Results of a Phase 1 Study of Quizartinib (AC220) As Maintenance Therapy in Subjects with Acute Myeloid Leukemia in Remission Following Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 428-428 ◽  
Author(s):  
Brenda M. Sandmaier ◽  
Samer K Khaled ◽  
Betul Oran ◽  
Guy Gammon ◽  
Denise Trone ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Phase 3 ◽  
Equity Ownership ◽  
Grade 3

Abstract FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Hematopoietic cell transplantation (HCT) is a recommended treatment for patients with FLT3-ITD(+) AML. However, a high rate of relapse after a HCT is observed when compared to FLT3-ITD(-) patients with the 2 year relapse rate of 30% vs. 16% in FLT3-ITD(+) and FLT3-ITD(-) patients, respectively (Brunet, J. Clin. Oncol. 2012). Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that has shown a high level of single agent activity in nearly 500 patients with FLT3(+) relapsed or refractory AML and is currently in a Phase 3 study. This Phase 1 study examined maintenance therapy with quizartinib in AML patients (aged 18 years or older) in remission after receipt of an allogeneic HCT. Dose escalation was conducted using a modified 3+3 design, where 6 subjects were enrolled at each dose level. Two dose levels were tested; dose level 1 (DL1) at 40 mg and dose level 2 (DL2) at 60 mg given daily in continuous 28 day cycles. Dose limiting toxicities (DLTs) were assessed for the first 2 cycles and subjects were allowed to continue up to a maximum of 24 cycles. Thirteen subjects were recruited and enrollment was completed in June 2013. The median age was 43 (range 23 to 61) years. All subjects had received an HLA-matched allogeneic HCT (3 related and 10 unrelated) a median of 56 (range 41 – 70) days before study enrollment. All subjects were positive for the FLT3-ITD mutation by local testing at the time of diagnosis. Seven subjects were enrolled at DL1, including one who relapsed after 22 days on study and was replaced per protocol as deemed not evaluable for DLTs. There was 1 DLT of Grade 3 gastric hemorrhage which resolved and the subject was able to continue on a reduced dose (30 mg) of quizartinib. Six subjects were enrolled at DL2, including one subject who experienced 1 DLT of Grade 3 anemia but was able to continue on a reduced dose (30 mg). Of the 13 total subjects, 10 (77%) received quizartinib for more than a year. Six (45%) subjects are continuing to receive quizartinib currently (15, 16, 18, 18, 23, and 23 cycles) and 2 (15%) subjects have completed 24 cycles. Three subjects (23%) discontinued due to AE: Grade 4 neutropenia (Cycle 4), Grade 2 corneal epithelium defect (Cycle 9), and Grade 3 autoimmune hemolysis (Cycle 15); 1(8%) discontinued for disease relapse (Cycle 1) and 1 (8%) for protocol non-compliance (Cycle 13). The most common (≥20%) treatment-related adverse events (AEs) were diarrhea (38%; 5 subjects), neutropenia (31%; 4 subjects), nausea (23%; 3 subjects) and leukopenia (23%; 3 subjects). This is the first study conducted to determine whether or not quizartinib can be safely administered as post-transplant maintenance therapy in patients with AML. The data from this study support the use of post-transplant maintenance therapy with quizartinib and show early evidence indicating a reduced relapse rate with only 1 relapse reported out of 13 subjects, which compares favorably to historical reference data. No MTD was identified but 60 mg daily was selected as the highest dose for continuous daily administration based on Phase 2 study data in relapsed or refractory subjects (J Cortes, Blood (ASH Annual Meeting Abstracts) 2013 [Abstract]). Quizartinib maintenance has been included in the current Phase 3 QUANTUM-R study comparing quizartinib vs. salvage chemotherapy in relapsed or refractory FLT3-ITD(+) AML. Disclosures Sandmaier: Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding. Khaled:Ambit Bioscience Corporation: Research Funding; Astellas Pharma, Inc: Research Funding. Oran:Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding. Gammon:Ambit Bioscience Corporation: Employment, Equity Ownership. Trone:Ambit Bioscience Corporation: Employment, Equity Ownership. Frankfurt:Astellas Pharma, Inc: Research Funding; Ambit Bioscience Corporation: Research Funding.

Results Of a Phase 1 Study Of Quizartinib (AC220, ASP2689) In Combination With Induction and Consolidation Chemotherapy In Younger Patients With Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 623-623 ◽  
Author(s):  
Jessica K Altman ◽  
James M. Foran ◽  
Keith W. Pratz ◽  
Denise Trone ◽  
Guy Gammon ◽  
...  
Keyword(s):  
Dose Level ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Newly Diagnosed ◽  
Consolidation Chemotherapy ◽  
Phase 1 Study ◽  
Level 1 ◽  
Grade 3 ◽  
Dose Levels

