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.

scholarly journals Efficacy and Safety of Pomalidomide in Combination with Prednisone in Patients with Myelofibrosis and Anemia — Final Results of a Prospective Phase 2 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1764-1764
Author(s):  
Lucia Masarova ◽  
Naval G. Daver ◽  
Tapan M. Kadia ◽  
Naveen Pemmaraju ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Hemorrhagic Stroke ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Prospective Phase

Abstract INTRODUCTION: Pomalidomide (POM) is a potent second-generation immunomodulatory agent that has been suggested to have a better toxicity and safety profile than thalidomide and lenalidomide. In patients with myelofibrosis (MF) and anemia, the combination of POM plus prednisone showed up to 36% responses per International Working Group for Myelofibrosis Research and Treatment criteria (IWG-MRT). OBJECTIVE: We present an efficacy and safety data of a prospective phase 2 study of POM in MF patients with anemia after a median follow up of 37.5 months (range, 2-98 months). This report substantiate on previously published results (Daver et al., Leuk Res, 2014; Daver et al., Leuk Res, 2013) and represents final analysis of the study. METHODS: Newly diagnosed or previously treated patients ≥ 18 years with MF and anemia (hemoglobin < 10 g/dL or transfusion [PRBC] dependency) in a need for therapy were eligible. Patients were treated with single POM 3 mg / daily (3 weeks on / 1 week off) or POM 0.5 mg daily continuously with prednisone taper for first 3 months. Responses were re-assessed according to IWG-MRT 2013 criteria. RESULTS: Seventy patients with MF (primary MF, n = 64) of median age of 68 years were enrolled between 07/2009 - 03/2013. Cohort with POM 3 mg (n=21) was closed after 3 months due to excessive toxicity (Daver et al, Leuk Res, 2013). Nine patients who remained on the therapy continued on POM 0.5 mg daily along with 49 additionally enrolled patients, accounting for 58 patients included in this analysis (Table 1). The median time on therapy was 7 months (range, 2-97 months); with 19 patients (33%) treated with more than 12 cycles. Median follow-up from enrollment to data cut-off (May 2018) was 32.5 months (range, 1-99). In total, IWG-MRT responses were identified in 9 patients (16%); only one of them was originally treated with POM 3 mg. The median time on study for responding patients was 16 months (range, 8-71 months). Responses included Clinical Improvement (CI) in hemoglobin in 3 patients (5%); PRBC independence in 6 (10% all, 26% of PRBC dependent patients), and CI spleen in 2 patients (3% all, 20% of patients with splenomegaly). Two patients achieved combined responses; CI spleen with CI hemoglobin and CI spleen with PRBC independence (1 each). Overall median response duration was 8.4 months (range, 3.7-30.3); and it was longer for PRBC independence (30.3 months; range, 8-30.3), and CI spleen (14 months; range, 13-15). Additional 13 patients (without achievement of IWG-MRT response) derived clinical benefit while on study and continued on therapy for a median of 24.5 months (range, 12-93). Observed benefit in these patients included improvement of thrombocytopenia [1], improvement of performance status and/or reduced frequency of PRBC [11], and disease stabilization [1]. One patient progressed to acute leukemia (AML) on a study after 7 cycles of therapy. The treatment was well tolerated with 26 patients (45%) experiencing at least one adverse event (AE) regardless of causality. The most frequent AE were neutropenia (12%); rash (10%); fatigue (10%); and gastrointestinal symptoms (diarrhea/constipation, nausea; 9%). Grade 3/4 AE occurred in 12 patients (21%). All enrolled patients discontinued study due to the following reasons: no response / loss of response [42]; progression to AML [1]; toxicity [4]; stem cell transplantation (SCT) [2]; patient's preference [4]; death [2]; unrelated medical conditions [3]. Reasons for treatment discontinuation due to drug related AE were thrombocytopenia in 2 patients, pneumonitis in 1 patient and allergic reaction in 1 patient. By the time of data cut-off, 43 patients (74%) died with 20 known causes of death: MF progression [4]; AML [2], other medical conditions [7], sepsis [3], myocardial infarction and hemorrhagic stroke [2 each], SCT complications and mesenteric artery ischemia [1 each]). Two of these deaths occurred while on a study; one due to hemorrhagic stroke and one of unknown cause after 31 and 42 months on study, respectively. CONCLUSION: Pomalidomide with prednisone is safe therapy with good anti-anemia activity in patients with MF. It could lead to transfusion independence in one third of patients for a median duration of about 30 months. ClinicalTrials.gov Identifier: NCT00946270. Table 1. Disclosures Daver: Alexion: Consultancy; ImmunoGen: Consultancy; Pfizer: Research Funding; Karyopharm: Research Funding; Otsuka: Consultancy; Novartis: Consultancy; ARIAD: Research Funding; Incyte: Consultancy; Pfizer: Consultancy; BMS: Research Funding; Sunesis: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Consultancy; Kiromic: Research Funding; Incyte: Research Funding; Karyopharm: Consultancy; Novartis: Research Funding. Kadia:BMS: Research Funding; BMS: Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding. Pemmaraju:plexxikon: Research Funding; Affymetrix: Research Funding; celgene: Consultancy, Honoraria; SagerStrong Foundation: Research Funding; samus: Research Funding; stemline: Consultancy, Honoraria, Research Funding; abbvie: Research Funding; cellectis: Research Funding; novartis: Research Funding; daiichi sankyo: Research Funding. Cortes:novartis: Research Funding. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy.

