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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 8013-8013
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 8511-8511
    Abstract: 8511 Background: Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor that induces apoptosis in multiple myeloma (MM) cells in vitro. It has shown synergistic activity with bortezomib (V) and dexamethasone (d). Combination of the CD38 monoclonal antibody daratumumab (D) with Ven is hypothesized to further increase anti-myeloma activity based on dual mechanisms of pro-apoptotic effects on tumor cells and enhanced immune stimulation. Methods: This ongoing Phase 1/2, nonrandomized, multicenter study (NCT03314181) is evaluating safety, efficacy and pharmacokinetics (PK) of VenDd +/- V in patients (pts) with relapsed/refractory MM. In Part 1, pts with t(11;14) who received ≥1 prior line of therapy (PI and an immunomodulatory drug) were treated with VenDd [Ven QD + D 16 mg/kg IV + d 40 mg weekly]. In Part 2, pts irrespective of t(11;14) status, non-refractory to PIs and who received 1–3 prior lines of therapy were treated with VenDVd [Ven QD + D 16 mg/kg IV + V (1.3 mg/m 2 ) + d (20 mg)]. A randomized, open-label expansion (Part 3) will further evaluate and compare safety and efficacy of VenDd (400 or 800 mg Ven dose levels) with control DVd in pts with t(11;14). Results: As of Dec 05, 2019, 48 pts were enrolled. Part 1 included 24 pts with t(11;14), median age 63 (range 51–76). Part 2 included 24 pts, median age 65 (range 41–80) of which 6 (25%) had t(11;14). Frequent adverse events (AEs; VenDd/VenDVd) were fatigue (71%/25%), diarrhea (58%/46%), nausea (46%/50%), insomnia (33%/50%), upper respiratory tract infection (33%/21%), cough (42%/9%), and dyspnea (25%/25%). Frequent Grade ≥ 3 AEs in pts on VenDd were neutropenia (17%), hypertension (12%), fatigue and hyperglycemia (8% each), and in pts on VenDVd were insomnia (21%), diarrhea and thrombocytopenia (8% each). Nine pts had infection-related Grade ≥ 3 AEs (5 VenDd, 4 VenDVd). Eighteen pts had a serious AE (11 VenDd, 7 VenDVd) with pyrexia (n = 3) being most common. One pt on VenDVd died of progressive disease. PK analyses showed that addition of D and V did not impact Ven exposure. Median follow-up time (VenDd/VenDVd) was 10 and 9 months. Overall response rate in VenDd/VenDVd was 96%/92% and 96%/79% had ≥ very good partial response rate. Median progression free survival and duration of response were not reached. Conclusions: Pts treated with VenDd +/- V continue to demonstrate a tolerable safety profile with encouraging efficacy, notably among pts with t(11;14) treated with VenDd. Safety, efficacy, PK, and cytogenetics analyses will be updated for presentation. Clinical trial information: NCT03314181 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 16 ( 2012-06-01), p. 1953-1959
    Abstract: This phase I study evaluated elotuzumab, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma (MM). Patients and Methods Three cohorts were enrolled and treated with elotuzumab (5.0, 10, or 20 mg/kg intravenously) on days 1, 8, 15, and 22 of a 28-day cycle in the first two cycles, and days 1 and 15 of each subsequent cycle; lenalidomide 25 mg orally [PO] on days 1 to 21; and dexamethasone 40 mg PO weekly. Dose-limiting toxicities (DLTs) were assessed during cycle 1 of each cohort, and clinical responses were evaluated during each cycle. The first five patients received up to six cycles of therapy; subsequent patients were treated until disease progression. Results Twenty-nine patients with advanced MM and a median of three prior MM therapies were enrolled; 28 patients were treated, three each in the 5.0-mg/kg and 10-mg/kg cohorts and 22 in the 20-mg/kg cohort. No DLTs were observed up to the maximum proposed dose of 20 mg/kg. The most frequent grade 3 to 4 toxicities were neutropenia (36%) and thrombocytopenia (21%). Two patients experienced a serious infusion reaction (one grade 4 anaphylactic reaction and one grade 3 stridor) during the first treatment cycle. Objective responses were obtained in 82% (23 of 28) of treated patients. After a median of 16.4 months follow-up, the median time to progression was not reached for patients in the 20-mg/kg cohort who were treated until disease progression. Conclusion The combination of elotuzumab, lenalidomide, and low-dose dexamethasone was generally well tolerated and showed encouraging response rates in patients with relapsed or refractory MM.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
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  • 4
