Ixazomib-Lenalidomide-Dexamethasone (IRd) Combination before and after Autologous Stem Cell Transplantation (ASCT) Followed By Ixazomib Maintenance in Patients with Newly Diagnosed Multiple Myeloma (NDMM): A Phase 2 Study from the Intergroupe Francophone Du MyéLome (IFM)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 674-674 ◽  
Author(s):  
Philippe Moreau ◽  
Cyrille Hulin ◽  
Denis Caillot ◽  
Gerald Marit ◽  
Aurore Perrot ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Induction Therapy ◽  
Research Funding ◽  
Single Agent ◽  
Response Rates ◽  
Consolidation Therapy ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Consolidation Phase ◽  
Grade 3

Abstract Background Frontline ASCT is the standard of care for patients with symptomatic NDMM less than 66 years of age. 3-drug combinations are the standard induction regimens prior to ASCT. Consolidation therapy after ASCT is aimed at improving disease control through deepening responses. Maintenance therapy is administered with the objective of prolonging response duration. The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone (IRd) was recently evaluated in NDMM, was generally well tolerated and appeared active (Kumar et al, Lancet Oncology 2014;13:1503-12). We analyzed the safety and efficacy of the triplet IRd combination prior to, and as consolidation after ASCT followed by ixazomib maintenance in the initial management of MM in patients younger than 66 years in a phase 2 study (NCT01936532). Methods Patients received 3 cycles of induction therapy with Ixazomib 4 mg on days 1, 8 and 15 plus Lenalidomide 25 mg on days 1 through 21 and dexamethasone 40 mg on days 1-8-15 and 22 of a 28-day cycle followed by Melphalan 200 mg/m2 and ASCT. Two months after ASCT, patients received an early consolidation with 2 cycles of IRd identical to induction therapy followed by a late consolidation phase with 6 additional cycles of IR without dexamethasone. One month after the last consolidation cycle, patients received maintenance therapy with Ixazomib single-agent 4 mg on days 1, 8 and 15 of a 28-day cycle, during 12 months. The primary end-point was the complete response (CR) rate after extended consolidation therapy. The secondary objectives were to evaluate the overall response rate (ORR) after induction, after ASCT, after consolidation and after maintenance, to evaluate the safety of induction therapy, the feasibility of extended consolidation, the feasibility of maintenance with Ixazomib, the duration of response, progression-free and overall survival. Responses (central lab, Dr Dejoie, Nantes) were assessed according to the IMWG criteria. Toxicity was evaluated according to NCI CTCAE, version 4.03. Results From 11/2014 to 04/2015, 42 patients (21 males, 21 females, median age 60 years (43-65)) with NDMM were enrolled in 10 centers from IFM. ISS was 1 in 12 cases (29%), 2 in 23 cases (54%) and 3 in 7 patients (17%), respectively. Adverse cytogenetics (17p deletion, and/or t(4;14); central lab, Dr Avet-Loiseau) was observed in 8 patients (19%). Induction with IRd was very well tolerated. Out of 120 cycles administered for 42 patients, only 13 cases of non-hematologic grade 3-4 toxicities were reported: infections (8 cases), abdominal pain (2), atrial fibrillation (1), thrombosis (1), and DRESS syndrome leading to study withdrawal (1). No renal or liver toxicity was reported. No cardiac failure and no ischemic heart disease was documented. No grade 3-4 peripheral neuropathy was described. Response rates increased at each step of the strategy. Following 3 induction cycles of IRd, the ORR was 81%, including 12% CR plus 24% very good partial response (VGPR), and 2 patients progressed (5%). Following ASCT, the VGPR rate or better was 78% including 38% CR. Following consolidation (early 2 cycles + extended 6 cycles), the VGPR rate or better was 80% including 44% CR. The feasibility of the consolidation phase with IRd (2 cycles) and IR (6 cycles) was excellent: 34 / 37 patients who started consolidation completed the 8 planned cycles (3 discontinuations: 2 patient decisions, 1 progression to plasma cell leukemia). 34/42 patients (81%) were able to receive maintenance therapy with Ixazomib following extended consolidation. Results of maintenance and of minimal residual disease evaluation will be presented during the meeting. At the cut-off date of June 30 2016, with a median follow-up of 16 months, 3 patients / 42 (7%) have progressed, 2 during induction and 1 during consolidation, and 2 (5%) died from progressive disease. Conclusions The all-oral triplet combination IRd administered as induction prior to, and as consolidation following ASCT is safe, convenient, and effective, leading to 80% VGPR and 44% CR before maintenance. Final results on response rates following maintenance and MRD data will be presented during the meeting. Updated results on PFS and OS will also be presented. Disclosures Moreau: takeda: Honoraria; celgene: Honoraria; janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Hulin:celgene: Honoraria; janssen: Honoraria; takeda: Honoraria. Facon:Millenium/Takeda: Consultancy; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Roussel:celgene: Honoraria; takeda: Honoraria; janssen: Honoraria. avet-Loiseau:takeda: Honoraria; janssen: Honoraria; celgene: Honoraria; amgen: Honoraria. Attal:sanofi: Consultancy; amgen: Consultancy, Research Funding; janssen: Consultancy, Research Funding; celgene: Consultancy, Research Funding.

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

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

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

An Open-Label Phase 2 Study Of Ofatumumab In Combination With a Novel AKT Inhibitor (Afuresertib) In Previously Treated Patients With Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4175-4175
Author(s):  
Christine I. Chen ◽  
Susi Snitzler ◽  
Trina Wang ◽  
Harminder Paul ◽  
Lisa W Le ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Treatment Phase ◽  
Phase 2 ◽  
Akt Inhibitor ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3

