scholarly journals Decitabine Followed By Clofarabine, Idarubicin, and Cytarabine (DAC-CIA) in Relapsed/Refractory Acute Myeloid Leukemia (AML)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2817-2817 ◽  
Author(s):  
Nitin Jain ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Gautam Borthakur ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Advisory Board ◽  
Entire Group ◽  
Cell Transplant ◽  
Trisomy 8 ◽  
Npm1 Mutation ◽  
Hypoplastic Marrow ◽  
Grade 3 ◽  
Refractory Aml

Abstract Background: Patients with relapsed/refractory AML have dismal outcomes with currently available chemotherapy regimens. Preclinical and clinical evidence suggests that the use of hypomethylating agents such as decitabine prior to standard chemotherapy may be synergistic (Benton et al. BJH 2014, Qin et al. CCR 2007; Scandura et al. Blood 2011). Methods: Patients aged ≥18 to 65 years with relapsed/refractory AML (up to salvage 2) were enrolled in this investigator-initiated trial (NCT01794702). Other eligibility criteria included ECOG PS 0-2 and adequate organ function. Chemotherapy regimen consisted of Induction cycle with decitabine (20 mg/m2 IV days 1-5), clofarabine (15 mg/m2 IV days 6-9), idarubicin (10 mg/m2 IV days 6-8), and cytarabine (1 gm/m2 IV days 6-10). Consolidation cycle consisted of decitabine (20 mg/m2 IV days 1-5), clofarabine (15 mg/m2 IV days 6-8), idarubicin (8 mg/m2 IV days 6-7), and cytarabine (1 gm/m2 IV days 6-8). Results: Fifty-Fourpatients (female, n=16) have been treated. Median age was 44 years (range 20-66). Majority of the patients (29/54, 54%) were in salvage 1. Cytogenetics were diploid (n=25), complex (n=15), CBF (n=5), 11q23 abnormality (n=2), trisomy 8 (n=2), inv 3 (n=2), misc (n=3). Six patients had a TP53 mutation and 6 patients had an NRAS mutation. Seven patients had NPM1 mutation. No patient had a FLT3 ITD or D835 mutation. Median number of cycles administered was 1 (range 1-3). Grade 3 mucositis was seen in 2 patients and grade 3 transaminitis in 8 patients. Thirty-three patients had one or more infections. Early deaths occurred in 4 (7%) patients within 4 weeks, and 8 (15%) patients within 8 weeks. Twenty six (48%) patients achieved CR/CRi (Table 1). Median time to CR was 42 days. An additional 3 patients had a >50% decrease in bone marrow blast count (bone marrow response) and an additional 3 patients had aplastic/hypoplastic marrow at the end of induction. Patients younger than 40 years had a significantly increased likelihood of achieving a CR/CRp/CRi (71% vs. 33%, p = 0.01) (Table 2). Eighty percent of patients with CBF AML and 64% of patients with diploid cytogenetics achieved a CR/CRp/CRi. CR rate in patients with complex cytogenetics was 20%. Twenty-five (46%) patients underwent allo-SCT (20 CR/CRp/CRi, 2 with 50% marrow blast reduction, 3 with aplastic/hypoplastic marrow). 13/21 (62%) patients younger than 40 years of age were able to undergo allo-SCT as compared to 12/33 (36%) of patients 40 years of older (p = 0.09). Ten patients have relapsed (including six after allo-SCT). Twenty patients are alive (13 after stem cell transplant, 1 is still on study, 4 are receiving further salvage regimens after DAC-CIA failure, 2 lost to follow-up). Median survival of the entire group is 6.0 months (figure 1). Conclusions: The sequential treatment of decitabine followed by chemotherapy is safe and effective with a CR/CRp/CRi rate of 48% and with 25/54 (46%) patients able to proceed to an allo-SCT. Disclosures Jain: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; Incyte: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Novimmune: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Infinity: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; BMS: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Kiromic: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding. DiNardo:Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Results of A Phase I Study of Ruxolitinib in Patients (pts) with Relapsed/Refractory Acute Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3617-3617
Author(s):  
Naveen Pemmaraju ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Tapan M. Kadia ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Phase I ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Median Number ◽  
Trisomy 8 ◽  
Off Label ◽  
Common Grade ◽  
Grade 3 ◽  
Refractory Aml

