grade 3 and 4 AEs, respectively. Serious AEs occurred in 23 (92%) patients, regardless of causality; the most common were pneumonia (24%), device-related infection (16%), and pyrexia (16%). Two patients had fatal on-study AEs (pneumonia and disease progression), assessed as unrelated to blinatumomab. Seven patients (cohort I, n=3; cohort II, n=2; cohort III, n=2) had grade 3 neurologic AEs (grade 3 AEs occurring in >1 patient were disorientation, encephalopathy, aphasia, and epilepsy [n=2 each]). There were no grade 4 or 5 neurologic events. Conclusions: In this phase 2 study, a stepwise dosing regimen (9, 28, and 112 μg/day) was established as the preferred dosing for blinatumomab in DLBCL. Treatment with blinatumomab showed an acceptable safety profile and resulted in objective and durable responses in heavily pretreated patients with r/r DLBCL. Disclosures Viardot: Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Travel support Other; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel support, Travel support Other; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Travel support Other. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Libicher:Amgen Inc.: Consultancy. Degenhard:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Stieglmaier:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Zhang:Amgen Inc.: Employment. Nagorsen:Amgen Inc.: Blinatumomab-related Patents & Royalties, Employment, Equity Ownership. Bargou:Amgen Inc.: Consultancy, Honoraria.

scholarly journals Open-Label, Phase 2 Study of Blinatumomab after First-Line Rituximab-Chemotherapy in Adults with Newly Diagnosed, High-Risk Diffuse Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4077-4077 ◽  
Author(s):  
Deborah A. Katz ◽  
Michael P. Chu ◽  
Kevin A. David ◽  
Catherine Thieblemont ◽  
Nicholas J. Morley ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Metabolic Response ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
First Line ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Background: Rituximab combined with chemotherapy (R-chemotherapy) is the standard of care first-line treatment for diffuse large B-cell lymphoma (DLBCL). Despite success with R-chemotherapy, 30% to 50% of patients with high-risk DLBCL will relapse, and outcomes are poor among patients who relapse within one year of diagnosis. Given the challenge of successful salvage, novel first-line therapies are needed. Blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct that directs cytotoxic T cells to lyse CD19-expressing B cells, has shown efficacy as salvage therapy in patients with relapsed or refractory DLBCL. This open-label, multicenter, phase 2 study (ClinicalTrials.gov, NCT03023878) assessed the efficacy and safety of blinatumomab after first-line R-chemotherapy for patients with newly diagnosed, high-risk DLBCL. Methods: Patients (≥18 y) had proven high-risk DLBCL (International Prognostic Index [IPI] 3−5 and double/triple hit or double MYC/BCL2 expressor) and Eastern Cooperative Oncology group performance status ≤2. To be eligible for blinatumomab, patients were required to achieve complete metabolic response (CMR), partial metabolic response (PMR), or stable metabolic response by PET/CT after a run-in period with 6 cycles of R-chemotherapy (R-CHOP, R-DA-EPOCH, or R-CHOEP). Blinatumomab was given by continuous intravenous infusion in a single 84-day cycle 1 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 42 days, followed by a 28-day treatment-free interval) and an optional 28-day cycle 2 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 14 days) for patients without progressive metabolic disease (PMD). The primary endpoint was the incidence and severity of adverse events (AEs). Additional endpoints were objective response rate (ORR [CMR + PMR]) per Lugano criteria, minimal residual disease (MRD) by plasma cell−free circulating tumor DNA, overall survival (OS), and pharmacokinetics (PK). Results: Of 47 patients enrolled, 17 (36%) discontinued R-chemotherapy run-in (protocol criteria, n=6; patient request, n=5; disease progression, n=3; ineligibility, n=1; AE, n=1; death, n=1) and 30 (64%) completed the run-in (2 did not proceed to blinatumomab). Of 28 patients who received blinatumomab, 26 (93%) had high or high-intermediate IPI; 8 (29%) were double/triple hit and 10 (36%) were double protein expressors (Table). In total, 26 (93%) patients completed cycle 1; ten of 11 (91%) patients completed optional cycle 2. Blinatumomab PK were consistent with those in previous studies. After the R-chemotherapy run-in before starting blinatumomab, 24 patients had objective metabolic responses and 4 had no metabolic response (NMR). After blinatumomab treatment, the ORR (within 12 weeks of starting blinatumomab) was 89% (25/28 patients; 95% CI, 72−98; Table). The 4 patients with NMR before blinatumomab had objective responses after blinatumomab treatment. Three patients with objective responses before blinatumomab relapsed after blinatumomab. Twenty-six (93%) patients were still alive with a median follow-up time of 8.6 months; 2 died (disease progression; n=1; infection not related to treatment, n=1). Nine of 13 (69%) patients during the R-chemotherapy