Abstract Introduction Ofatumumab is a novel anti-CD20 monoclonal antibody which led to impressive single-agent responses of 47-58% in a phase 2 study of CLL patients (pts) with refractory disease (Wierda et al 2010). Unfortunately, response durations were short (median 5.6-7.1 mos). In order to improve upon these results, we combined ofatumumab with a novel pan-AKT kinase inhibitor, afuresertib (GSK2110183). The AKT pathway plays a centralized role in tumor differentiation, migration, proliferation and survival and is frequently aberrantly activated in CLL (Longo et al 2007). Single agent afuresertib is very well-tolerated with minimal myelotoxicity in relapsed/refractory hematologic malignancies (Spencer et al ASH 2011). We present an interim analysis of the initial 19 of 31 planned pts in an ongoing trial of ofatumumab and afuresertib in relapsed/refractory CLL. Methods Previously treated CLL pts who have received at least one prior fludarabine-containing regimen with disease progression are eligible. During the initial 6 month Treatment Phase, ofatumumab 2000mg IV is administered weekly for 8 doses, then once every 4 week cycle for 4 doses (dose/schedule identical to the pivotal phase 2 trial) with afuresertib 125mg orally daily. An initial 10 day Lead-in Phase with afuresertib alone allows for evaluation of pharmacodynamic (PD) changes in phosphoproteins and pharmacokinetic (PK) studies. Pts are assessed for safety and response on day 1 of each cycle. Pts achieving SD, PR or CR by the end of the Treatment Phase proceed to the Maintenance Phase with single-agent afuresertib for a maximum of 12 mos (12 cycles). Results Demographics: To date, 19 pts have been enrolled. Median age is 65 yrs (range 43-76), baseline median Hb 108g/L (range 80-145), absolute lymphocytes 29.7 x109/L (range 1.0-464.9), β2M 4.42mg/L (range 1.42-3.21), bulky nodes ≥5cm in 5 pts (32%), organomegaly in 8 pts (42%), del17p/del11q on FISH in 9 pts (47%), and ZAP70+ in 13 pts (68%). Eight pts (42%) were fludarabine-refractory; only 2 pts had received prior alemtuzumab. The median number of prior therapies was 2 (range 1-6). Toxicity: Hematologic: 4 pts (21%) developed Gr 3-4 neutropenia during at least 1 cycle; 1 pt (5%) had a febrile neutropenia event. Only 2 pts (10.5%) have developed Gr 3-4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Most common related grade 3-4 toxicities were GI: dyspepsia (53%), diarrhea (37%), nausea (21%), temporally related to oral afuresertib and easily managed symptomatically. Infusion reactions to ofatumumab were frequent (12 pts; 63%) with grade 3 reactions in 3 pts. Five pts (26%) developed non-infectious pneumonitis, with 3 pts requiring hospitalization. Two pts with preexisting atrial arrhythmias sustained exacerbation with weekly ofatumumab infusions. Most infections were mild, with only 1 grade 3 cellulitis. Efficacy: Of the 19 response-evaluable pts receiving a median of 6 cycles (range 1-9), 8 pts (42%) have achieved a PR, 11 SD (58%), and no CR. Response onset was rapid at a median 0.9 mos (range 0.8-2.8). At a median follow-up of 6.8 mos (range 0.3-12.9 mos), 5 pts (26%) have progressed and one patient has died after cycle 1 on therapy due to progressive CLL. PD Studies: CD19+ cells are assayed for phosphorylated AKT and its downstream targets RAS40 and GSK3 in addition to phospho-proteins of alternative pathways including ERK and pS6 by multiplexed phospho-flow cytometry. Peripheral blood samples are collected at screening and on cycle 1 day 10, after dosing with afuresertib. Of the 7 patients evaluated thus far, 5 demonstrated constitutive AKT phosphorylation at baseline. Partial inhibition of AKT signaling evidenced by increased phosphorylation of AKT and inhibition of GSK3 and/or RAS40 phosphorylation in response to BCR stimulation was observed post-treatment, indicating target engagement by afuresertib. PK Studies: Afuresertib exposure (Cmax and AUC) was similar when afuresertib was administered alone or in combination with ofatumumab. Conclusion Preliminary results from this phase 2 study suggests that a combination of ofatumumab plus a novel oral AKT inhibitor, afuresertib, has activity in previously treated CLL and is generally well-tolerated with minimal myelotoxicity. Response data are encouraging but whether durable responses can be achieved requires more mature follow-up. Disclosures: Chen: Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria. Off Label Use: Off-label use of ofatumumab and afuresertib for the treatment of relapsed/refractory CLL. Smith:GSK: Employment, Equity Ownership. Johnston:Roche: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Lundbeck: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

