ALBERT

Description: Multiple myeloma (MM) is a bone marrow-based malignancy characterized by expansion of plasma cells that produce monoclonal immunoglobulin. Although many new options are available to treat MM, patients develop resistance to these agents. Thus, new therapeutic options are necessary for patients. Vincristine has been used to treat MM but its neurotoxic side effects and low level of anti-MM activity have limited its clinical use. Pharmacokinetic studies on a different formulation of this vinca alkaloid, vincristine sulfate liposomes injection (VSLI, Marqibo®), have shown that the altered distribution and elimination phases with this drug may lead to increased exposure within the tumor versus traditional vincristine. Thus, this new agent offers the potential to both reduce the neurotoxicity and increase the anti-MM effects compared to standard vincristine. In the present study, we evaluated the anti-MM effects of Marqibo and vincristine using two severe combined immunodeficiency (SCID) murine models of human MM. These models were developed from intramuscular (i.m.) implantation of bone marrow biopsies from a MM patient before (LAGκ-1A) and following (LAGκ-1B) the development of both melphalan and bortezomib resistance clinically and have been successfully passaged. One week following implantation i.m., mice were treated with Marqibo, vincristine or vehicle alone. Marqibo was administered intravenously (i.v.) once weekly for three weeks at 0.5, 1, and 2.5 mg/kg and vincristine was given three times per week (M, W, F) i.v. at 0.3 mg/kg. Mice were bled in order to obtain sera to measure human immunoglobulin (Ig) G levels and tumor volume measured weekly. hIgG levels were measured by ELISA and tumor volume using standard calipers. Treatment of LAGk-1A–bearing mice with Marqibo at 0.5, 1 and 2.5 mg/kg inhibited paraprotein secretion as determined by hIgG levels (P = 0.0001; P = 0.0002; P = 0.0055, respectively) compared to mice receiving vehicle. A reduction in tumor volume, compared to control mice, was also observed in mice treated with Marqibo at the specified doses (P = 0.0001; P = 0.0001; P = 0.0001, respectively) and also when compared to vincristine (P = 0.0006; P = 0.0003; P = 0.0001, respectively). In fact, mice treated with vincristine showed no reduction in tumor volume compared to vehicle alone-treated mice. Marqibo at 0.5 mg/kg contained almost half the quantity of free vincristine compared to vincristine administered at 0.3 mg/kg, yet a significant inhibition of both human paraprotein secretion and reduction of tumor volume was observed in LAGκ-1A-bearing mice treated with this dose of Marqibo. The vincristine dose was administered three times more often than Marqibo, contained almost 100% more free vincristine compared to Marqibo at 0.5 mg/kg and most importantly was less effective. Mice bearing a slower growing MM tumor, LAGκ-1B, have recently begun treatment using the same doses and schedules as the LAGκ-1A study. This study is currently ongoing but preliminary data show inhibition of tumor volume growth and inhibition of IgG levels using Marqibo at 0.5, 1 and 2.5 mg/kg (hIgG; P = 0.011, P = 0.0045 and P = 0.0060, respectively). The results of this study show that Marqibo, a novel liposomal formulation of vincristine, produces anti-MM effects in this SCID-hu model of human MM whereas vincristine showed no anti-MM tumor volume growth activity. Further studies are currently being conducted to explore the optimal schedule and effects of this new agent in combination with other active MM agents. These studies should provide the rationale for further clinical development of Marqibo for the treatment of MM patients.

Description: The decision to provide prophylactic platelet transfusions to patients with hematologic malignancy and chemotherapy induced thrombocytopenia (CIT) is often based solely on the platelet count being below a somewhat arbitrary threshold. The ability to rapidly assess the overall (net) coagulation status (thrombotic and hemorrhagic tendencies) of these patients may help limit transfusion to those with a measurable bleeding tendency and reduce overall platelet product consumption. We performed pre- and post-platelet transfusion whole blood thromboelastography (TEG) in 20 pts with leukemia (16) or lymphoma (4) and CIT. Citrated venous blood was obtained prior to and 1 hour after single transfusions of 5 units of random donor platelets. Normal ranges were derived from TEG evaluation of 18 normal controls. Correlation between absolute and % changes in maximum TEG amplitude (MA, mm) and time to initial clot formation (R, min) and absolute and % changes in platelet count was assessed. Pts were defined as normal if MA = 45.7 to 64.9 and R = 8.3 to 19.9; hypocoagulable if MA19.9; hypercoagulable if MA〉64.9 and/or R

