Talon Therapeutics Research Articles

An Evaluation of Molecular Response in a Phase 2 Open-Label, Multicenter Confirmatory Study in Patients (pts) with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (r/r ALL) Receiving Treatment with the BiTE® Antibody Construct Blinatumomab

An Evaluation of Molecular Response in a Phase 2 Open-Label, Multicenter Confirmatory Study in Patients (pts) with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (r/r ALL) Receiving Treatment with the BiTE® Antibody Construct Blinatumomab

Bortezomib in Combination with Dexamethasone, Cyclophosphamide, Etoposide, and Cisplatin (V-DCEP) for the Treatment of Multiple Myeloma

IntroductionDespite therapeutic advances in multiple myeloma, disease relapse is common. Combination therapy with dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) has been utilized as an effective salvage regimen for over a decade, and a recent study reported that DCEP provided an overall response rate of 45.1% when used as salvage therapy in patients who had previously received novel agents (Park S, et al. 2014). Aside from hematologic toxicities, DCEP is generally well-tolerated. In fact, the toxicity profile of DCEP has been compared to high dose cyclophosphamide in the setting of stem cell mobilization and is considered less toxic than the latter. Based upon the synergy noted when proteasome inhibitors are combined with genotoxic therapy, we have combined bortezomib with DCEP in a series of relapsed myeloma patients. Herein we report our experience with the addition of bortezomib to DCEP in relapsed/refractory disease.Patients and MethodsWe performed a retrospective evaluation of patients with relapsed/refractory multiple myeloma treated at Emory University Hospital from October 2011 until March 2014. Patients received dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) at standard doses in combination with bortezomib at either a dose of 1 mg/m2 or 1.3 mg/m2 administered on Days 1 and 4 of each cycle given every 28 days. Indications for receiving V-DCEP are either cytoreduction prior to SCT (cohort 1) or as salvage therapy (cohort 2).ResultsAmong the 51 patients (49% male and 51% female) included in analysis, the median age at the time of diagnosis is 58 years (range 30-78) and the time of treatment with V-DCEP is 62 years (range 33-79). Among patients that received V-DCEP as cytoreduction prior to SCT, median prior lines of therapy were 1 (0-8). Among the patients that received V-DCEP as salvage therapy, median number of prior lines of therapy was 3 (1-6). ISS 3 disease was seen in 70% of patients and high risk disease in 72.5% of pts (del 17p: 31%; PCL: 19%; extramedullary disease: 33%; complex CTG: 11%) and t(4;14): 6%). Median time from diagnosis to initiation of V-DCEP therapy among cohort 1 is 18 months (0-86) and among cohort 2 is 31 months (12-105) months. Median serum creatinine before C1D1 is 1.17 (0.61-6) and serum bilirubin is 0.6 (0.1-2.8). 31% of patients needed dose reductions from our standard protocol due to organ dysfunction. 47% of patients received ≥2 cycles. The median time to next cycle is 28 days (20-46) and time to next treatment after V-DCEP is 35 days (25-451) suggesting good hematologic recovery. The overall response rate (≥PR) amongst both cohorts with V-DCEP is 47.8% (40% and 51.6% overall response for cohorts 1 and 2, respectively). Figure 1 illustrates response rates. 10 patients that presented with renal insufficiency had renal response including 2 of the 5 patients on hemodialysis. While the median PFS for cohort 1, as expected has not reached, for cohort 2, it is 8 months (95% CI 5.7-10.3). At a median follow-up of 17 months, from the time of V-DCEP initiation, median OS for cohort 2 is 10 months (95% CI 5-14.9). Median overall survival for this predominantly high risk group of patients from diagnosis in cohort 1 is 78 months (95% CI 47-108) and 49 (95% CI 17-80.7) months in cohort 2, respectively. While only 1 patient with grade 2 peripheral neuropathy (PN) received V-DCEP, change from baseline existing PN was seen in 19% of patients (no grade 3/4 events).ConclusionsDuring this era where minimizing alkylator therapy is a consideration, certain indications exist for using V-DCEP such as cytoreduction prior to SCT or as salvage therapy serving as bridge to next line of therapy. Addition of bortezomib to DCEP is deemed safe and is an effective cytoreductive regimen in the treatment of multiple myeloma. [Display omitted] DisclosuresGleason:Celgene: Consultancy; Novartis: Consultancy. Heffner:Amgen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Dana Farber CI: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Idera: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Spectrum: Honoraria, Research Funding; Talon Therapeutics: Honoraria, Research Funding. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Phase I Study of the Combination of Carfilzomib and Panobinostat for Patients with Relapsed and Refractory Myeloma: A Multiple Myeloma Research Consortium (MMRC) Clinical Trial

Introduction:Patients with myeloma ultimately become refractory to current therapies, requiring new approaches to treatment. Carfilzomib is a second generation proteasome inhibitor that has demonstrated significant activity in patients with relapsed and refractory disease. Panobinostat is a pan-deacetylase inhibitor that has been shown to be effective and overcome resistance in combination with bortezomib in refractory patients. In addition, patients treated with a combination of bortezomib/dexamethasone/panobinostat had a significant improvement in progression free survival (PFS) compared to bortezomib/dexamethasone alone. Based on preclinical data supporting combined HDAC and proteasome inhibition, we hypothesized that carfilzomib and panobinostat would be safe and effective in relapsed/refractory myeloma patients. Herein we report the initial findings of the MMRC multicenter phase I study of the combination.Methods:The primary objective is to determine the maximum tolerated dose (MTD) of the combination of panobinostat and carfilzomib using a standard 3+3 alternate dose escalation design with 4 cohorts. An additional 12 patient expansion group will be treated at the MTD to further assess the activity and safety of the combination. Secondary objectives are to evaluate the extended safety of this combination and to assess response, response duration and progression free survival (PFS). Panobinostat is administered orally three times weekly for three of four weeks, ranging from 15 to 20 mg. Carfilzomib is administered IV days 1, 2, 8, 9, 15, and 16, ranging from 20/27 mg/m2 to 20/45mg/m2. Cycles are repeated every 4 weeks. Dose limiting toxicities (DLT) are determined in the first cycle, and all adverse events are assessed according to CTCAE V4. Responses are assessed using IMWG criteria (plus MRs as per the EBMT criteria).Results:To date, 20 patients in four cohorts have been enrolled and all have completed the first cycle. Median age is 64.5 years (48-75). All patients had refractory and progressive disease; with a median number of 4) prior treatment lines. Three DLTs occurred. One patient had grade 4 thrombocytopenia with grade 3 acute kidney injury, one patient developed persistent grade 4 thrombocytopenia without bleeding and one patient had grade 3 diarrhea uncontrolled by maximal medical therapy. The MTD is panobinostat 20 mg and carfilzomib 20/36 mg/m2. The most common grade 3 toxicities were hematologic. Regardless of causality, grade 3 or higher anemia, thrombocytopenia and neutropenia occurred in 35%, 35%, and 20% of patients, respectively. The most common grade 3/4 or higher nonhematologic toxicities were fatigue (15%), anorexia (10%), hyponatremia (10%) and nausea (10%). The overall response rate is 50% with 30% PRs and 20% VGPR or better. The median PFS is 14.3 months.Conclusion:The combination of carfilzomib and panobinostat is well tolerated with no unexpected toxicities. Response, durability of response, and PFS are encouraging and warrant further study. DisclosuresKaufman:Millennium: The Takeda Oncology Co.: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Off Label Use: Carfilzomib treatment in amyloidosis . Zimmerman:Onyx: Honoraria. Heffner:Amgen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Dana Farber CI: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Idera: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Spectrum: Honoraria, Research Funding; Talon Therapeutics: Honoraria, Research Funding. Harvey:Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Research Funding; Acetylon: Research Funding; Amgen: Research Funding. Gleason:Celgene: Consultancy; Novartis: Consultancy. Lewis:Array BioPharma: Consultancy. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Vorinostat, Bortezomib, Cyclophosphomide, Thalidomide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients

The combination of vorinostat, a histone deacetylase (HDAC) inhibitor, is synergistic with proteasome inhibitors and IMIDs based upon preclinical and clinical data. Phase III trials with vorinostat in relapsed myeloma failed to demonstrate benefit due to excess toxicity that precluded chronic administration of the agent allowing patients to realize the clinical benefits. Herein we report on our experience combining vorinostat, or adding vorinostat to current treatments in the context of refractory myeloma.Methods: Forty RRMM pts that received vorinostat (V) (200mg orally daily on days 1-14) and bortezomib (B) (1.3 mg/m2 IV/SQ days 1,4,8, and 11) combinations, every 28 days from May 2008 until May 2014 at Emory University were reviewed. Cohort 1 consisted of 22 RRMM pts that received VBCyTD regimen (V,B, cyclophosphamide (Cy) (300 mg orally flat dose days 1, 8 and 15), thalidomide (T) (100 mg daily) and dexamethasone (D) 40 mg orally weekly), while cohort 2 consisted of 18 RRMM pts that received other combinations (VBCyD+lenalidomide (R): 4 pts; VBRD: 4 pts; VBCyD: 2 pts; VBD: 4 pts; VBTD: 4 pts and VCyTD+carfilzomib (Ca): 2 pts). The objectives are response assessment by IMWG criteria, progression-free survival (PFS) and overall survival (OS). Drug related adverse events (AEs) ≥grade 3 (CTCAE v3.0) were summarized.Results: Twenty-one males and nineteen females (median age at diagnosis: 56 years [range 28-89], median age at initiation of V treatment: 62 years [range 33-91]) that were heavily pretreated (median lines of therapy: 7 [range 3-14] were included in the analysis. Ninety-five percent of pts were B refractory and 85% pts were R refractory; 97.5% and 15% of pts underwent prior autologous and allogeneic SCT, respectively. High risk cytogenetic abnormalities were seen in 40% of pts. Time from diagnosis to initiation of V combination therapy is 58.5 months (range 18-138). The overall clinical benefit rate (≥SD) was 72.5%. Figure 1 illustrates response rates from both cohorts. Median PFS for cohort 1 is 3 months (95% CI 0.5-5.51) and for cohort 2 is 2 months (95% CI 0.8-3.2), respectively. At a median follow-up of 26 months from the time of V initiation, median OS for cohort 1 is 6 months (95% CI 0-13.6) and for cohort 2 is 3 months (95% CI 1.4-4.7). Median overall survival from diagnosis for these cohorts is 80 months (95% CI 70.2-89.8) and 70 (95% CI 55.6-84.4) months, respectively. ≥Grade 3 AEs include fatigue (15%); generalized weakness (12.5%); neutropenia (15%); and thrombocytopenia (35%).Conclusions: In heavily pretreated relapsed/refractory multiple myeloma patients with limited therapeutic options, vorinostat and bortezomib combination therapy offers clinical benefit with good response rates and acceptable tolerability, likely due to lower doses of vorinostat used. This data further supports the activity of HDAC inhibitors in the context of refractory myeloma. [Display omitted] DisclosuresGleason:Celgene: Consultancy; Novartis: Consultancy. Heffner:Amgen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Dana Farber CI: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Idera: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Spectrum: Honoraria, Research Funding; Talon Therapeutics: Honoraria, Research Funding. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

High-Dose Vincristine Sulfate Liposome Injection (Marqibo®) Is Not Associated With Clinically Meaningful Hematologic Toxicity

BackgroundThe treatment of hematologic malignancy patients with heavily pre-treated, advanced, relapsed, or refractory disease and those with advanced age, active infection, cardiovascular disease, recent surgery, or poor performance status may require therapies with limited hematologic toxicity and associated peripheral blood cytopenias. Cancer and concomitant chemotherapy related anemia, neutropenia, and thrombocytopenia in patients with hematologic malignancy complicate evaluation of hematologic toxicity related to new drugs. Vincristine sulfate liposome injection (VSLI; Marqibo®) is a new drug developed to optimize vincristine (VCR) pharmacokinetics and facilitate VCR dose-intensification and densification. VSLI is active in untreated and relapsed lymphomas, and was recently approved in the United States for relapsed and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. MethodsWe assessed the hematologic toxicity of VSLI 2.25 mg/m2 administered every 14 days (Cohort 1) or 7 days (Cohort 2) in 54 patients with metastatic uveal melanoma, a cancer not known to involve the bone marrow. Cohort 1 patients could have received 1 prior systemic therapy. Cohort 2 patients must not have received any prior systemic chemotherapy, immunotherapy, cancer vaccine, or hepatic arterial chemotherapy for metastatic disease. ResultsPatients in Cohort 2 received a higher median number of VSLI doses (6 vs. 4) over a shorter median time period (5.7 weeks vs. 8.7 weeks) resulting in a larger median cumulative exposure (22.6 mg vs. 17.7 mg) and near doubling of median dose density (4.0 mg/week vs. 2.2 mg/week) compared to patients in Cohort 1. Despite greater VSLI exposure and dose density, Cohort 2 had a smaller decrease from baseline in median neutrophil count and greater increase from baseline in median platelet count compared to Cohort 1. Both Cohorts experienced similar gradual decreases in hemoglobin concentration over time that were attributed to cancer-associated anemia and frequent blood sampling. Hematologic adverse events (AEs) were uncommon and mostly Grade 1 or 2. There were no Grade 4 hematologic AEs. ConclusionsVSLI at its approved dose resulted in a low incidence of clinically meaningful hematologic toxicity. A near doubling of median dose density did not have an impact on the reported incidence and severity of hematologic AEs. VSLI may be well suited for use alone or in combination with myelosuppresive drugs and in patients unable to tolerate peripheral blood cytopenias. Disclosures:Silverman:Talon Therapeutics: Employment. Deitcher:Talon Therapeutics: Employment, Equity Ownership.