Abstract Abstract 3617 Background: Outcomes in the treatment of AML remain overall poor. Novel targeted approaches to therapy are warranted. Ruxolitinib is a potent JAK1 and JAK2 inhibitor recently approved in the US for treatment of intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia MF, and post-essential thrombocytopenia MF and is being actively investigated as treatment for pts with acute leukemia. Objectives: To determine safety, maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of ruxolitinib in treatment of relapsed/refractory acute leukemia pts (AML or ALL). Methods: We conducted a single-center prospective phase I clinical trial (n=27) in which 3 different dose levels were tested (mg, oral, BID): 50 (n=4), 100 (n=5), 200 (n=18) as continuous daily dosing. One cycle of therapy was defined as 28 days. Inclusion criteria: Age >14 years, relapsed/refractory AML or ALL, adequate organ function (ALT and/or AST ≤1.5x upper limit of normal and serum creatinine ≤2.5mg/dL, ECOG PS 0–2, at least 2 weeks from prior leukemia therapy with exception of hydroxyurea. Toxicities were defined with CTCAE criteria, v4.0. Results: A total of 27 pts with acute leukemias were enrolled. All but one pt had AML (one pt with B-ALL). Median age at diagnosis was 66 years (range 25–88 years). 14 pts (52%) were male. 11 pts (41%) were PS=2 at enrollment. 5 pts had splenomegaly at baseline (range 4–21 cm). Baseline median laboratory parameters included: Hb (g/dL)= 9.2 (7.9–10.9), platelet (109/L)=22(3–271), WBC (109/L) =4(0.3–42.8), Blast % (PB)=23(0–97), Blast % (BM)=56 (1–99). The pt with only 1% BM blasts prior to starting therapy had persistent AML represented by extramedullary disease requiring further treatment. Baseline cytogenetics: diploid (n=9), Trisomy 8 (n=1), −5/-7/both (n=8), abnormal 11q (n=1), miscellaneous (n=8). Baseline molecular mutations: JAK2V617F (n=5), NRAS (n=3), MPL (n=1), FLT3-ITD (n=1), NPM1 (n=1), CEBPA (n=1), IDH2 (n=1), DNMT3a (n=1). Majority of pts (23 pts, 85%) were treated in salvage 2 (S2) or beyond: S2-S3 (n=11), ≥S4 (n=12). 7 pts had a prior non-leukemia malignancy (mantle cell lymphoma, breast, colon, lung, prostate, melanoma, T-cell lymphoma), all 7 of whom required prior chemotherapy, radiation, or surgery. 16 pts had prior diagnosis of either MPN or MDS. Median number of treatment cycles on protocol was 2 (range 1–4). Among 27 pts enrolled, 12 pts were found to be evaluable for DLT-assessment, responses below in Table. Only one pt required a dose reduction during study period (during cycle 3, from 200mg BID to 150mg BID in setting of drug-related Grade 3 thrombocytopenia). Most common Grade ≥3 non-hematologic event was infection (n=17)(most commonly pneumonia (n=9); most commonly occurring at 200mg po BID dosing level (8/17, 47%), followed by stroke (n=2), cerebral edema (n=1), fatigue (n=1), mucositis (n=1), elevation of alkaline phosphatase (n=1). 1 pt had CRp at 200mg po BID dosing (68 year old AML pt, received 6 prior AML therapies, Trisomy 8-positive, JAK2 mutation negative; achieved CRp after 2 cycles and was on study for total of 3 cycles). Among the 5 JAK2-positive pts, 4 were evaluable for response; median number of cycles was 1(range 1–3) and no CR/CRp were noted among this group. Conclusion: In this heavily pre-treated cohort of acute leukemia pts, 1 CRp was noted at highest dosing level (200mg po BID), in a relapsed/refractory AML pt, however this response was short (1 cycle). Most common grade ≥3 non-hematologic event during study period was infection, with pneumonia being most commonly reported. Disclosures: Off Label Use: Ruxolitinib off label investigational drug. Cortes:Incyte: Research Funding. Ravandi:Incyte: Research Funding. Verstovsek:Incyte: Research Funding.

Cryotherapy Reduces Mucositis in Multiple Myeloma Patients Receiving High-Dose Melphalan Conditioning Prior to Autologous Stem Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4265-4265 ◽  
Author(s):  
Mabel Rodriguez ◽  
Nelly G. Adel ◽  
Sean Devlin ◽  
Sergio A Giralt ◽  
Heather Landau
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Research Funding ◽  
High Dose ◽  
Cell Transplant ◽  
Grade 3 ◽  
High Dose Melphalan ◽  
Hospital Days ◽  
Severe Mucositis