scholarly journals Updated Results of Phase 2 Study of Ruxolitinib in Combination with 5-Azacitidine in Patients with Myelofibrosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 352-352 ◽  
Author(s):  
Lucia Masarova ◽  
Srdan Verstovsek ◽  
Jorge E. Cortes ◽  
Naveen Pemmaraju ◽  
Prithviraj Bose ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Phase 2 ◽  
Bone Marrow Fibrosis ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Grade 3

Abstract Background: JAK1/2 inhibitor ruxolitinib (RUX) abrogates symptoms and organomegaly in patients with myelofibrosis (MF). Combination with azacitidine (AZA) may further improve its efficacy. Methods: We initiated a single institutional, single arm, prospective, phase 2 study of RUX AZA combination in adult patients with MF and < 20% blasts. Previous therapy with RUX or AZA was not allowed. RUX 5 - 20 mg orally twice daily was given continuously since cycle 1. AZA 25 - 75 mg/m2 on days 1 - 5 of each 28-day cycle was added starting cycle 4. Responses were assessed per International Working Group for Myelofibrosis Research and Treatment 2013 criteria (IWG-MRT). Enrollment cut-off for this analysis was December 31st, 2017 to allow > 6 months of follow-up for all enrolled patients. We plan to present updated results with additional 5 months of enrollment at the meeting. Results: Fifty two pts were enrolled on study between 03/2013-12/2017, and were evaluable for responses. Forty seven pts (84%) were treated with both agents (RUX and AZA), with a median of 25 cycles (range, 1-55). Median age was 66 years (range, 48-87). Thirty four pts (65%) had int-2/high DIPSS score, 40 pts (77%) had spleen ≥5 cm. Thirty pts (58%) were JAK2V617F positive. Among 36 pts tested for non-driver mutations (28-gene panel); 7 pts had ASXL1, 6 had TET2, 3 had IDH1/2 and 2 had EZH2 and TP53. After a median follow-up of 22+ months (range, 1-59+); 21 pts (40%) are on therapy with a median overall follow-up of 30+ months. The most common reasons for therapy discontinuation were elective stem cell transplantation (n=12), and uncontrolled disease (n=8), including progression to acute leukemia (n=4). Four pts (8%) primarily discontinued therapy due to drug related toxicity (cytopenias). Three treatment unrelated deaths occurred on study; one each due to sepsis, meningitis and metastatic melanoma. Thirty eight pts (73%) had objective response on a study (Table). Median time to response was 1.8 months (range, 0.7-19). Seven responses (21% of responders) occurred after the addition of AZA with a median time to response of 2 months. These responses included spleen and symptom clinical improvements in 26% and 16% of pts, respectively. In total, 26 (65%), and 23 (58%) pts had palpable spleen reduction by > 50% at any time on study, and at week 24, respectively. JAK2V617F allele reduction was noted in 13 (81%) of 16 evaluable pts. Thirty one pts (60%) had available bone marrow for sequential evaluation. Nineteen pts (61%) had a documented improvement in bone marrow fibrosis, collagen or osteosclerosis, with a median time to first response of 12 months (range, 6-18). The most common grade ≥3 non-hematologic toxicity on a study was infection (34%), constipation (21%), and nausea (14%). New onset of grade ≥3 anemia, thrombocytopenia and neutropenia occurred in 33%, 30% and 16% of pts, respectively. Conclusion: Concomitant RUX with AZA was feasible with overall IWG-MRT response rate of 73%, including >50% spleen reduction in 65% of pts. Moreover, 61% of pts achieved improvement in bone marrow fibrosis, collagen or osteosclerosis. ClinicalTrials.gov Identifier: NCT01787487. Table. Disclosures Verstovsek: Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cortes:novartis: Research Funding. Pemmaraju:novartis: Research Funding; daiichi sankyo: Research Funding; Affymetrix: Research Funding; plexxikon: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; SagerStrong Foundation: Research Funding. Bose:Blueprint Medicines Corporation: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding; Celgene Corporation: Honoraria, Research Funding. Daver:Pfizer: Consultancy; Novartis: Research Funding; ImmunoGen: Consultancy; Alexion: Consultancy; Incyte: Consultancy; Karyopharm: Research Funding; Sunesis: Research Funding; Otsuka: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Sunesis: Consultancy; Daiichi-Sankyo: Research Funding; ARIAD: Research Funding; Incyte: Research Funding; Kiromic: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

