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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 448-448 ◽  
Author(s):  
Christian Schmidt ◽  
Anna-Katharina Zoellner ◽  
Vindi Jurinovic ◽  
Martin Sökler ◽  
Roswitha Forstpointner ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Tumor Burden ◽  
Primary Efficacy ◽  
Primary Efficacy Endpoint ◽  
Advisory Committees ◽  
Low Toxicity ◽  
Grade 3 ◽  
One Year ◽  
Support Research

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

Phase II Randomized, Multicenter Study of Lenalidomide Vs Best Investigator’s Choice in Relapsed/Refractory Mantle Cell Lymphoma: Results of the MCL-002 (SPRINT) Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 626-626 ◽  
Author(s):  
Marek Trneny ◽  
Thierry Lamy ◽  
Jan Walewski ◽  
Wojciech Jurczak ◽  
David Belada ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Tumor Burden ◽  
Advisory Committees ◽  
First Response ◽  
Mantle Cell ◽  
Grade 3 ◽  
Prognostic Profile

Abstract Introduction: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin’s lymphoma with poor outcome, especially after failure of first-line treatment. Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, has shown activity in single-arm phase II studies of patients with relapsed/refractory (R/R) MCL. The present controlled randomized study compared the efficacy and safety of lenalidomide vs investigator’s choice (IC) in patients with R/R MCL. Methods: MCL-002 (SPRINT), a European multicenter, open-label, phase II study enrolled patients with up to 3 relapses or who failed prior therapy and were ineligible for intensified treatment or stem cell transplantation (NCT00875667). Oral lenalidomide was given at 25 mg/day on days 1-21 of each 28-day cycle until progressive disease (PD) or intolerability. The IC treatment consisted of single-agent therapy with cytarabine, rituximab, gemcitabine, fludarabine, or chlorambucil. Patients who progressed on IC per investigator judgment were allowed to crossover to lenalidomide. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), time to first response, duration of response (DOR), overall survival (OS), and safety. Response assessments were centrally reviewed using the modified IWG criteria. Results: 254 patients with R/R MCL were randomized 2:1 to lenalidomide (n=170) or IC (n=84). Patients had median age 68.5 years, were predominantly male (73%), and had received a median of 2 prior therapies. 91% had stage III/IV disease at diagnosis, with 34% high-risk MIPI, 43% high tumor burden, and 20% bulky disease at baseline. Overall, patients on the lenalidomide arm had a worse prognostic profile than the IC arm due to higher tumor burden and disease risk (>5 percentage points for a number of parameters). After a median time of 2.9 months, 39 patients (46%) from the IC arm crossed over to lenalidomide due to PD. Overall, 84 patients remain on lenalidomide (15 having crossed over from IC) and 11 patients on IC without PD. At a median follow-up time on study of 15.9 months, the risk reduction for PFS was 39% (HR=0.61 [95% CI, 0.44-0.84]; P=0.004; Table) in favor of lenalidomide (median PFS: 8.7 months lenalidomide vs 5.2 months IC). ORR was significantly improved for lenalidomide vs IC (40% vs 11%; CR/CRu 5% vs 0%). Median time to first response was 4.3 months for lenalidomide (not reached for IC). Median DOR (16.1 vs 10.4 months) and OS on mature data (27.9 vs 21.2 months) were longer for lenalidomide vs IC. Efficacy results were consistent among subgroups. Safety data in 250 patients receiving ≥1 dose showed more dose reductions in lenalidomide-treated patients (41%) vs IC (17%), due in part to a longer median duration of lenalidomide treatment vs IC, and to strict dose modification rules for lenalidomide. The most common grade 3/4 adverse events (AEs) were neutropenia (lenalidomide 44% vs IC 34% [without increased risk of infection]), thrombocytopenia (18% vs 28%), and leukopenia (8% vs 11%). Tumor flare reaction occurred in lenalidomide patients only (10%; 2% grade ≥3); 1 patient in each arm experienced tumor lysis syndrome. Invasive second primary malignancies were identified in 4% and 5% of lenalidomide and IC treated patients, respectively. Conclusions: The MCL-002 study demonstrated a statistically significant and clinically meaningful improvement in PFS for lenalidomide over best IC monotherapy in patients with advanced R/R MCL despite a worse prognostic profile in the lenalidomide arm at baseline. In addition, ORR and CR rates, TTR, DOR, and OS were improved for lenalidomide over IC. The DOR has been remarkably consistent in various studies with lenalidomide in MCL patients. The safety profile for lenalidomide was as expected and no new safety signals were identified. The results of this first randomized, controlled study of lenalidomide showed superior efficacy compared to IC in patients with R/R MCL with a manageable toxicity profile. Table Efficacy of lenalidomide vs IC in R/R MCL Efficacy Lenalidomide (n=170) IC (n=84) P PFS (Lenalidomide vs IC)  Median PFS, mo (95% CI) 8.7 (5.54-12.14) 5.2 (3.67-6.95)  Sequential HR (95% CI) 0.61 (0.44-0.84)  Sequential log-rank test p-value 0.004 ORR, n (%) 68 (40) 9 (11) <0.001 CR/CRu, n (%) 8 (5) 0 (0) 0.043 Median DOR, mo 16.1 10.4 0.421 Median OS, mo 27.9 21.2 0.52 Disclosures Trneny: Celgene, Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Walewski:Celgene: Consultancy, Other, Research Funding; Janssen-Cilag: Consultancy; Mundipharma : Consultancy, Research Funding; Roche: Consultancy, Honoraria, Other, Research Funding. Jurczak:Celgene, Eisai, Gilead, Janssen, Pharmacyclics, Pfizer, Roche, Novartis, Spectrum, Takeda, Teva: Research Funding. Belada:Celgene: Research Funding. Mayer:Janssen Research & Development: Research Funding; Roche: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding. Biyukov:Celgene: Employment. Patturajan:Celgene: Employment. Casadebaig Bravo:Celgene: Employment. Arcaini:Celgene, Roche, Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Results of a Phase II Study of Obinutuzumab in Combination with Lenalidomide in Previously Untreated, High Tumor Burden Follicular Lymphoma (FL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 125-125 ◽  
Author(s):  
Loretta J. Nastoupil ◽  
Jason R. Westin ◽  
Fredrick B. Hagemeister ◽  
Hun Ju Lee ◽  
Luis Fayad ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Nk Cell ◽  
Tumor Burden ◽  
Advisory Board ◽  
Advisory Committees ◽  
High Tumor Burden ◽  
Equity Ownership ◽  
Grade 3