Description: VSLI is a nanoparticle formulation of vincristine sulfate (VCR) encapsulated in sphingomyelin/cholesterol (SM/Chol) liposomes called Optisomes™. In preclinical studies, VSLI has provided targeted, increased, and sustained delivery of VCR to tumor cells compared to administration of conventional or non-SM/Chol liposome-encapsulated VCR. VSLI is being developed to improve patient outcomes without increased VCR-related peripheral neuropathy (PN). We report an integrated analysis of the PN profile of VSLI from two distinct multi-center clinical studies: A Phase 1 dose-escalation study in adult subjects with relapsed/refractory ALL of weekly VSLI plus pulse dexamethasone at doses ranging from 1.8 to 2.4 mg/m2 without dose capping A Phase 2 study in adult subjects with relapsed/refractory NHL of biweekly VSLI at a dose of 2.0 mg/m2 without dose capping Subjects with prior history of Grade 3 or 4 PN related to chemotherapeutic agents were not eligible for either study. Subject characteristics, VSLI dosing details, and relevant clinical outcomes are provided in the Table. Results are presented as median (range) unless otherwise stated. ALL (N=36, 12F/24M) NHL (N=119, 55F/64M) Age (years) 32 (19–2) 60 (25–87) Body surface area (m2) 2.1 (1.5–2.8) 1.9 (1.3–2.6) Prior VCR exposure 100% 97% Total VSLI dose (mg) 19 (10–8) 14 (3–66) Objective Response rate 22% 25% VSLI dose to complete response (mg) 12 (9–3) n/a VSLI dose to objective response (mg) n/a 14 (8–9) Peripheral neuropathy (PN) rate, n (%) 22 (61) 50 (42) Grade 1 12 (33) 24 (20) Grade 2 7 (19) 18 (15) Grade 3 2 (6) 8 (7) Grade 4 1 (3) 0 VSLI dose to PN onset (mg) 14 (4–2) 12 (3–4) VSLI dose to Grade 3/4 PN (mg) 23 (20–3) 19 (3–4) Discontinuations due to PN, n (%) 3 (8) 7 (6) The median cumulative VSLI doses (including pre- and post-PN onset) for ALL and NHL subjects who experienced PN were 24 mg (range: 10–38 mg) and 18 mg (range: 3–66 mg), respectively, compared to 12 mg (range: 11–28 mg) and 11 mg (range: 3–54 mg) in ALL and NHL subjects who did not experience PN. Six of the 22 ALL subjects (27%) who experienced PN achieved CR, compared to 1 of 14 (7%) subjects without PN (p〉0.05). Nineteen of the 50 NHL subjects (38%) who experienced PN responded to VSLI, compared to 11 of 69 (16%) subjects without PN (p=0.01). In general, the PN observed in these lymphoid malignancy populations, with near universal prior VCR exposure, was primarily mild and moderate in grade and rarely required VSLI discontinuation. Despite prior VCR exposure, and residual PN in some, the amount of VCR delivered as VSLI in both ALL and NHL subjects prior to PN onset was greater than the PN trigger cumulative doses reported for conventional VCR (5 mg for PN; 15 mg for severe PN). In both studies, subjects who experienced PN received higher cumulative doses of VSLI and achieved more responses compared to subjects who had not experienced PN. The pharmacokinetic profile, targeted delivery, and VCR dose-intensification facilitated by VSLI have the potential to produce meaningful response rates without therapy-limiting PN.

