ALBERT

Description: Background: Standard chemotherapies for relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) are often unsuccessful. Pre-treatment ("priming") with hypomethylating agents such as decitabine has been shown to sensitize AML cells to chemotherapeutics, prompting a phase 1/2 study (NCT01729845) of MEC preceded by decitabine priming (d/MEC) in relapsed/refractory AML/MDS. Methods: Patients ≥18 years with relapsed/refractory AML or high-risk MDS (〉10% blasts) requiring first or subsequent salvage therapy were eligible if they had adequate organ function and a treatment-related mortality (TRM) score of

Description: Background: Although some adults with AML or high-risk MDS will experience long-term disease-free survival after initiation of curative-intent therapy, most patient will require therapy re-induction therapy either for primary induction failure of disease recurrence after an initial complete remission (CR) was achieved. The outcomes with standard regimens for relapsed/refractory AML are generally poor, with CR rates often not exceeding 15-20%. Data from a large single arm phase 2 study in poor-risk relapsed/refractory AML suggested tolerability and encouraging activity of a combination of G-CSF, cladribine, cytarabine, and mitoxantrone (G-CLAM). Given recent data suggesting benefit of escalated doses of anthracyclines in AML, the goal of our phase 1 study was to determine the maximum tolerated dose (MTD) of mitoxantrone within G-CLAM in adults with relapsed/refractory AML or high-risk MDS and estimate the efficacy of this regimen. Patients and Methods: Adults ≥18 years of age with relapsed or refractory AML (APL excluded) or high-risk MDS (〉10% blasts) were eligible if they had a treatment-related mortality (TRM) score of ≤6.9 (corresponding to a risk of early death with standard induction chemotherapy of ≤3%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5-times upper limit of normal). Excluded were patients with concomitant illness with expected survival 7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia or infection or constitutional symptoms, if recovery to grade ≤2 within 14 days. Results: 26 patients (14M, 12F), median age 57 (range: 37-77) years, median TRM score 1.73 (range: 0.29-3.92) with relapsed/refractory AML (n=23), or high-risk MDS (n=3) and cytogenetically favorable (n=2), intermediate (n=13), and adverse (n=11) disease characteristics were enrolled. One DLT occurred at dose level 1 (nausea) and 2 at dose level 4 (encephalitis and cardiogenic shock), establishing G-CLAM with mitoxantrone at 16 mg/m2/day as the MTD in our study. 2 patients (8% [95% exact confidence interval: 1-25%]) died within 28 days of treatment initiation from sepsis and cardiogenic shock, respectively. Overall, 13/26 patients (50% [30-70%]) achieved a CR (n=8) (31% [14-52%]), CRp (n=1) (4% [0-20%]), or CRi (n=4) (15% [4-35%]) with 1-2 cycles of re-induction therapy; one patient each achieved a leukemia-free state and partial remission (in a patient presenting with myeloid sarcomas); nine patients (35% [17-56%]) had persistent disease. We were unable to assess response in 2 patients due to early death (n=1) and refusal for marrow re-assessment (n=1). 7/13 responders (54%) had no evidence of residual disease by flow cytometry at best response. Among responders, median times to an absolute neutrophil count ≥500/µL and a platelet count of 50,000/µL were 33 (range: 17-51) and 31 (range: 18-54) days, respectively. Besides infections and neutropenic fever, nausea, hypoxia (fluid overload/infection-related), and maculopapular rash were the most common grade ≥3 adverse events. Conclusion G-CLAM with mitoxantrone up to 16 mg/m2/day is feasible, well tolerated, and effective in relapsed/ refractory AML/high-risk MDS. A phase 2 study based on these findings has been initiated. Disclosures Scott: Celgene Corporation: Consultancy, Speakers Bureau. Becker:Igenica: Research Funding. Walter:Pfizer, Inc.: Consultancy; Amgen, Inc.: Research Funding; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Covagen AG: Consultancy; AstraZeneca, Inc.: Consultancy.