Abstract FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that has shown the highest level of single agent activity seen with a FLT3 targeted agent in FLT3+ relapsed AML to date. This Phase 1 dose escalation study is the first study to report data with quizartinib in combination with standard induction and consolidation chemotherapy in patients aged 18-60 years with newly diagnosed AML, regardless of FLT3-ITD status. The dose escalation was conducted using a modified 3+3 design, where 6 pts were enrolled at each dose level. The pts were given cytarabine 200 mg/m2 x 7 days and daunorubicin 60 mg/m2 x 3 days (7+3) for induction and high dose cytarabine 3 g/m2(HiDAC) q12hours on days 1, 3, and 5 for consolidation. Quizartinib was administered daily for either 7 or 14 days, starting at Day 4 of induction and/or consolidation chemotherapy. Patients were allowed to proceed directly to a stem cell transplant after achieving a response or receive further quizartinib as maintenance therapy after consolidation if they were not transplant eligible. Three dose levels were tested; dose level 1 (DL1) at 60 mg for 7 days, dose level 2 (DL2) 60 mg for 14 days, and dose level -1 (DL-1), 40 mg for 14 days. Through May 31, 2013 18 pts were enrolled in the study, and the safety information at all 3 dose levels are presented. The median age of pts was 43 years (range 22 to 60). Of the 18 patients, 16 had the FLT-ITD mutation. At DL1, one of the 6 patients had a DLT (grade 3 hyponatremia). At DL2, two of the 6 patients had a DLT (grade 3 QTc prolongation and grade 4 pericarditis) which exceeded the pre-specified criteria so DL-1 was then explored. At DL-1, one of the 6 patients had a DLT (grade 3 constrictive pericarditis). The most common (20%) treatment-related adverse events (AEs) were nausea (42%), diarrhea (32%), anemia (26%), febrile neutropenia (26%), neutropenia (21%), fatigue (21%), pyrexia (21%) and thrombocytopenia (21%). The most common (10%) Grade 3 or 4 treatment-related AEs were febrile neutropenia (26%), thrombocytopenia (21%) anemia (21%)), neutropenia (21%), leucopenia (16%), and nausea (11%). The data from this Phase 1 study demonstrates for the first time that quizartinib can be safely administered with induction and/or consolidation chemotherapy in newly diagnosed younger patients with AML. The MTD was identified as 40 mg for 14 days or 60 mg for 7 days. The efficacy results from this Phase 1 study will be available at the time of presentation. Based on these findings, multiple Phase 3 studies in newly diagnosed AML patients are planned. Disclosures: Altman: Novartis: Consultancy; Araid: Consultancy; BMS: Consultancy; Teva: Consultancy; Astellas: Consultancy. Foran:Astellas: Research Funding. Trone:Ambit: Employment. Gammon:Ambit: Employment. Cortes:Ambit: Research Funding.

Clinical Safety and Activity In a Phase 1 Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, In Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1777-1777 ◽  
Author(s):  
Brad Kahl ◽  
John C. Byrd ◽  
Ian W. Flinn ◽  
Nina Wagner-Johnston ◽  
Stephen Spurgeon ◽  
...  
Keyword(s):  
Clinical Research ◽  
Research Funding ◽  
Phase 1 ◽  
Selective Inhibitor ◽  
Phase 1 Study ◽  
Non Hodgkin Lymphoma ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 1777 Introduction: The class I phosphatidylinositol 3-kinases (PI3Ks) regulate cellular functions relevant to oncogenesis. Expression of the PI3K p110δ isoform (PI3Kδ) is restricted to cells of hematopoietic origin where it plays a key role in B-cell proliferation and survival. In non-Hodgkin lymphoma (NHL) cells, constitutive PI3Kδ-dependent PI3K pathway activation is frequently observed. CAL-101 is an isoform-selective inhibitor of PI3Kδ that inhibits PI3K signaling and induces apoptosis of NHL cell lines in vitro. Methods and Patients: This Phase 1 study evaluated the safety, pharmacokinetics and activity of orally administered CAL-101 in patients with relapsed or refractory hematologic malignancies. Sequential cohorts of patients were enrolled at progressively higher dose levels with cohort expansion based on toxicity profile and plasma exposure. CAL-101 was administered orally once or 2 times per day (QD or BID) continuously in 28-day cycles for up to 12 cycles (with the potential for more prolonged therapy on an extension protocol thereafter). Tumor response was evaluated based on standard criteria but without a requirement for PET imaging. Results: At data cutoff, the study had enrolled 55 patients with NHL; 28 patients had indolent NHL (follicular lymphoma n=15, small lymphocytic lymphoma n=6, Waldenstrom's macroglobulinemia n=4, marginal zone lymphoma n=3) and 27 had aggressive NHL (mantle cell lymphoma [MCL] n=18, diffuse large B-cell lymphoma [DLBCL] n=9). Patient characteristics included 69% males (38 vs 17 females), median age [range] of 68 [32-82] years, 44% with refractory disease and 56% with relapsed disease. The median [range] number of prior therapies was 5 [1-12]. The proportion of patients with specific prior therapies included: indolent NHL-rituximab 96%, alkylator 86%, anthracycline 50%, purine analog 36%; aggressive NHL-rituximab 100%, alkylator 100%, anthracycline/anthracenedione 96%, plus bortezomib 72% in MCL patients. CAL-101 dose levels were 50 mg BID (n=2), 100 mg BID (n=11), 150 mg BID (n=8), 200 mg BID (n=16), 350 mg BID (n=9) and 300 mg QD (n=9). The median [range] number of treatment cycles was 4 [1-16], with 16 (29%) patients continuing on treatment (11 on study and 5 on the extension protocol after 12 cycles). Symptomatic adverse events were infrequent, usually low-grade, and not clearly CAL-101-related. Grade ≥3 hematological laboratory abnormalities included neutropenia n= 5 (9%), lymphopenia n=3 (5%), and thrombocytopenia n=3 (5%) with uncertain relationship to CAL-101. Grade≥3 ALT/AST elevations occurred in 18 (33%) patients with onset 2–8 weeks after CAL-101 initiation and resolution 2–4 weeks after CAL-101 interruption; after resolution of ALT/AST changes, most patients were rechallenged at the same or a reduced dose of CAL-101 and the majority of these patients were able to resume treatment without recurrence of transaminase elevations. Partial responses were observed at all dose levels, with respective overall n/N (response rates) in evaluable patients of 15/24 (62%) for indolent NHL, 10/16 (62%) for MCL and 0/9 (0%) for DLBCL. Respective response rates by relapsed or refractory status were 9/13 (69%) and 6/11 (55%) for indolent NHL and 8/11 (73%) and 2/5 (40%) for MCL. The median duration of response had not been reached in indolent NHL patients; 5 patients have had response durations of ≥6 months with response durations ranging to >16 months. The median [range] duration of response was 3 months [1 month to 8 months] in MCL. Pharmacodynamic data have supported drug activity; plasma concentrations of chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases within 1 cycle of CAL-101 treatment (p<0.001 for both comparisons). An evaluation of pharmacokinetics indicated minimal increases in plasma Cmax and AUC at CAL 101 doses >150 mg BID; these data, taken together with the tumor regression results, have proved helpful in supporting Phase 2–3 dose selection. Conclusions: CAL-101, an oral PI3Kδ isoform-selective inhibitor, shows acceptable safety and promising pharmacodynamic and clinical activity in patients with indolent NHL and MCL. The high rate of tumor regressions and protracted durations of tumor control in heavily pretreated patients support advancing CAL-101 into additional studies, both as a single agent and in combination with chemo/immunotherapy. Disclosures: Kahl: calistoga: Consultancy, Research Funding. Off Label Use: CAL-101 for relapsed lymphoma. Byrd:Calistoga Pharmaceutical Inc.: Equity Ownership. Flinn:calistoga: Research Funding. Wagner-Johnston:calistoga: Research Funding. Spurgeon:calistoga: Research Funding. Furman:GlaxoSmithKline: Clinical research funding, Consultancy, Research Funding, Speakers Bureau; Genentech: Clinical Research Funding, Consultancy, Research Funding, Speakers Bureau; Cephalon: Speakers Bureau, Speakers bureau; Calistoga: Consultancy, Honoraria; Celgene: Clinical Research, Consultancy, Research Funding. Brown:Genzyme: Research Funding; Celgene: Consultancy, Research Funding; Calistoga: Consultancy; Genentech: Consultancy. Coutre:calistoga: Research Funding. Lannutti:Calistoga Pharmaceutical Inc.: Employment. Ulrich:Calistoga Pharmaceuticals: Employment, Equity Ownership. Webb:Calistoga Pharmaceuticals: Employment. Peterman:Calistoga Pharmaceuticals: Employment. Holes:Calistoga Pharmaceuticals: Employment.