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.

scholarly journals Phase 2 Study of Nilotinib 400 Mg Twice Daily in Newly Diagnosed Patients with Accelerated Phase of Chronic Myeloid Leukemia, Results after 5.7 Years of Follow-up

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3011-3011 ◽  
Author(s):  
Lucia Masarova ◽  
Jorge E. Cortes ◽  
Keyur P. Patel ◽  
Susan M. O'Brien ◽  
Graciela M. Nogueras González ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 2 ◽  
Advisory Committees ◽  
Free Survival ◽  
Genetics Research ◽  
Phase 2 Study ◽  
Grade 3

Abstract OBJECTIVES Nilotinib is a potent, second generation inhibitor of BCR-ABL tyrosine kinase (TKI) and represent a standard of care for patients with chronic myeloid leukemia (CML), including accelerated phase (AP-CML). In 2005, we initiated a phase 2 study of nilotinib 400 mg twice daily as a frontline therapy in patients with AP-CML, and herein present the efficacy and safety data after a median follow-up of 68.4 months (range, 0.3-124.8). METHODS This was a prospective, single institution, phase 2 study in patients of age ≥18 years with a newly diagnosed, untreated AP-CML (except for <1 month of previous imatinib) defined according to MD Anderson criteria (Kantarjian, 1988). Patients were treated with nilotinib 400 mg twice daily (BID). Data are presented on an intention to treat analysis with a cutoff date of June 30st, 2018. Response criteria are standard. Fisher exact test and χ2 were used for analysis of categorical variables; and survival probabilities were estimated using the Kaplan-Meier method. Time to events (e.g., overall survival, event free survival) was calculated from the date of treatment to the date of an event or to last follow-up as previously reported (Cortes et al, 2010). RESULTS Twenty two patients of a median age of 53.7 years (range, 26-79.7) were enrolled. Table 1 summarizes clinical characteristics of all patients. The median treatment duration was 47.3 months (range; 0.3-124.4), and the median follow-up 68.4 months (range, 0.3-124.8). All patients discontinued study as of January 2017 due to planned study closure; but 11 patients (50%) continued on nilotinib off protocol at data cut-off (400 mg BID [3]; 300 mg BID [2]; and 200 mg BID [6]). Median time to treatment discontinuation in the remaining 11 patients was 12.9 months (range, 0.3-112); reason for discontinuation was: inadequate response [3], toxicity [2], non-compliance/financial [4]; elective discontinuation after sustained MR4.5 >2 years [1]; and death due to stroke [1]. Sixteen patients (73%) achieved complete hematologic response (CHR). Overall rates of CCyR, MMR, MR4.5 and CMR (undetectable transcripts with at least 100,000 ABL copies) were 73%, 73%, 55%, and 41%, respectively. Median times to CCyR, MMR, and MR4.5 were 2.9 months (range, 2.7-6.4), 5.7 months (range, 2.7-99.2) and 6.0 months (range, 2.7-36), respectively. Seven patients (32%) achieved sustained MR4.5 >2 years. In total, 4 patients lost their best achieved response (CHR [1], CCyR [2] and MR4.5 [1]) while on study. All events were associated with acquired ABL domain mutation; Y253H [2], T315I [1], and F359I [1] with a median time to detection of 16.7 months (range, 7-40). During the study conduct, one patient progressed to blast phase after 2 months on nilotinib. Two patients died while on study, one due to stroke and one due to unrelated medical condition, after being on therapy for 3 and 0.4 months, respectively. One patient electively discontinued nilotinib after being in sustained MR4.5 for 107 months, and remains in MR4.5 after 6 months off therapy. Estimated overall survival and event free survival at 5 years were 84% and 70%, respectively (Figures 1a & 1b). On univariate analysis, age >55 years was associated with lower rate of MMR (p = 0.034; HR 0.34; 95% CI 0.12-0.92); MR4 (p = 0.013; HR 0.25; 95% CI 0.08-0.75); and MR4.5 (p = 0.01; HR 0.15; 95% CI 0.04-0.63). Overall survival was inferior in patients older than 55 years (p = 0.014; HR 2.4; 95% CI 2.36-not estimated); and in those with > 1 AP-CML defining abnormality (p = 0.018; HR 9.53; 95% CI 0.98-92). The most frequent non-hematologic adverse events (AEs) were hyperbilirubinemia (63% of patients), rash (63%), hypertension (59%), and transaminitis (50%). Grade ≥3 AEs observed in more than one patient were hyperbilirubinemia (n=2), and transaminitis (=2). Two patients developed arterio-thrombotic AEs: stroke and myocardial infarction (one each). Hematologic AEs included (all grades; grade ≥3): anemia (36%; 9%), thrombocytopenia (32%; 14%) and neutropenia (14%; 9%). Two patients (9%) discontinued therapy due to nilotinib related AE, one for G3 peripheral neuropathy and one for G3 hyperbilirubinemia with G2 thrombocytopenia. CONCLUSION Nilotinib is safe and highly effective in patients with AP-CML, and induces fast and durable responses. More than 50% of patients can achieve MR4.5. Clinical trial.gov: NCT00129740. Disclosures Cortes: novartis: Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding. Verstovsek:Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kadia:Celgene: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding.