Description: Abstract 3696 Poster Board III-632 Platinum based regimens such as ICE with or without Rituximab (RICE) have been widely used to treat relapsed or refractory lymphoid malignancies prior to transplantation. However, a significant portion of patients do not respond to treatment, and improved therapies are needed. Vorinostat (V) is an oral HDAC inhibitor with moderate toxicity and has clinical activity against a variety of tumors including cutaneous T cell lymphoma. Preclinical data demonstrated marked anti-tumor synergism between V and platinum analogues as well as etoposide. We present data from a phase I, open-label, multicenter, dose escalation study estimating the maximally tolerated dose of V that can be combined with RICE or ICE (V-RICE or VICE) in patients with relapsed or refractory lymphoid malignancies or untreated T- or Mantle Cell Lymphoma. Other endpoints include tolerability, exploratory anti-tumor activity and impact of above regimen on stem cell reserve. Patients (aged ≥18 years, an ECOG performance status of 0-2, measurable disease, no active central nervous system involvement, adequate bone marrow, hepatic and renal function, no active arrhythmias on EKG) were sequentially enrolled on escalating doses of V combination therapy using the “two stage” design introduced by Storer with single patient cohorts until a dose limiting toxicity (DLT) is observed, followed by cohorts of 4 patients. A DLT was defined as any gastrointestinal grade 3 NCI-CTCAE adverse event (AE) lasting longer than 7 days, or any related non-hematologic grade 4 or 5 AE; any event that prevents the completion of one full cycle of therapy (5 days of V) due to toxicity from V; or any AE at the discretion of the principal investigator. Therapy consisted of V ranging from 400 mg daily to 700 mg BID days 1 to 5 in combination with standard RICE or ICE on days 3 to 5 every 21 days. A total of 18 patients have been enrolled on this study thus far (9 in stage 1, 9 in stage 2) and 14are fully evaluable to date, including: Hodgkin lymphoma (4), T-cell lymphoma (3); mantle cell lymphoma (2); diffuse large B cell lymphoma (2); follicular lymphoma (2), and chronic lymphocytic leukemia (1). Baseline characteristics (n=14) included: median age 55 (range: 33-67), male 10 (71%), stage III/IV 14 (100%), median number of prior therapies 2 (range: 0-6), elevated LDH 5 (35%), prior anthracycline 13 (93%), prior platinum 2 (14%), refractory diseases 5 (36%), relapsed diseases 8 (57%), untreated disease 1 (7%). A maximum V dose of 700 mg BID was attained in stage I (Table). The dose adjustment schema of stage II has ranged from 600 mg BID to 400 mg BID currently. Among the 14 evaluable patients, six received only1 cycle of treatment (3/5 patients declined the second cycle; 2/5 patients developed DLT), 8 completed 2 cycles. Eight of 14 (57%) patients experienced non-hematologic AEs≥ grade 3 with most common being nausea, vomiting, or diarrhea seen in 6 and grade 4 hypokalemia in 2. Twelve patients (86%) responded including 1 with complete remission (CR), 2 with unconfirmed CR, and 9 with partial responses. One patient had stable disease and one had disease progression. Nine of 12 patients (75%) who attempted peripheral blood stem cell collection following VICE/V-RICE were successful (〉5×106 CD34+/kg) Collectively, these findings indicate that the combination of vorinostat with RICE or ICE, is feasible and active in patients with lymphoid malignancies. Special attention should be given to the management of the frequent gastrointestinal AEs. Pending identification of the MTD, phase II evaluation of VICE or V-RICE regimen will be designed to formally define its efficacy. Table Summary of DLTs and responses at various dose levels Stage Dose level Dose n DLTs responses I 1 400 mg QD 2 0 PR(1); SD (1) 2 300 mg BID 1 0 PR (1) 3 400 mg BID 1 0 PD (1) 4 500 mg BID 2 0 PR (1); CR (1) 5 600 mg BID 1 0 PR (1) 6 700 mg BID 2 1 PR (2) II 5 600 mg BID 4 3 PR (1); CRu (3) 4 500 mg BID 1 1 PR (1) Total - - 14 5 12 (86%) Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4343 Background: Outcomes in relapsed/refractory AML are dismal. Given the high prevalence of multidrug resistance (MDR), many clinical studies have tested whether MDR