Long Term Results Of a Phase 2 Study Of Vincristine Sulfate Liposome Injection (Marqibo®) Substituted For Non-Liposomal Vincristine In CHOP With Or Without Rituximab For Patients With Untreated Aggressive Non-Hodgkin's Lymphomas

IntroductionDespite significant advances over the past decade in the treatment of CD20+ aggressive Non-Hodgkin Lymphomas (NHL), such as Diffuse Large B-cell Lymphoma (DLBCL), outcomes, particularly in older patients with unfavorable prognositic features, remain unsatisfactory. Vincristine sulfate liposome injection (VSLI; Marqibo® M) is active as a single-agent and in combination with rituximab in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory Ph-negative adult acute lymphocytic leukemia. MethodsWe evaluated VSLI (2.0 mg/m2 without any dose cap) substituted for non-liposomal vincristine (VCR) in R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), creating R-CHMP in 60 patients with untreated DLBCL. The primary endpoint was overall response rate (ORR), defined as the proportion of patients that achieved a complete response (CR), unconfirmed CR (CRu), or partial response (PR). Secondary efficacy endpoints included progression free survival (PFS) and overall survival (OS). ResultsThe ORR was 95% (57/60) including CR in 54 (90%) patients and CRu in 1 (2%) patient. Median PFS and OS were not reached at median follow-up of 8 and 10.2 years, respectively. The 10-year PFS and OS were 64% and 87%, respectively. In the DLBCL patients over the age of 60 years, R-CHMP resulted in an ORR of 91%, 10-year PFS of 48%, and 10-year OS of 65%. In the DLBCL patients age >60 years with an age-adjusted International Prognostic Index (aaIPI) of 2-3, the ORR was 92% (all CR), median PFS was 118 months, and the 10 year PFS and OS were 27% and 50%, respectively.Despite median and maximum cumulative VSLI delivery of VCR of 22.8 mg and 35.2 mg, respectively, the safety profile of R-CHMP was comparable to that reported for R-CHOP. Grade 3 peripheral neuropathy (PN) was reported in 2 (3%) patients, there was no reported Grade 4 PN, and there was no reported Grade 3 or 4 constipation.Progression Free Survival % (95% CI)Overall Survival % (95% CI)Patient Group3 years5 years10 years3 years5 years10 yearsDLBCL Patients (n=60)81 (71-91)81 (71-91)64 (50-77)92 (85-99)87 (78-95)87 (68-89)Age ≤ 60 yrs (n=28)82 (68-96)82 (68-96)78 (63-94)96 (89-100)93 (83-100)93 (83-100)aaIPI 0-1 (n=26)85 (71-99)85 (71-99)81 (65-96)96 (89-100)92 (82-100)92 (82-100)aaIPI 2-3 (n=2)10050501005050Age > 60 yrs (n=32)80 (66-95)69 (52-86)48 (27-69)88 (76-99)81 (68-95)65 (48-82)aaIPI 0-1 (n=19)89 (75-100)70 (48-92)56 (32-81)95 (85-100)84 (68-100)74 (54-94)aaIPI 2-3 (n=13)67 (41-94)67 (41-94)27 (0-67)77 (54-100)77 (54-100)50 (21-79) ConclusionsR-CHMP (M = Marqibo) in patients with untreated DLBCL resulted in a high ORR and encouraging PFS and OS without apparent increased toxicity compared to historical experience with R-CHOP. In particular, elderly DLBCL patients with an unfavorable prognosis, based on aaIPI, experienced remarkable PFS and OS. These data compare favorably with previously reported studies in a comparable patient population. This enhanced activity likely reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A randomized Phase 3 cooperative group trial comparing R-CHMP versus R-CHOP in older patients with untreated DLBCL is ongoing. Disclosures:Off Label Use: Marqibo (VSLI) is approved for adults with Ph- relapsed/refractory acute lymphoblastic leukemia. Deitcher:Talon Therapeutics: Employment, Equity Ownership. Silverman:Talon Therapeutics: Employment. Sarris:Inex Pharmaceuticals (nowTekmira): Consultancy. Cabanillas:Inex Pharmaceuticals (nowTekmira): Consultancy.

Vincristine Sulfate Liposome Injection (Marqibo®) and Rituximab For Patients With Relapsed and Refractory Diffuse Large B-Cell Lymphoma Or Mantle Cell Lymphoma In Need Of Palliative Therapy

BackgroundDespite advances in combination immuno-chemotherapy and hematopoietic cell transplant (HCT) and improvements in long-term disease-free survival and cure rates for patients with diffuse large B-cell lymphoma (DLBCL) and other B-cell aggressive non-Hodgkin lymphomas (NHL), nearly half of patients will fail therapy and require disease palliation. Vincristine sulfate liposome injection (VSLI; Marqibo®) was developed to optimize vincristine (VCR) pharmacokinetics, dose-intensification, and target-tissue delivery. VSLI is active in relapsed and refractory NHL as a single-agent and in untreated aggressive NHL as replacement for non-liposomal VCR in CHOP±R combination chemotherapy. Because of a primarily non-hematologic toxicity profile, VSLI may be useful in patients considered unable to tolerate myelosuppressive therapies. MethodsTwenty-two patients with heavily pre-treated, relapsed and refractory CD20+ DLBCL or mantle cell lymphoma (MCL) were treated with combination therapy consisting of VSLI 2.0 mg/m2, without a dose cap, every 2 weeks plus 4 weekly doses of rituximab 375 mg/m2. Objective response rate (ORR), consisting of achievement of complete response (CR) or partial response (PR), was the primary efficacy endpoint. Secondary efficacy endpoints included response duration, time to progression (TTP), and overall survival (OS). Safety variables included adverse events and neurologic assessments. ResultsThe ORR was 59% (13/22) including CR in 6 (27%) patients and PR in 7 (32%) patients. Stable disease was documented in an additional 3 (14%) patients. Median response duration, TTP and OS were 147 days, 121 days and 322 days, respectively. The median number of VSLI doses was 5, the median individual VSLI dose was 3.5 mg, and the maximum cumulative VSLI dose was 43 mg. There were no toxicity-associated deaths during the study period. Treatment-related Grade 3 peripheral neuropathy and constipation were reported in 4 patients and 1 patient, respectively. There was no Grade 4 neuropathy. Grade 3 febrile neutropenia developed in 2 patients. ConclusionHigh dose VSLI plus rituximab, as palliative therapy for heavily pre-treated, predominantly older, patients with advanced, relapsed and refractory DLBCL and MCL, was generally well-tolerated and resulted in a meaningful ORR of 59%, median response duration of approximately 5 months, and median OS of almost 11 months. The toxicity profile of this combination was predictable and manageable with limited hematologic toxicity. Despite near universal prior VCR exposure (96%) and doses of VSLI normally unachievable with non-liposomal VCR, peripheral neuropathy and constipation incidences were modest. Older patients, those who are multiply relapsed, and others who are unlikely to tolerate prolonged periods of myelosuppression are often considered best suited for palliative therapy intended to prolong and maintain quality life. VSLI combined with rituximab may provide such palliation. Disclosures:Off Label Use: Marqibo is currently approved for the treatment of adults with Ph- relapsed/refractory ALL. Deitcher:Talon Therapeutics: Employment, Equity Ownership. Silverman:Talon Therapeutics: Employment.