scholarly journals The MP0250-CP201 Mirror Study: A Phase 2 Study Update of MP0250 Plus Bortezomib and Dexamethasone in Relapse/Refractory Multiple Myeloma (RRMM) Patients Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1899-1899 ◽  
Author(s):  
Norbert Grząśko ◽  
Stefan Knop ◽  
Hartmut Goldschmidt ◽  
Marc S Raab ◽  
Jan Dürig ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Proteasome Inhibitors ◽  
Immunomodulatory Drugs ◽  
Phase 2 ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Grade 3

Background Bone marrow neovascularization is a hallmark of multiple myeloma and progression is associated with a substantial increase in pro-angiogenic factors that promote bone marrow angiogenesis, including vascular endothelial growth factor (VEGF-A) and hepatocyte growth factor (HGF). At present, anti-angiogenic agents are not part of treatment strategies in multiple myeloma, neither alone nor in combination with approved agents. MP0250 is a first-in-class, tri-specific multi-DARPin® drug candidate neutralizing VEGF-A and HGF as well as binding to human serum albumin to increase plasma half-life. This is a report on early safety and efficacy of MP0250 in combination with bortezomib plus dexamethasone (Vd) in RRMM patients that have previously been exposed to proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs). Aims To assess the efficacy and safety of MP0250 in combination with bortezomib and dexamethasone in patients with RRMM (MiRRoR, NCT03136653). Trial Design This trial is recruiting adults ≥18 years of age with RRMM who have progressed after at least two prior treatment regimens including bortezomib and an IMiD. Patients were enrolled to receive iv MP0250 on day 1 + subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, oral dexamethasone 20 mg on days 1-2, 4-5, 8-9, 11-12 of each 21-day cycle. Patients will receive treatment until there is documented disease progression or unacceptable toxicity. Methods The primary endpoint is efficacy in terms of overall response rate (ORR) per International Myeloma Working Group criteria. Secondary endpoints include safety, immunogenicity, progression-free survival (PFS) and duration of response (DOR). Exploratory endpoints include overall survival, and pharmacokinetics. Exploratory biomarkers for HGF and cMET in bone marrow biopsies are detected by IHC; MM specific markers, circulating HGF and VEGF levels are measured using patient plasma samples. Results As of 01 July 2019, 20 patients (7 ongoing) received a total of 137 doses (1-33 cycles) of MP0250 at the maximum tolerated dose of 8 mg/kg on Day 1 of each 21-day cycle in combination with Vd. Median age was 61 years (46-76), median time since diagnosis was 6.7 years. Median number of prior therapies was 4 (range, 2-9). All 20 patients had prior exposure to IMiDs and PIs and 9 patients received PI-based regimens as their immediate prior line of therapy before start of MP0250 + Vd. Importantly, 6 out of these 9 patients achieved responses ≥ Partial Response (PR). Treatment had been discontinued in 40% of patients due to PD, 15% due to Adverse Event (AE), 5% due to physician's decision and in 1 case at patient's request. The most frequent drug-related grade 3/4 AEs were hypertension in 7/1 patients, thrombocytopenia in 4/1 patients, grade 3 proteinuria in 4 patients and grade 3 anemia in 4 patients. There were no infusion-related reactions. No treatment-related deaths were reported. 20 patients received ≥ 1 dose of MP0250 + Vd and had at least 1 assessment of response and were included in the efficacy analysis. 1 patient (5%) achieved Complete Response, 4 patients achieved Very Good Partial Response (20%) and 3 patients achieved PR (15%) for an ORR of 40%. DOR at cutoff date is 6 months (range, 2-21). Pharmacokinetic data show sustained exposure over multiple cycles with a mean half-life of 11 days (range, 6-17). No indication of ADA-mediated drug clearance was observed. Summary Combining MP250 at 8 mg/kg with standard doses of bortezomib and dexamethasone was generally well tolerated with discontinuation due to AE in only 15% of patients. No unexpected toxicity was observed and AEs consistent with the toxicity profile of the individual agents. Analysis of the preliminary efficacy results showed an encouraging ORR of 40%. Recruitment to this Phase 2 study is ongoing. Disclosures Knop: Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Goldschmidt:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: 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, Research Funding; Amgen: Consultancy, Research Funding; John-Hopkins University: Research Funding; MSD: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; John-Hopkins University: Research Funding; Chugai: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Molecular Partners: Research Funding; Mundipharma: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dürig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene: Consultancy, Other: Travel or accommodations, Speakers Bureau. Bringhen:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gamberi:Amgen: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Castellano Acosta:Molecular Partners AG: Employment. Lang:Molecular Partners AG: Employment. Lemaillet:Molecular Partners AG: Employment. Sudhir:Molecular Partners AG: Employment.