Introduction: FL, the most common indolent non-Hodgkin lymphoma, is characterized by a defective immune microenvironment that suppresses normal T-cell and natural-killer (NK)-cell activity. The clinical course is often depicted by high initial response rates coupled with a prolonged natural history and repeated relapses with most patients (pts) succumbing to their disease. Effective, well tolerated therapies are desirable. Obinutuzumab (O) is a humanized, type II anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity (ADCC). Lenalidomide (len) is an immunomodulatory agent that binds the cereblon E3 ubiquitin ligase complex resulting in recruitment, ubiquitination, and degradation of transcription factors Aiolos and Ikaros resulting in T-cell and NK-cell activation. Therefore, combining O with len is anticipated to be synergistic in augmenting the innate and adaptive immune response in FL. The combination has been shown to be well tolerated and effective in relapsed FL (Fowler ICML 2017). Therefore, we sought to explore the efficacy and safety of O-len in previously untreated, high tumor burden FL. Methods: We conducted as single-center, phase 2 study in previously untreated, stage II, III, or IV, high tumor burden (defined by GELF) FL (grade 1, 2 or 3A). Pts received 1000mg of O on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6, and day 1 of even numbered cycles, cycle 8-30. Cycle length was 28 days. Len was administered as 20mg on days 1-21 of cycles 1-6. Pts in a complete response (CR) after 6 cycles received reduced dose len (10mg on days 1-21) for cycles 7-18. Among pts in a partial response (PR) after 6 cycles, len was continued at 20mg for the next 3-6 cycles or until CR, whichever occurred first, len was then dose reduced to 10mg on days 1-21 for the remainder of 18 cycles. The primary endpoint was progression-free survival (PFS) at 2 years (according to Lugano 2014 criteria). Secondary endpoints included: safety, CR, PR, overall response (ORR), and overall survival (OS). Results: 90 pts with high tumor burden FL were enrolled. Median age was 58 years (range 33-84), 52% (N=47) were male, 67 (74%) had an ECOG performance status of 0, 9 (10%) had stage II, 23 (26%) stage III, and 58 (64%) had stage IV disease. The majority had grade 1/2 FL (80%). Twenty-one percent had low risk FLIPI scores, 37% intermediate risk, and 42% were high risk. With a median follow-up of 22 months (range 1-30 months), the 2-year PFS estimate is 96% (95% CI 92-100%) with only 2 pts experiencing progression to date. The ORR is 98% (85 CR, 1 PR), 92% achieved a CR at the first response assessment (cycle 4, day 1). Correlative studies are underway including serial circulating tumor DNA measurements. No deaths have been observed to date. Eleven pts (12%) discontinued therapy as a result of an adverse event (AE), upper respiratory infection was the most common reason (N=5). Other reasons included bradycardia with sick sinus syndrome, urinary tract infection, constipation, abdominal pain, fatigue, foot neuroma (N=1 for each instance). The most common grade 3 or higher AEs include neutropenia (16%, grade 3 N=5, grade 4 N= 9), rash (10%), lung infection (4%), neutropenic fever (1%). Conclusions: O-Len was associated with very high CR rates and 2-year PFS estimates in untreated, high tumor burden FL. The toxicity profile was manageable. Further study of this effective, immune therapy approach in untreated FL is warranted. Figure Disclosures Nastoupil: Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria. Westin:Genentech: Other: Advisory Board, Research Funding; Unum: Research Funding; Novartis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board; Kite: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta Pharma: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Kite Pharma: Consultancy, Research Funding; Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; VelosBio: Research Funding; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria. Neelapu:Acerta: Research Funding; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Allogene: Consultancy; Cell Medica: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; Poseida: Research Funding; Karus: Research Funding; Novartis: Consultancy; Incyte: Consultancy; BMS: Research Funding; Cellectis: Research Funding; Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding. Fowler:ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: 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, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy. OffLabel Disclosure: Lenalidomide in untreated follicular lymphoma

Safety of Treatment (Tx) with Pomalidomide (POM) and Low-Dose Dexamethasone (LoDEX) in Patients (Pts) with Relapsed or Refractory Multiple Myeloma (RRMM) and Renal Impairment (RI), Including Those on Dialysis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 374-374 ◽  
Author(s):  
Karthik Ramasamy ◽  
Meletios A. Dimopoulos ◽  
Niels W.C.J. van de Donk ◽  
Barbara Gamberi ◽  
Frank Bridoux ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Median Number ◽  
Comparable Efficacy ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Phase ◽  
Grade 3 ◽  
Dose Modifications ◽  
Support Research