Phase II Study of Nelarabine With Hyper-CVAD in Patients With Previously Untreated T cell Acute Lymphoblastic Leukemia (T-ALL) and Lymphoblastic Lymphoma (LL)

Abstract Abstract 1501 Introduction: Hyper-CVAD achieves high rates of complete remission (CR) and improves clinical outcomes in patients (pts) with T-ALL/LL. However, about 50% of pts will relapse. Nelarabine is a novel agent active in relapsed/refractory T lymphoid malignancies, but its activity in frontline therapy of T-ALL/LL remains unclear. We therefore studied the efficacy and safety of nelarabine in combination with hyper-CVAD in frontline therapy for pts with T-ALL/LL. Methods: In this phase II trial we enrolled 36 pts with T-ALL/LL who were treated at our institution from August 2007 to April 2012. Pts received two cycles of nelarabine either during or shortly after the intensified consolidation; two more cycles were given during the maintenance phase. Nelarabine was administered at a dose of 650mg/m2IV daily for 5 days. Pts with bulky mediastinal disease could receive radiation therapy followed by 24 cycles of vincristine, prednisone, mercaptopurine, methotrexate (POMP maintenance). Maintenance cycles 18 and 19 consisted of methotrexate/asparaginase and hyper-CVAD, respectively. CNS prophylaxis included 8 intrathecal treatments of methotrexate alternating with ara-C. Results: 36 pts with T-ALL/LL were enrolled with a median age of 38 years (19–78). Male to female ratio was 26 to 10. Twenty-one pts (58.3 %) had T-ALL, 15 (41.3 %) had LL. Eighteen pts had diploid karyotype; 14 pts had bulky mediastinal disease, and 4 had CNS involvement. Thirty-three (91.6 %) pts achieved CR and 2 (5%) PR. Flow cytometry based MRD negative CR was seen in 8/15 (53%) pts with T-ALL who achieved a CR and had MRD status assessed at the time of CR. With a median follow up duration of 19 months (2–57+), 21 pts (58.3%) are still in remission and alive, 10 (27%) had a relapse (two alive and 8 died) and one pt was lost to follow up, 3 pts did not respond and one died during CR. Probability of CR duration at 3 years was 66%. Three-year probabilities for overall survival (OS) and disease free survival (DFS) were 62% and 61%, respectively. Median OS and DFS have not yet been reached. Thirty (83%) pts had at least one infection grade ≥3. Thrombotic episodes occurred in 6 pts (17%) (4 PE, 2 DVT). Sixteen (44%) pts had G1–2 peripheral neuropathy. Because of neuropathy, the nelarabine dose had to be reduced to 650 mg/m2on alternating days (D1, 3, 5) in two patients and was withheld in another. Conclusions: Nelarabine can be safely combined with Hyper-CVAD in pts with newly diagnosed pts with T-ALL/LL. The combination of nelarabine with hyper-CVAD is active and can achieve MRD negative CR in T-ALL/LL. Disclosures: Kantarjian: Genzyme: Research Funding. Thomas: Pfizer: Consultancy, Honoraria; Talon Therapeutics: Honoraria. Ravandi: Genzyme: Research Funding. Burger: Pharmacyclics: Consultancy, Research Funding. Faderl: Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Minimal Residual Disease in Adults with Advanced Relapsed Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia Treated with Marqibo® (vinCRIStine sulfate LIPOSOME injection)

AbstractAbstract 4805Minimal residual disease (MRD) testing in acute lymphoblastic leukemia (ALL) has been primarily used in the frontline treatment setting following achievement of morphologic remission where absence of detectable disease (molecular remission) may predict for a more favorable outcome. Potential utility of post-induction MRD testing in the advanced, relapsed/refractory adult Philadelphia chromosome (Ph) negative ALL setting has not been reported.We assessed MRD in the pivotal Phase 2 RALLY Study (HBS407, NCT00495079) of weekly high-dose (2.25 mg/m2 without any dose cap) vincristine sulfate liposome injection (VSLI, Marqibo®) monotherapy in 65 patients with either B- or T-cell lineage, Ph-negative ALL in 2nd or greater relapse or that had progressed following 2 or more lines of prior anti-leukemia therapy. All patients were heavily pretreated, all had received prior standard vincristine (VCR), 48% had undergone a prior hematopoietic cell transplant, and 43% were refractory to their immediate prior line of therapy. The median bone marrow blast percentage at presentation was 82%.Complete response (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 13 (20%) patients based on principal investigator (PI) assessment (predefined primary endpoint) and in 11 (17%) patients as assessed by an independent response review committee (IRRC). Two patients assessed as CR/CRi by a PI were classified as bone marrow blast (BMB) responders (morphologic remission lacking neutrophil and platelet count recovery) by the IRRC. MRD data from the first bone marrow demonstrating VSLI-induced CR/CRi based on site-specific flow cytometry methodology were available in 12 of the 13 CR/CRi patients. Molecular remission was confirmed in 8 of 12 (67%) patients. Response and VSLI treatment details for the MRD-negative and MRD-positive groups are provided in the tableMRD Negative N = 8MRD Positive N = 4PI Response AssessmentCR51CRi33BMB Responder00IRRC AssessmentCR61CRi03BMB Responder20Response Duration, Median (Range)140 days (32–162)87 days (35–210)Overall Survival, Median (Range)230 days (121–321)203 days (71–327)VSLI Doses, Median (Range)9 (4–18)5 (4–10)VSLI Exposure (mg of VCR), Median (Range)35.9 (17.4–58.6)20.1 (15.8–33.4)Most (83%) patients who achieved a CR were MRD-negative. Half of the CRi patients, based on PI assessment, were MRD-negative. Both of the BMB responders, based on IRRC assessment, were MRD-negative. Median response duration, overall survival, number of VSLI doses, and cumulative VSLI dose expressed as milligrams of VCR were larger in patients who were MRD-negative.VSLI monotherapy administered as a third-, fourth-, or fifth-line therapy in adults with advanced, relapsed/refractory Ph-negative ALL was able to induce morphologic remission in 13 of 65 (20%) of patients and molecular remission in 8 of 12 (67%) evaluable morphologic remissions. MRD negativity may result from greater VSLI exposure and may be associated with more favorable response durations. MRD assessment may help to determine remission status particularly in patients with morphologic remission and incomplete recovery of either (i.e., CRi) or both (i.e., BMB Response) the peripheral blood platelet count and neutrophil count secondary to extensive prior myelotoxic therapy. Disclosures:Goldberg:Eisai: Speakers Bureau. Silverman:Talon Therapeutics: Employment. Deitcher:Talon Therapeutics: Employment, Equity Ownership.