An Open-Label, Phase 2, Multicenter Study Of The Safety Of Long-Term Treatment With Siltuximab (an Anti-Interleukin-6 Monoclonal Antibody) In Patients With Multicentric Castleman’s Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1806-1806 ◽  
Author(s):  
Frits Van Rhee ◽  
Corey Casper ◽  
Peter M Voorhees ◽  
Luis E Fayad ◽  
Helgi van de Velde ◽  
...  
Keyword(s):  
Disease Control ◽  
Research Funding ◽  
Phase 1 ◽  
Extension Study ◽  
Development Research ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Equity Ownership ◽  
Grade 3 ◽  
Entire Treatment

Abstract Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disease driven by interleukin (IL)-6 overproduction. There is no established standard of care for MCD, and patients are usually managed by a variety of strategies with only modest success. Treatment with siltuximab, an anti-IL-6 mAb, demonstrated clinical and radiologic responses in MCD patients in a phase 1 study (Kurzrock et al. Clin Cancer Res 2013;19:3659-70). A phase 2 extension study to assess the safety of long-term treatment with siltuximab in MCD patients is currently ongoing. We report the interim analysis results based on 19 patients who had sustained disease control on siltuximab in the phase 1 study and continued to receive siltuximab 11 mg/kg q3w IV in the phase 2 extension study. Safety monitoring focused on infections, hyperlipidemia, neutropenia, thrombocytopenia, GI perforations, and liver function based on the potential risks from the mechanism of action of IL-6 blockade. Investigator assessed disease control and survival status were also collected. When these 19 patients started the phase 1 study, median age was 44 (range 18, 76) yrs, 63% were male, median disease duration was 4.8 mos (37% newly diagnosed), 53% had hyaline vascular and 47% had plasmacytic histological type, all were HIV- and HHV-8-negative, 32% were therapy-naïve, and 68% had prior therapy (including 21% with prior cancer-related surgery and 63% with prior systemic therapy for MCD). At the data cutoff for this interim analysis of the extension study (January 2013), patients had received in total a median of 81 doses (maximum 129) of siltuximab during a median treatment duration of 5.1 (range 3.4, 7.2) yrs, with 74% of patients treated >4 yrs. All 19 patients are alive and continuing siltuximab treatment. Over the entire treatment duration (ie, both studies), upper respiratory tract infection (89%); nausea (63%); vomiting (58%); diarrhea (53%); hypercholesterolemia (47%); hypertriglyceridemia, pain in extremities, headache, rash, and hepatic function abnormal (each 42%) were most commonly reported. The incidence of AEs reported in the different system-organ classes was similar or lower in the treatment periods of 2 to 4 yrs and more than 4 yrs compared with the treatment period of 0 to 2 yrs. 63% of patients reported at least one grade ≥3 AE (mostly grade 3, none grade 5) during the entire treatment period, most commonly in the following system-organ classes: gastrointestinal (32%); infections (26%); and blood/lymphatic system disorders or general disorders/administration-site conditions (each 21%). Grade ≥3 hypertension was reported in 3 patients; grade ≥3 nausea, cellulitis, and fatigue in 2 patients each; other grade ≥3 AEs were reported in single patients. Two patients had at least one serious infection during phase 1, and none were reported during phase 2 extension study (overall incidence 0.0226 per pt-yr). Eight patients had low-grade hypertriglyceridemia in phase 1, with no additional cases reported during extension study (overall incidence 0.1250 per pt-yr). No patient had grade ≥3 thrombocytopenia, and only 1 patient had grade ≥3 neutropenia during the entire treatment period (overall incidence 0.0103 per pt-yr). Only 1 case of grade ≥3 abnormal hepatic function was reported (in phase 1). No GI perforations occurred. No patient developed infusion-related reactions during the extension study. Only 3 patients had SAEs during the extension study, including unrelated syncope and dyspnea. One patient developed grade 3 polycythemia (Hb 18.8 g/dL), which was controlled without complications. Based on independent radiologic review of images from the phase 1 study, 1 patient had CR, 11 had PR, and 7 had SD at initiation of extension study. All 19 patients have sustained disease control (SD or better) by investigator assessment, including 8 patients who had their dosing interval increased to q6w after established prolonged PR/CR (median q6w treatment duration 11 mos). After a median follow-up of 5.1 yrs, the OS rate in these 19 patients is 100%. In conclusion, the 19 patients with MCD in this extension study have received siltuximab for a prolonged period of time (median 5.1 yrs, up to 7.2 yrs). All patients are alive and maintain disease control. Prolonged siltuximab treatment is well tolerated, with no evidence of new or cumulative toxicity or treatment discontinuations and with a low rate of serious adverse events including serious infections. Disclosures: Van Rhee: Janssen Research & Development: Research Funding. Casper:Janssen Research & Development: Research Funding. Voorhees:Janssen Research & Development: Research Funding; Abbott: Consultancy; GlaxoSmithKline: Consultancy; Celgene: Membership on an entity’s Board of Directors or advisory committees; MedImmune: Membership on an entity’s Board of Directors or advisory committees. van de Velde:Johnson & Johnson: Equity Ownership; Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Qin:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Qi:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Tromp:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Kurzrock:Janssen Research & Development: Research Funding.