run-in were MRD positive, all of whom converted to MRD negative after treatment with blinatumomab. After treatment with blinatumomab, 17 of 18 (94%) patients were MRD negative; the MRD positive patient had PMD. During blinatumomab treatment, 11 (39%) patients had grade ≥3 AEs, and 5 (18%) had grade ≥4 AEs. Two (7%) patients discontinued treatment due to AEs (grade 3 neurotoxicity; grade 4 neutropenia). Consistent with previous blinatumomab reports, neurologic events (NEs) were reported in 17 (61%) patients, including 3 (11%) with grade 3 NEs and 1 (4%) with NEs leading to treatment discontinuation. No patients had grade ≥3 cytokine release syndrome. Other grade ≥3 events of interest included neutropenia and febrile neutropenia (n=4; 14%) and infection (n=3; 11%). Conclusions: In patients with newly diagnosed, high-risk DLBCL, blinatumomab monotherapy after first-line R-chemotherapy led to an 89% ORR, and safety was consistent with that in earlier studies in DLBCL. Thus, blinatumomab is a potential treatment option for patients with newly diagnosed disease. Disclosures Katz: Stemline: Speakers Bureau; Dova: Consultancy. Chu:Celgene: Honoraria; Teva: Consultancy; AstraZeneca: Honoraria; Amgen Inc.: Honoraria; Gilead: Honoraria. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Morley:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, conference support ; TAKEDA: Other: conference support ; Janssen Pharmaceuticals: Other: speaker fees; ROCHE: Membership on an entity's Board of Directors or advisory committees, Other: conference support; ABBVIE: Other: speaker fees. Chen:Amgen Inc.: Employment, Equity Ownership. Kalabus:Amgen Inc.: Employment, Equity Ownership. Morris:Amgen: Employment, Equity Ownership. Anderson:Amgen Inc.: Employment, Equity Ownership. Avilion:Amgen Inc.: Employment, Equity Ownership. González-Barca:Takeda: Honoraria; Kiowa: Consultancy; Celtrion: Consultancy; Janssen: Consultancy, Honoraria; Celgene: Consultancy; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.

scholarly journals A Phase 2 Study of the Safety and Efficacy of INCB050465, a Selective PI3Kδ Inhibitor, in Combination with Ruxolitinib in Patients with Myelofibrosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 353-353 ◽  
Author(s):  
Naval G. Daver ◽  
Marina Kremyanskaya ◽  
Casey O'Connell ◽  
Kim-Hien Dao ◽  
Stephen T Oh ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 2 ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Percent Change ◽  
Phase 2 Study ◽  
Equity Ownership ◽  
Median Percent Change

Abstract Introduction: Despite the demonstrated efficacy of ruxolitinib (Rux) in patients (pts) with myelofibrosis (MF), suboptimal or declining responses to Rux occur, possibly due to persistent PI3K/AKT activation with chronic JAK inhibitor therapy. We evaluated the combination of INCB050465, a potent and highly selective PI3Kδ inhibitor (≥19,000-fold selectivity for PI3Kδ vs other isoforms) and Rux in pts with MF with suboptimal response to chronic Rux monotherapy. Methods: Pts with primary, post-polycythemia vera or post-essential thrombocythemia MF with suboptimal response or loss of response (palpable spleen >10 cm below left subcostal margin [LSM], or splenomegaly 5-10 cm below LSM and presence of 1 symptom score ≥5 or 2 symptom scores ≥3 using the Screening Symptom Form) after ≥6 months of Rux monotherapy (5-25 mg twice daily, stable dose for ≥8 weeks [wks]), and ECOG performance status ≤2 were eligible for this phase 2 study (NCT02718300). All pts in Part 1 (safety run-in) and Part 2 (expansion) received oral INCB050465 once-daily (QD) for 8 wks followed by once-weekly (QW) at the same dose plus Rux (existing stable dose for ≥8 wks). Part 1 assessed up to 3 dose levels of INCB050465 (5, 10, and 20 mg). In Part 2, pts were randomized to treatment groups (TGs) in a 1:1 ratio between two doses of INCB050465 determined in Part 1. Primary endpoints were to identify tolerated INCB050465 dose in combination with Rux (Part 1) and percent change in spleen volume from baseline through wk 12 (Part 2). Results: At data cutoff (May 01, 2018), 10 and 18 pts were enrolled in Parts 1 and 2, respectively. INCB050465 doses of 10 mg (TG10, n=3) followed by 20 mg (TG20, n=7) were explored in Part 1. No DLTs were observed, thus the 5 mg dose was not assessed, and the 10 mg (TG10, n=11) and 20 mg (TG20, n=7) doses were expanded in Part 2. In Part 1 (n=10) (median age, 69 years [60-79]; males, 60%), median spleen volume (cm3) was 3058 (996-5324) at baseline. Five pts (50%) discontinued treatment due to progressive disease (n=1, TG10), physician decision (n=1; TG20), adverse event (AE; n=1; TG20, blood bilirubin increased), consent withdrawal (n=1; TG10), and decision to proceed to transplant (n=1; TG10). Median percent change in spleen volume was +4.3% and -2.0% at wks 12 and 24, respectively (Figure). By wk 16, 40% of pts reported that their MF-related symptoms were much improved on the Patient Global Impression of Change (PGIC) form. In Part 2 (n=18) (median age, 63.5 years [41-89]; males, 38.9%), median spleen volume (cm3) was 2201 (327-3569) and median total symptom score (TSS; by the Myeloproliferative Neoplasms Symptom Assessment