Abstract Abstract 4265 Background: High-dose melphalan (MEL) followed by autologous stem cell support has been an integral component of multiple myeloma (MM) therapy since the 1980's. In general, high-dose melphalan is well-tolerated however grade 3 and 4 mucositis has been reported in up to 75% of patients (Lilleby et al. Bone Marrow Transpl, 2006). The efficacy of cryotherapy in preventing mucositis was initially documented in patients receiving infusional 5- fluorouracil (Rubenstein et al. Cancer, 2004). It is presumed that vasoconstriction reduces exposure of the oral mucosa to chemotherapy. Due to similar pharmacokinetic properties of melphalan including its short half life, cryotherapy has been used in MM patients undergoing MEL and stem cell transplant (SCT) with small series and one randomized trial supporting its use (Lilleby et al. Bone Marrow Transpl, 2006). At Memorial Sloan-Kettering Cancer Center, ice chips administered for 30 minutes before, during and after melphalan administration was adopted in March 2011 for all MM patients receiving MEL (≥ 140 mg/m2). In this study we sought to determine if the incidence of mucositis has been reduced since instituting cryotherapy into our standard practice. Methods: We retrospectively identified MM patients who received MEL 140 or 200 mg/m2 prior to SCT between January 1, 2009 and June 12, 2012 using our pharmacy database and electronic medical record. We analyzed two groups of patients by date of SCT and confirmed that patients transplanted prior to 3/2011 did not receive cryotherapy while all others did. Mucositis grade was recorded as documented by medical staff or determined by the investigators using the CTCAE version 4 criteria. Disease and treatment characteristics were collected in addition to narcotic use, total parenteral nutrition (TPN) requirement, and days of hospitalization. Fisher's exact test was used to compare the proportion of patients with mucositis, severe mucositis (defined as grade 3 or higher) and those requiring patient controlled analgesia (PCA), by cryotherapy use. Logistic regression was used to adjust for prior radiation and the number of prior lines of therapy. The number of hospital days was compared using a t-test. Results: During the study period, 214 patients underwent one or more autologous SCTs for MM; for patients who had more than one, only the initial SCT was included in this analysis. Of 214 patients, 85 (40%) received cryotherapy of whom 34% developed mucositis compared to 47% who did not receive cryotherapy (P = 0.08). Grade 3 mucositis was seen in 2% and 16% of patients who did and did not receive cryotherapy respectively (P = 0.004). No patient in either group developed grade 4 mucositis. After adjusting for radiation and lines of prior therapy the association between grade 3 mucositis and cryotherapy remained significant (OR: 0.13 (0.02, 0.47); P = 0.01). PCA use was lower in patients who received cryotherapy (19%) compared to those who did not (37%) (P = 0.01), with the median duration of use being 5 days in both groups. TPN was not required for any patient. Hospital days were similar in both groups (P = 0.88). Conclusion: Cryotherapy administration at the time of high-dose melphalan reduces the incidence of severe mucositis and PCA use. Cryotherapy is readily available and should be offered to all MM patients receiving ≥ 140 mg/m2 of melphalan. Disclosures: Landau: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding.

scholarly journals Flotetuzumab (FLZ), an Investigational CD123 x CD3 Bispecific Dart® Protein-Induced Clustering of CD3+ T Cells and CD123+ AML Cells in Bone Marrow Biopsies Is Associated with Response to Treatment in Primary Refractory AML Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1410-1410 ◽  
Author(s):  
John E. Godwin ◽  
Carmen Ballesteros-Merino ◽  
Nikhil Lonberg ◽  
Shawn Jensen ◽  
Tarsem Moudgil ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Refractory Aml