An Open-Label Phase 2 Study of Lenalidomide in Combination with Oral Dexamethasone in the Previously Untreated, Symptomatic Patients with Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2895-2895 ◽  
Author(s):  
Christine Chen ◽  
Harminder Paul ◽  
Luisa Del Rizzo ◽  
Lisa W Le ◽  
Ellen Nong Wei ◽  
...  
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Starting Dose ◽  
Daily Dose ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Abstract 2895 Introduction: Lenalidomide is an immunomodulatory agent with promising anti-tumor activity in CLL. The use of lenalidomide in this disease, however, can be complicated by tumor lysis syndrome (TLS) and frequent tumor flare (TF). From our experience using low-dose lenalidomide (starting dose 2.5mg, titrating to a target of 10mg daily), TLS can be prevented but TF remains frequent (Chen et al. JCO 2010). In addition, when using low-dose single-agent lenalidomide, few complete responses (CR) are achieved. We therefore proposed the combination of lenalidomide and pulse dexamethasone, aiming to enhance anti-tumor activity through both synergy and mitigation of toxicities such as TF, enabling escalation to higher doses of lenalidomide. Our previous observation of “rebound” peripheral lymphocytosis when using intermittent dosing of lenalidomide led to the current use of continuous daily dosing. We present an interim analysis of the initial 18 of 31 planned pts in this ongoing trial of lenalidomide and dexamethasone as first-line CLL therapy. Methods: Eligible pts were previously untreated with symptomatic CLL (cytopenias, symptomatic adenopathy/organomegaly, constitutional symptoms, lymphocyte doubling count <12 mos). The starting dose for lenalidomide is 5mg daily continuously, with 5mg escalations every 28 days to a maximum of 25 mg, and dexamethasone 12 mg daily orally days 1–7, 14, 21 of each 28 day cycle, both to a maximum of 18 cycles. Supportive measures: allopurinol for TLS prophylaxis, DVT prophylaxis with low dose ASA, sulfatrim for PJP prophyaxis. Results: Demographics: To date, 18 pts have been enrolled: median age 61 yrs (range 40–84), male 13 pts (72%), Rai stage III-IV 13 pts (72%), baseline median Hb 98g/L (range 77–137), absolute lymphocytes 194.5 ×109/L (range 9.3–469.9), ß2M 319 nmol/L (range 253–813; normal <170), bulky nodes 15 pts (83%), organomegaly 9 pts (50%), del17p/del11q on FISH 3 pts (17%), ZAP70+ 12 pts (67%) and unmutated IgVH in 9 of 17 pts tested (53%). Seventeen pts have received at least 1 cycle and are evaluable for toxicity and response. The median number of cycles received is 8 (range 1–18). Hematologic toxicity: 9 pts (53%) have developed Gr 3–4 neutropenia during at least 1 cycle; 4 pts (24%) febrile neutropenia; 6 pts (35%) have required GCSF support. Only 2 pts (12%) have developed Gr 3–4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Non-desquamating rash (65%), fatigue (59%), diarrhea (53%), cough (53%), insomnia (47%), and constipation (47%), are common (most grade 1–2). Grade 3–4 toxicities include: atrial fibrillation with pulmonary embolism (1 pt), fatigue (2 pts), insomnia (1 pt), skin rash (1 pt), diarrhea (1 pt), muscle weakness (1 pt), infection (1 pt). Infections are frequent (all grades in 50% of pts, grade 3 in 6%), primarily affecting upper airway/lungs. One pt developed H1N1 influenzae, complicated by aspergillus pneumonia and multiorgan failure. In contrast to the high rate of TF from our previous single-agent lenalidomide trial (88%), TF is considerably less common in the current trial (5 pts; 29%). No TLS has been noted. Dose modifications/study withdrawals: The maximum 25mg dose has been achieved in 4 pts, with a median tolerated daily dose of 15 mg (range 2.5–25 mg). Grade 3–4 neutropenia is the most common cause of dose interruptions/reductions. Responses: All 17 pts have achieved stable disease (SD) or better with overall responses 59%: 9 PR (53%), 7 SD (41%), 1 CR (6%). Responses were reached at a median of 4 months (range 1.8–9.6). No patients have progressed to date. Correlatives: Recent studies have identified cereblon (CRBN) as a direct target of lenalidomide with expression required for anti-tumor activity. CRBN protein was detected by Western blot analysis in CD19-selected cells derived from screening blood samples of all 17 pts evaluated to date and correlation with response is ongoing. Conclusion: Preliminary results from this phase 2 study suggests that lenalidomide plus dexamethasone has significant activity in previously untreated CLL, is generally well-tolerated, and dramatically reduces the incidence of TF symptoms. This may facilitate dose escalation beyond the 10mg daily dose used in our previous single agent study and lead to higher quality responses. Rebound lymphocytosis has not been noted with continuous dosing. Response data are encouraging but whether this combination can achieve durable CR is forthcoming. Disclosures: Chen: Celgene: Honoraria, Research Funding; Lundbeck: Consultancy; GlaxoSmithKline: Research Funding; Janssen: Consultancy, Research Funding. Off Label Use: Lenalidomide is not approved for use in chronic lymphocytic leukemia. Johnston:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Trudel:Celgene: Honoraria, Research Funding, Speakers Bureau.

Long-Term Follow-up of a Phase 2 Study of Single Agent Lenalidomide in Previously Untreated, Symptomatic Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 718-718
Author(s):  
Christine Chen ◽  
Harminder Paul ◽  
Trina Wang ◽  
Lisa W Le ◽  
Vishal Kukreti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Grade 3

Abstract Abstract 718 Introduction: In a previously reported phase 2 study of single agent lenalidomide in 25 untreated CLL patients (pts), we reported an overall response rate (ORR) of 56% (14 pts), 40% SD (10 pts) and no CR at a median follow-up of 20.7 months (Chen et al. JCO 2010;29:1175). Although an amended protocol with conservative lenalidomide dosing was used to mitigate tumor lysis and severe myelosuppression observed in the first 2 accrued pts, we continued to observe frequent toxicities of grade 3–4 neutropenia (72%) and tumor flare (TF 88%). We now report long-term efficacy and toxicity from this study at a median follow-up of 47 months (mos). Methods: Patients were eligible if previously untreated and symptomatic (cytopenias, symptomatic adenopathy/organomegaly, constitutional symptoms, lymphocyte doubling count <12 mos). The amended starting dose for lenalidomide was 2.5mg daily on days 1–21 of a 28 day cycle, with slow monthly dose escalations (2.5mg cycle 1, 5mg cycle 2, 10mg cycle 3 and if required for response, further 5mg increments to a maximum of 25mg daily were allowed). Results: Longterm toxicities: Hematologic toxicities were common: grade 3–4 neutropenia (76%), thrombocytopenia (28%), anemia (20%). With longer term use, neutropenia tended to recur (12% of all cycles) and 10 pts required GCSF support (5 routinely during each cycle). Most common non-hematologic toxicities (all grades) were TF (88%), fatigue (76%), rash (60%), muscle cramping (40%), diarrhea (40%). All non-hematologic toxicities were mild (grade 1–2), except for 1 pt each with grade 3 rash and diarrhea. Although TF was most common during cycle 1, repeat flare symptoms upon resuming lenalidomide after the 7 day rest period of each cycle were noted in 16% of all 898 cycles administered, and as late as at cycle 28. Infections were mild (most respiratory, skin) with only 2 grade 3 events (disseminated zoster, S.pneumoniae bacteremia). Other malignancies: 2 pts developed transformed large cell lymphoma 7 and 18 mos after study discontinuation, 1 pt developed squamous cell carcinoma of skin at cycle 51, and 1 pt developed recurrence of remote non-small cell lung cancer at cycle 34. Dose modifications/discontinuation: The median highest dose achieved for all 25 pts was 15 mg (range 2.5–25 mgs); 8 pts were able to escalate to the maximal 25mg dose. Ten pts (40%) required dose reductions for grade 3 cytopenias [neutropenia (2), thrombocytopenia (2), both (2)], febrile neutropenia (2), and diarrhea (2). Of all 25 pts, the median duration on therapy was 31.1 mos (range 28 days – 60.6 mos). Twelve pts (52%) currently remain on study, receiving a median of 59 cycles of therapy (range 48–66). Causes of discontinuation for 13 pts included: treatment-related toxicity (8), lack of response/progressive disease (4), and recurrence of remote lung cancer (1). Toxicities leading to discontinuation included: prolonged cytopenias (3), recurrent infections (1), atrial fibrillation (1), disseminated herpes zoster (1), persistent grade 2 diarrhea (1), and grade 3 skin rash (1). Efficacy: With extended median follow-up from 20.7 to 47 mos, the ORR improved from 56% (14 pts) to 72% (18 pts), with 3 pts in PR upgrading to CR, and 1 SD to PR. Although the median time to response was 7.7 mos, responses occurred as quickly as 1.8 mos to as late as 27.0 mos of therapy. For the 3 CR pts, prolonged therapy with an additional 14.9, 28.3 and 40.6 mos beyond the time of first response was required to achieve CR. To date, 7 pts have progressed with 3-year PFS 68.8% (95% CI:52–91%) and OS 85.3% (95% CI:71.1–100%). Correlatives: Cereblon (CRBN), recently identified as a direct protein target of lenalidomide, was evaluated by gene expression profiling and Western blot and found to be uniformly expressed in all 19 evaluable day 1 pt samples regardless of lenalidomide response. Thus, baseline CRBN expression does not appear to be a useful predictive biomarker of response in this population. The mechanism by which CRBN is linked to response is reported by Trudel et al, ASH 2012. Conclusions: Long-term followup of this study demonstrates that when using low doses of single agent lenalidomide in CLL, prolonged therapy is feasible and may be required for the achievement of durable, high quality responses. Maximal daily doses of 25mg can be reached and may also be needed for optimal response, though recurrent myelosuppression remains limiting. Disclosures: Chen: Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Lundbeck: Consultancy; Janssen: Consultancy, Research Funding. Off Label Use: Lenalidomide is not approved for use in chronic lymphocytic leukemia. Kukreti:Roche: Honoraria; Celgene: Honoraria; Janssen Ortho: Honoraria. Trudel:Celgene: Honoraria, Research Funding, Speakers Bureau.