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.

Bortezomib, Bendamustine, and Rituximab in Patients with Relapsed or Refractory Follicular Lymphoma: Encouraging Activity in the Phase 2 VERTICAL Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 933-933 ◽  
Author(s):  
Nathan Fowler ◽  
Brad S Kahl ◽  
Peter Rosen ◽  
Jeffrey Matous ◽  
Amanda Cashen ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Clin Oncol ◽  
Board Of Directors ◽  
Research Funding ◽  
High Risk Population ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 933 Follicular lymphoma (FL) is an incurable, indolent B-cell non-Hodgkin lymphoma. Although survival has improved with the introduction of rituximab (Rituxan®, R), relapse is inevitable and new therapies are needed. Bortezomib (Velcade®, V) plus rituximab is active in relapsed or refractory (rel/ref) FL (de Vos et al, ASH 2006). Bendamustine (Treanda®, B) plus R has also shown activity in rel/ref FL (Robinson et al, J Clin Oncol 2008), and V has been safely combined with B in patients (pts) with advanced multiple myeloma (Fenk et al, Leuk Lymph 2007). The single-arm, multicenter, phase 2 VERTICAL study was conducted to determine the efficacy and safety of V and R in combination with B (VBR) in pts with rel/ref FL. Here we report preliminary phase 2 efficacy and safety findings from pts treated with VBR at doses determined in the dose-escalation phase of this study (Matous et al, ASCO 2009). Pts with rel/ref FL who had received ≥4 prior doses of R (no prior V or B), and had ≥1 measurable tumor mass, no active central nervous system lymphoma, Karnofsky Performance Status (KPS) ≥50%, adequate hematologic, renal, and hepatic function, and no grade ≥2 peripheral neuropathy (PN) were eligible. Pts could receive up to five 35-d cycles of V 1.6 mg/m2 (d 1, 8, 15, 22), B 90 mg/m2 (d 1, 2), and R 375 mg/m2 (d 1, 8, 15, 22, cycle 1; d 1, cycles 2–5). Response was assessed by the investigator using International Working Group criteria (Cheson et al, J Clin Oncol 2007). Adverse events (AEs) were graded using the CTCAE v3.0, and by laboratory assessment of hematologic toxicity. Sixty-three pts received VBR; median age was 58 years, 63% were male and 25% had KPS ≤80%. At diagnosis, 47% had grade 1, 26% grade 2, and 8% grade 3 histology, and 18% unknown histology; 35% had high-risk Follicular Lymphoma International Prognostic Index score. Pts had received a median of 2 prior therapies (range 1–11), and 39% were refractory to their last prior rituximab-containing therapy. The median time from diagnosis was 48 months. As of data cut-off (14 Aug 2009), pts had received a median of 3 cycles (range 1–5); 29 pts remain on therapy and 10 have completed treatment. In the 49 pts with at least one post baseline response assessment, to date, the overall best response rate was 84%; 23 (47%) pts achieved a complete response (CR) and 18 (37%) a partial response (PR). VBR was generally well tolerated, with manageable toxicities. The most common treatment-related AEs were primarily grade 1 and 2 and included nausea (79%; 3% grade 3), fatigue (65%; 10% grade 3), diarrhea (57%; 3% grade 3), and vomiting (44%; 5% grade 3). Other non-hematologic grade 3/4 AEs that occurred in more than one pt included syncope (n=2; 3%) and PN (see below). Grade 3/4 neutropenia, thrombocytopenia, and anemia were seen in 25%, 6%, and 3% of pts, respectively. Treatment-related serious AEs were reported in 17 (27%) pts, including 3 (5%) with febrile neutropenia and 1 (2%) with grade 3 herpes zoster who did not receive antiviral prophylaxis and discontinued therapy. Of the 17 (27%) pts with treatment-related PN, only 4 (6%) had grade 3 (2 discontinued therapy; no grade 4); PN has resolved in 5 (29%) pts to date. There was one on-study death (cardiac arrest) that was considered treatment-related. Additional follow-up is required to assess long-term outcomes, including progression-free and overall survival. VBR is active in this heavily pre-treated, high-risk population, with high CR rates, and was generally well tolerated. Efficacy and safety data will be updated and reported at ASH. Disclosures: Fowler: Millennium Pharmaceuticals, Inc.: Research Funding. Kahl:Milllennium: Consultancy, Research Funding; Cephalon: Consultancy, Research Funding. Rosen:Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Southern California Lymphoma Group, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen : Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tower Cancer Research Foundation: Employment. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Amin:Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncotype DX: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Williams:Milllennium: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Cephalon: Research Funding. Smith:Genentech: Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Shi:Millennium Pharmaceuticals, Inc.: Employment. Parasuraman:Milllennium: Employment. Cheson:Millennium Pharmaceuticals, Inc.: Consultancy, Speakers Bureau; Cephalon: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau.