  • 5
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 489-489
    Abstract: Introduction: Daratumumab is an anti-CD38 IgGκ monoclonal antibody that has been combined successfully with lenalidomide and dexamethasone. The combination of daratumumab with lenalidomide and dexamethasone (DRd) has been compared with lenalidomide and dexamethasone alone (Rd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM) in a randomized phase 3 study (Dimopoulos MA, et al. N Engl J Med 2016; in press). In a pre-specified interim analysis, the DRd combination demonstrated significantly longer progression-free survival (PFS) in addition to deep and durable responses compared with the Rd arm. We performed subgroup analyses to further examine these efficacy data according to prior treatment exposure. Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to Rd (lenalidomide: 25 mg PO on Days 1-21 of each 28-day cycle; dexamethasone: 40 mg PO weekly) with or without daratumumab (16 mg/kg IV qw for 8 weeks, q2w for 16 weeks, then q4w until progression). The primary endpoint was PFS. Pts who were refractory to lenalidomide were not eligible. All analyses were performed in pts who received 1 to 3 prior lines of therapy. Results: Median follow-up was 13.5 months. Pts who were lenalidomide-naive prior to the start of study treatment (DRd, n=226; Rd, n=219) demonstrated significantly longer PFS with DRd vs Rd (median: not reached [NR] vs 18.4 months; HR, 0.36; 95% CI, 0.25-0.52; P 〈 0.0001), with estimated 12-month PFS rates of 83.0% vs 59.9%, respectively. ORR was significantly higher with DRd vs Rd (96% vs 79%), with ≥VGPR rates of 76% vs 47% and ≥CR rates of 44% vs 21%, respectively (P 〈 0.0001 for all). In the lenalidomide-exposed subgroup (DRd, n=46; Rd, n=45), median PFS was NR in both treatment groups (HR, 0.49; 95% CI, 0.22-1.12; P=0.0826); estimated 12-month PFS rates were 84.1% vs 63.1%, respectively. ORR was higher with DRd vs Rd but did not reach statistical significance (87% vs 71%; P=0.0729); however, rates of ≥VGPR (78% vs 38%; P=0.0001) and ≥CR (44% vs 12%; P=0.0011) were significantly improved with DRd vs Rd, respectively. For bortezomib-naive pts (DRd, n=44; Rd, n=45), PFS was significantly longer with DRd vs Rd (median: NR vs 15.8 months; HR, 0.34; 95% CI, 0.13-0.86; P=0.0170), with estimated 12-month PFS rates of 85.4% vs 69.2%, respectively. ORR was significantly higher with DRd vs Rd (98% vs 82%; P=0.0158), with trends toward increased rates of ≥VGPR (74% vs 55%; P=0.0544) and ≥CR (42% vs 23%; P=0.0576). In the bortezomib-exposed pts (DRd, n=228; Rd, n=219), median PFS was NR in DRd vs 18.4 months in Rd (HR, 0.35; 95% CI, 0.24-0.50 P 〈 0.0001); estimated 12-month PFS rates were 82.8% vs 58.7%, respectively. Significant differences in ORR (93% vs 77%), rate of ≥VGPR (77% vs 43%) and rate of ≥CR (44% vs 19%) were observed with DRd vs Rd, respectively (P 〈 0.0001 for all). Among bortezomib-refractory patients (DRd, n=54; Rd, n=49), the PFS benefit of DRd compared with Rd was maintained (median: NR vs 10.3 mo, respectively; HR, 0.46; 95% CI, 0.25-0.85; P=0.0117; Figure). The estimated 12-month PFS rates were 70.8% vs 44.4%, respectively. Similar to bortezomib-exposed pts, ORR (92% vs 68%; P=0.0024), rate of ≥VGPR (75% vs 36%; P=0.0001), and rate of ≥CR (46% vs 13%; P=0.0003) were all significantly higher with DRd vs Rd for bortezomib-refractory pts. Updated data will be presented at the meeting. Conclusions: Among pts who received 1 to 3 prior lines of therapy, significantly longer PFS and higher ORR were observed with DRd vs Rd among pts who previously received bortezomib or were refractory to bortezomib or were lenalidomide-naive. Higher rates of deeper responses were observed in pts who previously received lenalidomide or bortezomib. Follow-up is ongoing to assess PFS in pts who received 1 to 3 prior lines of therapy and previously received lenalidomide. These results further strengthen the significant benefit of combining daratumumab with Rd for RRMM. Figure Progression-free Survival in Bortezomib-refractory Patients who Received 1 to 3 Prior Lines of Therapy Figure. Progression-free Survival in Bortezomib-refractory Patients who Received 1 to 3 Prior Lines of Therapy Disclosures Moreau: Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Kaufman:Pharmacyclics: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Sutherland:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Lalancette:Celgene: Honoraria; BMS: Honoraria. Iida:Celgene: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding. Prince:Janssen: Honoraria; Celgene: Honoraria. Cochrane:BMS: Other: Received sponsorship to attend international meetings; Novartis: Other: Received sponsorship to attend international meetings; Celgene: Other: Received sponsorship to attend international meetings; Takeda: Other: Received sponsorship to attend international meetings. Khokhar:Janssen: Employment. Guckert:Johnson & Johnson: Equity Ownership; Janssen: Employment. Qin:Janssen: Employment. Oriol:Janssen: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 6