PX-171-004, An Ongoing Open-Label, Phase II Study of Single-Agent Carfilzomib (CFZ) in Patients with Relapsed or Refractory Myeloma (MM); Updated Results From the Bortezomib-Treated Cohort.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 303-303 ◽  
Author(s):  
David Siegel ◽  
Luhua Wang ◽  
Robert Z Orlowski ◽  
Jonathan L. Kaufman ◽  
A. Keith Stewart ◽  
...  
Keyword(s):  
Renal Insufficiency ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Cell Transplant ◽  
Phase 2 ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Ortho Biotech ◽  
Grade 3

Abstract Abstract 303 Background: Carfilzomib (CFZ) is a novel proteasome inhibitor that binds its target selectively and irreversibly, resulting in greater and more sustained proteasomal inhibition compared to BTZ (Demo et al, Cancer Res 2007). CFZ overcomes BTZ-resistance in vitro (Kuhn et al, Blood 2007) and in a previous Phase 2 study (PX-171-003), single-agent CFZ achieved durable responses and maintained disease control [e.g. ≥ Stable Disease (SD)] in patients with progressive multiple myeloma (MM) despite treatment with essentially all available agents. PX-171-004 is an ongoing Phase 2 study of CFZ monotherapy in MM patients with relapsed or refractory disease following 1–3 prior therapies. Here we report updated data for the BTZ-treated cohort. Methods: Patients with relapsed or refractory (defined as < 25% response or disease progression during therapy) MM were enrolled and stratified based on prior BTZ exposure (e.g. BTZ-naïve and BTZ-treated). For the BTZ-treated cohort, tolerability and response to prior BTZ [≥ Minor Response (MR)] was not required. CFZ 20 mg/m2 IV was administered on Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. The primary endpoint was Overall Response Rate (ORR) [≥ Partial Response (PR)] by IMWG criteria. Secondary endpoints included Clinical Benefit Response (CBR = ORR + MR) and safety. Results: Thirty-five BTZ-treated patients were enrolled. Six (17%) patients had previously received BTZ exclusively as a single agent, 15 (43%) received BTZ as part of a chemotherapy combination and 10 (29%) received BTZ as part of a stem cell transplant (SCT) regimen. An additional 4 (11%) received BTZ in a chemotherapy combination as well as part of a separate transplant regimen. Other prior therapies included alkylators (89%), SCT (81%), thalidomide (69%), lenalidomide (37%), and anthracyclines (31%). Six (17%) patients had disease refractory to BTZ and 9 (26%) additional patients had discontinued BTZ due to toxicities. At baseline, 19 (54 %) patients had an ECOG score ≥ 1, 17 (49%) patients had neuropathy of Grade ≥ 1, 9 (26%) patients had impaired renal function (CrCl <60 mL/min) and 9 (26%) had diabetes. The median time since diagnosis was 3.6 years (range 1.2–13.2). To date, the mean number of CFZ doses administered was 29.3 (∼5 four-week cycles; range 4–72 doses, 0.7–12 cycles). Thirty-three patients who initiated therapy were evaluable for response per protocol. The ORR was 18% (6/33), including 1 CR and 5 PRs. An additional 4 (12%) patients had MR (CBR= 30%) and 13 (39%) had SD for ≥ 6 weeks. For evaluable patients who were either refractory or intolerant to their prior BTZ therapy, responses to CFZ included 1 PR and 1 MR and 8 SDs. The most common adverse events (AEs) (≥ 30% patients) were primarily Grades 1/2 and included fatigue (57%), nausea (54%), vomiting (37%), dyspnea (34%), diarrhea (34%), anemia (31%), increased creatinine (31%) and upper respiratory tract infection (31%). Grade 3/4 AEs occurring in ≥ 10% of patients were anemia (14.3%) and neutropenia (11.4%). There were no reports of febrile neutropenia. Dose modifications were rarely required. Peripheral neuropathy (PN) was uncommon (4 patients, 11%); only 1 patient had a Grade 3 event that lasted < 36 hours and did not result in missed doses or dose modification. None of the 9 patients with baseline renal impairment were discontinued for renal AEs. To date, 6 (17%) patients have completed the full 12-cycle protocol at the initial dose and schedule, 6 (17%) remain on study and 1 patient has received > 19 cycles on a recently initiated extended treatment protocol. Conclusions: In a BTZ-exposed population that includes BTZ treatment failures and significant comorbidities (e.g. diabetes, renal insufficiency, etc), the 18% ORR (CBR 30%) is notable for this steroid- and anthracycline-sparing regimen. Single-agent CFZ is well tolerated, even in patients with renal insufficiency, and both myelosuppression and PN are uncommon. These data support the continuing evaluation of CFZ as a safe and effective treatment option in MM. Disclosures: Siegel: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang:Proteolix, Inc.: Research Funding. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Kukreti:Celgene: Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. McDonagh:Proteolix: Research Funding. Belch:Ortho Biotech: Honoraria, Research Funding. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Le:Proteolix, Inc.: Employment. Kunkel:Proteolix: Consultancy, Employment. Bennett:Proteolix: Employment. Kauffman:Proteolix, Inc.: Employment. Vij:Proteolix, Inc.: Consultancy, Research Funding.