Abstract Background: RI occurs in ≈ 20%-30% of newly diagnosed MM pts and is associated with poor prognosis (Knudsen et al. Eur J Haematol. 2000; Kyle et al. Mayo Clin Proc. 2003). Data from 2 pivotal trials (MM-002, MM-003) suggested comparable efficacy and tolerability of POM + LoDEX in pts with or without moderate RI (Siegel ASH 2012; Weisel ASCO 2013). However, these trials excluded pts with severe RI. MM-013 (NCT02045017) is a European multicenter, open-label phase 2 study designed to assess the efficacy, safety, and pharmacokinetics of POM + LoDEX in RRMM pts with moderate or severe RI, including those on dialysis. Methods: The trial is enrolling RRMM pts (N = 80) across 3 cohorts: cohort A (moderate RI, estimated glomerular filtration rate [eGFR] ≥ 30 to < 45 mL/min/1.73 m2, n = 33), cohort B (severe RI without dialysis, eGFR < 30 mL/min/1.73 m2, n = 33), and cohort C (severe RI requiring dialysis, n = 14). Pts must have MM-related RI and have received ≥ 1 prior Tx (including lenalidomide). POM 4 mg is administered on days 1-21 of a 28-day cycle and LoDEX 40 mg/day (20 mg for pts aged > 75 yrs) on days 1, 8, 15, and 22 until progressive disease (PD) or unacceptable toxicity. At the time of submission of this abstract, 17 pts terminated Tx; this abstract focuses on tolerability in these pts. Results: This trial is still recruiting; at the time of data cutoff for this abstract, 39 pts were enrolled. Data are included for 17 pts who discontinued Tx. Of all 39 pts, 12 were assigned to cohort A, 18 to cohort B, and 9 to cohort C. The median age of the total population was 72 yrs (range, 52-86 yrs), with 67.7% being male. The median number of prior lines of therapy was 4.0 (3.5 in cohort A, 5.0 in cohort B, and 3.0 in cohort C). This distribution was similar in the 17 pts who discontinued Tx so far (4, 7, and 6 in cohorts A, B, and C, respectively), with a median age of 72 yrs and 58.8% being male. Reasons for discontinuation of Tx were PD (7 pts), adverse events (AEs; 3 pts), death (5 pts: 2 pts due to PD, 2 pts due to infections, 1 pt due to hyperkalemia), and other reasons (2 pts: 1 pt aged 86 yrs with general health problems, 1 pt with increasing RI). Median Tx duration in these pts was 6.9 weeks in cohort A, 12.6 weeks in cohort B, and 12.9 weeks in cohort C. The dosage of POM was reduced to 3 mg in 3 pts (1 patient in each cohort), in all cases due to an AE (thrombocytopenia in 2 pts, pneumonia in 1 pt). However, no further Tx reductions occurred. The most frequent toxicity of any grade in the pts who discontinued was hematologic (82.4% [14 pts]), notably neutropenia in 58.8% (50% in cohort A, 42.9% in cohort B, 83.3% in cohort C), anemia in 52.9% (50% in cohort A, 28.6% in cohort B, 83.3% in cohort C), and thrombocytopenia in 52.9% (75% in cohort A, 14.3% in cohort B, 83.3% in cohort C). Grade 3/4 neutropenia occurred in 47.1%; grade 3/4 thrombocytopenia occurred in 35.3%. Notably, febrile neutropenia was reported in only 1 pt in cohort A. Granulocyte colony-stimulating factor was used in 52.9% of pts. Non-hematologic AEs were less frequent. Infections occurred in 7 pts (41.2%), all of which were pulmonary infections, with the exception of 1 case of nasopharyngitis. Asthenia (23.5%) and fatigue (23.5%) occurred predominantly in cohort C. No thromboembolic events or secondary primary malignancies have been reported to date. Conclusions: These data suggest that the combination of POM and LoDEX can be safely administered in pts with RI. A starting dose of POM 4 mg can be used throughout all stages of RI, and the side effects seen in this population have been previously reported with POM use (ie, mainly hematologic events and infections). Rates of neutropenia and thrombocytopenia are similar to reports in a non-RI population. Dose modifications should be considered in pts who develop neutropenia and thrombocytopenia; in pts showing signs of infections, dose interruptions may be considered. Disclosures Off Label Use: Pomalidomide in MM patients with renal insufficiency.. Dimopoulos:Janssen: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Onyx: Honoraria; Novartis: Honoraria; Amgen: Honoraria. van de Donk:Janssen Pharmaceuticals: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Gamberi:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kueenburg:Celgene Corporation: Consultancy, Honoraria. Rosettani:Celgene Corporation: Employment. Collins:Celgene Corporation: Employment. Lersch:Celgene Corporation: Employment. Bacon:Celgene Corporation: Employment, Equity Ownership. Weisel:Noxxon: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support; Novartis: Other: Travel Support; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel Support. Sonneveld:Amgen: Honoraria, Research Funding; Karyopharm: Research Funding; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

scholarly journals Obinutuzumab (GA101) in Combination with Pixantrone for the Treatment of Patients with Relapsed Aggressive B-Cell Lymphoma:Â a Phase II Trial (GOAL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1678-1678 ◽  
Author(s):  
Georg Hess ◽  
Andreas Hüttmann ◽  
Julia Meissner ◽  
Reinhard Marks ◽  
Martin Dreyling ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Median Number ◽  
Phase Iii ◽  
Advisory Committees ◽  
Phase Iii Trial ◽  
Grade 3 ◽  
One Year