Introduction The infiltration of immune cells into tumors has been associated with therapeutic effects in preclinical models and patients with cancer. In AML, we have previously reported that immune infiltrated TME is predictive of failure to cytotoxic chemotherapy, but associated with response to immunotherapy, specifically FLZ (Uy ASH 2018, Rutella ASH 2018). Furthermore, FLZ also affects immune infiltration in the TME (Rutella ASH 2018). NK cells play an important role in AML control (Ruggieri Science 2012). FLZ (MGD006/S80880) is a humanized DART® molecule that bridges CD123 on AML with CD3 on T cells and mediates anticancer activity via T-cell activation and cytolytic activity against the bound cancer cell. While this is well described in vitro, little evidence of this interaction is available in vivo. Methods Patients (pts) were treated on the recommended phase 2 dose (RP2D) of FLZ (multi-step lead-in dose followed by 500ng/kg/day, in 28-day cycles). We studied the bone marrow (BM) tissue samples for 6 primary refractory pts at baseline and after treatment. Response assessment was performed at day 25±3 days of each cycle. Serial BM samples were evaluated using 2 different staining panels (PD-L1, FoxP3, CD8, CD3, CD103 / CD123, CD3, CD57, CD16) on consecutive slides. Slides were stained using a Leica BondRx autostainer and fluorescence imaged using a Polaris Vectra 3 and analyzed using inForm software. A density-based clustering algorithm developed and run in QuPath was used to quantify CD3+ T cell clusters. Results Six pts with primary refractory AML were included in this report. Pts were heavily pretreated (median prior lines of therapy was 3, range 2-9), and had adverse cytogenetic risk (ELN 2017). Three pts had a complete remission (CR) after 1 cycle of therapy (CR, CRh, CRi), two went on the receive allogeneic stem cell transplant (HSCT). In baseline BM samples, CD3 and CD8 cell infiltrates were higher in CR vs non-responders (CD3+ 18.3% ±6.9 vs 9.3% ±1.8; CD8+ 9.4% ±3.5 vs 4.8% ±1.2; mean±SEM). Two of the three CR patients, who underwent HSCT, developed clusters (Figure 1) in their on-treatment biopsies with 65 and 22 clusters of an average of 34 and 17 T cells per cluster, respectively. All clusters in CR pts were found on or adjacent to CD123+ cells. The BM biopsy of the CR pt with no detected clusters had no unequivocal evidence of residual/recurrent leukemic blasts. This pt had their dose interrupted early due to non-treatment related AE (infectious complication) and did not receive a full cycle of treatment; the response was transient and the pt relapsed shortly thereafter. NK cells (CD57+CD16+) were increased in post treatment biopsies of CR vs non-responders (0.93 ±0.31 vs 0.27 ±0.13; mean±SEM) with the largest fold increase in CR (28 vs 9). Lastly, post treatment biopsy PD-L1 expression was higher in non-responders than CR (23% vs 16%) with non-responders exhibiting the largest fold change in total PD-L1+ cells (10.9 vs 2.2). Summary Consistent with its proposed mechanism of action, these data highlight for the first time, the dynamic induction of an increase in T-cell infiltration, and clustering around CD123 AML cells in the bone marrow microenvironment of two AML patients that responded to FLZ. In pts with resistance to FLZ (non-responders) PD-L1 induction was significantly higher indicating that in some pts treatment with sequential check point inhibitor could obviate this mechanism of resistance A trial combining FLZ with sequential administration of a PD-1 inhibitor (MGA012) is currently recruiting pts. Figure 1. Baseline and on-treatment IHC of BM biopsies of a FLZ-treated CR pt showing cluster formation following treatment. Disclosures Bifulco: Ventana: Other: advisory board; PrimeVax: Equity Ownership, Other: ScientificBoard; BMS: Other: Advisory Board; Providnece: Patents & Royalties: Imaging processing; Halio Dx: Other: advisory board. Wigginton:macrogenics: Employment, Equity Ownership; western oncolytics: Consultancy, Other: consultancy. Muth:MacroGenics, Inc.: Employment, Equity Ownership. Davidson-Moncada:MacroGenics, Inc.: Employment, Equity Ownership. Fox:Akoya: Research Funding; Bristol Myers Squibb: Research Funding; Definiens: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Research Funding; Ultivue: Membership on an entity's Board of Directors or advisory committees.

Clinical Activity of Azacitidine In Combination with the Oral mTOR Inhibitor Everolimus (RAD001) In Relapsed and Refractory AML: Interim Analysis of a Phase Ib/II Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3301-3301
Author(s):  
Andrew H Wei ◽  
Sonali Sadawarte ◽  
John Catalano ◽  
Anthony P. Schwarer ◽  
Sharon Avery ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Overall Response Rate ◽  
Mtor Inhibitor ◽  
Response Rate ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Phase Ib ◽  
Overall Response ◽  
Refractory Aml

Abstract Abstract 3301 Background Although the demethylating agent azacitidine has an established role in myelodysplastic syndromes and encouraging activity in oligoblastic acute myeloid leukemia (AML), information regarding its role in relapsed and refractory AML is still emerging. The French ATU reported an overall response rate (ORR; CR/CRi+PR) in relapsed and refractory AML of 11% (Itzykson et al. ASH 2009 #1054). In a similar population, azacitidine salvage therapy produced a CR/CRi rate of 19% (Ayari S, et al. ASH 2009 #2044). Rapamycin, an inhibitor of the AKT downstream target mammalian Target Of Rapamycin (mTOR), is reported to specifically target leukemic stem cells and orally bioavailable rapamycin derivatives, such as everolimus (RAD001), are in active clinical development. Clinical responses with single agent everolimus in relapsed, refractory AML, however, have been modest (Yee et al, Clin Cancer Research 2006 and Boehm et al, European Journal of Internal Medicine 2009). Aim Building on our experience combining everolimus with low dose cytarabine (submitted to ASH, 2010), we have sought to investigate the feasibility and preliminary efficacy of combining everolimus with azacitidine in relapsed and refractory AML. Methods Phase Ib/II open label dose escalation study. Patients were treated with azacitidine 75 mg/m2 s.c. daily on days 1–5 and 8–9 of each 28-day cycle with either 2.5, 5 or 10 mg everolimus orally on days 5–21 for a maximum of 12 cycles. Results This preliminary analysis includes 20 patients (M 14, F 6), median age 64 years (range 17–76) receiving 2.5 mg (n=6), 5 mg (n=12) or 10 mg (n=2) everolimus. 9 (45%) had chemotherapy refractory and 11 (55%) relapsed AML after 1 (n=8), 2 (n=10) or 3 (n=2) previous lines of therapy. 7/17 (41%) had poor risk and 10/17 (59%) intermediate risk cytogenetics. 6/19 (32%) had secondary AML. The overall response rate (ORR) in 14 evaluable patients was 36% (2 CR, 3 PR). Stable disease (SD) was observed in 7 (50%) patients and 2 (14%) had progressive disease. Absolute bone marrow blast reductions from baseline in the 5 responders ranged from 9 to 88% (Figure 1). Grade 3/4 non-hematologic toxicities are summarized as follows: 2.5 mg everolimus cohort- septicemia (n=1) and mucositis (n=1, dose limiting toxicity; DLT), 5 mg everolimus cohort- septic arthritis (n=1, DLT). Febrile neutropenia during the first cycle of therapy was reported in 5/20 (25%). Safety analysis in the 10 mg everolimus cohort is ongoing. With a median follow up of 82 days, 30 day mortality was 0%. Enrolment continues to a planned 40 patients. Of interest, 2 out of 3 patients with FLT3-ITD+ AML refractory to high-dose cytarabine and antracyclines, had a striking reduction in bone marrow blasts after commencing azacitidine + everolimus (2.5 mg) therapy, with the absolute blast count falling from 95% to 16% and 92% to 5%, respectively, and lasting for at least 5 months in both. One of these patients has so far proceeded to allogeneic stem cell transplant (allo-SCT). Another patient with 3rd relapse of AML after failing allo-SCT, achieved CR after 3 cycles of treatment with azacitidine + everolimus (2.5 mg) and remains in CR after 157 days. Conclusion In relapsed and refractory AML, azacitidine in combination with the mTOR inhibitor everolimus was well tolerated and demonstrates substantial clinical activity in this advanced AML population. Further evaluation of this promising combination is ongoing. Disclosures: Wei: Novartis: Advisory board, Research Funding; Celgene: Research Funding. Off Label Use: AML therapy. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants.