Phase 2 Study of Carfilzomib (CFZ) with or without Filanesib (FIL) in Patients with Advanced Multiple Myeloma (MM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 728-728 ◽  
Author(s):  
Jeffrey A Zonder ◽  
Saad Usmani ◽  
Emma C. Scott ◽  
Craig C. Hofmeister ◽  
Nikoletta Lendvai ◽  
...  
Keyword(s):  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Objective Response ◽  
Phase 2 ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Background: FIL (ARRY-520), a specific kinesin spindle protein (KSP) inhibitor, represents a novel class of agent under investigation for the treatment of patients (pts) with MM. Prognosis of pts refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) is poor. These pts have a median survival of 9 months underscoring the importance of novel therapeutic strategies incorporating new mechanisms of action. FIL has shown interesting preliminary activity as a single agent as well as in Phase 1 studies in combination with bortezomib (BTZ) and with CFZ, all with a manageable safety profile. Methods: This trial is an ongoing, randomized, multicenter, open-label Phase 2 study for pts with relapsed and refractory MM who received at least 2 prior regimens, including BTZ and an IMiD, and with disease refractory to the last regimen as per IMWG criteria. No prior treatment with CFZ is allowed. Approximately 75 pts will be randomized 2:1 to receive CFZ (20/27 mg/m2 intravenous [IV] on Days 1, 2, 8, 9, 15 and 16) plus FIL (1.25 mg/m2 IV on Days 1, 2, 15 and 16) or single-agent CFZ, at the same dose as in the combination, in a 28-day cycle. Prophylactic filgrastim is administered in the CFZ + FIL arm. The primary endpoint is progression-free survival (PFS). Patients with progressive disease (PD) on CFZ are allowed cross-over to the CFZ + FIL arm if they continue to meet eligibility criteria. Results: As of 15 June 2015, 72 pts have been randomized (23 CFZ, 49 CFZ + FIL) with a median age of 65 years. Pts who could have potentially received ≥ 2 cycles of treatment (20 CFZ, 30 CFZ + FIL) were evaluable for efficacy. These pts were heavily pretreated with a median of 4 and 5 prior regimens in the CFZ and CFZ + FIL arm, respectively. A total of 25% and 30 % of pts, respectively, received prior pomalidomide. The objective response rate (ORR) was 10% in the CFZ arm and 30% in the CFZ + FIL arm. In the CFZ arm, 2 pts achieved a partial response (PR) and 2 pts (10%) achieved an MR. In the CFZ + FIL arm, 3 pts achieved a very good partial response and 6 pts achieved a PR, with 2 additional pts (7%) achieving an MR. In the population of pts who were refractory to both prior BTZ and prior IMiDs, the ORR was 14% and 35%, respectively. Grade 3-4 hematological laboratory abnormalities (≥ 5% of pts) were leukopenia (9% CFZ vs. 21% CFZ + FIL), neutropenia (14% vs. 24%), thrombocytopenia (14% vs. 24%), and anemia (9% vs. 26%). Neutropenia and thrombocytopenia were reversible. No adverse events (AEs) of febrile neutropenia were reported. The only Grade 3-4 non-hematological AE occurring in ≥ 5% of pts was dyspnea (5% vs.11%). The most common reason for treatment discontinuation was confirmed PD (39% vs. 28%) or Investigator discretion in case of unconfirmed PD or clinical PD (17% vs. 12%). Conclusions: The combination of FIL and CFZ was well-tolerated and noticeably increased the ORR compared to CFZ alone in heavily pretreated pts with advanced MM. The preliminary efficacy in pts who are double refractory to IMiDs and BTZ who were randomized to CFZ + FIL appears higher than in pts treated with CFZ alone (in the CFZ arm of this trial and in previously published reports involving such pts). Updated safety and efficacy data, including PFS, will be presented at the meeting. Table. Efficacy evaluable pts (potential to have received ≥ 2 cycles of treatment) CFZ (N = 20) CFZ + FIL (N = 30) Prior regimens, median (range) 4 (2,11) 5 (2,11) N cycles on study, median (range) 4 (1 - 16) 4 (1 - 15+) % ORR (≥ PR) 10 30 % CBR (≥ MR) 20 37 N (%) IMiD & BTZ Refractory 14 (70) 20 (67) % ORR (≥ PR) 14 35 % CBR (≥ MR) 21 40 CBR = clinical benefit rate Disclosures Zonder: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support. Off Label Use: carfilzomib; treatment of myeloma, but not in combination with filanesib. Usmani:Celgene Corporation: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Berdeja:Onyx: Research Funding; Array: Research Funding; Takeda: Research Funding; Acetylon: Research Funding; Janssen: Research Funding; BMS: Research Funding; MEI: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Curis: Research Funding. Anderson:Onyx: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Hari:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Singhal:Celgene: Speakers Bureau. Valent:Takeda/Millennium: Speakers Bureau; Celgene: Speakers Bureau. Faber:Celgene: Consultancy. Schiller:Sunesis: Honoraria, Research Funding. Schreiber:Array BioPharma: Employment. Oliver:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Tunquist:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Raje:Eli Lilly: Research Funding; Millenium: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; BMS: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy; Amgen: Consultancy; Celgene Corporation: Consultancy; Acetylon: Research Funding.

scholarly journals An Phase 2 Study of Lenalidomide in Combination with Oral Dexamethasone in Previously Untreated, Symptomatic Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4163-4163
Author(s):  
Christine I Chen ◽  
Harminder Paul ◽  
Susi Snitzler ◽  
Lisa W Le ◽  
Ellen Nong Wei ◽  
...  
Keyword(s):  
Research Funding ◽  
Single Agent ◽  
Continuous Treatment ◽  
Phase 2 ◽  
10Mg Daily ◽  
Phase 2 Study ◽  
Daily Dose ◽  
Grade 3 ◽  
Anti Tumor Activity ◽  
Higher Doses