Design of the Hallmarq Trial, a Phase 3 Study of Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) in Adults with Newly Diagnosed, Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia

Abstract 4300 Background:Adult acute lymphoblastic leukemia (ALL) is a lethal and fulminant disease and one distinct from childhood ALL. There are approximately 2400 new cases per year in the US; approximately 80% of these will be Philadelphia chromosome (Ph) negative. Despite remarkable success in treatment of childhood and adolescent ALL, adult ALL patients are underserved by existing treatment options as reflected by the poor survival rates and extremely poor outcomes in the relapsed setting. Complete response (CR) rates in the front-line setting range from 90% in patients <30 years old to 57% in patients >60 years old and 3-year disease free survival ranges from 47% to 12% respectively. The unmet medical need in adult ALL is most pronounced in those age 60 and older. VSLI was recently granted accelerated FDA approval as a single-agent for the treatment of adults with advanced, relapsed and refractory Ph-negative ALL and has successfully completed a Phase 2 trial as a component of multi-agent therapy. Trial Design:HALLMARQ (NCT01439347) is a Phase 3, multi-national, randomized study to evaluate the substitution of VSLI for standard vincristine (VCR) in the induction, consolidation, and maintenance phases of combination chemotherapy in the treatment of patients ≥ 60 years old with newly diagnosed Ph-negative ALL. The chemotherapy “backbone” utilized in this trial is modified from the Cancer and Leukemia Group B 8811 protocol. Asparaginase product usage is optional. The total duration of protocol-specified therapy is up to 24 months. VCR is dosed at 1.4 mg/m2 with a per dose cap at 2 mg. VSLI is dosed at 2.25 mg/m2without a dose cap. A protocol-specified dose reduction algorithm applicable to both VSLI and VCR will be used to minimize Grade 3 neurotoxicity while also facilitating continued dosing. Growth factors (e.g., granulocyte colony-stimulating factor) and bowel regimens (e.g., daily stool softener) are recommended and will be prescribed according to investigator preference and institutional guidelines. The primary endpoint is overall survival (OS) and the study is powered for superiority. Secondary endpoints include remission rate, overall response rate, event-free survival, and safety and tolerability. Minimal residual disease (MRD) at multiple time points and pharmacokinetic parameters are being assessed. Conclusion:The HALLMARQ Trial will provide new insights into the frontline treatment of ALL in adults ≥60 years old as well as confirm the clinical benefit of VSLI monotherapy demonstrated in the Phase 2 RALLY Study that supported the initial product approval. HALLMARQ is based on a Special Protocol Assessment with the FDA and is currently enrolling.*On behalf of the HALLMARQ investigators. Disclosures:Deitcher:Talon Therapeutics: Employment, Equity Ownership. Silverman:Talon Therapeutics: Employment.

Neurotoxicity Profile of Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) Monotherapy in Adults with Relapsed Acute Lymphoblastic Leukemia and Universal Prior Standard Vincristine Exposure

AbstractAbstract 3568 Background:VinCRIStine sulfate LIPOSOME injection (VSLI, Marqibo®) is a nanoparticle formulation of vincristine sulfate (VCR) that encapsulates the drug in long-circulating sphingomyelin and cholesterol liposomes. The unique pharmacologic properties of VSLI impart superior nonclinical efficacy and pharmacokinetic properties versus standard VCR. Decades of clinical experience with standard VCR has established peripheral neuropathy as the most notable toxicity and one that underpins the common practice of individual dose capping which limits cumulative dosing. We recently conducted clinical trials to support VSLI accelerated approval for the treatment of adults with relapsed and refractory Philadelphia chromosome negative acute lymphoblastic leukemia (ALL). Here we present data on the neurotoxicity profile of weekly VSLI at the approved dose. Methods:Eighty-three subjects received weekly VSLI 2.25 mg/m2as a 1-hour infusion, with no dose cap, for treatment of advanced, relapsed and/or refractory ALL; Sixty-five patients were enrolled in a pivotal, Phase 2 study and 18 patients were enrolled in an expanded cohort in a Phase 1 study. Signs and symptoms of peripheral neuropathy were proactively assessed using a detailed 15-point evaluation. The pooled data from these studies are the primary safety population for VSLI. Neurotoxicity data are presented here in comparison to two published studies that prospectively evaluated standard VCR induced peripheral neuropathy in patients with Hodgkin disease, non-Hodgkin lymphoma or acute lymphoblastic leukemia (Haim et al, Cancer 1994; 73:2515–2519 and Verstappen et al Neurology 2005; 64:1076–1077. Results:The median individual VSLI dose per infusion was 4.1 mg (range 3.1–5.5) and the median cumulative dose was 18.4 mg (range 3.5–70.1). All patients had prior exposure to VCR containing regimens that resulted in 80% of patients entering the studies with Grade 1 or Grade 2 residual neuropathy. The most common neurological adverse events were constipation (56.6%) and peripheral neuropathy (37.3%). Serious adverse events (SAEs) were reported in 76% of patients and were consistent with advanced ALL. The most frequently reported neuropathy-associated SAEs in patients treated with VSLI were peripheral neuropathy (4.8%) and constipation (3.6%). Incidence of paraesthesia, the only neuropathy uniformly reported across VSLI and VCR studies, was greater in the VCR studies than following much higher dosages and dose density (based on BSA of 1.8) of VSLI.StudyDoseDose Density (mg/week)Paraesthesia Rate (%)Haim1.4 mg/m2/3 weeks0.8478Verstappen4 mg/3 weeks1.3360Verstappen2 mg/3 weeks0.6734VSLI2.25 mg/m2/week4.0423 Conclusions:Experience with VCR has established a clear relationship between dose intensity and symptoms of peripheral neuropathy. Administration of VSLI at a dose of 2.25 mg/m2with no dose cap did not result in any new or unexpected toxicity. Although neuropathy remains a significant toxicity associated with VSLI, the frequency and severity of neuropathic AEs was no greater than what would be expected from a standard VCR regimen. Despite administration of higher doses and dose density, incidence of peripheral neuropathy following exposure to VSLI was lower than previously reported with standard VCR. This is significant given that the individual and cumulative doses of VSLI were 2–3 fold greater than what is generally achieved with standard VCR. VSLI facilitates increasing the tolerable dose and dose density and may result in improved clinical response with similar or less toxicity than VCR.*On behalf of the RALLY trial investigators Disclosures:Deitcher:Talon Therapeutics: Employment, Equity Ownership. Silverman:Talon Therapeutics: Employment.

Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) Facilitates Increased Delivery of Vincristine Sulfate to Target Cancer Tissues.