Abstract Background: A substantial proportion of patients fail first line treatment of diffuse large B-cell lymphoma. Currently available salvage therapies are often ineffective and cannot be tolerated, especially for elderly patients. Thus, probably less than 25% of patients achieve a long lasting remission. Regimens like gemcitabine/oxaliplatin, or bendamustin, both in combination with rituximab are available for elderly or after failure of HDT, however induce only short lived responses. Obinutuzumab (GA101) is a type II anti-CD20 antibody, with preclinical evidence of superiority over rituximab in xenograft models of MCL and DLBCL. Recently a large phase III trial failed to show a benefit in patients with untreated DLBCL, although a subset analysis showed a potential benefit in a subset GCB DLBCL of patients, its value in relapsed disease is not yet finally determined. Although desirable, cumulative dose-related, progressive cardiotoxicity eliminates anthracyclines from relapse treatments. With pixantrone, a drug related to anthracyclines, a re-exposition against this drug class has been shown to be feasible, a best EOT-ORR of 37% (20% CR/CRu) was observed in a phase III trial. We thus initiated a trial combining both agents for the first time. The trial has opened in Q3/2015 and recruitment of 70 patients is completed as of 7/2018. Primary endpoint is the ORR, secondary endpoints being safety, PFS and OS. We report about available data after enrollment of the last patient. Methods: this is a multicenter, national, prospective trial. Main inclusion criteria: histologically proven DLBCL, FL grade IIIb or transformed iNHL (20% Quorum), no curative option available, relapsed and measurable disease, ECOG < 3, sufficient BM reserve, no severe concomitant diseases and given informed consent. There was no upper limit of prior treatment lines. Treatment consisted of up to 6 cycles of pixantrone 50mg/m² day 1, 8 and 15 of each cycle, obinutuzumab 1000 mg flat dose day 1, 8 and 15 of cycle one and day 1 of each subsequent cycle. Interim staging was scheduled after 3 cycles. Results: Basic data are available of 67 patients, all were caucasian, 37 were female the other 30 male and median age was 75 years. Most of the patients suffered from DLBCL (49 pts, 68%), 68% had advanced stage at diagnosis and the median secondary IPI was 3. Data collection is ongoing, until now data of 32 patients are fully available and updated results will be presented. Median number of prior therapies was 2 (1 to 6). Treatment seemed to be well tolerated, median number of cycles applied was 3, pre-mature stop of treatment was primarily based on progression. Response evaluation: at this time 13/32 (40.6%) evaluable patients responded with 5 patients achieving CR/CRu (15.6%) and 8 a PR. One year after initiation of treatment 54% of patients remained alive. Median follow up is 8.2 months. Median PFS and OS is 82 day and not reached, 1 year PFS and OS are 37% and 54%, respectively, no patient experienced relapse if the patient remained free from relapse at one year. Observed toxicity was predominantly hematologic. The following hematologic grade 3/4 adverse events were observed: leukopenia (9.4%) neutropenia (75%), thrombocytopenia (12.5%). The febrile neutropenia rate was 6.3%. Non-hematologic grade 3/4 adverse events were very rare, no single side effect was observed with a frequency of 5% or more. Summary: the combination of Obinutuzumab and Pixantrone is feasible and safe. Early response rates are interesting. Importantly, although some patients experience progress early, a promising proportion shows long lasting remissions. Molecular analyses are ongoing, as well as a detailed analysis on the impact of factors such as of number of prior treatments, status at inclusion. Figure. Figure. Disclosures Hess: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Marks:BMS: Honoraria; Merck: Honoraria; Servier: Honoraria. Dreyling:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Acerta: Consultancy; Sandoz: Consultancy. Keller:Takeda: Consultancy, Research Funding; MSD: Consultancy; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy; BMS: Consultancy; Celgene: Research Funding. Ernst:Novartis: Research Funding. Viardot:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria. Lenz:Novartis: Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Celgene Corp.: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria.

scholarly journals Carfilzomib and Dexamethasone Vs Bortezomib and Dexamethasone in Patients with Relapsed Multiple Myeloma: Results of the Phase 3 Study Endeavor (NCT01568866) According to Age Subgroup

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1844-1844 ◽  
Author(s):  
Antonio Palumbo ◽  
Meletios A. Dimopoulos ◽  
Philippe Moreau ◽  
Wee-Joo Chng ◽  
Hartmut Goldschmidt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Odds Ratio ◽  
Research Funding ◽  
Phase 3 ◽  
Advisory Committees ◽  
Younger Age ◽  
Grade 3 ◽  
Support Research