reversal agents such as cyclosporine (CSA) could increase the efficacy of conventional chemotherapeutics but results have been inconsistent. More recently, HMG-CoA reductase inhibitors (e.g. pravastatin) have been investigated after demonstration that cholesterol synthesis inhibition can restore chemosensitivity of AML cells in vitro. As studies further suggested the HMG-CoA inhibitors could downregulate MDR function, we attempted to improve the efficacy of mitoxantrone and etoposide in patients with relapsed/persistent AML by combining CSA and pravastatin in a single-arm, open-label phase 1/2 trial. Patients and Methods: Adult patients with relapsed/refractory non-APL AML and a treatment-related mortality score of 180 days post-HCT. Planned treatment included induction and consolidation therapy with pravastatin, CSA, and increasing doses of mitoxantrone and etoposide. All patients received pravastatin 320mg PO every 6 hours on days 1–10. The starting dose level (level 1) used etoposide 60mg/m2/day and mitoxantrone 5mg/m2/day via continuous infusion on days 5–9. CSA started 6 hours before the first doses of mitoxantrone/etoposide; after loading with 6mg/kg over 2 hours and 4mg/kg over 6 hours, CSA was infused at 18mg/kg/day on days 5–9. CSA levels were monitored on Day 6 and 8 to maintain levels 48 hours except of febrile neutropenia (FN), infection, or hyperbilirubinemia; and 2) any Grade ≥4 non-hematologic toxicity except FN/infection, constitutional symptoms if recovery to Grade ≤2 within 14 days, and hyperbilirubinemia. An “adaptive” Bayesian phase 1–2 design that monitored both toxicity and response was used. The maximal acceptable rate of toxicity was 30%, the minimum acceptable rate of efficacy 20% (historical rate of 15% in this population), stopping when posterior probability 〉90%. A maximum of 45 patients would be treated in cohorts of 3. Results: Between October 2010 and February 2012, 10 patients (median age 52 [range 40–58] years) were treated, including 4 patients (all at dose level 1) who received therapy off protocol. Two patients had secondary AML, and 6 had complex cytogenetics. PS was 1 (7 patients) or 2 (3 patients). Average TRM score was 4.32 for on-study patients. All patients had received at least 2 prior regimens, and 7 received 3 prior therapies. One patient had undergone HCT. The average CSA level on Day 6 was 1,366.3ng/mL (range 713–2,082ng/mL) and 1,199.8ng/mL on Day 8 (range 526–1,593ng/mL). Efficacy (CR or CRi)/DLTs for on-study patients were: level 1 (n=3): 0/1 (grade 4 acute kidney injury); level 2 (n=3): 0/2 (grade 4 acute kidney injury; sepsis/multiorgan failure). Among the 7 patients treated at level 1, other toxicities included septic shock (n=1), FN (4), mucositis (2), and decreased left ventricular ejection fraction (1). One off-study patient achieved CR after 1 course and received 1 cycle of consolidation with pravastatin, etoposide, and mitoxantrone but experienced CNS relapse after CR duration of only 46 days. Based on the results of the on-study patients, the statistical monitoring mandated early study closure for lack of efficacy & excessive toxicity. Conclusion: In the targeted, heavily pretreated patient population, the study regimen was excessively toxic and failed to achieve acceptable efficacy. Further clinical testing, if any, should be limited to less heavily pretreated, otherwise “fit” patients with AML. This trial was registered at ClinicalTrials.gov as NCT01342887. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (〉10% blasts). Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival 7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms. Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

Description: Background: Most adults with AML or high-risk MDS will ultimately require salvage therapy. However, the likelihood of achieving a complete remission (CR) with standard salvage regimens is often 15-20% or less. Emerging data suggest that pre-treatment (“priming”) with a hypomethylating agent such as decitabine can sensitize AML cells to chemotherapeutics, prompting a dose-escalation study of MEC preceded by decitabine-priming in relapsed/refractory AML and high-risk MDS. Methods: This single arm study aimed to estimate the maximum tolerated dose (MTD) of decitabine-primed MEC in adults ≥18 years with relapsed/refractory high-risk MDS (〉10% blasts) or AML requiring first or subsequent salvage therapy. Previous treatment with hypomethylating agents or MEC (but not the combination) was acceptable. Trial participation required a treatment-related mortality (TRM) score of