A Phase 1 Study Of TH-302, An Investigational Hypoxia-Targeted Drug, In Patients With Advanced Leukemias

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3920-3920 ◽  
Author(s):  
Marina Konopleva ◽  
Damian R Handisides ◽  
Mary Ann Richie ◽  
Juliana M Benito ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Research Funding ◽  
Phase 1 ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Bolus Administration ◽  
Employment Equity ◽  
Phase 1 Study ◽  
Equity Ownership ◽  
Grade 3

Abstract Background TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard designed to be selectively activated in hypoxic conditions. Preclinical data in mice with acute lymphoblastic leukemia (ALL) have demonstrated marked expansion of hypoxia in areas of marrow leukemia infiltrates (Benito et al., PLoS One 2011). TH-302 also exhibited specific hypoxia-dependent cytotoxicity when tested against primary ALL and acute myelogenous leukemia (AML) samples in vitro (Benito et al., ASH 2012). Based on these findings, a phase 1 study of TH-302 was designed for advanced leukemias. Methods Eligible patients had ECOG ≤ 3, relapsed/refractory leukemias for which no standard therapy options were available, and acceptable hepato-renal function. A standard 3+3 dose-escalation design was used with 40% dose increments. TH-302 was administered IV over 30-60 min daily, either by 30 min-bolus administration or as a continuous infusion on days 1-5 of a 21-day cycle. The objectives were to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of TH-302 with these schedules and to assess preliminary clinical activity of TH-302. Results A total of 49 patients with previously treated AML (n=39), ALL (n=9) or CML in blast phase (n=1) received TH-302 at bolus doses of 120 (n=4), 170 (n=4), 240 (n=3), 330 (n=3), 460 (n=20), 550 (n=4) mg/m2 or continuous doses of 330 (n=8) or 460 (n=3) mg/m2. Two of 3 evaluable patients treated with bolus TH-302 (550 mg/m2) experienced DLTs of grade 3 esophagitis; bolus administration MTD was established at 460 mg/m2. Two of 3 patients treated with continuous infusion of TH-302 (460 mg/m2) experienced DLTs of grade 3 mucositis or grade 3 hyperbilirubinemia; continuous administration MTD was established at 330 mg/m2. Thirteen patients received greater than 1 cycle. Generally, a significant rapid cytoreduction was evident early in the cycle, but was not maintained prior to initiation of the next cycle. Two AML patients who received 550 mg/m2 bolus TH-302 had complete resolution of leukemia cutis. One AML patient at 550 mg/m2 bolus TH-302 had a complete response with incomplete platelet recovery (CRp), and one AML patient at 440 mg/m2 bolus TH-302 had a CR. Conclusions In patients with advanced leukemias, MTDs were established for daily bolus infusion and 5-day continuous infusion of TH-302 at 460 mg/m2 and 330 mg/m2, respectively. Increased incidence of skin and mucosal toxicity were observed at higher dose levels with both administration schedules. Clinical activity of single-agent TH-302 has been noted with a few objective responses, but the majority of cytoreductions were transient. Disclosures: Konopleva: Threshold Pharmaceuticals: Research Funding. Handisides:Threshold Pharmaceuticals: Employment, Equity Ownership. Kroll:Threshold Pharmaceuticals: Employment, Equity Ownership. Kantarjian:Ariad: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