Description: Novel formulations of standard chemotherapy allowing increased drug delivery without additional toxicity may improve outcomes for patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Vincristine sulfate liposomes injection (VSLI, Marqibo®) is VCR encapsulated in sphingomyelin (55%)/cholesterol (45%) nanoparticle liposomes called Optisomes™. Pharmacokinetic studies have shown that the altered distribution and elimination phases of VSLI may lead to increased VCR exposure compared to traditional VCR, and may account for the increased efficacy observed in preclinical models. Activity of VCR is dose and time-dependent, but neurotoxicity limits dosing to 1.4 mg/m2 (capped at 2.0 mg). VSLI, however, may be given without dose capping. We conducted a phase 1, open-label, dose-escalation study of VSLI in adults with relapsed or refractory ALL to determine the safety, maximum tolerated dose (MTD), and activity of this formulation. Subjects received VSLI intravenously weekly at doses of 1.5, 1.825, 2.0, 2.25 or 2.4 mg/m2. Dexamethasone 40 mg was given days 1–4 and 11–14 of each 4 week cycle. Thirtysix eligible subjects, all of whom had been previously treated with VCR, received at least 1 dose of VSLI. All were Philadelphia chromosome negative except for one. Median number of doses received for all subjects was 4; total medium cumulative dose was 9.09 mg/m2 (19.20 mg). MTD of VSLI was 2.25 mg/m2 based on dose-limiting toxicities of grade 3 motor neuropathy, grade 4 seizure and grade 4 hepatotoxicity observed in 1 subject each at the 2.4 mg/m2 dose level. The most common toxicities (constipation [67%], fatigue [61%], pyrexia [50%], anemia [50%], peripheral neuropathy [50%; mostly grade 1–2]) were as expected. Complete response (CR) was achieved in 7 of 36 (19%) subjects based on intent to treat analysis (Table). Overall response rate (including 1 PR) was 22%. Four subjects (11%) achieved hematologic improvement, 13 (36%) had stable disease, and 9 (25%) progressed. CR rate was 29% for the 7 subjects treated with VSLI as second salvage. Five of 7 subjects who achieved CR were able to undergo allogeneic stem cell transplant (SCT). In conclusion, VSLI appears to be an effective therapeutic option which may permit potentially curative SCT. A phase 2 international multi-center trial of single agent VSLI in subjects with relapsed ALL is currently accruing. Table. VSLI Clinical Activity (CR) by Dose Level and Salvage Status 1.5 mg/m2 n = 5 1.825 mg/m2 n = 3 2 mg/m2 n = 3 2.25 mg/m2 n = 18 2.4 mg/m2 n = 7 Total n = 36 1st salvage 1/1 0/1 -- 2/7 1/4 4/13 (31) 2nd or later salvage 1/4 1/2 0/3 1/11 0/3 3/23 (13)

Description: Introduction: Vincristine sulfate (VCR) is a lipophilic, cell-cycle specific, antineoplastic agent that inhibits cell division by specifically binding to tubulin in mitotic spindles. The activity of VCR is dose and time-dependent, but central and peripheral neuropthy prohibits its use beyond doses of 1.4 mg/m2 (capped at 2 mg). Marqibo is a formulation of VCR encapsulated in a sphingomyelin/cholesterol liposome (OPTISOME) with a longer half-life than VCR. In murine models using L1210 or P388 lymphoid leukemia cell lines, Marqibo demonstrated greater anti-tumor activity compared with VCR. Marqibo was therefore an appropriate agent to study in relapsed or refractory ALL. Methods: Two clinical trials have been completed. First, a phase II trial of single agent Marqibo given at 2 mg/m2 (no dose capping) every 2 weeks enrolled 16 patients (pts) [Thomas et al, Cancer 106:120, 2006]. A multicenter dose escalation phase I trial using weekly Marqibo (1.5, 1.825, 2.0, 2.25, 2.4 mg/m2) in combination with pulse dexamethasone followed. There were no restrictions on the number of prior therapies. Subjects with grade 2 or greater central or peripheral neuropathy were ineligible. Results: In total, 52 pts with relapsed or refractory ALL were treated in the two studies combined. Median age was 34 years (range, 19–77), 31 males/21 females, with a median number of prior salvage regimens of 2 (range, 1–3). Nine pts had confirmed Philadelphia positive disease (8 in the pre-imatinib era, 1 resistant to tyrosine kinase inhibitor therapy). All pts had previously received conventional VCR therapy. There were 8 complete remissions and 3 partial remissions for an overall response rate of 21% [95% CI, 11, 35]. An additional 12 pts (23%) achieved hematological improvements (e.g., clearance of marrow blasts, platelet transfusion independence). Five responders were able to undergo allogeneic stem cell transplantation following therapy with Marqibo. The maximum tolerated dose in the phase I trial was 2.25 mg/m2 owing to grade 3 motor neuropathy, grade 4 seizure, and grade 4 hepatotoxicity observed in 1 patient each at the 2.4 mg/m2 dose level. Grade 1–2 peripheral neuropathy was manageable with dose modifications and anti-neuralgia agents such as gabapentin. Commonly observed toxicities included febrile neutropenia, myelosuppression, abdominal pain, nausea, constipation, diarrhea, fatigue, and infusion-related pyrexia. Conclusions: In reviewing the clinical experience to date, Marqibo with or without pulse dexamethasone has provided clinically meaningful activity in heavily pre-treated adults with ALL. A multicenter trial of single agent Marqibo in the setting of second salvage therapy for adults with relapsed ALL is underway. A phase III multicenter trial of Marqibo in combination with standard chemotherapy for de novo elderly ALL is in the planning phase.