Abstract Introduction: Although lenalidomide, as an immunomodulatory agent, has anti-tumor activity in CLL, its use in this disease is complicated by tumor lysis (TLS) and tumor flare (TF), especially when used frontline. From our experience using low-dose lenalidomide (10mg daily), TLS can be prevented but TF remains frequent and few CRs are achieved (Chen et al. 2010). The current trial tests the combination of lenalidomide and dexamethasone, aiming to enhance anti-tumor activity through synergy and mitigation of toxicities such as TF, enabling escalation to higher doses of lenalidomide. We hypothesized that higher doses of lenalidomide with dexamethasone, given over a finite 18 cycles, may achieve deeper and more durable responses, without requiring long term continuous treatment. Final analysis of 31 patients is presented. Methods: Eligible patients had treatment-naïve, symptomatic CLL. The starting dose for lenalidomide was 5mg daily continuously, with 5mg escalations every 28 days to a maximum of 25 mg, and dexamethasone 12 mg daily orally days 1-7, 14, 21 of each 28 day cycle, both to a maximum of 18 cycles. Supportive measures: allopurinol for TLS prophylaxis, DVT prophylaxis with ASA, sulfatrim for pneumocystis prophylaxis. Results: Demographics: 31 pts were enrolled: median age 59 yrs (range 40-84), male 21 pts (68%), Rai stage III-IV 18 pts (58%), median peripheral lymphocytes 185 x109/L (range 9.3-509), β2M 4.1 mg/L (range 1.7-10.9); normal <3.2), bulky nodes 3 pts (10%), organomegaly 16 pts (52%). High risk features included: del17p/del11q on FISH in 6 pts (19%), ZAP70+ in 17 of 27 pts tested (63%) and unmutated IgVH in 16 of 26 pts tested (62%). All 31 pts received at least 1 cycle and were evaluable for toxicity and response. Hematologic toxicity: 19pts (61%) developed Gr 3-4 neutropenia during at least 1 cycle; 6 pts (19%) developed febrile neutropenia. Nine pts (29%) developed Gr 3-4 thrombocytopenia, without bleeding. Gr 3-4 neutropenia occurred in 14% and Gr 3-4 thrombocytopenia in 5% of the 431 cycles administered to all patients. Nonhematologic toxicity: Most common toxicities (all grades) included: non-desquamating rash (64%), diarrhea (61%), insomnia (55%), fatigue (52%), and edema (51%). Infections (all grades) were frequent (25 pts; 80%) but Grade 3-4 infections developed in only 4 pts (13%), including pneumonia (3 pts), and bacteremia (1 pt). Other common grade 3-4 toxicities included rash (3 pts), tumor flare (3 pts), abdominal pain (2 pts), and fatigue (2 pts). In contrast to the high rate of TF from our previous single-agent lenalidomide trial (88%), TF was considerably less common (9 pts; 29%). No TLS was noted. Dose modifications/study withdrawals: The median number of cycles received was 18 (range 1-18), with 58% completing protocol treatment. A median daily dose of 20mg (range 2.5-25mg) was reached. Dose reductions of lenalidomide were required in 14 pts (45%), most due to cytopenias. Reasons for early study discontinuation: toxicity (5 pts), patient withdrawal (5 pts), progressive disease (1 pt), and unrelated death (1 pt). Efficacy: All 31 pts achieved stable disease (SD) or better on study. Overall response rate was 74%: 21 PR (68%), 8 SD (26%), 2 CR (6%). Responses were reached at a median of 3.7 mos (range 0.8-13.7), though best response was not achieved until median 5 mos (range 0.8-25). At a median follow-up of 26 mos, 9 pts have progressed, only one during the treatment period. Duration of response was prolonged with greater depth of response: CR 28.6 mos, PR 17.9 mos, SD 4.6 mos. Median PFS was 27.8 months (95%CI: 22.1%-NA). The median OS has not been reached. Correlatives: Cereblon (CRBN) is a direct target of lenalidomide with expression required for anti-tumor activity. CRBN protein was detected by Western blot analysis in CD19-selected cells from screening blood samples of all 28 pts evaluated. Expression of CRBN substrates IKZF1 (Ikaros) and IKZF3 (Aiolos) pre and post-treatment and correlation with response and PFS are under evaluation and will be reported. Conclusion: Final results from this phase 2 study suggests that lenalidomide plus dexamethasone has significant activity in previously untreated CLL, is generally well-tolerated, and dramatically reduces the incidence of TF symptoms. This approach facilitates dose escalation beyond the 10mg daily dose used in our previous single agent study and achieves durable responses, without continuing therapy until progression. Disclosures Chen: Lundbeck: Honoraria; Janssen: Honoraria; Roche: Honoraria; Sanofi: Research Funding; Celgene: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria. Off Label Use: Lenalidomide is not currently approved for use in CLL.. Trudel:BMS: Honoraria; Merck: Research Funding; Novartis: Consultancy, Honoraria; Amgen: Honoraria, Speakers Bureau; GSK: Honoraria, Research Funding; Celgene: Consultancy, Equity Ownership, Honoraria, Speakers Bureau.

scholarly journals Phase 3 Study of Pomalidomide with Cyclophosphamide and Dexamethasone Versus Pomalidomide and Dexamethasone in Asian Patients with Relapsed/Refractory Myeloma (RRMM) - Interim Analysis of a Trial By the Asian Myeloma Network (AMN)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Wee-Joo Chng ◽  
Xinhua Li ◽  
Cindy Lin ◽  
Jin Seok Kim ◽  
Hiroshi Handa ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Research Funding ◽  
Response Rate ◽  
Prior Exposure ◽  
Phase 2 ◽  
Asian Patients ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Experienced Grade