Results of the Phase 3 Study of Lenalidomide Versus Placebo As Maintenance Therapy Following Second-Line Treatment for Patients with Chronic Lymphocytic Leukemia (the CONTINUUM Trial)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 230-230 ◽  
Author(s):  
Robin Foà ◽  
Anna Schuh ◽  
Andrey Zaritskey ◽  
Sergey Semochkin ◽  
David Simpson ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Line Treatment ◽  
Second Line ◽  
Primary Analysis ◽  
Phase 3 ◽  
Significant Difference ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Despite recent advances in available treatments, chronic lymphocytic leukemia (CLL) remains an incurable disease, and the vast majority of patients (pts) will relapse and require additional lines of therapy. Thus, prolonging remission is a key treatment goal in CLL. This multicenter, randomized, double-blinded phase 3 trial (NCT00774345) was designed to evaluate the efficacy and safety of lenalidomide (LEN) vs placebo (PBO) as maintenance therapy in previously treated CLL pts. Methods: Eligible CLL pts must have had at least a partial response (PR) to second-line therapy. Pts were randomized 1:1 to receive either LEN 2.5 mg once daily on days 1-28 of the first 28-day cycle, or matching PBO. If LEN was well tolerated, escalation to 5 mg/day was permitted from cycle 2, and further escalation to 10 mg/day at cycle 7 and thereafter. Pts were stratified by their response at the end of second-line therapy (PR, nodular PR, complete response [CR], or CR with incomplete bone marrow recovery; vs minimal residual disease [MRD]-negative CR by flow cytometry); age (≤ 70 vs > 70 years); and presence of at least one of the following poor prognostic factors: del(11q), del(17p), unmutated IGHV, or b2M > 0.4 mg/L (Yes vs No vs Unknown). Co-primary endpoints were progression-free survival (PFS; IRAC assessed) and overall survival (OS). Secondary endpoints included: safety, tumor response, duration of response, second PFS (PFS2, time from randomization to second disease progression or death), and health-related quality of life (HRQoL). Results: Overall, 314 pts were enrolled (LEN, n = 160; PBO, n = 154). Baseline characteristics were balanced between the treatment arms: median age was 63 years (range 37-82) and 63 years (range 37-84), 71.9% and 72.1% were male, 9.4% and 11.7% had MRD-negative CR to second-line treatment, and 47.5% and 47.4% had at least one poor prognostic factor, in the LEN and PBO arms, respectively. On review of the primary analysis, 30 Sept 2015 data cutoff, the required number of progression events to complete the co-primary analysis had occurred, and the data monitoring committee recommended that the study be unblinded. Median follow-up time was 31.5 months, and the median PFS was significantly longer for LEN vs PBO: 33.9 vs 9.2 months, respectively (HR 0.40 [95% CI 0.29, 0.55]; P < 0.001). At the time of the analysis there were 86 deaths and there was no significant difference in the OS (HR 0.96 [95% CI 0.63, 1.48]; P = 0.856). Subsequent CLL therapy was received by 35.7% of pts in the LEN arm and 58.4% of pts in the PBO arm, of these pts 16% in the LEN arm and 20% in the PBO arm were treated with a BTK or PI3K inhibitor. Median PFS2 was significantly longer for LEN vs PBO: 57.5 vs 32.7 months, respectively (HR 0.46 [95% CI 0.29, 0.70]; P <0.001). Median number of treatment cycles received was 18 vs 9 cycles, for LEN vs PBO, respectively; a higher proportion of pts in the LEN arm started ≥25 cycles vs the PBO arm (38.9% vs 24.0%, respectively). Median dose intensity in the LEN arm was 4.2 mg/day. The most common adverse events (AEs) of all grades were neutropenia (66.2% vs 30.5%) and diarrhea (40.8% vs 16.2%) in the LEN vs PBO arm, respectively. Febrile neutropenia occurred in 1.9% vs 0%, deep vein thrombosis in 1.9% vs 0%, and pulmonary embolism in 2.5% vs 0.6% of pts in the LEN vs PBO arm, respectively. Most common grade 3/4 AEs were neutropenia (59.9% vs 22.7%), thrombocytopenia (16.6% vs 6.5%), and diarrhea (8.3% vs 0.6%) in the LEN vs PBO arm, respectively; all other grade 3/4 AEs occurred in <5% of pts in either arm. While there was a significant difference in the incidence of neutropenia, the rate of grade 3/4 infections was 16.6% for LEN vs 10.4% for PBO-treated pts. There were 13 (8.3%) vs 14 (9.1%) pts with at least one invasive second primary malignancy (SPM) in the LEN vs PBO arm, respectively. Hematologic invasive SPMs occurred in 7 vs 2 pts, and solid tumor invasive SPMs occurred in 7 vs 12 pts, in the LEN vs PBO arm, respectively. Overall, 44 pts in the LEN arm and 41 pts in the PBO arm died; 1 pt died on treatment in the LEN arm, and 2 pts in the PBO arm. There was no clinically meaningful difference in HRQoL for LEN vs PBO, as measured by FACT-Leu and EQ-5D, during maintenance treatment. Conclusions: LEN maintenance therapy significantly improved PFS from 9.2 to 33.9 months following second-line treatment in pts with CLL. The incidence of invasive SPMs was similar in both arms, and LEN maintenance treatment had an expected and acceptable safety profile. Disclosures Foà: Roche: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Gilead,: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau; Pfizer, Ariad: Speakers Bureau; Genentech, Janssen, BMS: Consultancy. Schuh:Gilead: Consultancy, Honoraria, Research Funding; Roche, Janssen, Novartis, Celgene, Abbvie: Consultancy, Honoraria. Zaritskey:Novartis: Consultancy; Janssen: Consultancy. Semochkin:Celgene, Sandoz, Novartis, Astellas, Janssen Pharmaceuticals, Bristol-Myers Squibb: Speakers Bureau; Celgene, Bayer Healthcare, Astellas Pharma Inc.: Research Funding; City Clinical Hospital 52, Moscow, Russia: Consultancy. Simpson:Amgen Pharmaceuticals: Research Funding; Celgene, Roche, Janssen: Honoraria. Vokurka:Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Zhang:Celgene Corporation: Employment, Equity Ownership. Purse:Celgene Corporation: Employment, Equity Ownership.

scholarly journals A Phase 1 Study of Flotetuzumab, a CD123 x CD3 DART® Protein, Combined with MGA012, an Anti-PD-1 Antibody, in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2662-2662 ◽  
Author(s):  
Andrew H. Wei ◽  
Chun Yew Fong ◽  
Pau Montesinos ◽  
Maria Calbacho ◽  
Jordi Sierra Gil ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Research Support ◽  
Employment Equity ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Support Research