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1866-1866
    Abstract: Introduction: Daratumumab, a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, is approved in combination with standard-of-care regimens for the treatment of newly diagnosed multiple myeloma (NDMM) and RRMM. When combined with standard of care regimens across four phase 3 studies, daratumumab demonstrated ≥44% reductions in the risk of progression or death, nearly doubled complete response (CR) or better rates, and tripled minimal residual disease (MRD)-negative rates at the 10-5 sensitivity threshold in pts with RRMM or NDMM (Palumbo A, et al. N Engl J Med 2016. 375[8]:754-766; Dimopoulos MA, et al. N Engl J Med 2016. 375[14] :1319-1331; Mateos MV, et al. N Engl J Med 2018. 378[6]:518-528; Facon T, et al. N Engl J Med 2019. 380[22] 2104-2015). In the phase 3 POLLUX study (median follow-up 44.3 months), D-Rd reduced the risk of disease progression or death by 56% and significantly increased the overall response rate (ORR) versus Rd alone (93% vs 76%; P 〈 0.0001) in patients (pts) with RRMM. Here, we present updated efficacy and safety analyses of POLLUX after 〉 4 years of median follow-up. Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to Rd (lenalidomide 25 mg PO on Days 1-21 of each 28-day cycle; dexamethasone 40 mg per week) ± daratumumab (16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, then Q4W until disease progression). Cytogenetic risk was determined by local fluorescence in situ hybridization or karyotyping; pts with high cytogenetic risk had t(4;14), t(14;16), and del17p abnormalities. PFS on subsequent line of therapy (PFS2), an exploratory endpoint, was defined as time from randomization to progression after next line of subsequent therapy or death. Results: A total of 569 pts were randomized (D-Rd, n = 286; Rd, n = 283). At a median follow-up of 51.3 months, D-Rd significantly prolonged progression-free survival (PFS) versus Rd (median 45.8 vs 17.5 months; hazard ratio [HR], 0.43; 95% confidence interval [CI] , 0.35-0.54; P 〈 0.0001; Figure). D-Rd also prolonged PFS versus Rd among pts with 1 prior line of therapy, among pts with 1-3 prior lines of therapy, and regardless of cytogenetic risk status (Table). A PFS benefit with D-Rd was also observed among pts who received prior lenalidomide (median 38.8 vs 18.6 months; HR, 0.34; 95% CI, 0.19-0.59; P 〈 0.0001) and among pts refractory to bortezomib (median 34.3 vs 11.3 months; HR, 0.41; 95% CI, 0.25-0.68; P = 0.0004). D-Rd was associated with a significantly higher ORR versus Rd (93% vs 76%), including higher rates of ≥very good partial response (81% vs 49%) and ≥CR (57% vs 24%; all P 〈 0.0001). Median time to next therapy for D-Rd versus Rd was not reached in the D-Rd group versus 22.8 months in the Rd group (HR, 0.39; 95% CI, 0.30-0.49; P 〈 0.0001). D-Rd significantly prolonged PFS2 versus Rd (median 53.3 vs 31.6 months; HR, 0.54; 95% CI, 0.43-0.68; P 〈 0.0001). In the D-Rd group, 121 deaths were observed versus 133 deaths in the Rd group; follow-up for overall survival is ongoing. The median duration of treatment was 34.3 months in the D-Rd arm versus 16.0 months in the Rd arm. The most common (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs) observed with D-Rd versus Rd included neutropenia (56% vs 42%), anemia (18% vs 22%), thrombocytopenia (15% vs 16%), pneumonia (16% vs 10%), and diarrhea (10% vs 4%). Similar rates of discontinuations due to TEAEs were observed for D-Rd versus Rd (16% vs 15%). The incidence of invasive second primary malignancies was 4.9% and 5.7% for the D-Rd and Rd groups, respectively. Additional efficacy data, including minimal residual disease, and safety analyses will be presented at the meeting. Conclusion: After 〉 4 years of median follow-up, D-Rd continues to demonstrate a significant PFS benefit and higher rates of deeper responses versus Rd alone in pts with RRMM. Although significant PFS benefit was observed with D-Rd in RRMM pts regardless of prior lines of therapy or cytogenetic risk status, the