Form [MPN-SAF]) was 30 (3-61) at baseline. One pt in TG20 discontinued treatment due to physician decision. Median percent change in spleen volume was -0.3% and -5.2% at wks 12 and 24, respectively (Figure). By wk 16, 33.3% of pts reported that their MF-related symptoms were much or very much improved on the PGIC. Median percent change in TSS by the MPN-SAF was -21.9% and -27.8% at wks 12 and 24, respectively. MPN-SAF TSS was a planned longitudinal endpoint only for Part 2 and updated data for Part 2 pts will be presented. In both Parts 1 and 2, nonhematologic treatment-emergent AEs (TEAEs) occurring in ≥3 pts were primarily grade (Gr) 1/2 (Table). Most common new or worsening Gr 3/4 hematologic AEs were thrombocytopenia (Gr 3: 4 pts [14.3%]; Gr 4: 4 pts [14.3%]) and neutropenia (Gr 3: 2 pts [7.1%]; both pts had Gr 2 neutropenia at baseline). No serious TEAEs of interest were reported. TEAEs led to INCB050465 dose interruption in 11 pts (thrombocytopenia [n=8 events], pyrexia [n=2 events], and abdominal pain, diarrhea, alanine aminotransferase increased, and aspartate aminotransferase increased [n=1 event each]), and to Rux dose interruption in 3 pts (pyrexia [n=2 events] and thrombocytopenia [n=1 event]). Conclusion: The add-on strategy of INCB050465 plus Rux demonstrated preliminary efficacy in MF pts with suboptimal spleen and/or symptom response to chronic Rux monotherapy. The dosing regimen (QD for 8 wks followed by QW) of INCB050465 in this study seemed to mitigate AEs observed with other PI3K inhibitors (limited Gr 3/4 TEAEs and no TEAEs of colitis or rash reported). Long term dosing strategies will be explored in Part 3 of the study, and additional trials are underway to identify optimal dosing of INCB050465 for enhanced safety and efficacy in combination with other agents. Disclosures Daver: Karyopharm: Research Funding; Novartis: Consultancy; Alexion: Consultancy; Karyopharm: Consultancy; Otsuka: Consultancy; ImmunoGen: Consultancy; ARIAD: Research Funding; Sunesis: Consultancy; BMS: Research Funding; Incyte: Consultancy; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Sunesis: Research Funding; Daiichi-Sankyo: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy. Kremyanskaya:Incyte: Research Funding. O'Connell:Incyte: Research Funding. Dao:Incyte: Consultancy. Oh:Takeda: Research Funding; Janssen: Research Funding; CTI Biopharma: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding. Gerds:Celgene: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Erickson-Viitanen:Incyte: Employment, Equity Ownership. Zhou:Incyte: Employment, Equity Ownership. Assad:Incyte Corporation: Employment, Equity Ownership. Yacoub:Seattle Genetics: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Speakers Bureau.

scholarly journals Carfilzomib in Relapsed or Refractory Multiple Myeloma Patients with Early or Late Relapse Following Prior Therapy: An Analysis of Overall Survival in Subgroups from the Randomized Phase 3 Aspire and Endeavor Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1964-1964
Author(s):  
Maria-Victoria Mateos ◽  
Hartmut Goldschmidt ◽  
Jesus F San-Miguel ◽  
Julie Blaedel ◽  
Mihaela Obreja ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Late Relapse ◽  
Employment Equity ◽  
Advisory Committees ◽  
Prior Therapy ◽  
Equity Ownership ◽  
Grade 3 ◽  
Line Of Therapy ◽  
Post Hoc

Abstract Introduction: Carfilzomib is an irreversible proteasome inhibitor with proven efficacy as a single agent and in doublet and triplet combinations (Siegel et al, Blood. 2012;120:2817-25; Dimopoulos et al, Lancet Oncol. 2017;18:1327-37; Siegel et al, J Clin Oncol. 2018;36:728-34). The phase 3 ASPIRE and ENDEAVOR trials demonstrated that treatment with carfilzomib-based regimens led to superior efficacy outcomes (progression-free survival [PFS], overall survival [OS], and overall response rate [ORR]) compared with standard regimens in patients (pts) with relapsed or refractory multiple myeloma (RRMM) (ASPIRE: carfilzomib-lenalidomide-dexamethasone [KRd] vs lenalidomide-dexamethasone [Rd]; ENDEAVOR: carfilzomib-dexamethasone [Kd] vs bortezomib-dexamethasone [Vd]). A previous subanalysis of these trials found that carfilzomib improved PFS and ORR, regardless of whether pts experienced an early or late relapse following the immediate prior therapy (Mateos et al, ASH 2017). Here we performed post hoc analyses of ASPIRE and ENDEAVOR to examine OS and updated safety in the ASPIRE and ENDEAVOR early or late relapse subgroups. Methods: ASPIRE and ENDEAVOR enrolled pts with RRMM (1-3 prior lines of therapy). Pts in both studies received carfilzomib twice weekly in 28-day cycles. In ASPIRE, pts were randomized to KRd or Rd, and those in the KRd arm received carfilzomib 27 mg/m2, which was discontinued after cycle 18. In ENDEAVOR, pts were randomized to Kd or Vd. The Kd group received carfilzomib 56 mg/m2; the Vd group received 21-day bortezomib cycles (1.3 mg/m2). In ENDEAVOR, treatment was continued until progression or unacceptable toxicity. Early relapsers were defined as pts who relapsed ≤1 year after initiating the most recent prior line of therapy (as assessed by investigator), while late relapsers were those who relapsed