scholarly journals Phase 1 Dose Escalation Study of MDM2 Inhibitor DS-3032b in Patients with Hematological Malignancies - Preliminary Results

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 593-593 ◽  
Author(s):  
Courtney D DiNardo ◽  
Joseph Rosenthal ◽  
Michael Andreeff ◽  
Oleg Zernovak ◽  
Prasanna Kumar ◽  
...  
Keyword(s):  
Research Funding ◽  
Hematological Malignancies ◽  
Single Agent ◽  
Advisory Board ◽  
Wild Type ◽  
Plasma Exposure ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Dose Levels ◽  
Refractory Aml

Abstract Background:MDM2, a negative regulator of the tumor suppressor p53, is overexpressed in a number of cancers including hematological malignancies. Disrupting the MDM2-p53 interaction represents an attractive approach to treat cancers expressing wild-type functional p53, and the inhibition of MDM2 and antitumor activity with the small molecule DS3032b has been demonstrated in preclinical studies and in patients with solid tumors. Here, we report the initial results of the Phase I trial aimed at characterizing the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles and preliminary efficacy of DS3032b in in patients with hematological malignancies. Methods:This study (NCT02319369) is a dose escalation study of DS-3032b as an oral single agent with a starting dose of 60 mg and escalating through 90 mg, 120 mg, 160 mg and 210 mg dose levels guided by a modified continuous reassessment method using a Bayesian logistic regression model following escalation with overdose control principle. The drug was administered orally once daily (QD) in 21 of 28 days per cycle (QD 21/28). The patient population included relapsed/refractory AML and high-risk MDS. Results:Thirty eight subjects with relapsed/refractory AML or high-risk MDS were enrolled in the study in 5 dose levels; 60 mg (7 pts), 90 mg (6 pts), 120 mg (12 pts), 160 mg (8 pts) and 210 mg (5 pts). Twenty four (63%) subjects were males. The median age was 68.5 (range 30-88) years, with approximately two-thirds over 65 years. Thirty-seven of 38 patients were p53 wild type, and one subject had known pathogenic insertion mutation with an allele frequency of about 20%. DS-3032b was tolerated up to 160 mg QD in the 21/28 days schedule that was determined to be the maximum tolerated dose. All subjects experienced at least one treatment emergent adverse event (TEAE) of any grade, and 93% subjects experienced a grade ≥3 TEAE at a data cut off on May 2, 2016. The most common (≥20%) TEAEs of any grade regardless of attribution were nausea (73%), diarrhea (57%) vomiting (33%), fatigue (37%), anemia (33%), thrombocytopenia (33%), neutropenia (20%) hypotension (30%), hypokalemia (23%) and hypomagnesemia (20%). A total of 5 subjects experienced dose limiting toxicities; two subjects in the 160 mg cohort due to grade 3 hypokalemia and grade 3 diarrhea, and three subjects in the 210 mg cohort due to grade 3 nausea and vomiting, grade 2 creatinine elevation/ renal insufficiency, and grade 3 anorexia and fatigue.. Preliminary PK results showed plasma exposure (Cmax and AUClast) increased with dose; and approximately 2-fold drug accumulation was observed on Day 15 following the daily oral dosing. Increase in the serum levels of macrophage inhibitory cytokine (MIC-1) as a p53 target gene was used as a circulating pharmacodynamic biomarker, where magnitude of MIC-1 serum level increase corresponded with DS3032 plasma exposure. Clinical activity of single agent DS-3032b was observed from the reduction in bone marrow blasts by the end of cycle 1 (4 weeks) in 15 of 38 patients. Complete remission was observed in 2 subjects with AML; 1 subject each at 120 mg and at 160 mg, with a remission duration of >4 and >10 months, respectively. One subject with MDS achieved marrow CR with platelet improvement, of 4 months duration, at the 120 mg dose level. Of note, each of these three subjects developed a TP53 mutation while on treatment, two at the time of disease progression and one subject who remains in an ongoing response. Further evaluation of DS-3032b in rational combinations such as with hypomethylating agents is being planned. Conclusions: Disruption of MDM2-p53 interaction by DS-3032b appears to be a promising approach to treat haematological malignancies. MDM2 expression/amplification in leukemic blasts is being investigated as a potential predictor of response. Rational combinations with agents targeting different mechanistic pathways may offer the most promise for further development. Disclosures DiNardo: Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Zernovak:Daiichi Sankyo: Employment. Kumar:Daiichi Sankyo: Employment. Gajee:Daiichi Sankyo: Employment. Chen:Daiichi Sankyo: Employment. Rosen:Daiichi Sankyo: Employment. Song:Daiichi Sankyo: Employment. Kochan:Daiichi Sankyo: Employment. Limsakun:Daiichi Sankyo: Employment.