Abstract Introduction: Carfilzomib is a selective proteasome inhibitor that is approved in the United States and other countries for the treatment of relapsed and refractory multiple myeloma. The randomized, open-label, multicenter, phase 3 study ENDEAVOR (NCT01568866) met its primary end point, demonstrating a statistically and clinically significant improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) compared with bortezomib and dexamethasone (Vd) (median 18.7 vs 9.4 months; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.44-0.65; 1-sided P <0.001) (Dimopoulos et al, J Clin Oncol 2015;33:abstr 8509; Dimopoulos et al, Haematologica 2015;100[s1]:abstr LB2071). Herein we present results of a preplanned subgroup analysis of efficacy and safety outcomes of the ENDEAVOR study according to age. Methods: Adult patients with relapsed multiple myeloma (RMM; 1-3 prior regimens) were eligible. Patients in the Kd arm received K (30-min intravenous [IV] infusion) on days (D) 1, 2, 8, 9, 15, and 16 (20 mg/m2 on D1, 2 [cycle 1]; 56 mg/m2 thereafter) and dexamethasone (20 mg) on D1, 2, 8, 9, 15, 16, 22, and 23 of 28-day cycles. The Vd arm received V (1.3 mg/m2; IV or subcutaneously) on D1, 4, 8, and 11 and dexamethasone (20 mg) on D1, 2, 4, 5, 8, 9, 11, and 12 of 21-day cycles. Treatment was administered until disease progression or unacceptable toxicity. The primary end point of the study was PFS; secondary end points included overall survival, overall response rate (ORR), duration of response (DOR), safety, and rate of peripheral neuropathy (PN). The present analyses evaluated outcomes in patients grouped according to age (ie, <65, 65-74, and ≥75 years of age). Results: A total of 929 patients were enrolled (intent-to-treat population; <65 years: Kd, n=223; Vd, n=210; 65-74 years: Kd, n=164; Vd, n=189; ≥75 years: Kd, n=77; Vd, n=66). Baseline patient and disease characteristics were generally well balanced between treatment arms within each age subgroup. PFS was improved with Kd vs Vd within each age subgroup (<65 years: median, not estimable vs 9.5 months [HR, 0.58; 95% CI, 0.44-0.77]; 65-74 years: median, 15.6 months vs 9.5 months [HR, 0.53; 95% CI, 0.38-0.73]; ≥75 years: median, 18.7 months vs 8.9 months [HR, 0.38; 95% CI, 0.23-0.65]) (Table). Kaplan-Meier PFS curves by age subgroup are shown in the Figure. ORRs in each age group were also higher in the Kd arm compared with the Vd arm in each subgroup (<65 years: 74% vs 61% [odds ratio, 1.82; 95% CI, 1.21-2.74]; 65-74 years: 77% vs 66% [odds ratio, 1.80; 95% CI, 1.12-2.89]; ≥75 years: 84% vs 59% [odds ratio, 3.75; 95% CI, 1.71-8.24]). Rates of grade ≥3 adverse events of interest, including hypertension are shown in the Table. Grade ≥3 hypertension, dyspnea, cardiac failure, renal failure were more common with Kd vs Vd within each age subgroup. Rates of grade ≥2 PN were lower in the Kd arm across all subgroups compared with the Vd arm (<65 years: 6% vs 27% [odds ratio, 0.17; 95% CI, 0.09-0.32]; 65-74 years: 8% vs 34% [odds ratio, 0.17; 95% CI, 0.09-0.32]; ≥75 years: 3% vs 43% [odds ratio, 0.035; 95% CI, 0.008-0.16]). Adverse events leading to treatment discontinuation occurred at similar frequencies in the Kd and Vd arms in the two younger-age subgroups (<65 years: 17% vs 15%; 65-74 years: 22% vs 22%), but at a higher frequency in the Vd arm for the oldest-age subgroup (≥75 years: 26% vs 35%). Deaths within 30 days post-treatment due to adverse events occurred at similar rates in the Kd and Vd arms within each age subgroup (<65 years: 3% vs 3%; 65-74 years: 5% vs 3%; ≥75 years: 4% vs 5%). Conclusions: Kd demonstrated clinically meaningful improvement in PFS and ORR compared with Vd within all age subgroups examined, with a trend toward a greater improvement in the eldest-age subgroup (≥75 years) than in the two younger-age subgroups (<65 and 65-74 years). The eldest-age subgroup in the Kd arm had an increased incidence of select grade ≥3 adverse events of interest, including cardiac failure and hypertension, compared with the younger-age subgroups in the Kd arm. Hypertension is a recognized but manageable complication in elderly patients and should be monitored. Overall, results suggest that Kd has a favorable benefit-risk profile in patients with RMM, irrespective of age. Disclosures Palumbo: Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Dimopoulos:Janssen: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Genesis: Honoraria; Janssen-Cilag: Honoraria. Moreau:Novartis, Janssen, Celgene, Millennium, Onyx Pharmaceuticals: Consultancy, Honoraria. Goldschmidt:Janssen, Celgene, Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria; Amgen, Takeda: Consultancy; BMS: Consultancy, Research Funding; Chugai, Millennium: Honoraria, Research Funding. Hájek:Janssen-Cilag: Honoraria; Celgene, Amgen: Consultancy, Honoraria. Facon:Onyx/Amgen: Membership on an entity's Board of Directors or advisory committees. Ludwig:Janssen Cilag: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Celgene Corporation: Honoraria, Speakers Bureau; Takeda: Research Funding. Niesvizky:Celgene, Millennium, Onyx: Consultancy, Speakers Bureau. Oriol:Celgene, Janssen, Amgen: Consultancy, Speakers Bureau. Rosiñol:Celgene, Janssen: Honoraria. Gaidano:Celgene: Research Funding; Morphosys, Roche, Novartis, GlaxoSmith Kline, Amgen, Janssen, Karyopharm: Honoraria, Other: Advisory Boards. Weisel:Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Support; Janssen: Consultancy, Honoraria, Other: Travel Support, Research Funding; Onyx: Consultancy, Honoraria; Novartis: Other: Travel Support; Takeda: Other: Travel Support; Noxxon: Consultancy. Gillenwater:Onyx, Amgen: Employment, Other: Stock. Mohamed:Onyx/Amgen: Employment, Other: Stock. Feng:Amgen/Onyx: Employment, Equity Ownership. Joshua:Celgene: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Phase I Trial of Systemic Administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and Human Interferon, in Patients with Relapsed or Refractory Multiple Myeloma (MM), Acute Myeloid Leukemia (AML), and T-Cell Neoplasms (TCL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3268-3268
Author(s):  
Martha Q. Lacy ◽  
Kah-Whye Peng ◽  
Stephen J. Russell ◽  
Amylou C. Dueck ◽  
Mrinal M. Patnaik ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Tumor Burden ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Background: We previously reported successful treatment of myeloma with an oncolytic virus, MMV-NIS. Preexisting immunity against measles made use of that virus unsatisfactory. The Indiana strain of Vesicular Stomatitis Viruses (VSV) are being developed as anticancer drugs for the treatment of a variety of malignancies. To ensure tumor selective replication and spread, we designed the VSV to encode interferon beta. Expression of IFNβ also serves as a STING agonist to activate host immunity against the cancer. The sodium iodide symporter (NIS) is inserted as a reporter gene into the viral genome to enable noninvasive monitoring of viral spread using PET/CT imaging. We report a Phase I clinical trial of intravenous administration of VSV-IFNβ-NIS for relapsed hematological malignancies including MM, AML, and TCL. Methods: Arm A consisted of patients with low tumor burden. Arm B included patients with high tumor burden. Both arms consisted of a classical 3+3 phase I trial, starting at 5x10^9 TCID50 (dose level 1) through 5x10^11 TCID50 (dose level 4), given as a single IV dose. In order to obviate potential toxicity from high interferon levels, Arm B received ruxolitinib 15 mg twice daily for 10 days beginning on day -1. The primary objective was determining the maximum tolerated dose (MTD) of VSV-IFNβ-NIS alone and in combination with ruxolitinib; secondary objectives include estimating the safety profile and preliminary efficacy. Correlative objectives include monitoring the pharmacodynamics of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding, changes in the immune profile of peripheral blood leukocytes, and immunohistochemistry for immune cell infiltrates in tumors. Adverse events (AEs) are reported herein based on CTCAE v4 with the exception of cytokine release syndrome (CRS) which is based on Lee (Blood 2014; 124(2):188-195) criteria. Results: To date, 10 patients have received IV VSV-IFNβ-NIS; 8 in Arm A and 2 in Arm B. In Arm A, 3 patients were treated at dose level 1, 3 at dose level 2 and 2 at dose level 3. At dose level 1, there were three grade 3 hematologic AEs (neutropenia [1], lymphopenia [2]), and no grade 3+ non-hematologic AEs. At dose level 2, there were two grade 3 hematologic AEs (anemia [1], lymphopenia [1]), and two grade 3 non-hematologic AEs (nausea [1], dehydration [1]). A grade 2 CRS by Lee criteria was also observed. At dose level 3, 2 patients have been enrolled and data are maturing for DLT evaluation. In Arm B (VSV + rux), 2 patients have been enrolled and data are maturing for dose limiting toxicity (DLT) evaluation. Other grade 1 and 2 toxicities have included fever, hypertension, headache, electrolyte abnormalities, nausea, vomiting, transient elevation of liver function tests and creatinine. All grade 1 and 2 toxicities resolved within 72 hours. Among the 6 patients evaluable for response, there was one partial remission (TCL patient treated at dose level 2), and 5 with progressive disease. Multiple cytokines increased at 4h post infusion of virus, but most returned to baseline levels by 24h.Viremia was detectable in all patients at the end of infusion, and to varying levels at 30 mins, 1, 2, 4, 24, 48h or 72 hours post virus infusion. No persistent viremia was observed. No infectious virus was recovered in buccal swabs or urine and neutralizing anti-VSV antibodies were present by day 29. Extensive immune phenotyping and ELIspot assays for shared antigens are ongoing. Conclusion: In the lowest dose levels tested to date, VSV-IFNβ-NIS has not led to any observed dose limiting toxicity. Dose escalation is ongoing and updated results will be reported. Disclosures Lacy: Celgene: Research Funding. Peng:Vyriad: Equity Ownership. Russell:Vyriad: Equity Ownership. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:spectrum: Consultancy, Honoraria; Physicians Education Resource: Consultancy; Ionis: Honoraria; janssen: Consultancy; Medscape: Consultancy; celgene: Consultancy; Apellis: Consultancy; Prothena: Honoraria; Amgen: Consultancy; annexon: Consultancy; Abbvie: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; Alnylam: Honoraria. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Al-Kali:Novartis: Research Funding. Naik:Vyriad: Equity Ownership. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: 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, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Lenalidomide In Combination With R-CHOP (R2-CHOP) In Patients With High Burden Follicular Lymphoma: Phase 2 Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 248-248 ◽  
Author(s):  
Herve Tilly ◽  
Franck Morschhauser ◽  
Olivier Casasnovas ◽  
Thierry Jo Molina ◽  
Nicolas Mounier ◽  
...  
Keyword(s):  
Complete Remission ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Tumor Burden ◽  
Phase 2 ◽  
Advisory Committees ◽  
High Burden ◽  
Grade 3