after >1 year. OS was summarized via Kaplan-Meier methods. In this post hoc analysis, P values were calculated for exploratory purposes. Data cutoff dates used here were April 28, 2017 for ASPIRE and July 19, 2017 for ENDEAVOR. Results: In ASPIRE, median OS for early relapsers was 36.0 months for KRd vs 27.7 months for Rd (hazard ratio [HR]: 0.807; 95% confidence interval [CI]: 0.586-1.110; P=0.0935) (Figure 1). For late relapsers in ASPIRE, median OS was 53.2 months for KRd vs 41.2 months for Rd (HR: 0.752; 95% CI: 0.606-0.932; P=0.0046). Rates of grade ≥3 treatment-emergent adverse events (TEAEs) in ASPIRE were similar for early and late relapsers (KRd vs Rd, 89.3% vs 82.0% for early relapsers and 86.9% vs 83.0% for late relapsers). In ENDEAVOR, early relapsers had a median OS of 28.6 months for Kd vs 21.7 months for Vd (HR: 0.807; 95% CI: 0.587-1.109; P=0.0920) (Figure 2). For late relapsers in ENDEAVOR, median OS was not evaluable (NE) for Kd vs 42.3 months for Vd (HR: 0.722; 95% CI: 0.576-0.905; P=0.0023). Grade ≥3 TEAEs (Kd vs Vd) in ENDEAVOR occurred in 77.0% vs 77.0% of early relapsers and 83.6% vs 69.0% of late relapsers. Conclusions: RRMM pts who received KRd and Kd had longer OS compared with those who received Rd and Vd, regardless of whether they had an early or late relapse following the most recent prior line of therapy. Late relapsers had a numerically greater magnitude of OS benefit with KRd and Kd compared with control arms than early relapsers. Rates of grade ≥3 AEs were consistent with those previously reported in ASPIRE and ENDEAVOR for the overall population. In conclusion, these findings underscore the impressive efficacy of carfilzomib-based therapy for the treatment of pts with RRMM. Figure 1. Figure 1. Disclosures Mateos: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Goldschmidt:Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; ArtTempi: Honoraria; Chugai: Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy. San-Miguel:Amgen: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; BMS: Honoraria; Celgene: Honoraria; Roche: Honoraria. Blaedel:Amgen: Employment, Equity Ownership. Obreja:Amgen: Employment, Equity Ownership. Yang:Amgen Inc.: Employment, Equity Ownership. Szabo:Amgen: Employment, Equity Ownership. Leleu:Abbvie: Consultancy, Honoraria, 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; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Safety and Efficacy of the Combination of Selinexor, Lenalidomide and Dexamethasone (SRd) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3165-3165 ◽  
Author(s):  
Darrell J White ◽  
Suzanne Lentzsch ◽  
Cristina Gasparetto ◽  
Nizar Bahlis ◽  
Christine I Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Introduction: The nuclear export protein Exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma. Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Lenalidomide in combination with dexamethasone has been approved for the treatment of relapsed/refractory multiple myeloma with an ORR of 60-76%. The STOMP study assessed the efficacy and safety of the all oral combination of selinexor, lenalidomide and dexamethasone (SRd) in patients with relapsed/refractory and newly diagnosed multiple myeloma. We previously reported the recommended phase 2 dose (RP2D) of once weekly selinexor 60 mg, lenalidomide 25 mg and dexamethasone achieved an ORR of 92% in patients with RRMM who were lenalidomide naive. Here we evaluated once weekly selinexor in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma. Methods: STOMP is a multicenter, open-label study with a dose escalation (phase 1) and expansion (phase 2) to assess the maximum tolerated dose, RP2D, efficacy and safety of SRd in patients with newly diagnosed multiple myeloma. Patients with newly diagnosed multiple myeloma were eligible if they had symptomatic myeloma per the International Myeloma Working Group (IMWG) guidelines with either hypercalcemia, renal failure, anemia, bone lesions (CRAB) criteria or myeloma defining events needing systemic therapy. Enrollment in this arm is ongoing. Results: As of July 01 2019, 8 patients (4 males and 4 females ) with newly diagnosed multiple myeloma were enrolled at the starting dose level of selinexor 60 mg on days 1, 8, 15, and 22; lenalidomide 25 mg daily 1-21and dexamethasone 40 mg weekly on a 28 day cycle. The median age was 74 years (range: 51-86 years). No dose limiting toxicities (DLT) were observed in 5 DLT evaluable patients, 3 patients were not DLT evaluable because 1 patient did not finish cycle 1 due to social reasons and 2 patients missed doses due to serious adverse events (SAEs) unrelated to study drugs.. Common treatment related hematologic AEs (Grades 1/2, ≥3) were neutropenia (0%, 75%), anemia (0%, 25%), and thrombocytopenia (0%, 25%). Common non-hematologic AEs were diarrhea (63%, 0%), nausea (50%, 0%), fatigue (0%, 38%) decreased weight (38%, 0%), constipation (25%, 0%), hypokalemia (25%, 0%), and hypomagnesemia (25%, 0%). Among 7 efficacy evaluable patients, 6 patients achieved a response (ORR of 86%) including 1 complete response, 1 very good partial responses, 4 partial responses (2 unconfirmed), and 1 patient achieved a