Multicenter Phase I Dose-Escalation Study of Lenalidomide in Patients with Relapsed Adult T-Cell Leukemia-Lymphoma (ATL) or Peripheral T-Cell Lymphoma (PTCL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2737-2737 ◽  
Author(s):  
Naokuni Uike ◽  
Michinora Ogura ◽  
Yoshitaka Imaizumi ◽  
Norio Asou ◽  
Atae Utsunomiya ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 2 ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Grade 3

Abstract Abstract 2737 Introduction: ATL is prevalent in Japan and has the worst prognosis among T-cell malignancies. PTCL also has a poor prognosis with currently available chemotherapeutic regimens, and both would benefit from better treatment modality. Lenalidomide is an immunomodulatory agent with direct tumoricidal and antiproliferative activity, and is approved for multiple myeloma (MM) in combination with dexamethasone after at least 1 prior therapy and for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion. We conducted a phase 1 study of lenalidomide in patients with relapsed ATL or PTCL to establish the recommended dose and schedule for a subsequent phase 2 study. Patients and Methods: This multicenter, phase 1, dose-escalation study assessed the safety, maximum tolerated dose (MTD), pharmacokinetics, and efficacy in patients with relapsed advanced ATL or PTCL. Dose-escalation was conducted according to the standard 3+3 design. Up to one PTCL patient was allowed to be included in each cohort of 3 patients. Patients in Cohort 1 received oral lenalidomide 25 mg daily on Days 1–21 of a 28-day cycle. Patients in Cohorts 2 and 3 received 25 and 35 mg/day, respectively, on each day of the 28-day cycle. Dose-limiting toxicity (DLT) was defined as febrile neutropenia lasting 5 or more days; thrombocytopenia (platelets <10,000/uL or bleeding requiring platelet transfusion); ALT/AST elevation of Grade 4 or that of Grade 3 lasting 7 or more days; and/or clinically unacceptable Grade 3 or higher other non-hematological adverse events (AEs). Treatment was continued until the development of unacceptable toxicity or progressive disease (PD). Response was assessed by internationally accepted standard criteria for ATL and PTCL. Results: From July 2010–June 2012, 13 Japanese patients (9 ATL and 4 PTCL; age 32–74 years [median, 64]; 1–11 prior therapies [median, 1]) were enrolled: 3 in Cohort 1, 6 in Cohort 2, and 4 in Cohort 3. The 3 patients in Cohort 1 received lenalidomide for 21, 103, and 637 days, respectively, until PD with no instances of DLT. In Cohort 2, 1 patient experienced DLT (thrombocytopenia, platelets <10,000/uL) and 4 patients received lenalidomide for 37, 56, 138, and 387 days, respectively, until PD in 3 patients and unrelated death in one. The sixth patient is still receiving lenalidomide for 28+ days without a DLT. In Cohort 3, 2 patients had DLTs (thrombocytopenia, platelets <10,000/uL in one patient and Grade 3 prolongation of QTc interval in one patient on concomitant fluconazole with preexisting cardiac disease and grade 1 QTc prolongation at baseline), 1 patient received lenalidomide for 71 days before withdrawal of consent, and 1 patient is still receiving lenalidomide for 323+ days without a DLT. Based on these results, 25 mg daily per 28-day cycle was regarded as the MTD. Other Grade 3/4 non-DLT AEs occurring in 2 or more patients included neutropenia (n=8), lymphocytopenia (n=7), thrombocytopenia (n=3), skin rash (n=3), hyperbilirubinemia (n=2), and increased ALT/AST (n=2). Among the 9 ATL patients, 3 achieved partial responses (PR) with hematological complete response in 2 patients, including the disappearance of skin lesions in 1 patient. These responses occurred between 54 and 57 days, and lasted for 92, 279+ and 505 days. Among the 4 PTCL patients, 1 achieved a PR at day 106 with >75% reduction in lymph nodes, which lasted for 282 days. PK profiles of patients in the study were generally consistent with that observed in Japanese MM patients. Plasma exposure of lenalidomide increased with increasing dose with a mean Cmax on Day 1 for 25 mg and 35 mg of 493 ng/mL and 628 ng/mL, respectively, and a mean AUC24 of 2774 ng/mL and 3062 ng/mL, respectively. There was no evidence of accumulation following multiple dosing for 8 days. Conclusions: This phase 1 study identified lenalidomide 25 mg daily per 28-day cycle as the dose and schedule for a subsequent phase 2 study in patients with ATL or PTCL. Based on the preliminary evidence of antitumor activity in ATL and PTCL patients, a phase 2 study in patients with relapsed ATL in Japan is planned. Disclosures: Off Label Use: Lenalidomide (CC-5013) is an investigational agent in Japan; this abstract assesses its use in adult ATL patients. Tobinai:Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Zenyaku: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomedics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Solasia Pharma: Clinical trials, Clinical trials Other, Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding; Pfizer: Research Funding; GSK: Research Funding; Chugai/Roche: Research Funding; Takeda: Clinical trials, Clinical trials Other, Research Funding.