Background Acute myeloid leukemia (AML) blasts and leukemic stem and progenitor cells typically express higher levels of CD123 than their normal hematopoietic stem cell counterparts, making CD123 an attractive target. Leukemic CD123 expression is associated with poor prognosis, high-risk disease, and increased risk of induction failure (Vergez et al 2011). Single-agent flotetuzumab, an investigational CD123 x CD3 bispecific DART protein, has shown evidence of clinical activity in a Phase 1 study of relapsed/refractory (R/R) acute myeloid leukemia (AML). In this study, flotetuzumab led to T-cell activation which in turn was associated with PD-1 induction on T lymphocytes, enhanced IFNɣ secretion, and upregulation of PD-L1 expression by AML blasts (ASH 2018 Rutella, ASH 2018 Uy). In vitro studies have shown synergistic T-cell mediated cytotoxicity of an AML cell line (KG1A) with flotetuzumab in the presence of PD-1/PD-L1 axis blockade compared to flotetuzumab alone. MGA012, also known as INCMGA00012, is an investigational anti-PD-1 antibody that has shown clinical activity in a Phase 1 study (SITC 2018 Mehnert). We hypothesize that combined checkpoint inhibition with MGA012 together with redirected T‐cell killing of CD123+ cells with flotetuzumab may show enhanced activity over flotetuzumab alone. Methods This is a Phase 1 dose escalation study designed to characterize the safety, tolerability, dose-limiting toxicities, maximum tolerated dose (MTD) or maximum administered dose (if no MTD is defined), pharmacokinetics, and preliminary anti-leukemic activity of flotetuzumab in combination with MGA012, each administered intravenously (IV) in patients with R/R AML. Response evaluation will be determined by modified ELN 2017 criteria. Activity is measured by complete response (CR) (complete remission [CR], or CR with partial hematologic recovery [CRh], or CR with incomplete hematological recovery [CRi], or morphologic leukemia-free state [MLFS]) rate, relapse-free survival, or mortality rate at 1 and 3 months. The impact of flotetuzumab/MGA012 combination on overall survival and event-free survival will be explored. Eligible patients will consist of adults with relapsed or refractory AML (any subtype except acute promyelocytic leukemia) who have exhausted standard of care options. In Induction Cycle 1, patients will be treated with a step-up lead in dose of flotetuzumab, followed by continuous infusion flotetuzumab, starting at week 2 of Cycle 1 and continuing through each 28-day cycle. MGA012 will be administered every two weeks. Depending on response, patients will transition to either consolidation or second induction. Eligible patients who achieve CR/CRh/CRi can receive maintenance MGA012 alone for up to 12 months. Disclosures Wei: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, 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: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria. Fong:Novartis: Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Astellas: Consultancy. Montesinos:Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Gil:Jazz Pharmaceuticals: Honoraria; Gilead: Honoraria; Daiichi-Sankyo: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria; Abbvie: Honoraria. Perez De Oteyza:Celgene: Speakers Bureau. Rowe:BioSight: Consultancy. Wolach:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker. Sun:MacroGenics, Inc.: Employment, Equity Ownership. Baughman:MacroGenics, Inc.: Employment, Equity Ownership. McNulty:MacroGenics, Inc.: Employment, Equity Ownership. Bonvini:MacroGenics, Inc.: Employment, Equity Ownership. Wigginton:Western Oncolytics: Other: clinical advisory board; MacroGenics, Inc.: Employment, Equity Ownership. Davidson-Moncada:MacroGenics, Inc.: Employment, Equity Ownership.

scholarly journals Bosutinib or Imatinib in Older Vs Younger Patients with Newly Diagnosed Chronic Myeloid Leukemia in the Phase 3 BFORE Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1734-1734 ◽  
Author(s):  
Michael W. Deininger ◽  
Vamsi Kota ◽  
Jeff H. Lipton ◽  
Dragana Milojkovic ◽  
Valentín García Gutiérrez ◽  
...  
Keyword(s):  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Age Groups ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Younger Patients ◽  
Equity Ownership ◽  
The Difference ◽  
Grade 3