minimal response. With a median follow-up of 6.1 months, median progression-free survival was not reached. Conclusions: The all oral combination of SRd has promising activity with 6 of 7 efficacy evaluable patients achieving an objective response in patients with newly diagnosed multiple myeloma and no new or unexpected safety signals. Disclosures White: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Lentzsch:Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Bahlis:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Chen:Janssen: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Lipe:Celgene: Consultancy; amgen: Research Funding; amgen: Consultancy. Schiller:Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Sangamo Therapeutics: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Onconova: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding. Tuchman:Karyopharm: Honoraria; Prothena: Research Funding; Roche: Research Funding; Alnylam: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Kotb:Karyopharm: Equity Ownership; Janssen: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Leblanc:Janssen: 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; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Sebag:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Venner:Sanofi: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria; J&J: Research Funding; Takeda: Honoraria; Celgene: Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baljevic:Karyopharm: Other: Internal Review Committee participant; Cardinal Health Specialty Solutions: Consultancy; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Nilotinib Shows Safety and Efficacy in Older Patients (≥ 65 years) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase Comparable with That in Younger Patients with Chronic Myeloid Leukemia in Chronic Phase: Results From ENESTnd,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3768-3768 ◽  
Author(s):  
Richard A. Larson ◽  
Udomsak Bunworasate ◽  
Anna G. Turkina ◽  
Stuart L. Goldberg ◽  
Pedro Dorlhiac-Llacer ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status > 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group (< 65 vs ≥ 65 yrs) in the 2 nilotinib arms. Safety data are reported for any pt who received ≥ 1 dose of nilotinib (n = 279, Nil300; n = 277, Nil400). Results: 36 pts (13%) and 28 pts (10%) were ≥ 65 yrs old in the Nil300 and Nil400 arms, respectively. Of the pts aged ≥ 65 yrs, 51/64 (80%) had an ECOG performance status of 0 at baseline and 60/64 (94%) had intermediate or high Sokal risk scores. Of the older pts, 8 (22%) on Nil300 and 6 (21%) on Nil400 had type 2 diabetes at baseline. CCyR rates by 24 mo were 83% and 68% among older pts treated with Nil300 and Nil400, respectively, and 87% for pts aged < 65 yrs in each nilotinib arm. By 24 mo, MMR was achieved by 72% and 61% of older pts on Nil300 and Nil400, respectively; in pts aged < 65 yrs, the respective rates were 71% and 67%. All 5 pts who progressed to AP/BC on treatment (2 on Nil300 and 3 on Nil400) were aged < 65 yrs. The frequency of grade 3/4 hematologic adverse events (AEs) was low in older pts; no pts had grade 3/4 neutropenia and only 1 older pt reported grade 3/4 thrombocytopenia in each nilotinib arm (Table). Transient, asymptomatic lipase elevations were reported in 11% and 16% of older pts treated with Nil300 and Nil400, and 7% of younger pts in each arm. Hyperglycemia occurred in 23% and 16% of older pts on Nil300 and Nil400, respectively, and 4% of younger pts in each arm; regardless of age, no pt discontinued study due to hyperglycemia. Among the 12 older pts with grade 3/4 hyperglycemia (8 on Nil300; 4 on Nil400), 9 pts had type 2 diabetes at baseline. There were no QTcF increases of > 60 msec from baseline in older pts and 3 in nilotinib-treated pts < 65 yrs old (1 on Nil300; 2 on Nil400). QTcF prolongation of > 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of > 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts < 65 yrs of age (4/244 [2%] on Nil300; 3/252 [1%] on Nil400). No sudden deaths occurred on study. Discontinuation occurred in approximately 25% of older and younger pts with Nil300, of which, 6% and 9%, respectively, were due to AEs/lab abnormalities. Discontinuation from study with Nil400 was 46% in older pts and 19% in younger pts; of which, 36% and 10% were due to AEs/lab abnormalities. Conclusions: Older pts treated with nilotinib demonstrated high rates of cytogenetic and molecular responses and low rates of progression. Nilotinib was generally well tolerated by older pts. In older pts, Nil300 had numerically higher rates of CCyR and MMR and was generally better tolerated (as evidenced by fewer AEs and discontinuations) vs Nil400. These data support the use of Nil300 in older pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Indoximod Combined with Standard Induction Chemotherapy Is Well Tolerated and Induces a High Rate of Complete Remission with MRD-Negativity in Patients with Newly Diagnosed AML: Results from a Phase 1 Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 332-332
Author(s):  
Ashkan Emadi ◽  
Vu H. Duong ◽  
Jeremy Pantin ◽  
Mohammad Imran ◽  
Rima Koka ◽  
...  