greatest benefit was observed when used in patients treated earlier with D-Rd. The significant improvement in PFS2 suggests a potential survival benefit, but OS data is still immature. No new safety concerns were identified with this additional follow-up. Disclosures Kaufman: Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Takeda: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AbbVie: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Amgen: Consultancy. Usmani:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Bahlis:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. White:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Cook:Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding. Ho:Novartis: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Janssen: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs. Moreau:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Krevvata:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Ukropec:Janssen: Employment, Equity Ownership. Renaud:Janssen: Employment, Equity Ownership. Trivedi:Janssen: Employment, Equity Ownership. Kobos:Janssen: Employment. Dimopoulos:Sanofi Oncology: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
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  • 7
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 432-432
    Abstract: Abstract 432 Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces significant antibody-dependant cytotoxicity (ADCC) against primary myeloma cells in the presence of either autologous or allogeneic peripheral lymphocytes (PBMC), which is significantly enhanced when PBMC effector cells were pretreated with lenalidomide (Tai et al., Blood 112:1329, 2008). The primary objective of the phase 1 portion of the study is to evaluate the maximum tolerated dose (MTD) of elotuzumab in combination with lenalidomide and low dose dexamethasone in patients with relapsed MM. The study is also evaluating safety, pharmacokinetics (PK) and clinical response. Lenalidomide (25 mg PO) is given on Days 1-21 of a 28-day cycle. Elotuzumab in three escalating dose cohorts (5, 10 and 20 mg/kg) is administered by IV infusion on Days 1, 8, 15 and 22 of the 28-day cycle in the first two cycles and then on Days 1 and 15 of each subsequent cycle. Dexamethasone is given weekly at 40 mg PO. Initially, patients received 6 cycles of treatment unless withdrawn earlier due to disease progression or unacceptable. toxicity. The protocol was amended to allow for patients in the 10 and 20 mg/kg cohorts to receive treatment for up to 12 months following enrollment of the last patient. Key entry criteria: age ≥ 18 years; MM with at least one relapse; measurable disease M-protein component in serum and/or in urine; and prior lenalidomide treatment, if any, more than 6 weeks of first dose. To date, 24 patients with a median age of 60 years have been enrolled in the study and 23 patients have received study drug. The median time from initial diagnosis of MM was 5 years and patients had received a median of 3 prior MM treatments. Patients had been previously treated with thalidomide (58%), bortezomib (67%) or lenalidomide (21%) and 42% were refractory to their most recent MM therapy. Patients have been treated in the 3 cohorts; 3 patients each in the first two cohorts (5 and 10 mg/kg elotuzumab) and 17 patients (7 in dose-escalation phase and 10 in the expansion phase) in the third cohort (20 mg/kg). No dose limiting toxicities were identified during the dose-escalation phase of the study and no MTD was established. One patient discontinued in the first cycle due to grade 4 allergic reaction resulting from elotuzumab infusion in the expansion phase of the study. Additional SAEs (1 of each) included grade 2 atrial fibrillation (related to lenalidomide/dexamethasone) and unrelated grade 4 ruptured diverticulum, grade 3 neutropenic fever and grade 3 diarrhea.. Other common grade 3 or 4 AEs included neutropenia (25%) and thrombocytopenia (25%), which were managed by dose withholding or dose reduction of lenalidomide. Approximately 25% of patients experienced grade 1 or 2 chills and/or pyrexia associated with elotuzumab infusion. The best clinical response (IMWG criteria) in the 13 patients who have received at least two cycles of treatment is shown in the table below. Preliminary PK analysis of elotuzumab suggests a serum half-life of 10-11 days at 10 and 20 mg/kg. Elotuzumab at all three doses resulted in near complete saturation of CS1 sites on plasma cells and NK cells in bone marrow and NK cells in the peripheral compartment. In conclusion, the combination of elotuzumab with lenalidomide and low-dose dexamethasone has a manageable adverse event profile and compared to historical data for lenalidomide and high-dose dexamethasone, the preliminary efficacy data (≥ PR of 92%) are very encouraging. Additional safety, efficacy and PK/PD data will be presented at the meeting. Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Off Label Use: Lenalidomide/dexamethasone in combination with elotuzumab in patients with relapsed/refractory multiple myeloma. Vij:Celgene: Research Funding, Speakers Bureau. Harousseau:Celgene France: Advisory Board; Janssen Cilag France: Advisory Board; Celgene: Honoraria; Janssen Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kaufman:Celgene: Consultancy, Research Funding; Millennium: Consultancy; Genzyme: Consultancy; Merck: Research Funding. Mazumder:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Leleu:Celgene: Research Funding, Speakers Bureau. Fry:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Jagannath:Millennium: Advisory Board; Merck: Advisory Board.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
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  • 8
    In: The Lancet Oncology, Elsevier BV, Vol. 15, No. 11 ( 2014-10), p. 1195-1206
    Type of Medium: Online Resource
    ISSN: 1470-2045
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
    detail.hit.zdb_id: 2049730-1
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  • 9
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2006-2006
    Abstract: Introduction: Subcutaneous (SC) administration offers several potential advantages for patients (pts) and healthcare providers, including shorter administration times, reduced administration volume, and fewer infusion-related reactions. Daratumumab (DARA), a human IgGκ anti-CD38 monoclonal antibody, has direct on-tumor and immunomodulatory effects. DARA is approved for intravenous (IV) administration as monotherapy for RRMM and in combination with standard of care regimens for RR and newly diagnosed MM. Previous analyses demonstrated that maximum DARA trough concentration (Ctrough), which occurs at the end of weekly dosing, was highly correlated with efficacy in MM (Xu XS, et al. Clin Pharmacol Ther 2017. 101[6] :721-724), but no relationship was observed between DARA concentrations and adverse events. SC administration of DARA in combination with recombinant human hyaluronidase enzyme PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) is being evaluated in an open-label, phase 1b trial (PAVO) to identify a fixed SC dose which is safe and achieves a similar or greater maximum Ctrough as compared with the 16 mg/kg IV dose. Here, we present the clinical pharmacology of SC DARA, including the development of a combined IV-SC population PK (PPK) model. Methods: In PAVO, eligible RRMM pts received ≥2 prior lines of therapy. In Part 1, 2 sequential cohorts received fixed dose regimens of a mix and deliver SC formulation of DARA and rHuPH20 (DARA MD) at 1,200 mg (n = 8; 60 mL) and 1,800 mg (n = 45; 90 mL) doses in 20 and 30 minutes, respectively, on the same schedule as the approved DARA monotherapy IV regimen (QW for Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter; 4-week cycles). A dose that was safe and provided similar or greater Ctrough values on Cycle 3 Day 1 (C3D1) compared with the 16 mg/kg IV dose was selected for Part 2. In Part 2, a concentrated co-formulation of DARA (1,800 mg) and rHuPH20 (30,000 U; in 15 mL) in a single, pre-mixed vial (DARA SC) was administered over 3-5 minutes by manual SC injection. Co-primary endpoints were safety and Ctrough at the end of QW dosing. Serial PK sampling was performed after the first and last weekly dose; sparse PK and immunogenicity was collected at additional timepoints. A mixed-effects 2-compartment PK model based on Michaelis-Menten approximation of target-mediated drug disposition was developed, and PK data used in this PPK analysis were from Part 1 of PAVO (n = 53) and from GEN501/MMY2002 (IV DARA monotherapy; n = 223) studies. Model-based simulations were conducted to facilitate dose selection. Results: In Part 1, the mean C3D1 Ctrough following 1,800 mg DARA MD was similar or higher than that observed for 16 mg/kg IV (Table). The PPK model predicted approximately 88% of pts receiving DARA MD 1,800 mg would achieve the effective concentration of 274 μg/mL vs 73% of pts receiving DARA MD 1,200 mg and 80% of pts receiving 16 mg/kg IV. Simulated PK profiles indicated that both DARA MD doses result in smaller peak-to-trough