Description: Abstract 3650 Background: Traditional salvage strategies for relapsed lymphoma are less effective when disease recurs after modern front line therapies (e.g. R-CHOP, BEACOPP). Furthermore, typical multi-agent regimens require inpatient hospitalization and carry the risk of significant non-hematologic toxicity from drugs such as ifosfamide, high-dose cytarabine, and cisplatin. Bendamustine (Treanda ®, T) has both broad spectrum clinical activity in lymphoma and a moderate side effect profile, though limited data exist on the utility of this agent as part of a dose-intense rescue approach. We, thus, hypothesized that bendamustine could safely supplant ifosfamide within the RICE regimen yielding a feasible, effective, outpatient multi-agent salvage strategy (TREC) for patients with relapsed or refractory lymphoma. Methods: Eligibility included: relapsed/refractory lymphoma (untreated T-NHL or MCL was allowed during stage 1), age ≥18 years, performance status of 0–2, measurable disease, no active CNS involvement, ANC 3 1,500/μL, platelets 3 100,000/μL, adequate hepatic and renal function, no active arrhythmias, and no known HIV. The primary objective of the study was to define a maximally tolerated dose (MTD) of bendamustine associated with a dose limiting toxicity (DLT) rate of ≤25%. A DLT was defined as any related non-hematologic grade ≥4 adverse event (AE), or inability to complete one full cycle of therapy due to toxicity. Therapy was delivered in the outpatient setting and consisted of bendamustine ranging from 60 mg/m2 to 120 mg/m2 daily on days 1 and 2 in combination with carboplatin (AUC = 5 on day 1), etoposide (100 mg/m2 on days 1 to 3) and rituximab (375 mg/m2, for CD20+ disease only on either day 2 or 3) every 21 days for up to 2 cycles with G-CSF support. Single patient dose escalation occurred until a DLT was observed, followed by cohorts of 4 patients up to a maximum dose of 120mg/m2 × 2. Response was measured by standard criteria (Cheson 2007). AEs were graded using the CTCAE v4.0 Results: Twenty-four patients were treated, 4 in stage 1, and 20 in stage 2 with no DLTs observed. Baseline features included median age = 58 (range 18 – 72) years, median prior therapies = 1 (range 0 – 2), and refractory to last regimen = 16 (of 22 evaluable, 73%). All B-NHL patients had disease progression following prior rituximab. Histologies included Hodgkin lymphoma (HL, n = 8), diffuse large B-cell (DLBCL, n = 9), mantle cell (n = 2), T-NHL (n = 2), follicular (n = 2), and lymphoplasmacytic lymphoma (n = 1). Twenty-three patients received 2 cycles and one received 1 cycle due to disease progression. All cycles were given in the outpatient settings. Thirteen non-hematologic AEs ≥ grade 3 (SAEs) were observed in 9 patients. The most common related SAEs were dehydration (2), and febrile neutropenia (2). Responses were observed in 16 patients (67%) with 9 CR, and 7 PR. Response rates in HL and DLBCL were 88% (6CR, 1PR), and 56%. Mobilization of peripheral blood stem cells (PBSC) was successful in all 15 attempts immediately following the second cycle of T(R)EC (median yield: 5.58×106CD34/kg, range 3.96 – 11.68). At the last update with a median follow up of 8 (range 2 – 18) months, 19 (79%) patients are alive, and 13 (54%) are progression free, including 10 of 12 who subsequently underwenttransplant. Conclusions: This multicenter phase I trial confirms the ability to safely replace ifosfamide with 120mg/m2 × 2 of bendamustine, yielding the TREC regimen for patients with relapsed/refractory lymphoma. The outpatient administration, manageable toxicity profile, effective use for PBSC mobilization, and preliminary response data are encouraging. These data support future evaluation of TREC, including our ongoing expansion cohorts further investigating outcomes in patients with DLBCL and HL. Disclosures: Budde: Teva: Research Funding. Gopal:TEVA: Research Funding.