Keyword(s):  
Dose Level ◽  
Induction Chemotherapy ◽  
Residual Disease ◽  
Phase 1 ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Background Successful allogeneic stem cell transplantation (HSCT) in treatment of patients (pts) with acute myeloid leukemia (AML) is dependent upon graft-versus-leukemia, suggesting that intact immune surveillance is essential for eradicating minimal residual disease. Myeloblast-induced T-cell tolerance through overexpression of indoleamine 2,3-dioxygenase (IDO) is thought to play a significant role in immune evasion through upregulation of tryptophan (Trp) catabolism and kynurenine production, resulting in a Trp-poor environment that leads to immune system suppression. Indoximod is a small-molecule inhibitor of the IDO pathway that acts directly on immune cells to reverse IDO pathway-mediated suppression. We are assessing the safety and preliminary efficacy of indoximod in combination with standard induction chemotherapy in patients (pts) with newly diagnosed AML. Methods In this open-label, multicenter, phase 1 study (NCT02835729), eligible pts with newly diagnosed AML were treated with indoximod in combination with induction chemotherapy (idarubicin 12 mg/m2/d x3 days with cytarabine 100 mg/m2/d x7 days). Using a "3+3" design, indoximod (600 mg [dose level 0], 1000 mg [dose level 1], 1200 mg [dose level 2]) was given orally every 8 hours (Q8h) starting on day 9 of induction. Regimen limiting toxicity (RLT) was defined as any ≥ grade 3 non-hematologic adverse event (AE) that was not incontrovertibly related to the underlying AML or cytarabine or idarubicin. After induction, pts received up to 4 cycles of high dose cytarabine (HiDAC) consolidation while continuing indoximod. Patients continued on maintenance indoximod for up to 6 months from completion of consolidation therapy. Indoximod was discontinued 4 weeks prior to HSCT in eligible patients and not restarted as maintenance post-HSCT. Results As of July 15, 2018, 31 pts were enrolled (median age 55 years, range 18-78; 77% male). Six patients did not proceed with study therapy due to a diagnosis of acute promyelocytic leukemia, issues with medical insurance coverage, consent withdrawal, critical illness, and intestinal myeloid sarcoma preventing oral intake. Pts who received ≥1 dose of indoximod were included in the intention-to-treat (ITT) analysis (n=25), and pts who received ≥80% of their scheduled indoximod doses were included in the per-protocol (PP) analysis (n=19). Reasons for not completing ≥80% of indoximod doses were: consent withdrawal (n=3), inability to swallow (n=2) and physician decision (n=1). Of the 19 PP patients, 16 (84%) had either unfavorable karyotype or adverse mutation profile and 3 (16%) had secondary AML (s-AML). Indoximod combined with induction chemotherapy was well tolerated; no RLT was observed. The most frequent grade ≥3 non-hematologic treatment-emergent AEs in the ITT population, regardless of attribution, were febrile neutropenia (60%), hypoxia (16%), atrial fibrillation (12%), pneumonia (12%), hypocalcemia (12%), and hypotension (12%). Among 25 ITT pts, 21 (84%) achieved a remission (CR/CRh/CRi/CRp), and 15 of 19 (79%) in the PP analysis achieved remission. Among 12 pts with measurable residual disease (MRD) available in remission, 10 (83%) had MRD <0.02% (MRD-neg). Eleven of 19 pts (58%) received ≥1 cycle of HiDAC and 5 (26%) received maintenance indoximod. All 11 patients who received HiDAC #1 became MRD-neg. Median relapse-free and overall survival have not been reached. IDO Composite Scores in bone marrow were calculated by multiplying percentage of stained mononuclear cells by grade of staining intensity determined by 3 independent pathologists. Median composite IDO1 score in tested pt samples (n=11) was 0.76 (range, 0.1-2.2). Expression of IDO1 mRNA at baseline varied significantly among patient samples analyzed (fold changes (FC) range: 0.1-84, normalized to β-Actin expression). IDO1 mRNA was significantly upregulated in post-induction samples compared to baseline (FC range: 1.7-248) in 10 out of 12 paired samples. Conclusions Indoximod is well tolerated in combination with standard AML induction therapy. Rates of morphologic response and of MRD-neg status are very promising. The recommended phase 2 dose (RP2D) was 1200 mg oral Q8h and a placebo-controlled randomized phase 2 study is under development. Disclosures Emadi: NewLink Genetics: Research Funding. Loken:Hematologics, Inc: Employment, Equity Ownership. Kennedy:NewLink Genetics: Employment, Equity Ownership. Link:NewLink Genetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Munn:NewLink Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Bosutinib Vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia (CML) in the BFORE Trial: 18 Month Follow-up

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 896-896
Author(s):  