scholarly journals Updated Study Results of CX-01, an Inhibitor of CXCL12/CXCR4, and Azacitidine for the Treatment of Hypomethylating Agent Refractory AML and MDS

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3915-3915 ◽  
Author(s):  
Eric Huselton ◽  
Amanda F Cashen ◽  
John F. DiPersio ◽  
Meagan Jacoby ◽  
Iskra Pusic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Pilot Study ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Advisory Committees ◽  
Study Results ◽  
Equity Ownership ◽  
Grade 3 ◽  
Refractory Aml

Hypomethylating agents (HMAs) are standard first line therapy for patients with high risk MDS and older patients with AML. Outcomes for patients who do not respond or progress on HMAs are poor, and there are no standard treatment options for these patients. The interaction between leukemic blasts and the bone marrow microenvironment is thought to play an important role in disease pathogenesis and possibly chemotherapy resistance, so we hypothesized that blocking the CXCL12/CXCR4 axis with CX-01 may improve response rates to azacitidine in patients who have failed HMA therapy. CX-01 is a low molecular weight heparin derivative with minimal anticoagulant activity that binds CXCL12 as well as neutralizes PF4, a negative regulator of megakaryopoiesis. We report updated study results of a single institution a pilot study (NCT02995655) that enrolled patients with HMA-refractory (received 4 or more cycles of HMA without response or disease progression on HMA therapy) AML or MDS (INT-1 or greater). Patients received 7 day continuous infusion of CX-01 (0.25 mg/kg/hr) and azacitidine 75 mg/m2 daily days 1-7, in 28 day cycles. The primary objective of this trial was to assess the overall response rate (ORR). 20 patients were enrolled between May 2017 and February 2018. The median age was 74 years (range 62-88 years) and 35% were female. Nine patients had MDS and 11 had AML, with 7 patients having antecedent MDS and 2 having therapy-related AML. Half of the patients had high risk cytogenetic abnormalities and 3 had TP53 mutations. Patients had a median of 2 prior lines of therapy (range 1-3) with median of 6 prior cycles of HMA therapy (range 4-20). Only 4 patients had a confirmed response to prior HMA therapy. Of the 20 patients that were enrolled, 15 were considered evaluable for response with a bone marrow biopsy after cycle 2. Of the 5 unevaluable patients, 3 were removed from the trial before completing C1 due to transaminitis, discovery of a second primary malignancy, and an elevated PTT on day 2. One patient had grade 5 sepsis during C1, and another withdrew for unrelated reasons. As expected with azacitidine therapy in this patient population, hematologic toxicity was common with 16 instances of grade 3/4 neutropenia/leukopenia, 5 instances of grade 3/4 anemia, and 10 instances of grade 3/4 thrombocytopenia. Other common grade 3/4 adverse events were various infections (20), febrile neutropenia (13), hypertension (10), electrolyte disturbance (9), and transaminitis (3). Mild prolongations in PTT (22) and INR (7) were common, and there was one instance of grade 3 PTT prolongation, two instances of grade 3 epistaxis, and one instance of grade 3 hematuria. The incidences of bleeding were not thought related to CX-01 infusion. The 15 evaluable patients received a median of 3 cycles of CX-01 and azacitidine (range 2-9). Of 15 evaluable patients, there was 1 CR and 3 bone marrow CRs (mCR, with incomplete blood count recovery), 9 stable disease, and 2 progressive disease for an ORR of 27%. Of the 3 patients with a mCR after cycle 2, two had hematologic improvement of their neutrophil and platelet counts, respectively, by the end of cycle 4. A patient with stable disease also had hematologic improvement in platelets. The median OS of evaluable patients was 221 days (95% CI 179 days-not reached) and median overall survival was not significantly different between AML patients at 221 days and MDS patients at 248 days (p = 0.8). In this pilot study we demonstrated the feasibility of treating HMA-refractory AML and MDS with CX-01 and azacitidine. While this study is limited by its small sample size, we observed higher than expected response rate and favorable OS compared to historical controls. Figure Disclosures Cashen: Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. DiPersio:Incyte: Consultancy, Research Funding; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Magenta Therapeutics: Equity Ownership; Amphivena Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Consultancy. Jacoby:Celgene: Speakers Bureau; Novo Nordisk: Consultancy; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy.