Abstract Introduction: Bosutinib is approved for newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) and CML resistant or intolerant to prior therapy. Efficacy and safety of first-line bosutinib and imatinib were assessed in older vs younger patients in the ongoing phase 3 BFORE trial (NCT02130557). Methods: In all, 536 patients were randomized 1:1 to receive bosutinib or imatinib (400 mg once daily). We compared outcomes in patients aged ≥65 years (older group) vs <65 years (younger group) after 24 months of follow-up. Efficacy (excluding complete cytogenetic response [CCyR]) was assessed in the intent-to-treat (ITT) population (Philadelphia chromosome-positive [Ph+] and negative patients) of both age groups and safety in patients who received ≥1 dose of study drug. CCyR was assessed in the modified ITT population (Ph+ patients with e13a2/e14a2 transcripts [N=487]). Results: In the bosutinib arm (n=268), 53 were older and 215 were younger patients. In the imatinib arm (n=268; 3 untreated), 48 (2 untreated) were older and 220 (1 untreated) were younger patients. Sokal risk scores were balanced between treatment arms but higher in the overall older (8.9% low, 70.3% intermediate, 20.8% high) vs younger (44.1% low, 34.7% intermediate, 21.1% high) populations, reflecting that age is part of the score. Bosutinib was discontinued in 32.1% of older and 28.4% of younger patients; the most common primary reason was treatment-related adverse events (AEs; 18.9% and 15.3%, respectively). Imatinib was discontinued in 32.6% of older and 33.8% of younger patients, most frequently due to suboptimal response or treatment failure (13.0% and 13.2%, respectively). The percentage of patients who discontinued treatment due to treatment-emergent AEs (TEAEs) was similar in the older vs younger group in both arms (bosutinib: 22.6% vs 19.1%; imatinib: 8.7% vs 12.3%). In older vs younger patients, median (range) duration of treatment was similar: 24.8 months (0.3-33.3) vs 24.9 months (0.3-33.5) for bosutinib and 25.6 months (2.9-33.1) vs 24.5 months (0.7-33.4) for imatinib. Median relative dose intensity was slightly lower in older vs younger patients in the bosutinib arm (92.8% vs 99.3%) but was 100% in both age groups in the imatinib arm. The difference in rates of major molecular response (MMR) at 12 months (primary endpoint) with bosutinib vs imatinib was consistent across age groups (older: 43.4% vs 35.4%; younger: 47.4% vs 36.4%; P=0.7879 for test of interaction), as was the difference in rates of CCyR by 12 months (older: 68.8% vs 69.0%; younger: 79.3% vs 65.8%; P=0.1689). MR rates at 24 months (and MR1 at 3 months) were generally similar in older vs younger patients within each arm and higher with bosutinib than with imatinib (Table 1). Time to achieve MMR on bosutinib was not different in older vs younger patients (hazard ratio: 1.227; P=0.2380, after adjustment for baseline and time-dependent covariates in a multivariable proportional subdistribution hazards model). Rates of common TEAEs in each treatment arm were similar (<10% difference) between age groups, except for higher rates of anemia, rash, and decreased appetite in older patients in the bosutinib arm; higher rate of pruritus in older patients in both arms; and higher rate of peripheral edema and lower rate of neutropenia in older patients in the imatinib arm (Table 2). In older vs younger patients in the bosutinib arm, there were higher rates of grade 3/4 TEAEs (75.5% vs 61.4%), serious TEAEs (39.6% vs 23.3%), and dose delays (69.8% vs 58.1%) and reductions (52.8% vs 37.2%) due to TEAEs. In older vs younger patients in the imatinib arm, rates of grade 3/4 TEAEs (43.5% vs 47.9%), and dose delays (39.1% vs 38.8%) and reductions (23.9% vs 21.5%) due to TEAEs were similar, but the rate of serious TEAEs was higher (28.3% vs 16.9%). Conclusions: In the phase 3 BFORE trial, bosutinib showed clinical activity in older and younger patients with newly diagnosed CP CML. Difference in rates of MMR at 12 months for bosutinib vs imatinib was consistent in older and younger patients. MR rates at 24 months were similar in older and younger patients and higher with bosutinib than with imatinib. Although the incidence of grade 3/4 TEAEs, serious TEAEs, and dose modifications due to TEAEs were higher in older vs younger bosutinib-treated patients, treatment discontinuation rates were similar between age groups, suggesting that, regardless of patient age, TEAEs were manageable with bosutinib. Disclosures Deininger: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Kota:Pfizer: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Lipton:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Milojkovic:Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. García Gutiérrez:Incyte: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Leip:Pfizer: Employment, Equity Ownership. Nick:Pfizer: Employment, Equity Ownership. Hochhaus:Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Gambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Cortes:Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Brummendorf:Merck: Consultancy; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding.

A Phase I Study of Bendamustine Combined with Lenalidomide and Dexamethasone in Patients with Refractory or Relapsed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1856-1856 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Amy O’Sullivan ◽  
Silvana Lalo ◽  
Carrie Kruppa ◽  
Diane Gardner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Advisory Board ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1856 Poster Board I-882 Background: Lenalidomide is an analog of thalidomide that has shown significant clinical activity in patients with relapsed or refractory multiple myeloma (MM), both as a single agent and in combination with dexamethasone. Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. Bendamustine combined with lenalidomide may be an effective treatment option for MM patients, particularly those with preexisting or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable stage 2 or 3 MM that was refractory to or progressed after 1 or more prior therapies, including lenalidomide, received bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as determined by the IBMTR/ABMTR, was reached. Study drug doses were escalated through 4 levels (Table), with 3–6 patients enrolled at each level depending on the rate of dose-limiting toxicity (DLT). After determining the MTD, up to an additional 12 patients will be enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: To date, 11 patients have been enrolled, with a median age of 63 years (range, 38–75 years). The MTD of bendamustine and lenalidomide has not been identified at this point; currently, patients are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, DLT included 1 grade 4 neutropenia at dose level 2. Nine of 11 patients are currently eligible for response assessment. A partial response was observed in 67% of patients, including 1 very good partial response and 5 partial responses (PR). Two patients experienced stable disease and 1 exhibited progressive disease. Grade 3/4 adverse events included grade 3 neutropenia, thrombocytopenia, anemia, hyperglycemia, and prolonged QTC, and 1 grade 4 neutropenia. Conclusions: Bendamustine, lenalidomide, and dexamethasone form a well-tolerated and highly active regimen even in heavily pretreated MM patients, with a PR rate of 67%. Additional updates on response and MTD will be available at the time of presentation. Disclosures: Lentzsch: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bendamustine is not FDA approved for the treatment of multiple myeloma in the USA. Burt:Millennium: Honoraria; Celgene: Honoraria. Mapara:Resolvyx: Consultancy, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Gentium: Equity Ownership; Celgene: Spouse is consultant , has received research funding, and participates on advisory board; Cephalon: Spouse has received funding for clinical trial and participates on advisory board. Redner:Biogen: Equity Ownership; Wyeth: Equity Ownership; Glaxo-Smith-Kline: Equity Ownership; Pfizer: Equity Ownership; Genzyme: Membership on an entity's Board of Directors or advisory committees. Roodman:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Zonder:Amgen: Consultancy; Pfizer: Consultancy; Cephalon: Consultancy; Millennium: Consultancy, Speaking (CME only); no promotional talks.