Background Pomalidomide is an immunomodulatory drug that has been approved for the treatment of relapse refractory myeloma. A previous small randomized phase 2 study in the United States showed that combination of Pomalidomide, cyclophosphamide and dexamethasone induce a greater response rate than pomalidomide and dexamethasone1. In our prior study, AMN0012, we should that in patients with sub-optimal response to pomalidomide and dexamethasone, the addition of cyclophosphamide can increase response resulting in improvement of progression free survival. In the current study, we seek to randomize Asian patients with RRMM between PCD and PD to confirm the benefit of PCD. Method We conducted a prospective randomized trial of pomalidomide (4mg daily for 21 days followed by 7 days rest) plus dexamethasone 40mg once weekly for 4 weeks with or without cyclophosphamide (400mg once a week) in patients with relapse and refractory myeloma that has to be refractory to lenalidomide and has prior exposure to proteasome inhibitors. Each cycle is 4 weeks. Patients from Singapore, Japan and Korea (NCT03143049) were included in this Asian Myeloma Network trial. The trial was started in Sep 2017 and is still ongoing. To date, 53 patients have been recruited so far. This interim report presents data available up till the data cut-off date of 24 June 2020. Results Forty-six patients have available base line information and safety data and is included in this interim analysis. 50% of patients are male and median age of the cohort is 68 years old. 39% and 28% of patients are International Stage System (ISS) stage 2 and 3 respectively. 20% of patients have abnormal creatinine clearance. Median prior line of treatment is 3. All patients are refractory to lenalidomide and 96% have prior exposure to bortezomib. In addition, 12 patients (26%) and 5 (11%) have been treated with Carfilzomib and Ixazomib respectively. 15 (33%) patients had prior high dose melphalan and autologous stem cell transplant. 20 (44%) patients required dose reduction of pomalidomide, cyclophosphamide or dexamethasone. 89% of patients experience adverse events (AEs) of any grade. Of the 297 episodes of AEs, 43% are grade 3 or higher, with 50% of these episodes related to the study drugs. 57% of patients experienced serious AEs (SAEs) of any grade. Of the 74 episodes of SAE, 89% are grade 3 or higher, with 49% of these episodes related to the study drugs. Almost all of these events are related to cytopenias and infections. 20 (44%) of the patients develop grade 3 neutropenic fever and 9 (20%) patients have grade 3 or higher pneumonia. Only 1 patient experienced grade 3 peripheral neuropathy, 1 patient develop grade 3 pulmonary embolism, 1 patient developed grade 3 venous thromboembolism, and 1 patient experienced grade 3 renal impairment. At a median follow-up of 10.9 months, 9 of the 46 patients have died, and 21 have progressed. Three patients withdrew due to toxicity. While the overall response of the study population is not part of this interim analysis, we assessed the response of patients from the National University Cancer Institute, Singapore which has the highest number of patients recruited to get an idea of the therapeutic efficacy. Of the 14 patients recruited at NCIS, 1 patient achieved CR, 3 VGPR, 7 PR, producing a response rate of 79%. Conclusion In this interim analysis of a prospective randomized study of pomalidomide and dexamethasone with or without cyclophosphamide in Asian patients, we demonstrated the feasibility and efficacy of this combination. Longer follow-up and final analysis of the study will be needed to ascertain the therapeutic advantage of PCD over PD in relapse and refractory myeloma that is refractory to lenalidomide. References 1. Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. 2. Soekojo CY, Kim K, Huang SY, Chim CS, Takezako N, Asaoku H, Kimura H, Kosugi H, Sakamoto J, Gopalakrishnan SK, Nagarajan C, Wei Y, Moorakonda R, Lee SL, Lee JJ, Yoon SS, Kim JS, Min CK, Lee JH, Durie B,Chng WJ. 3. Pomalidomide and dexamethasone combination with additional cyclophosphamide in relapsed/refractory multiple myeloma (AMN001)-a trial by the Asian Myeloma Network. Blood Cancer J. 2019 Oct 8;9(10):83. Disclosures Chng: Novartis: Honoraria; Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Clofarabine Plus Low-Dose Cytarabine Induction Followed by Consolidation with Clofarabine Plus Low-Dose Cytarabine Alternating with Decitabine as Frontline Therapy for Patients (pts) with Acute Myeloid Leukemia (AML) ≥ 60 Years (yrs).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2058-2058
Author(s):  
Sameer A Parikh ◽  
Hagop Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
Tapan Kadia ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Research Funding ◽  
Low Dose ◽  
Single Agent ◽  
Disease Free Survival ◽  
Response Rates ◽  
High Response ◽  
Multiple Drugs ◽  
Low Dose Cytarabine

Abstract Abstract 2058 Poster Board II-35 Therapy of AML for elderly pts (≥ 60 yrs) remains challenging with low response rates, short durability of responses, and high toxicity rates following conventional therapy with standard-dose ara-C/anthracycline combinations. Clofarabine is a novel deoxyadenosine nucleoside analogue with single agent activity in frontline AML for older pts with ≥ 1 unfavorable prognostic factors. We have recently reported results of a randomized study suggesting higher response rates and comparable safety profile with the combination of clofarabine plus low-dose cytarabine over clofarabine alone. We have designed the current study of clofarabine plus low-dose cytarabine induction followed by consolidation with clofarabine plus low-dose cytarabine alternating with decitabine to maintain high response rates and improve disease-free survival based on the following hypotheses: 1) to extend duration of therapy by administering lower doses of the agents; and 2) to provide multiple drugs with different mechanisms of action to decrease risk of resistance. Pts were eligible if ≥ 60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, creatinine > 1.5 mg/dL, cardiac ejection fraction < 40%, and prior therapy with clofarabine or decitabine. Induction therapy consisted of clofarabine 20mg/m2 i.v daily × 5 days plus cytarabine 20mg s.c. twice daily × 10 days in a laminar air flow room. Responding pts could receive up to 17 courses of consolidation therapy of clofarabine plus cytarabine (over 3 and 7 days, respectively) during consolidation courses 1-2, 6-8, 12-14) alternating with decitabine 20mg/m2 i.v. daily for 5 days during courses 3-5, 9-11, and 15-17. All pts received antibiotic prophylaxis with levofloxacin, valacyclovir and itraconazole (or equivalent). Forty pts have been enrolled with a median age of 70 yrs (range 60-80) of whom 22 (55%) had secondary AML (antecedent hematologic disorder in 11 pts). Two pts had received previous azacitidine for MDS. Fourteen pts (35%) had abnormal cytogenetics of whom 10 (25%) had monosomy 5, 7, or both. Four patients (10%) had a FLT3/ITD mutation. Of the 34 pts evaluable for response, 20 (59%) achieved CR and 2 (6%) CRp for an OR rate of 65%. Only 2 pts required 2 courses to CR. The OR rate for patients with diploid versus abnormal cytogenetics was 80% vs 50%; for pts with prior MDS versus no prior MDS 76% and 50%; and 75% for patients with FLT3 mutation. The median time to CR/CRp was 38 days (range 27-103). With a median follow up of 3.5 months (range 0.7-8.1), 2 pts relapsed (CR duration of 3.3 and 4.2 months, respectively); responses are ongoing in the remainder. Three pts (9%) died during induction therapy (one during re-induction) before a response could be established. The median number of consolidation cycles received by pts in CR was 3 (range 1-5). Most toxicities were ≤ grade 2 and included nausea/vomiting, diarrhea, rash, headache and mucositis. Six pts developed grade 3 elevations in serum transaminases which resolved at the end of induction therapy. Myelosuppression and neutropenic fever were common, but prolonged myelosuppression was rare. In conclusion, clofarabine plus low-dose cytarabine achieves high response rates with a manageable toxicity profile and low induction mortality in elderly pts with previously untreated AML. Time-to-event parameters will be provided with more extensive follow up. Disclosures: Off Label Use: Clofarabine and Decitabine in AML. Kantarjian:Genzyme: Consultancy, Research Funding. Faderl:Genzyme: Consultancy, Research Funding; Eisai: Research Funding, Speakers Bureau.