AbstractAbstract 2457 Background:Standard vincristine sulfate (VCR) plasma pharmacokinetics (PK) is described by a bi-exponential profile with a very short half-life followed by a longer elimination half-life; the volume of distribution is large, suggesting wide and diffuse distribution and perhaps tissue binding. These PK characteristics may limit optimal therapeutic activity of VCR by limiting Cmaxand drug exposure in target tissues involved with cancer. VinCRIStine sulfate LIPOSOME injection (VSLI, Marqibo) is a sphingomyelin- and cholesterol-based nanoparticle formulation of VCR that was designed to be different from and overcome the dosing and pharmacokinetic limitations of standard VCR. The objectives for development of VSLI were to: 1) increase the plasma circulation time; 2) increase tumor tissue delivery by preferential extravasation from fenestrated (“leaky”) vasculature; 3) accumulation in tumor tissues; and 4) slow release of VCR in tumor tissues instead of the systemic circulation. VSLI recently received accelerated FDA approval for use in adults with advanced, relapsed and refractory Philadelphia chromosome negative ALL and is in development for pediatric ALL and aggressive NHL. Methods:The PK and tissue distribution of VCR was evaluated in Sprague-Dawley rats following a single IV bolus dose (2.0 mg/m2) of VSLI or VCR, utilizing 3H-VCR as a marker. The tissue levels of total VCR were measured for up to 72 hours post-dose. PK analysis was performed using noncomparmental methods with the WinNonlin software package. Results:The PK profile and calculated parameters of VSLI in rats showed a substantially lower total vincristine clearance (CL) and volume of distribution (Vdz) and correspondingly greater area under the plasma concentration versus time curve (AUC) compared to standard VCR. VSLI has a long circulation time and remains in the plasma instead of being widely distributed in tissues. For most tissues from VSLI treated animals, tissue to plasma concentration ratios increased over time and peaked at 72 h after VSLI injection, indicating progressive accumulation of radiolabeled drug from plasma into the tissues. The rank order of tissues based on Cmax demonstrated that total VCR concentrations in MPS tissues (i.e., spleen, liver, lymph nodes and bone marrow) and in ovaries were substantially higher than in other organs or tissues. The lowest radioactivity levels were observed in brain, spinal cord, nerves and muscle. Higher exposures, as measured by AUCinf, of VCR were observed in plasma (83 fold), spleen (12 fold), lymph nodes (10 fold), liver (4 fold) and bone marrow (2 fold) following a radiolabeled dose of VSLI compared to VCR.AUCinf, ng eq*hr/gSpleenLiverLymph nodeBone marrowVSLI381,15428,20266,33340,936VCR30,7656,4966,42017,767 Conclusion:The long circulation time and small, 100 nm, mean nanoparticle size of VSLI facilitate extravasation from fenestrated vasculature and accumulation in tissues involved in hematologic malignancies such as lymph nodes, bone marrow and spleen. Slow release of VCR in target tissues following administration of VSLI results in higher and prolonged tissue drug levels providing superior drug delivery to tissues than the same doses of standard formulation of VCR. Disclosures:Silverman:Talon Therapeutics: Employment. Deitcher:Talon Therapeutics: Employment, Equity Ownership.

Vincristine Sulfate Liposomes Injection (VSLI, Marqibo): Interim Results From a Phase I Study in Children and Adolescents with Refractory Cancer

AbstractAbstract 1497 Background:Vincristine is active in many pediatric cancers, but cumulative neuromuscular toxicity is often dose limiting and requires a maximum dose cap. Liposomal carriers are capable of increasing the therapeutic index of anticancer agents by altering pharmacokinetic behavior. Vincristine sulfate liposomes injection (VSLI, Marqibo®) is a novel preparation of standard vincristine encapsulated in sphingomyelin/cholesterol liposomes. Clinical trials have demonstrated safety, tolerability and activity in adults with leukemias, lymphomas and solid tumors. Pediatric experience with VSLI is limited. Design:This single center Phase I dose-escalation study is designed to determine the maximum tolerated dose (MTD) and to assess safety, pharmacokinetics and activity of VSLI in pediatric patients with relapsed/refractory cancer. Patients with active central nervous system disease or ≥grade 2 sensory or motor neuropathy are excluded. Dose escalation is per a standard 3 + 3 Phase I trial design with enrollment following a rolling 6 strategy. VSLI is administered IV over 60-minutes every 7 days (± 3 days) for 4 consecutive weeks for a 28-day treatment cycle (4 doses/cycle). Cycles may be delayed by up to 1 week for toxicity. Two dose levels have been tested to date: 1.75 mg/m2 and 2.25 mg/m2(adult MTD). No individual dose cap is employed. A validated HPLC tandem mass spectrometry assay was used to quantitate total (liposomal encapsulated and non-encapsulated) vincristine. Results:9 patients have been treated (Table): 6 with acute lymphoblastic leukemia (ALL) and 3 with solid tumors. All patients were heavily pre-treated and 2 had prior stem cell transplants. 6 of 9 completed at least 1 cycle of therapy, with 1 each removed early for alternative therapy, complications of ALL, or dose-limiting toxicity (DLT). Most treatment-related adverse events were reversible grade 1 and 2 severity including hepatic transaminase elevation, parasthesia, low white blood cell count, neutropenia and fatigue. 2 patients evaluable for hematologic toxicity developed grade 4 neutropenia that spontaneously and rapidly resolved. No DLT occurred on dose level 1. Grade 4 aspartate aminotransferase elevation was observed in one patient at the second dose level and this dose level is being expanded. 1 patient treated at dose level 1 had dose de-escalation starting with Cycle 2 Dose 3 due to neuropathy. No patient was taken off study due to neurotoxicity. 7 of 9 patients received a VSLI dose that exceeded the 2 mg dose limit set for standard vincristine. 6 patients were evaluable for response: 1 had a complete remission (CR) (minimal residual disease negative by flow cytometry); 3 had stable disease (SD); and 2 had progressive disease (PD). First-dose pharmacokinetic analysis revealed wide interpatient variation (Table). The median (range) maximum concentrations (Cmax) of total vincristine (ng/ml) were 1,485 (845-2,120) and 2,450 (1,690-3,690) at dose levels 1 and 2 respectively. The median plasma half-life (T½) was 8.5 and 13.5 hours at dose levels 1 and 2 respectively (range 1.8 to 40.4 hours). Conclusions:VSLI appears to be safe, tolerable and demonstrates preliminary activity in pediatric patients with refractory ALL and solid tumors. The toxicity spectrum appears to be similar in children and adults. Clearance of total vincristine in our study is approximately 100-fold lower in comparison to administration of standard vincristine. VSLI allows for intensification of vincristine therapy in children with cancer. Accrual to the Phase I component at the adult recommended dose is ongoing and an expanded Phase II cohort in pediatric patients with ALL is planned.DiagnosisAge (yr)Dose LevelDose (mg)Doses GivenBest ResponseCmax (ng/ml)T½ (hr)AUC0-inf (ng/ml·hr)Cl (ml/min/m2)ALL1813.72NE8456.18,9383.3ALL1512.54SD1,87010.261,8900.47Solid1712.9 (2.1*)12SD1,28019.645,8810.63ALL1112.52NE1,0601.86,5864.52Solid1312.34PD1,6906.727,2501.08ALL121212CR2,12040.477,4290.38Solid221.38SD3,62013.537,6031.03ALL1423.41NE1,69010.725,1731.47ALL1424.14PD2,45019.344,0880.85Solid: solid tumors; NE: not evaluable for response; AUC: area under the concentration curve; Cl: clearance.*dose de-escalation with Cycle 2 Dose 3.This study was sponsored by Talon Therapeutics and is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Disclosures:No relevant conflicts of interest to declare.