Abstract Background Single-agent studies of lenalidomide in relapsed/refractory follicular lymphoma (FL) have demonstrated significant activity. Recent studies reported that the combination of lenalidomide and rituximab yields high response rates in patients with FL. Three recent phase 1 studies have shown that lenalidomide administered on 10 to 14 days of 21-day cycle of R-CHOP could be safe in the initial treatment of aggressive or indolent B-cell lymphomas. Two of these studies determined 25 mg of lenalidomide as the recommended daily dose. This multicenter, open label, phase 2 trial (NCT01393756) investigated the combination of lenalidomide with R-CHOP in patients (pts) with high burden FL. Methods Pts with previously untreated FL grade 1, 2 or 3a and a high tumor burden according to GELF criteria were eligible. Pts received an induction therapy with 6 cycles of R2-CHOP given every 3 weeks (25 mg oral lenalidomide on days 1-14) followed by two additional rituximab infusions. Pegfilgrastim was administered on day 4 and oral aspirin prophylaxis (100 mg) was given daily during the cycles. Lenalidomide dose was adapted to toxicities. Pts responding to induction therapy received rituximab maintenance every 8 weeks for 2 years. The primary endpoint was the complete remission (CR/CRu) rate, according to IWRC 99, at the end of induction treatment. Secondary endpoints were safety, progression free survival, duration of response and overall survival. Results Eighty pts were enrolled from 16 LYSA centres between December 2010 and January 2012. Median age was 57 y (range 29-71); 50% were male; 92% Ann Arbor stage III-IV; 28% B symptoms, 69% ECOG performance status = 0; 25% mass >10cm; 53% bone marrow involved; 40% LDH elevated; 63% FLIPI 3-5. Sixty-eight pts (85%) received the complete induction regimen. Median interval between R2-CHOP cycles remained 21 days during treatment. Thirty-three pts (41%) experienced at least one dose reduction of lenalidomide. The complete remission (CR/CRu) rate was 74% (CI 95%: 63%-83%) and ORR was 94% (CI95%: 86%-98%).Current median follow-up is 13 months. So far, 9 pts (11%) experienced a progression/relapse. Hematologic toxicity was in the range of that observed with R-CHOP regimen with 65% grade 4 neutropenia; 12.5% grade 4 thrombocytopenia; 7.5% febrile neutropenia and no toxic death. Grade 1-2 sensory neuropathy was observed in 28 pts (36%), one pt had a grade 3 neuropathy. Twenty-nine pts (36%; grade 1-2: 27; grade 3: 2) had reversible skin toxicity, usually during the course of the first cycle. Five episodes of thrombosis occurred during treatment or follow-up, 3 were related to venous access devices and only one required discontinuation of lenalidomide. Three cases of neoplasm were observed during follow-up. Conclusion The combination of 25mg of lenalidomide for 14 days with 21-day R-CHOP cycles is well tolerated and yields a high rate of complete remission in patients with high tumor burden follicular lymphoma. Disclosures: Tilly: Roche: Honoraria; Celgene: 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; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Research Funding. Off Label Use: Use of lenalidomide to enhance R-CHOP efficacy in follicular lymphoma. Morschhauser:Celgene: advisory boards Other, Honoraria, Research Funding, Speakers Bureau. Casasnovas:ROCHE: Consultancy, Honoraria, Research Funding. Molina:Merck: Honoraria. Salles:roche: Consultancy, Honoraria, Research Funding; Celgene: Honoraria. Haioun:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: 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; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Phase I/IIa Study of the Human Anti-CD38 Antibody MOR202 (MOR03087) in Relapsed or Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3035-3035 ◽  
Author(s):  
Marc S Raab ◽  
Manik Chatterjee ◽  
Hartmut Goldschmidt ◽  
Hermine Agis ◽  
Igor W Blau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Dependent Cell ◽  
Grade 3 ◽  
Dose Levels ◽  
Support Research