Efficacy and Safety of Retreatment with Bortezomib in Patients with Multiple Myeloma: Interim Results From RETRIEVE, a Prospective International Phase 2 Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3866-3866 ◽  
Author(s):  
Maria Teresa Petrucci ◽  
Igor W. Blau ◽  
Paolo Corradini ◽  
Meletios A. Dimopoulos ◽  
Johannes Drach ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Bortezomib Treatment ◽  
Best Response ◽  
Phase 2 Study ◽  
Grade 3

Abstract Abstract 3866 Poster Board III-802 Bortezomib (Velcade®) retreatment has been shown to be active and well tolerated in patients with relapsed multiple myeloma (MM) in a number of retrospective studies and a small prospective phase 4 study (EVEREST). This large, prospective, international, multi-center, open-label phase 2 study was conducted to confirm the efficacy and safety of retreatment with bortezomib in MM patients who had previously responded (at least partial response [PR]) to bortezomib-based therapy as their most recent prior treatment. Patients had to have previously tolerated bortezomib 1.0 or 1.3 mg/m2 alone or in combination and have had a treatment-free interval (TFI; time from last dose of initial bortezomib treatment to first dose of bortezomib retreatment) of ≥6 months. Additional eligibility criteria included progressive disease or relapse from complete response (CR) by EBMT criteria, no MM therapy (except maintenance with dexamethasone, thalidomide, or interferon) since the last dose of initial bortezomib treatment, KPS ≥60, and adequate renal, hepatic, and hematologic function; patients with grade ≥2 peripheral neuropathy or neuropathic pain (as defined by NCI CTCAE v3.0) were excluded. Patients received bortezomib at the last tolerated dose (1.0 or 1.3 mg/m2) during initial treatment on days 1, 4, 8, and 11 for up to eight 21-day cycles, either alone or in combination with dexamethasone at the investigator's discretion. Response was assessed by EBMT criteria every 6 weeks during treatment and then every 2 months until disease progression. Adverse events (AEs) were graded according to NCI CTCAE v3.0. A total of 130 patients received at least 1 dose of bortezomib retreatment and were included in the safety population. Patients had a median age of 67 years, 57% were male, and 16% had KPS '70%. Median time from diagnosis of MM was 4.5 years (range 0–14 years); median number of prior therapies was 2; 15, 80, 23, and 12 patients had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib therapy). Best response by EBMT criteria to initial bortezomib treatment was CR in 26% and PR in 74% of patients; median time to progression and TFI after initial bortezomib treatment were 17.9 months and 14.3 months, respectively. Last tolerated dose of previous bortezomib therapy was 1.3 mg/m2 and 1.0 mg/m2 for 62% and 29% of patients, respectively; 9% received another dose. Patients received a median 7.0 (range 1–8) cycles of bortezomib retreatment (23% of patients completed all 8 cycles); 72% of patients received concomitant dexamethasone. A total of 126 patients were evaluable for response. In the 126 response-evaluable patients, the overall response rate (ORR; CR+PR) by best confirmed response (EBMT criteria) was 40%; in addition, 18% of patients achieved minimal response (MR), to give a CR+PR+MR rate of 58%. After a planned secondary efficacy analysis, the ORR (CR+PR) by single best response was 55% (75% ≥MR). Median time to best confirmed response (≥MR) was 2.9 months; time to first response was 1.5 months. Analysis of ORR by patient subgroups showed comparable results in patients who did versus did not receive concomitant dexamethasone (42% vs 32%), in those who received ≤1.0 mg/m2 vs 1.3 mg/m2 bortezomib (35% vs 41%), and in those aged ≤65 years vs >65 years (45% vs 36%). ORR was 67%, 39%, 33%, and 25% in patients who had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib), respectively. Analysis of best confirmed responses according to response to initial bortezomib showed that 63% and 52% of patients who achieved a CR or PR, respectively, to initial bortezomib treatment responded to retreatment. Most (98%) patients experienced a treatment-emergent AE; 60% experienced a grade 3/4 AE, and 32% experienced a serious AE; there were 8 deaths, 2 of which (due to sepsis and stroke) were possibly treatment-related. The most common grade 3/4 AEs were thrombocytopenia (35%), neutropenia (7%), diarrhea (7%), and pneumonia (5%). AEs leading to dose reductions or discontinuations were reported for 22% and 12% of patients, respectively. The incidence of neuropathy was 39%, including 9% grade 3; 4% of patients discontinued treatment due to PN; 61% of neuropathy events resolved or improved within a median 1.3 months. These results confirm that bortezomib retreatment is a well-tolerated, feasible, and active therapeutic option for heavily pretreated MM patients without evidence of cumulative toxicity. Disclosures: Petrucci: Janssen-Cilag: Honoraria; Celgene: Honoraria. Dimopoulos:Ortho-Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Drach:Janssen-Cilag: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Blade:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Johnson and Johnson: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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