Phase II Study of Nelarabine with Hyper-CVAD in Patients with Previously Untreated T Cell Acute Lymphoblastic Leukemia (T-ALL) and Lymphoblastic Lymphoma (LL)

AbstractAbstract 1501 Introduction:Hyper-CVAD achieves high rates of complete remission (CR) and improves clinical outcomes in patients (pts) with T-ALL/LL. However, about 50% of pts will relapse. Nelarabine is a novel agent active in relapsed/refractory T lymphoid malignancies, but its activity in frontline therapy of T-ALL/LL remains unclear. We therefore studied the efficacy and safety of nelarabine in combination with hyper-CVAD in frontline therapy for pts with T-ALL/LL. Methods:In this phase II trial we enrolled 36 pts with T-ALL/LL who were treated at our institution from August 2007 to April 2012. Pts received two cycles of nelarabine either during or shortly after the intensified consolidation; two more cycles were given during the maintenance phase. Nelarabine was administered at a dose of 650mg/m2IV daily for 5 days. Pts with bulky mediastinal disease could receive radiation therapy followed by 24 cycles of vincristine, prednisone, mercaptopurine, methotrexate (POMP maintenance). Maintenance cycles 18 and 19 consisted of methotrexate/asparaginase and hyper-CVAD, respectively. CNS prophylaxis included 8 intrathecal treatments of methotrexate alternating with ara-C. Results:36 pts with T-ALL/LL were enrolled with a median age of 38 years (19–78). Male to female ratio was 26 to 10. Twenty-one pts (58.3 %) had T-ALL, 15 (41.3 %) had LL. Eighteen pts had diploid karyotype; 14 pts had bulky mediastinal disease, and 4 had CNS involvement. Thirty-three (91.6 %) pts achieved CR and 2 (5%) PR. Flow cytometry based MRD negative CR was seen in 8/15 (53%) pts with T-ALL who achieved a CR and had MRD status assessed at the time of CR. With a median follow up duration of 19 months (2–57+), 21 pts (58.3%) are still in remission and alive, 10 (27%) had a relapse (two alive and 8 died) and one pt was lost to follow up, 3 pts did not respond and one died during CR. Probability of CR duration at 3 years was 66%. Three-year probabilities for overall survival (OS) and disease free survival (DFS) were 62% and 61%, respectively. Median OS and DFS have not yet been reached. Thirty (83%) pts had at least one infection grade ≥3. Thrombotic episodes occurred in 6 pts (17%) (4 PE, 2 DVT). Sixteen (44%) pts had G1–2 peripheral neuropathy. Because of neuropathy, the nelarabine dose had to be reduced to 650 mg/m2on alternating days (D1, 3, 5) in two patients and was withheld in another. Conclusions:Nelarabine can be safely combined with Hyper-CVAD in pts with newly diagnosed pts with T-ALL/LL. The combination of nelarabine with hyper-CVAD is active and can achieve MRD negative CR in T-ALL/LL. Disclosures:Kantarjian:Genzyme: Research Funding. Thomas:Pfizer: Consultancy, Honoraria; Talon Therapeutics: Honoraria. Ravandi:Genzyme: Research Funding. Burger:Pharmacyclics: Consultancy, Research Funding. Faderl:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Vincristine Sulfate Liposomes Injection (Marqibo®) Facilitates Durable Remissions and Potentially Curative Hematopoietic Stem Cell Transplantation in Adults with Advanced, Relapsed and/or Refractory Acute Lymphoblastic Leukemia

Abstract 4235A durable response in advanced, relapsed and/or refractory adult acute lymphoblastic leukemia (ALL) may be defined as remission that results in a meaningful prolongation of life or response that facilitates “bridging” to a subsequent, potentially curative, hematopoietic stem cell transplantation (HSCT). Vincristine sulfate liposomes injection (VSLI, Marqibo®) is a sphingomyelin/cholesterol (SM/Chol) nanoparticle formulation of standard vincristine sulfate (VCR) designed to facilitate dose intensification, prolonged drug delivery and enhanced lymphoid malignancy penetration and concentration without increased toxicity. Recently, VSLI was evaluated in a multi-institutional, Phase 1/2 (VSLI-06; NCT00144963) clinical trial and a multi-national, Phase 2 (HBS407; NCT00495079) clinical trial in a combined 101 adults (median age 31 years [range 18 to 83 years]) with advanced, relapsed and/or refractory ALL. All but 1 patient had Philadelphia chromosome negative disease. Thirteen patients (13%) had extramedullary disease, 37 (37%) had undergone a prior HSCT, and 100% had received at least one prior line of therapy including standard VCR. Study VSLI-06 (N = 36) was a dose-ascending trial of weekly VSLI (1.5 to 2.4 mg/m2) combined with pulse dexamethasone. Study HBS407 was a single-arm trial of weekly single-agent VSLI at the maximum tolerated dose established in VSLI-06 of 2.25 mg/m2. Overall, 19 (19%) patients received VSLI as a first salvage therapy, 57 (56%) patients received VSLI as a second salvage therapy, and 25 (25%) patients received VSLI as a third or greater salvage therapy. All patients had to be deemed ineligible for immediate HSCT in order to enroll in VSLI-06 or HBS407. In the combined study population, the overall response rate (complete remission [CR], CR with incomplete hematologic recovery [CRi], partial remission [PR], and bone marrow blast response [BMB]) was 31% (95% CI: 22–41) with a 20% (95% CI: 13–29) rate of CR+CRi. Despite delivering intensified individual (2.8–5.5 mg) and cumulative (up to 70.1 mg) doses of VCR, VSLI had a similar safety profile to that reported for the approved dose of standard VCR. VSLI enabled bridging to a post-VSLI HSCT in 12 of 65 (18%) patients in HBS407 and 5 of 36 (14%) patients in VSLI06 for a total of 17 of 101 (17%). All 17 post-VSLI HSCT patients were under the age of 60 years. Three of 12 post-VSLI HSCT patients from HBS407 remain alive at greater than 28, 33, and 35 months following VSLI, respectively. All 12 patients lived for greater than 100 days after post-VSLI HSCT. Long-term survival (greater than 12 months) was achieved in 27% of those able to receive post-VSLI HSCT. These outcomes, that are important to patients, may reflect the effectiveness of the VCR dose intensification facilitated by VSLI. The neuropathy associated with the dose intensified VCR administered as VSLI was predictable, manageable, and comparable to that published for standard VCR. The lack of early, pre-day 100, mortality following post-VSLI HSCT suggests that the sphingomyelin-based liposomal formulation did not adversely affect subsequent transplantation procedures. In conclusion, VSLI produced both clinically important endpoints of prolonged survival and achievement of response allowing for a bridge to HSCT for advanced, relapsed and/or refractory ALL. Disclosures:Schiller:Talon Therapeutics: Research Funding. Silverman:Talon Therapeutics: Employment, Equity Ownership. Deitcher:Talon Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Single-Agent Vincristine Sulfate Liposomes Injection (Marqibo®) Compared to Historical Single-Agent Therapy for Adults with Advanced, Relapsed and/or Refractory Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia

Abstract 2592There are no standard of care or approved treatments specifically for advanced, relapsed and/or refractory adult Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL). Pronounced toxicity of multi-agent salvage therapy, residual toxicity in heavily pre-treated subjects, and poor response to prior multi-agent therapy including hematopoietic stem cell transplant (HSCT) may prompt the use of single-agent salvage including investigational agents. We compared the efficacy and early plus induction (30-day) mortality rates for single-agent weekly intravenous vincristine sulfate liposomes injection (VSLI, Marqibo®) 2.25 mg/m2 (no dose cap) in adults with Ph- ALL in second or greater relapse or that had progressed following 2 or more lines of anti-leukemia therapy (RALLY Study, N=65) with those from the not previously described, single-agent (non-VSLI), second salvage, Ph- ALL subpopulation (N=56) from a large published report (O’Brien et al, Cancer 2008; 113:3186–91). Despite inclusion of subjects requiring third and greater salvage therapy in the RALLY Study, the O’Brien single-agent population represents the best historical comparator to the RALLY Study population. The most common of the 28 different agents used in the O’Brien study were vinorelbine (6), clofarabine (5), nelarabine (4), and topotecan (4). No subject in the O’Brien study received single-agent standard vincristine sulfate as second salvage. The table below highlights key characteristics of the two ALL populations as well as key efficacy and toxicity outcomes.RALLY Study VSLI (N=65)O'Brien 2008 Various Agents (N=56)Age (yrs), Median (range)31 (19–83)41 (17–73)Unfavorable Cytogenetics, N (%)33 (50.7)5 (8.9)Prior Lines of Therapy, N (%)Two 32 (49.2) Three 24 (36.9) ≥ Four 9 (13.8)Two 56 (100) Three 0 ≥ Four 0Prior HSCT, N (%)31 (47.7)0Prior Standard Vincristine, N (%)65 (100)56 (100)CR+CRi+PR, N (%)19 (29.2)2 (3.6)CR+CRi, N (%)13 (20.0)2 (3.6)CR+CRi Duration (wks), Median (range)23.1 (4.6–66.1)5 and 14*Overall Survival (wks), Median (range)19.9 (1.9–94.4)7.5 (0–110)Induction (30-day) mortality, N (%)8 (12.3)17 (30.4)Overall, the RALLY Study population was more advanced and heavily pre-treated than the O'Brien population. Despite the poorer prognosis, universal prior standard vincristine exposure, and majority of subjects requiring fourth or greater line therapy, single-agent VSLI 2.25 mg/m2 (no dose cap) resulted in a higher complete response (CR+CRi) rate, complete plus partial response (PR) rate, median complete response duration (* no median was calculated for the O'Brien Population because there were only 2 responders), and overall survival duration than was observed with a variety of third-line single-agent adult Ph- ALL salvage therapies. The median overall survival durations for the RALLY Study subjects achieving CR (7), CRi (6), and PR (6) were comparable. The majority of RALLY Study complete responders had a remission duration sufficient to facilitate a subsequent, and potentially curative HSCT. In fact, 12 (18.5%) of the 65 subjects in the RALLY Study were able to undergo a post-VSLI HSCT and 5 (7.7%) subjects were long-term survivors (post-VSLI survival greater than 1 year). Single-agent VSLI was associated with a more favorable early plus induction (30-day) mortality rate in the RALLY Study than observed in relation to other single-agent therapies. Single-agent weekly VSLI 2.25 mg/m2 has the potential to provide a relatively safe and effective induction treatment and “bridge” to HSCT compared to historical non-VSLI single-agent therapies. Disclosures:Deitcher:Talon Therapeutics: related to an employee with equity ownership. Deitcher:Talon Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Neurological Toxicity Profile of Weekly Vincristine Sulfate Liposomes Injection (Marqibo®) 2.25 mg/m2 Compared to Historical Standard Vincristine Sulfate 1.4 mg/m2, 2 mg, and 4 mg Administered Less Frequently

Abstract 4247 The accumulated clinical experience with standard vincristine sulfate (VCR) describes a safety profile most notable for the occurrence of a dose-related, symmetrical, sensorimotor and autonomic polyneuropathy. The various manifestations of neuropathy are the usual dose-limiting toxicities associated with standard VCR that limit the extent to which patients can derive clinical benefit from this therapy. Vincristine sulfate liposomes injection (VSLI, Marqibo®) is a sphingomyelin-based, liposomal formulation of VCR designed to intensify dose, prolong encapsulated drug circulation time, and target drug to sites of active cancer. We report here the neurological toxicity profile (Graded using CTCAE criteria v3.0) of weekly, single-agent IV VSLI 2.25 mg/m2 in 83 adult subjects with heavily pre-treated, relapsed and/or refractory acute lymphoblastic leukemia (ALL) and 100% past standard VCR exposure. Neuropathy signs and symptoms were rigorously evaluated at baseline and weekly during VSLI treatment in order to maximize adverse event detection. Findings were compared to baseline (post-standard VCR and before VSLI) neuropathy in the same VSLI treated population and to the best available published neurotoxicity data regarding standard VCR administration. In the study by Haim et al ([1] Cancer 1994; 73:2515–9), 104 VCR-naïve patients with lymphoma received multi-agent therapy including standard VCR 1.4 mg/m2 weekly to once every 28 days. In the study by Verstappen et al ([2] Neurology 2005; 64:1076–7), 114 VCR-naïve patients with lymphoma received multi-agent therapy including fixed dose standard VCR 2 mg or 4 mg every 3 weeks. Results are provided in the table below. NR = not reported. The baseline frequency of residual neuropathy in adults with ALL treated with weekly VSLI 2.25 mg/m2 was not unexpected considering that all patients received prior standard VCR. The on-study, incremental neuropathy burden was relatively modest. On-study neuropathy rates during and immediately following weekly VSLI 2.25 mg/m2 were comparable to or less than those reported in lymphoma patients receiving standard VCR at 1.4 mg/m2 every 1 to 3 weeks or at a fixed dose of 2 mg or 4 mg every 3 weeks, despite the dose intensification afforded by VSLI. Constipation, the most commonly reported neurological toxicity associated with standard VCR and VSLI, resulted in standard VCR dose reduction in 22% of patients reported by Haim et al compared to weekly VSLI dose reduction in only 5% of patients due to constipation. Frequent neurological assessments combined with a dose adjustment algorithm facilitated continued VSLI dosing in order to induce remission and minimization of Grade 3 or greater neurotoxicity. One VSLI patient developed peripheral motor neuropathy requiring drug discontinuation after 11 weekly doses. In the VSLI study, neurological toxicity was considered predictable and manageable. Disclosures: Schiller: Talon Therapeutics: Research Funding. Deitcher:Talon Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.