scholarly journals Ixazomib and Daratumumab without Dexamethasone (I-Dara) in Elderly Frail RRMM Patients. a Multicenter Phase 2 Study (IFM 2018-02) of the Intergroupe Francophone Du Myélome (IFM)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 83-83
Author(s):  
Magaret Macro ◽  
Cyrille Touzeau ◽  
Clara Mariette ◽  
Salomon Manier ◽  
Sabine Brechignac ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Response Rate ◽  
Phase 2 ◽  
Advisory Committees ◽  
Frail Patients ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Frailty Score

Abstract Purpose: Frail patients with multiple myeloma have an inferior outcome, especially in the relapse setting. This adverse prognosis is mainly related to a high discontinuation rate due to treatment related adverse events. The aim of this phase 2 study is to evaluate efficacy and tolerability of Ixazomib-Daratumumab (I-Dara) without Dexamethasone in elderly frail patients with relapsed myeloma (NCT03757221). Methods: Fifty Ixa-Dara naïve RRMM patients (1-2 prior therapy) were planned to receive oral Ixa (4 mg: days 1, 8, 15), IV Dara (16 mg/kg; days 1, 8, 15, 22, cycles 1-2; days 1, 15, cycles 3-6; days 1, cycles 7+) and IV Methylprednisolone before Dara (100 mg at day 1, 8, cycle 1 and then 60 mg). They were enrolled if frailty score was ≥2 by IMWG score and FIRST proxy score (Facon T et al, Leukemia, 2020). The primary endpoint was ≥very good partial response rate at one year. Secondary endpoints included ORR, PFS, OS & toxicity according to NCI-CTCAE version 5.0. Results: Among 52 patients screened during this ongoing trial, 44 were included between 03/2018 and 05/2021. Patient were at first (n=28) or second relapse (n=16). Thirty -eight patients (86%) were previously exposed to bortezomib and 8 (18%) were previously refractory to lenalidomide. Median age was 82 (80-84). All patients had a frailty score ≥2. In 22 patients ISS was stage I (n=5), II (n=10) or III (n=7). Eleven (32%) patients harbored high-risk cytogenetic, including t(4;14) (n=3) or del17p (n=8). The median duration of Tx among 23 pts with ongoing Tx was 6 months [0-27] at data cutoff (July 19)]. The median duration of Tx among 21 pts who stopped Tx was 7 months [0-21]: 13 had progressive disease. Six patients died during the study: Daratumumab-related bronchospasm (D1C1); Ixazomib-related overdose (C2); progressive disease (C2 & C4), sepsis (C1 & C2). Regarding toxicity, 28 ≥grade 3 AE occurred amongst 24 pts (54%). The most common grade 3-4 toxicities were thrombocytopenia (n=5), other cytopenias (n=4), infection (n=4) and gastrointestinal disorders (n=2). Fourteen out of 28 were SAE including 1 bronchospasm, 1 acute respiratory failure and 2 ixazomib overdoses. Overall response rate, including minimal response, was 86 % in pts with ongoing treatment and 71% in pts who stopped Tx; ≥VGPR rate was 33% and 6% respectively. Conclusions: These preliminary results show a favorable safety profile of ixazomib and daratumumab combination, without dexamethasone, in this specific population of very elderly frail patients with RRMM and high risk cytogenetic for almost one third of them. Efficacy results will be analyzed when the 50 patients will be enrolled in the study and evaluable for the primary endpoint. Disclosures Macro: GSK: Honoraria; Sanofi: Honoraria; Celgen/BMS: Honoraria; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Takeda: Honoraria, Other: Travel accomodation, Research Funding. Manier: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Consultancy, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vincent: Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Decaux: Amgen BMS Celgene Janssen Sanofi Takeda: Honoraria. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. OffLabel Disclosure: Ixazomib and Daratumumab association is not approved in NDMM or in RRMM

scholarly journals Frontline Treatment with Ibrutinib Plus Rituximab (IR) Followed By Short Course R-Hypercvad/MTX Is Extremely Potent and Safe in Patients (age ≤ 65 years) with Mantle Cell Lymphoma (MCL) - Results of Phase-II Window-1 Clinical Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3987-3987 ◽  
Author(s):  
Michael L. Wang ◽  
Preetesh Jain ◽  
Hun Ju Lee ◽  
F. B. Hagemeister ◽  
Felipe Samaniego ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Ki 67 ◽  
Best Response ◽  
Short Course ◽  
Free Induction ◽  
Grade 3