scholarly journals Safety and Tolerability of Lurbinectedin (PM01183) in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2722-2722
Author(s):  
Kelly S. Chien ◽  
Christopher B. Benton ◽  
Ayalew Tefferi ◽  
José Rodríguez ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Advisory Committees ◽  
Genetics Research ◽  
Grade 3 ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract Background: Trabectedin is an FDA-approved DNA minor groove binder (MGB) that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB with pre-clinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Methods: Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3+3 study design. Two dosing schedules were used: 3.5 mg, 5 mg, 7 mg, or 6 mg on days 1 and 8 or 2 mg, 3 mg, 1 mg, or 1.5 mg for 3 consecutive days on days 1 to 3. Patients 18 years or older with a diagnosis of advanced, relapsed/refractory AML (non-acute promyelocytic leukemia) and MDS were eligible and treated on study. Eligible patients had adequate hepatic, renal, and cardiac function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Patients with uncontrolled infection, human immunodeficiency virus, cardiac and neurological disorders, or those who were pregnant were ineligible. Clinical trial information: NCT01314599. Results: Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the days 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n=11), febrile neutropenia/infections (n=4), pulmonary toxicity (n=2), and renal failure (n=2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and two patients a morphologic leukemia-free state. Most (n=30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31±14% (n=4) vs. 8±8% (n=16), respectively (P=0.04). Conclusions: Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients. Disclosures Rodríguez: PharmaMar: Employment. Ravandi:Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Sunesis: Honoraria. Daver:Sunesis: Consultancy; Alexion: Consultancy; Daiichi-Sankyo: Research Funding; BMS: Research Funding; ImmunoGen: Consultancy; Kiromic: Research Funding; Incyte: Research Funding; Pfizer: Consultancy; Incyte: Consultancy; ARIAD: Research Funding; Karyopharm: Consultancy; Pfizer: Research Funding; Karyopharm: Research Funding; Novartis: Consultancy; Sunesis: Research Funding; Novartis: Research Funding; Otsuka: Consultancy. Jain:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Verastem: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Astra Zeneca: Research Funding; Servier: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Cellectis: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Cellectis: Research Funding; Verastem: Research Funding; Servier: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: 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; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maiti:Celgene Corporation: Other: Research funding to the institution. Martinez:PharmaMar: Employment. Siguero:PharmaMar: Employment. Al-Kali:Novartis: Research Funding.

scholarly journals A Phase I Study of IDH305 in Patients with Advanced Malignancies Including Relapsed/Refractory AML and MDS That Harbor IDH1R132 Mutations

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1073-1073 ◽  
Author(s):  
Courtney D DiNardo ◽  
Aaron D. Schimmer ◽  
Karen W.L. Yee ◽  
Andreas Hochhaus ◽  
Alwin Kraemer ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Research Funding ◽  
Advisory Board ◽  
Employment Equity ◽  
Equity Ownership ◽  
Idh1 Mutations ◽  
Grade 3 ◽  
Refractory Aml