Carlo Gambacorti-Passerini ◽  
Michael W. Deininger ◽  
Michael J. Mauro ◽  
Charles Chuah ◽  
Dong-Wook Kim ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Primary Endpoint ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of adults with CML resistant or intolerant to prior therapy. Here we compare the efficacy and safety of first-line bosutinib versus imatinib in patients with chronic phase (CP) CML enrolled in BFORE after ≥18 months of follow-up. Methods: BFORE (NCT02130557) is an ongoing, multinational, open label phase 3 study that randomized 536 patients 1:1 to 400 mg QD bosutinib (n=268) or 400 mg QD imatinib (n=268 [3 not treated]). The prespecified primary endpoint was major molecular response (MMR) rate at 12 months in the modified intent-to-treat (mITT) population, defined as Philadelphia chromosome‒positive (Ph+) patients with e13a2/e14a2 transcripts, and excluding Ph- patients and those with unknown Ph status and/or BCR-ABL transcript type (mITT: BOS, n=246; IM, n=241). Efficacy results refer to the mITT population unless otherwise noted. Results: MMR rate was higher with bosutinib versus imatinib at 18 months (56.9% vs 47.7%; P=0.042). Among all randomized patients (ITT) 18-month MMR rates were higher for bosutinib (56.7% vs 46.6%; P &lt;0.02). Earlier analyses (Table) showed complete cytogenetic response (CCyR) rate by 12 months (77.2% vs 66.4%; P=0.0075) was significantly higher with bosutinib versus imatinib. Rates of BCR-ABL1 transcript ratio ≤10% (International Scale) at 3 months (75.2% vs 57.3%), as well as MR4 at 12 months (20.7% vs 12.0%) and MR4.5 at 12 months (8.1% vs 3.3%), were all higher with bosutinib versus imatinib (all P &lt;0.025). By comparison at 18 months, rates of MR4 (24.4% vs 18.3%) and MR4.5 (11.4% vs 7.1%) were consistent with this trend. Also after ≥18 months follow-up, time to MMR (hazard ratio=1.36, based on cumulative incidence; P=0.0079) and time to CCyR (hazard ratio=1.33; P=0.0049) were shorter for bosutinib (Figure). Cumulative incidence of transformation to accelerated/blast phase disease at 18 months was 2.0% and 2.9% for bosutinb and imatinib, respectively, of which 2 bosutinib and 4 imatinib patients discontinued treatment due to transformation. Additional treatment discontinuations due to suboptimal response/treatment failure occurred in 11 (4.1%) and 35 (13.2%) of bosutinib and imatinib patients, respectively. Dose increases happened in 20% of bosutinib-treated and 31% of imatinib-treated pts There were 2 deaths and 9 deaths in the bosutinib and imatinib arms, respectively. One patient taking bosutinib died within 28 days of last dose, while 4 patients taking imatinib died with that period from last dose. Overall survival at 18 months was 99.6% vs. 96.6% for bosutinib and imatinib groups, respectively. Grade ≥3 diarrhea (8.2% vs 0.8%) and increased alanine (20.9% vs 1.5%) and aspartate (10.1% vs 1.9%) aminotransferase levels were more frequent with bosutinib. Cardiovascular, peripheral vascular, and cerebrovascular events were infrequent in both arms (3.4%, 1.9%, and 0.4% bosutinib vs 0.0%, 1.1%, and 0.8% imatinib; grade ≥3: 1.5%, 0%, and 0.4% vs 0%, 0%, and 0.4%). There were no deaths in the bosutinib arm and 1 death in the imatinib arm due to treatment-emergent vascular events. Treatment discontinuations due to drug-related toxicity occurred in 15.3% and 9.4% of bosutinib and imatinib patients, respectively. Conclusion: After 18 months of follow-up,the MMR benefit seen with bosutinib over imatinib was sustained. These results are in line with observations at 12 months where patients taking bosutinib had significantly higher response rates (primary endpoint) and achieved responses sooner than those on imatinib. Safety data were consistent with the known safety profiles. These results suggest that bosutinib may be an important treatment option for patients with newly diagnosed CP CML. Disclosures Gambacorti-Passerini: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Research Funding; BMS: Consultancy, Research Funding; Gilead: Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Mauro: Bristol-Myers Squibb: Consultancy. Chuah: Avillion: Honoraria; Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria. Kim: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, 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. Milojkovic: Novartis: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. le Coutre: BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; ARIAD: Honoraria. García Gutiérrez: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Crescenzo: Pfizer: Employment, Equity Ownership. Leip: Pfizer: Employment, Equity Ownership. Bardy-Bouxin: Pfizer: Employment, Equity Ownership. Hochhaus: Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Brümmendorf: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cortes: Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding.