Abstract Background: CD38 is a type II transmembrane glycoprotein that is expressed at high levels on multiple myeloma cells. MOR202 is a HuCAL-derived, human, IgG1 anti-CD38 monoclonal antibody showing effective antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and high activity in preclinical models of multiple myeloma. Patients and Methods: Here we reportinterimsafety and preliminary efficacy data from this ongoing, multicenter, MOR202 dose-escalation, phase I/IIa study in patients with relapsed or refractory disease who had failed ≥2 prior therapies for multiple myeloma, including an immunomodulatory drug and a proteasome inhibitor. The objectives are to evaluate the safety, maximum tolerated dose (MTD)/recommended dose and preliminary efficacy of MOR202 when administered as monotherapy or in combination with dexamethasone (DEX); pomalidomide (POM) + DEX; and lenalidomide (LEN) + DEX. Patients received MOR202 as a 2-hour intravenous infusion every 2 weeks (q2w; dose levels 0.01-16 mg/kg), 4 mg/kg weekly (q1w) and 4, 8 and 16 mg/kg q1w + DEX. The combination cohorts receiving MOR202 8 mg/kg with LEN + DEX and POM + DEX have been opened, and the 16 mg/kg q1w with LEN + DEX or POM + DEX, as well as confirmation cohorts, are planned. Results: As of 26 June 2015, 44 patients have been treated; 31 and 13 patients in the q2w and q1w dose levels, respectively. Median age was 69 years (range 44-80); median number of prior therapy lines was 4 (2-11). The MTD has not been reached. The most common treatment-emergent adverse events (TEAEs) at any grade were anemia (15 patients, 34%), fatigue (14 patients, 32%), infusion-related reactions (IRRs) and leukopenia (13 patients, 30% each), lymphopenia and nausea (11 patients, 25% each). Grade ≥3 TEAEs were reported for 28 patients (64%); the most common included lymphopenia (8 patients, 18%), leukopenia (5 patients, 11%) and hypertension (4 patients, 9%). IRRs arose mainly during the first infusion; all were grade 1-2 except for one patient (grade 3); no IRRs occurred in patients receiving MOR202 in combination with DEX. Infections were commonly reported (26 patients, 59%) but in the majority of the cases were not considered to be treatment-related. There have been no treatment-related deaths. Pharmacokinetic (PK) data demonstrated a significant target-mediated drug disposition effect for most patients treated q2w. By contrast, patients treated q1w (4 or 8 mg/kg) showed constant or slightly accumulating MOR202 trough levels, suggesting the potential for full target occupancy at 16 mg/kg. Long-lasting tumor control has already been observed in early monotherapy cohorts, including one partial response and one very good partial response in the weekly cohorts; efficacy analyses are ongoing. First data from the dose escalation of the weekly cohorts with DEX and the combination cohorts with LEN + DEX and POM + DEX will be presented. Conclusions: At doses up to 16 mg/kg,MOR202 was safe and well tolerated. Encouraging preliminary activity of MOR202 was observed, especially with the weekly regimen. PK data show the potential for full target occupancy in patients receiving MOR202 16 mg/kg q1w. This dosing schedule of MOR202 is currently being tested in combination with DEX, LEN + DEX, and POM + DEX. Disclosures Raab: MorphoSys: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; BMS: Consultancy. Goldschmidt:Chugai: Honoraria, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: 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, Research Funding, Speakers Bureau. Einsele:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ferstl:Bristol-Myers Squibb: Other: Advisory board; Novartis: Other: Case report presentation. Weisel:Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Support; Novartis: Other: Travel Support; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support; Onyx: Consultancy, Honoraria; Noxxon: Consultancy. Klöpfer:MorphoSys: Employment. Weinelt:MorphoSys: Employment. Härtle:MorphoSys: Employment.

scholarly journals Randomized Phase III Trial in Non-Transplant Eligible Patients with Newly Diagnosed Symptomatic Multiple Myeloma Comparing Melphalan-Prednisone-Thalidomide Followed By Thalidomide Maintenance (MPT-T) Versus Melphalan-Prednisone-Lenalidomide Followed By Maintenance with Lenalidomide (MPR-R); A Joint Study of the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) and the Nordic Myeloma Study Group (NMSG)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 179-179 ◽  
Author(s):  
Sonja Zweegman ◽  
Bronno van der Holt ◽  
Ulf-Henrik Mellqvist ◽  
Morten Salomo ◽  
Gerard M.J. Bos ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Incidence Rates ◽  
P Value ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
One Year