fluctuation compared to IV dosing, and that 1,800 mg provides higher Ctrough throughout the dosing period without increasing Cmax compared to IV dosing (Usmani SZ, et al. ASH 2016. Abs. 1149). Across a range of simulated body weights, exposure following DARA MD 1,800 mg was similar or slightly higher than for 16 mg/kg IV. Based on these data, the 1,800 mg dose was selected for further evaluation in Part 2. The primary PK endpoint of mean C3D1 Ctrough was slightly higher for DARA SC 1,800 mg than the DARA MD 1,800 mg cohort and 16 mg/kg IV dose (Table). The range of Ctrough observations for the SC cohorts were within the range observed with 16 mg/kg IV (Figure). The observed Cmax of DARA SC 1,800 mg after the first and last weekly dose was within the range of that for 16 mg/kg IV; inter-pt variability for SC administered DARA was also similar across all cohorts. One pt (1%) was positive for DARA anti-drug antibodies and 13% of pts were positive for anti-rHuPH20 antibodies in PAVO; all had no apparent clinical complications. Conclusions: The fixed DARA SC 1,800 mg dose provided a similar or higher C3D1 Ctrough when compared to historical data with 16 mg/kg IV. A combined IV-SC PPK model using a concentration- and time-dependent clearance of DARA described the PAVO data well. Immunogenicity of DARA and rHuPH20 was similar to previous experience. These data validated the dose selection of 1,800 mg for ongoing phase 3 clinical trials of DARA SC in MM, smoldering MM, and amyloidosis. Disclosures Clemens: Janssen Research & Development, LLC: Employment. Xu:Janssen Research & Development, LLC: Employment. Luo:Janssen Research & Development, LLC: Employment. Chari:Array Biopharma: Research Funding; Adaptive Biotechnology: 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; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy. Mateos:Janssen: 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; Celgene: 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; Amgen: 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; 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. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Kaufman:Abbvie: Consultancy; Roche: Consultancy; Janssen: Consultancy; Karyopharm: Other: data monitoring committee; BMS: Consultancy. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Plesner:Janssen: Consultancy; Celgene: Other: Independent Response Assessment Comittee. San-Miguel:Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Janssen: Honoraria. Sun:Janssen Research & Development, LLC: Employment. Farnsworth:Janssen Research & Development: Employment. Masterson:Janssen Research & Development, LLC: Employment. Hellemans:Janssen Research & Development: Employment. Qi:Janssen Research & Development, LLC: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1633-1633
    Abstract: Background: Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that is currently being evaluated as a targeted therapy for the treatment of t(11;14) relapsed/refractory multiple myeloma (RRMM). The combination of Ven with daratumumab (D) and dexamethasone (d) has shown promising efficacy with a tolerable safety profile in the phase 1/2 study (NCT03314181). VenDd is hypothesized to have increased anti-myeloma activity based upon complementary mechanisms of pro-apoptotic effects on tumor cells as well as potentially enhanced T-cell activation and clonal expansion, which has been shown to be associated with achieving deep sustained response to D-based therapy in MM. Results presented herein describe the immunomodulatory effects observed upon VenDd treatment in t(11;14) RRMM patients, including effects on the T-cell repertoire. Methods: Peripheral blood samples from t(11;14) RRMM patients (n=18) treated with VenDd (NCT03314181) were collected at day 1 of cycles 1-5 to characterize effects on B-, T-, and NK-cell populations by multicolor flow cytometry. TCRβ sequencing (ImmunoSEQ, Adaptive Biotechnologies) was also conducted on peripheral blood samples collected from t(11;14) RRMM patients (n=31) treated with VenDd at day 1 of cycles 1, 3, 5, and 9 to assess changes in T-cell clonality, defined as the extent of mono- or oligoclonal expansion by Simpson clonality index, and T-cell richness, defined as the number of clones with unique TCRβ rearrangements after computationally down-sampling to a common number of T-cells. Results: Consistent with previous findings with Ven, rapid and sustained depletion of B-cells (CD19+/CD5-) was observed in patients treated with VenDd (median absolute count: 115 cells/ml at baseline