scholarly journals Once-Weekly Carfilzomib with Dexamethasone Demonstrated Promising Safety and Efficacy in Patients with Relapsed or Refractory Multiple Myeloma Regardless of Age and Prior Bortezomib Exposure

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2129-2129
Author(s):  
Jesus G. Berdeja ◽  
Robert M. Rifkin ◽  
Roger Lyons ◽  
Hui Yang ◽  
Anita Zahlten-Kuemeli ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Phase 1 ◽  
Secondary Analysis ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: The multicenter phase 1/2 CHAMPION-1 study (NCT01677858) showed that once-weekly carfilzomib and dexamethasone was well tolerated and active in patients with relapsed or refractory multiple myeloma (MM) (Berenson et al. Blood. 2016;127:3360−3368). We present a secondary analysis of the efficacy and safety of once-weekly carfilzomib with dexamethasone in the CHAMPION-1 study according to prior bortezomib (BTZ) exposure and age. Methods: Patients with relapsed or refractory MM (1−3 prior therapies) were eligible. The primary objectives were to determine the maximum tolerated dose (MTD) of once-weekly carfilzomib with dexamethasone (phase 1) and to determine the overall response rate (ORR; phase 2). Secondary objectives included assessment of safety and tolerability, and evaluation of the clinical benefit rate and progression-free survival (PFS) in the phase 2 portion. Patients received carfilzomib as a 30-minute, intravenous (IV) infusion on days 1, 8, and 15 of 28 day cycles. Patients received carfilzomib at 20 mg/m2 on cycle 1, day 1; subsequent doses were escalated to 45, 56, 70, or 88 mg/m2, using a standard 3+3 escalation schema to determine the MTD. In the phase 2 portion, patients received carfilzomib at the MTD. All patients received dexamethasone 40 mg (IV or orally) on days 1, 8, 15, and 22 of 28 day cycles for cycles 1−8; dexamethasone was omitted on day 22 for cycles ≥9. The MTD of once-weekly carfilzomib (30-min IV infusion) with dexamethasone was established to be 70 mg/m2 (Berenson et al. Blood. 2016;127:3360−3368). In this secondary analysis, the efficacy and safety of once-weekly carfilzomib at this dose were evaluated by prior BTZ exposure (no prior exposure vs exposed but not refractory vs refractory) and age (<65 vs 65−74 vs ≥75 years). Results: The data cutoff date for this analysis was Nov 5, 2015.A total of 104 patients (phase 1 and 2; <65 years, n=34; 65-74 years, n=41; ≥75 years, n=29) received carfilzomib at a dose of 70 mg/m2 (no prior BTZ exposure, n=17; prior BTZ exposure but not BTZ-refractory, n=33; BTZ-refractory, n=54). The ORR for all 104 patients receiving the 70 mg/m2 dose was 77%; the median PFS was 14.3 months. Efficacy by prior BTZ exposure is presented in Table 1. The ORRs were 94%, 91%, and 63% for patients with no prior BTZ exposure, those exposed but not refractory to BTZ, and BTZ-refractory patients, respectively. The proportions of patients who achieved a complete response (CR) or better were 35% (no prior BTZ exposure), 21% (exposed to but not refractory to BTZ), and 9% (BTZ-refractory). The median PFS durations were 21.0, 19.4, and 5.3 months in these subgroups, respectively. The median treatment durations by age were 6.4 months (<65 years), 6.2 months (65-74 years), and 9.9 months (≥75 years); mean cumulative doses of carfilzomib received were 1876.8, 1846.5, and 2156.1 mg/m2, respectively. Efficacy and safety outcomes by age are shown in Table 2. The median PFS durations were 7.4 and 10.2 months for patients aged <65 and 65−74 years, respectively; the median PFS was not reached for those aged ≥75 years. The ORRs were 79%, 73%, and 79% for patients aged <65 years, 65−74 years, and ≥75 years, respectively. The ≥CR rates were 26% (<65 years), 15% (65-74 years), and 10% (≥75 years). Overall rates of treatment discontinuation were similar among age subgroups (Table 2). The rates of treatment discontinuation due to adverse events were 3% (<65 years), 17% (65−74 years), and 21% (≥75 years). The proportions of patients with at least one grade ≥3 adverse event were 56% (<65 years), 61% (65−74 years), and 76% (≥75 years). Rates of grade ≥3 adverse events of interest by age are shown in Table 2. Conclusions: Once-weekly carfilzomib (70 mg/m2) with dexamethasone was safe and active for patients with relapsed or refractory MM, regardless of prior BTZ exposure or age. As expected, the median PFS durations in the BTZ-naïve or -sensitive patients were longer relative to that in the BTZ-refractory patients. Although there were higher incidences of grade ≥3 adverse events and treatment discontinuations due to adverse events in older patients (≥65 years) relative to younger patients (<65 years), median PFS was not negatively affected by increasing age. Overall, once-weekly carfilzomib with dexamethasone had a favorable benefit-risk profile in patients with relapsed or refractory MM, irrespective of prior BTZ exposure or age. Disclosures Berdeja: Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Rifkin:Amgen/ONYX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Yang:Amgen Inc.: Employment, Equity Ownership. Aggarwal:Amgen: Employment, Equity Ownership. Iskander:Amgen Inc: Employment, Equity Ownership. Berenson:Amgen Inc: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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