Abstract Background Melphalan-based regimens, combined with Prednisone and Thalidomide (THAL)(MPT) or Bortezomib (V)(MPV), have been approved as standard therapy of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients. Similar to MPT and MPV also MP-Lenalidomide followed by Lenalidomide (LEN) maintenance (MPR-R) has a superior PFS compared to MP. We compared MPT followed by THAL maintenance (MPT-T) versus MPR-R in non-transplant eligible NDMM patients. Study design Patients were randomised to receive nine 4-weekly cycles of MPT (MEL 0.18 mg/kg days 1-4, PRED 2 mg/kg days 1-4 plus THAL 200 mg days1-28) followed by THAL maintenance 100 mg d1-28 until progression or nine cycles of MPR (MEL 0.18 mg/kg days 1-4, PRED 2 mg/kg days 1-4 plus LEN 10 mg days 1-21) followed by LEN maintenance 10 mg d1-21 until progression. In order to detect an improvement of progression free survival (PFS) with 90% power and a HR of 0.714 for patients receiving MPR-R, 668 patients had to be randomized. The study started in January 2009 and was closed for inclusion in October, 2012. This analysis is restricted to the first 560 eligible randomized patients, i.e. 280 per arm, including the minimum number of events (377) that were required for the primary endpoint. Results Patient characteristics are presented in table 1. The median follow up is 32.6 months. The results of FISH analysis on isolated plasma cells, being performed in 75% and 79% of patients treated with MPT-T and MPR-R respectively, are shown in table 1. Complete response (CR) rates on protocol were 10% (MPT-T) vs. 13% (MPR-R), (p=0.43), ≥ very good partial response (VGPR) rates were 49% vs. 44% (p=0.31), and ≥ partial response (PR) rates were 82% vs. 83% (p=0.91). The median PFS was 20 months (95% CI; 18-23) for MPT-T vs. 22 months (95% CI; 19-27) for MPR-R (HR = 0.86, 95% CI = 0.70-1.05, p-value adjusted for ISS =0.14). The median overall survival (OS) was 49 months (95% CI; 43-54) for MPT-T vs. 50 months (95% CI; 45-54) for MPR-R (HR = 0.79, 95% CI = 0.60-1.05, p-value adjusted for ISS =0.11). Del(17p) was associated with a lower PR rate (OR=0.45, 95% CI 0.22-0.95, p=0.003), worse PFS (HR=1.74, 95% CI 1.20-2.54, p=0.007) and decreased OS (HR=1.98, 95% CI 1.19-3.28, p=0.01). Grade ≥ 3 toxicity during induction and maintenance is presented in table 2. The dose intensity of THAL during induction was median 53% (mean 56%, SD 34%), vs. median 88% (mean 73%, SD 32%) for LEN during induction. There was a significantly higher discontinuation rate due to toxicity associated with THAL (28% within one year, and 58% within two years) vs LEN maintenance (10% within one year, and 16% within two years)(p<0.001). The median duration of THAL maintenance was 5 months, vs. median 16 months of LEN maintenance. The incidence rates for second primary malignancies (SPM) were 3.3/100 patient years (MPT-T) and 2.4/100 patient years (MPR-R)(p=0.33), with 3 (MPT-T) and 6 (MPR-R) cases of AML/MDS and 18 (MPT-T) and 11 (MPR-R) solid tumors (excluding non-melanoma skin cancers). Detailed analyses will be performed in order to allow cross trial comparisons. Table 1 Demographics MPT - T MPR - R Total 280 280 Male/Female % 53/47 58/42 Median age [range] 72 [60-91] 73 [60-87] < 75 years % 64 59 ≥ 75 years % 36 41 ISS at randomization n (%) I 67 (24) 72 (26) II 137 (49) 131 (47) III 73 (26) 74 (26) Unknown 3 (1) 3 (1) LDH n (%) Normal 248 (89) 232 (83) Elevated 20 (7) 29 (10) Unknown 12 (4) 19 (7) FISH analysis on isolated plasma cells , n (%) 210 (75) 222 (79) 1q amplification 52 (37) 50 (32) t(4;14) 16 (11) 16 (9) del(17p) 22 (12) 16 (8) Table 2 Toxicity MPT - T MPR - R CTCAE grade (%) 3 4 3 4 During induction therapy Anemia 4 - 13 1 Thrombocytopenia 4 1 23 8 Neutropenia 20 5 43 21 Infections 17 3 16 3 Neuropathy 8 - - - VTE* 3 3 3 2 During maintenance therapy Anemia 1 1 1 - Thrombocytopenia 1 - 1 1 Neutropenia 3 - 8 3 Neuropathy 15 - 1 - VTE* 1 1 1 - Conclusions Treatment of elderly NDMM patients with MPT followed by THAL maintenance or MPR followed by LEN maintenance resulted in similar PFS. In addition, response rates and OS were not significantly different. Discontinuation of maintenance therapy due to toxicity was significantly higher for THAL versus LEN and SPM incidence rates similar across the groups. * Venous Thromboembolic Event including both deep venous thrombosis and pulmonary embolism This trial was registered as EudraCT 2007-004007-34 Disclosures Zweegman: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mellqvist:Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Mundipharma: Honoraria. Bos:Celgene: Research Funding. van de Donk:Janssen: Research Funding; Celgene: Research Funding. Sonneveld:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Millenium: Honoraria, Research Funding. Waage:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 390-390 ◽  
Author(s):  
Mark A. Schroeder ◽  
H. Jean Khoury ◽  
Madan Jagasia ◽  
Haris Ali ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Janus Kinase ◽  
Cell Transplant ◽  
Employment Equity ◽  
Advisory Committees ◽  
Daily Dose ◽  
Equity Ownership ◽  
Grade 3 ◽  
Steroid Refractory

Abstract Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD. Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03. Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation. Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. Disclosures Schroeder: Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.

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