Abstract Introduction: Isocitrate dehydrogenase (IDH) enzymes catalyze the NADP-dependent interconversion of isocitrate and α-ketoglutarate. R132* IDH1 mutations lead to cellular accumulation of 2-hydroxyglutarate (2-HG), an oncometabolite that promotes tumorigenesis. IDH1 mutations are found in glioma (~80%), chondrosarcoma (~50%), cholangiocarcinoma (~20% intrahepatic), acute myeloid leukemia (AML; ~6-9%), and myelodysplastic syndrome (MDS; ~3%). IDH305 is a potent, orally available, mutant-selective, allosteric IDH1 inhibitor. IDH305 suppresses mutant IDH1-dependent 2-HG production and cell proliferation with an IC50 of 24 nM, and has antitumor activity in preclinical studies. Methods: The objectives of this ongoing phase I clinical trial in patients with advanced cancers are to evaluate the safety and tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, and preliminary antitumor activity of IDH305 (IDH305X2101, NCT02381886). This trial is specifically designed to evaluate the safety of IDH305 both across and within 3 broad disease areas: glioma, AML/MDS, and other/non-CNS solid tumors with the IDH1R132 mutation. IDH305 is orally administered twice a day (BID) in continuous 21-day cycles. The starting dose of 75 mg BID was determined from 4-week toxicology studies following ICH Guideline S9. Dose escalation is guided by a Bayesian hierarchical model (BHM), which evaluates the dose-limiting toxicity (DLT) relationship to the collective population, as well as to specific disease areas, across dose levels, to model the similarity in the rate of DLTs during the first cycle of treatment. The BHM permits the declaration of different maximum tolerated doses (MTDs)/recommended doses for expansion (RDEs) for 3 disease areas, if suggested by the data. Dose expansions in disease-specific cohorts are designed to further characterize safety and explore antitumor activity. Pre- and on-treatment specimens (blood, tumor) are being collected for PK and PD evaluations. Results: As of the data cut-off, March 30, 2016, 81 patients have been enrolled: glioma (n=32), AML (n=21), MDS (n=3), other/non-CNS solid tumors (n=24), and unknown (n=1). Patients were treated with IDH305 on a BID schedule at various doses: 75 mg (n=6), 150 mg (n=11), 300 mg (n=16), 450 mg (n=9), 550 mg (n=16), 750 mg (n=10), and 900 mg (n=13). During dose escalation, DLTs of Grade 3 elevated bilirubin were observed in 2 patients with solid tumors (2 at 550 mg BID), 1 patient with glioma (900 mg BID) who also experienced a DLT of Grade 3 elevated lipase, and 1 patient with AML (750 mg BID). A DLT of Grade 3 rash was observed in 1 patient with a solid tumor (750 mg BID). All DLTs resolved and were considered reversible. MTDs for each disease area were not determined. RDE was determined for glioma (550 mg BID) and solid tumors (550 mg BID). Dose escalation continues for AML/MDS. Across all 3 disease areas, the most common adverse events (AE) reported as suspected of being related to IDH305 (>10%, all grades) included: bilirubin increased (30.9%); aspartate aminotransferase (AST) increased (17.3%); alanine aminotransferase (ALT) increased (16.0%); and nausea (13.6%). Grade 3 AEs suspected to be related to IDH305 that occurred in >1 patient included: bilirubin increased (8.6%)/hyperbilirubinemia (2.5%); AST increased (2.5%); and ALT increased (3.7%). Among 24 AML/MDS patients (21 relapsed/refractory AML and 3 MDS), the most common suspected AEs reported as being related to IDH305 (>5%, all grades) included: raised bilirubin and lipase (8.3% each). There was one Grade 3 AE of increased bilirubin that was also a DLT. Objective responses were reported in 7 (33%) AML patients: complete remission in 2 (9.5%), complete remission with incomplete recovery in 1 (4.8%), and partial remission in 4 (19.0%) patients. Responses appear durable. PK, PD, and updated clinical safety and efficacy data will be reported. Conclusion: Preliminary clinical data suggest that IDH305 has a favorable safety profile and promising antitumor activity in IDH1-mutated AML. Studies to further evaluate the safety, tolerability, and antitumor activity of IDH305 as a single agent and in combination are ongoing. Disclosures DiNardo: Agios: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding. Schimmer:Novartis: Honoraria. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Carvajal:Novartis: Consultancy. Janku:Agios: Research Funding; Novartis: Consultancy, Research Funding. Bedard:Novartis: Research Funding. van den Bent:Novartis, Roche, AbbVie, Celgene, BMS: Consultancy. O'Keeffe:Novartis: Employment. Chen:Novartis Pharmaceuticals Corporation: Employment. Pagliarini:Novartis Institutes for Biomedical Research: Employment, Equity Ownership, Patents & Royalties. Schuck:Novartis: Employment. Myers:Novartis Institutes of Biomedical Research: Employment, Equity Ownership. Wei:Novartis: Honoraria, Research Funding.

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

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

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

scholarly journals Long Term Outcome of Lenalidomide-Dexamethasone (Rd) Vs Melphalan-Lenalidomide-Prednisone (MPR) Vs Cyclophosphamide-Prednisone-Lenalidomide (CPR) As Induction Followed By Lenalidomide-Prednisone (RP) Vs Lenalidomide (R) As Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 901-901
Author(s):  
Sara Bringhen ◽  
Massimo Offidani ◽  
Pellegrino Musto ◽  
Anna Marina Liberati ◽  
Giulia Benevolo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Community Based ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Grade 3 ◽  
To Receive

Abstract Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in >75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p<0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

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