Background - Combination of ibrutinib plus rituximab (IR) has generated significant efficacy and safety data in relapsed patients (pts) with MCL. In this single institution phase II trial, we investigated the efficacy and safety of using an IR combination followed by short course (4 cycles) of R-HCVAD/MTX-ara-C as consolidation in previously untreated young (age ≤ 65 years) pts with MCL. We hypothesized that using a chemo-free induction will mitigate the toxicities and risk of second cancers which are associated with the use of intensive chemoimmunotherapy regimen in these pts. Methods - We enrolled 131 previously untreated young (≤65 years) pts with MCL. This study is registered with a ClinicalTrials.gov identifier number NCT02427620. Pts received IR induction (part-A), until they achieved complete remission (CR) for up to a maximum of 12 cycles, followed by a maximum of 4 cycles of R-HCVAD/R-MTX-ara-C (part-B) as consolidation. None of the patients received stem cell transplant or maintenance therapy. The primary objective was to assess overall response rate (ORR), [defined as either a partial response (PR) or a complete response (CR)] after part A. Adverse events were coded as per CTCAE version 4. Among evaluable samples, minimal residual disease (MRD) by flow cytometry at best response, clonal evolution using circulating tumor DNA (ctDNA), baseline somatic mutations and baseline gene expression profile (GEP) are being evaluated. Results - Among the 131 pts, the median follow up was 22 months (1.4-48.70). Eighty percent were males. Median age was 56 yrs (range - 35-65). Forty nine percent had high Ki-67 (≥30%), 80% had low risk simplified MIPI score and 85% pts had initial marrow involvement. Fifteen pts had aggressive MCL (blastoid/pleomorphic), 17 pts had complex karyotype and 83% had positive SOX-11 expression. Median number of cycles on IR in part A was 7 (1-12). At week 16 on part A, the ORR was 95% (22% CR and 73% PR) and 5% pts had stable disease. Overall best response (ORR) on part A of therapy was 100% (88% CR and 12% PR) and at the time of last follow up after completion of part A and part B, ORR was 100% (94% CR). Among evaluable pts, MRD- negative CR rate assessed by bone marrow flow cytometry performed at best response at any phase of treatment was 78%. Among the 10 pts with TP53 mutations, 70% had a CR on part A alone. Overall, the median PFS and OS were not reached (3 year 85% and 97% respectively). Nine pts had relapsed after treatment, including 3 who transformed. Among these 9 pts, 7/9 pts had Ki-67% ≥ 30% and 3/9 pts had aggressive histology MCL. The PFS and OS were not significantly different among pts with high and low Ki-67% and among pts with/without achieving CR on part A and while PFS was significantly shorter in pts with aggressive MCL histology (p=0.005) but not the OS. Overall 3 pts died (one on study due to splenic hematoma, cardio-pulmonary arrest and was on IR for 1 month, one expired outside and was off study after discontinuation due to encephalitis and another expired outside and discontinued due to disease transformation). Twenty one pts came off study for various reasons [nine disease progression (including 3 transformation), 8 pt choice, 3 intolerance and one second cancer]. Grade 3-4 toxicities on part A were 4% myelosuppression and 8% each with fatigue, myalgia and rashes and 4% mucositis. None had grade 3-4 atrial fibrillation or bleeding. GEP was performed in 18 pts (2 PR, 16 CR on part A). Pts in PR had higher expression of HES1 while those in CR had significantly higher expression of CTLA4 and ITK genes compared with those in PR. Targeted DNA sequencing was done in 18 pts at baseline, one pt with PR had NSD2, KMT2C and another pt had TP53 mutations and had CR. Conclusions - Excellent responses were observed with IR combination which is a chemo-free induction treatment strategy for young pts with MCL. This treatment approach has a strong potential to change the treatment paradigm in MCL pts to minimize the toxicity from chemoimmunotherapy without compromising the treatment efficacy and safety. Disclosures Wang: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; Acerta Pharma: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; VelosBio: Research Funding; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria; MoreHealth: Consultancy, Equity Ownership; BioInvent: Consultancy, Research Funding; Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding. Lee:Seattle Genetics, Inc.: Research Funding. Westin:Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Unum: Research Funding; 47 Inc: Research Funding; Janssen: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Kite: Other: Advisory Board, Research Funding. Nastoupil:Bayer: Honoraria; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria; Janssen: Honoraria, Research Funding. Neelapu:Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Poseida: Research Funding; Cell Medica: Consultancy; Karus: Research Funding; Acerta: Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Cellectis: Research Funding; Incyte: Consultancy; Allogene: Consultancy; BMS: Research Funding. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: 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; Roche: 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.

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