A Phase I/II Study of Lenalidomide in Combination with Rituximab in Relapsed/Refractory Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2719-2719 ◽  
Author(s):  
Luhua Wang ◽  
Luis Fayad ◽  
Fredrick B. Hagemeister ◽  
Sattva Neelapu ◽  
Felipe Samaniego ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Employment Equity ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2719 Poster Board II-695 Background: Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods: Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results: The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion: Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures: Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

The Novel, Investigational NEDD8-Activating Enzyme Inhibitor MLN4924 In Adult Patients with Acute Myeloid Leukemia (AML) or High-Grade Myelodysplastic Syndromes (MDS): A Phase 1 Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 658-658 ◽  
Author(s):  
Ronan T Swords ◽  
Harry P Erba ◽  
Daniel J DeAngelo ◽  
Peter G Smith ◽  
Michael D Pickard ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Febrile Neutropenia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
High Grade ◽  
The Novel ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Phase 1 Study ◽  
Acute Myeloid

Abstract Abstract 658 Background: NEDD8-activating enzyme (NAE) regulates the NEDD8 conjugation pathway, and is required for the activity of the cullin-RING E3 ligases (CRLs). CRLs control the timed degradation of several substrates involved in cell-cycle regulation, signal transduction, DNA replication, and stress response, including proteins important for the survival of AML cells. We evaluated the preclinical anti-leukemic activity of MLN4924, a novel, investigational, first-in-class small molecule inhibitor of NAE, and based on the activity of MLN4924 in preclinical AML models (Swords RT et al, Blood 2010) we conducted a phase 1 study to evaluate the safety and tolerability of this agent in patients with AML and advanced MDS. Methods: The primary objectives of this study were to evaluate the safety and tolerability of MLN4924, to establish the maximum tolerated dose (MTD), and to determine the recommended phase 2 dose of MLN4924 in patients with AML and high-grade MDS. Secondary objectives included a preliminary assessment of efficacy, and analysis of pharmacokinetics and pharmacodynamics (via NAE-regulated proteins in peripheral blood mononuclear cells). Patients aged ≥18 years, with ECOG performance status 0–2, who had AML or high-grade MDS, and who were not candidates for potentially curative therapy, were eligible. MLN4924 was administered as a 60-minute IV infusion on days 1, 3, and 5 of a 21-day cycle for up to 12 months or until documented disease progression. Dose escalation was commenced at 25 mg/m2 and proceeded using a standard 3+3′ escalation method until the MTD was established. Response assessment was based on recently published guidelines (Döhner H et al, Blood 2010) and adverse events (AEs) were graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v3.0 (NCI Cancer Therapy Evaluation Program, 2006). Results: To date, 15 patients (9 males, 6 females; 14 AML, 1 high-grade MDS) have been enrolled and treated, including 3, 4, 3, 3, and 2 at dose levels of 25, 33, 44, 59, and 78 mg/m2, respectively. Median age was 62.3 years (range 29.3–84.0 years). By cytogenetics, 1 (7%), 5 (33%), and 7 (47%) patients had good-, intermediate-, and poor-risk disease (not available in 2). Prior antineoplastic therapies included cytarabine (n=7), azacitidine, daunorubicin (n=3 each), decitabine, etoposide, gemtuzumab, idarubicin, and mitoxantrone (n=2 each). To date, 3 patients have received ≥8 cycles; 6 remain on treatment. Two dose-limiting toxicities have been reported at the 78 mg/m2 dose level: one patient with multi-organ failure in Cycle 2, and one with reversible elevation of alanine aminotransferase in Cycle 1. The most common AEs were pneumonia (n=6), atelectasis, constipation, diarrhea, and febrile neutropenia (each n=4); most common grade ≥3 AEs were febrile neutropenia (n=4), elevated aspartate aminotransferase, and pneumonia (each n=3). Three patients have achieved a complete response (CR) to date. A 29-year-old woman with relapsed AML following allogeneic stem cell transplantation achieved a CR after cycle 1 at 25 mg/m2 before developing progressive disease at an extramedullary site during cycle 8. An 82-year-old man with history of high-risk MDS, which was unresponsive to azacitidine, that evolved into AML had a partial response in cycle 8 and a CR with incomplete recovery of blood counts (CRi) in cycle 10 at 33 mg/m2; the patient is currently in cycle 12 and has become transfusion-independent. A 71-year-old man with de-novo AML refractory to standard cytarabine plus daunorubicin induction achieved a CRi during cycle 1 at 44 mg/m2; although this was not maintained, the patient continued to benefit from treatment and is currently in cycle 11 with reduced transfusion dependence. Pharmacodynamic data are available for 9 patients; 7 show evidence of target inhibition in peripheral blood by changes in NAE-regulated proteins. Conclusion: The preliminary findings of this study indicate that the novel mechanism of action of MLN4924 through NAE inhibition results in observed activity in patients with relapsed or refractory AML, and suggest the successful translation of preclinical research in AML models into the clinic. Enrollment continues in expanded cohorts of AML and MDS patients at 59 mg/m2. Updated efficacy and safety data will be presented, together with data on MLN4924 pharmacokinetics and pharmacodynamics. Disclosures: Off Label Use: Investigational agent in clinical development for the treatment of acute myeloid leukemia or myelodysplastic syndromes. Erba:Millennium Pharmaceuticals, Inc.: Research Funding. DeAngelo:Deminimus: Consultancy. Smith:Millennium Pharmaceuticals, Inc.: Employment. Pickard:Millennium Pharmaceuticals, Inc.: Employment. Dezube:Millennium Pharmaceuticals: Employment, Equity Ownership. Giles:Millennium Pharmaceuticals, Inc.: Research Funding. Medeiros:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.

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