vs 13 cells/ml at C2D1 (89% decrease), p & lt;0.0001; vs 4 cells/ml at C5D1 (97% decrease), p & lt;0.01). Significant reduction in NK cells (CD16+/CD56+) was also observed upon VenDd treatment (median absolute count: 179 cells/ml at baseline vs 30 cells/ml at C2D1 (83% decrease), p & lt;0.0001; vs 16 cells/ml at C5D1 (91% decrease), p & lt;0.01), which is consistent with previous results with D-containing regimens. Within the circulating T-cell population, a significant and sustained decrease in CD4+ T-cells (median absolute count: 421 cells/ml at baseline vs 251 cells/ml at C2D1 (40% reduction), p & lt;0.0001; vs 211 cells/ml at C5D1 (50% reduction), p & lt;0.01) was observed, with naïve and central memory CD4+ T-cells being more sensitive than effector memory T-cells (median absolute count: 61 cells/ml at baseline vs 34 cells/ml (45% reduction) at C3D1, p & lt;0.01; 162 cells/ml at baseline vs 79 cells/ml (51% reduction) at C3D1, p & lt;0.001; 151 cells/ml at baseline vs 120 cells/ml (21% reduction) at C3D1, p & lt;0.01; respectively). A rapid and sustained decrease in immunosuppressive regulatory T-cells (CD4+/CD25 hi/CD127 dim) was observed in VenDd treated patients (median absolute count: 42 cells/ml at baseline vs 18 cells/ml at C2D1 (56% reduction), p & lt;0.0001; vs 15 cells/ml at C5D1 (63% reduction), p & lt;0.01). In contrast to the CD4+ T-cell subsets, a transient decrease in CD8+ T-cells was observed at C2D1 (median absolute count: 333 cells/ml at baseline vs 259 cells/ml at C2D1 (22% reduction), p & lt;0.001) with levels returning to near-baseline by C3D1, including effector memory CD8+ T-cells. TCR-sequencing revealed a significant increase in T-cell clonality upon treatment with VenDd (Figure 1A). A significant decrease in T-cell richness was observed (Figure 1B), indicating a focusing of the T-cell repertoire. The observed increases in T-cell clonality upon VenDd treatment were due to expansion of both newly detected clones and clones that were present at baseline (Figure 1C). Finally, the immunomodulatory effects of VenDd described herein were consistent between the Ven dose cohorts (400 and 800mg). Conclusions: Treatment of t(11;14) RRMM patients with VenDd resulted in selective depletion of B-cells, NK-cells, and immunosuppressive regulatory T-cells, but not CD8+ T-cell subsets. Increased T-cell clonality indicates focusing of the T-cell repertoire and generation of an adaptive anti-myeloma immune response upon treatment with VenDd. The study is continuing with a randomized, open-label expansion that will further evaluate the safety and efficacy of VenDd in patients with t(11;14) RRMM, including correlative studies between the observed immune modifications and patient outcome. Figure 1 Figure 1. Disclosures Bahlis: Genentech: Consultancy; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kaufman: Fortis Therapeutics: Research Funding; Sutro, Takeda: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Heidelberg Pharma: Research Funding; BMS: Consultancy, Research Funding; Janssen: Honoraria; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tecnofarma SAS, AbbVie: Honoraria; Amgen: Research Funding; Novartis: Research Funding; Incyte, celgene: Consultancy; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Baz: BMS, sanofi, Karyopharm, Janssen, AbbVie: Consultancy, Research Funding; Merck: Research Funding; GlaxoSmithKline: Consultancy, Honoraria; Oncopeptides: Consultancy. Quach: Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, 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; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Plesner: Genmab, Genentech, Roche: Research Funding; Janssen, Celgene, Takeda, Oncopeptides, AbbVie: Consultancy, Research Funding. Moreau: Celgene BMS: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria. Gibbs: AbbVie: Consultancy; Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria. Bueno: AbbVie: Current Employment, Current equity holder in publicly-traded company. Luo: AbbVie: Current Employment, Current equity holder in publicly-traded company. Mantis: AbbVie: Current Employment, Current equity holder in publicly-traded company. Vishwamitra: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Harrison: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Terumo BCT: Consultancy, Honoraria; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that is being investigated as therapy for the treatment of relapsed/refractory multiple myeloma.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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