Description: Abstract 2143 Background: The outcome of adults with relapsed/refractory ALL, and of those whose disease recurs after first salvage, in particular, is extremely poor. Second salvage therapy with single agents has historically produced a complete response (CR) in only 4% of patients. (O'Brien, S, et al. Cancer 2008; 113:3186-3191). Third salvage therapy has not been studied but would be expected to be even less effective. Conventional vincristine sulfate (VCR) is an effective anti-leukemia agent, widely used in the treatment of ALL as part of several intensive regimens. VCR is dosed at 1.4 mg/m2 with a 2 mg cap due to early onset of peripheral neuropathy. VSLI (Marqibo) is a nano-particle encapsulated formulation of VCR designed to facilitate dose intensification, improve duration of drug exposure, and enhance cancer and bone marrow drug delivery. Methods: Two distinct studies investigated VSLI in adult patients with advanced, relapsed/refractory ALL. Study VSLI-06 was a Phase 1/2, multi-center, 36 patient, dose-escalation study to determine safety, maximum tolerated dose, and anti-leukemia activity. Patients received VSLI intravenously (IV) weekly at doses of 1.5, 1.825, 2.0, 2.25 or 2.4 mg/m2 with no dose cap plus dexamethasone 40 mg on days 1–4 and 11–14 of each 4 week cycle. The RALLY Study was a Phase 2, multi-national, 65 patient study of single-agent VSLI (2.25 mg/m2 IV weekly without dose cap) in adults with ALL in second relapse or who had progressed following at least two prior lines of anti-leukemia therapy. All subjects had been previously treated with VCR, and all received at least one dose of VSLI. The median age in both studies was 32 years with a combined range of 19 to 83 years. Other than one subject in VSLI-06, all subjects were Philadelphia chromosome negative. Results: The combined overall response rate was 31% (31 of 101). The combined complete response (CR) rate including CR with incomplete platelet (CRp) or hematologic (CRi) recovery was 20% (20/101). This response rate was consistent across the studies (19.4% and 20%, respectively). Hematologic improvement (HI) was achieved in 4 patients (11%) in VSLI-06 and 9 (14%) in RALLY, thus reducing transfusions and hospital visits. Five patients were able to receive a post-VSLI hematopoietic stem cell transplant (HSCT) in VSLI-06, and 10 patients were able to receive a post-VSLI HSCT in RALLY. The table below summarizes key study characteristics. The most commonly reported safety events in the studies were similar and included constipation, neuropathy, fatigue, nausea, pyrexia, febrile neutropenia, and anemia. Conclusion: These two studies totaling 101 patients with similar populations of advanced relapsed/refractory ALL showed a combined 20% CR/CRp/CRi rate, dwarfing the rate in historical studies. This is particularly encouraging, given that 100% of subjects had received prior VCR and that historical control data were largely in a less heavily pre-treated population. Both VSLI alone and combined with pulse dexamethasone appear to be highly active. In total, 15% of combined study patients were able to “bridge” to HSCT. Use of VSLI in the frontline setting and in combination regimens should further improve ALL patient outcomes. Disclosures: Messerschmidt: Hana Biosciences, Inc.: Employment. Hagey: Hana Biosciences, Inc.: Employment. Deitcher: Hana Biosciences: Employment. Kantarjian: Hana Biosciences, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 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. 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.

Description: 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 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.

Description: Alfimeprase, a recombinantly produced 22.6 kilodalton metalloproteinase, is a genetically modified variant of fibrolase. Alfimeprase, like fibrolase, proteolytically cleaves both the alpha and beta chains of fibrin(ogen) independent of plasminogen activation to plasmin and directly dissolves thrombi. Readily abundant alpha-2 macroglobulin acts as an endogenous circulating alfimeprase inactivator, forming a covalent, irreversible bond with alfimeprase which results in an inactive complex. Based on the direct thrombolytic effect of alfimeprase, rapid activity was hypothesized. We performed a Phase 2, randomized, double-blind, controlled, dose-ranging study to compare the safety and efficacy of one or two instillations of three intraluminal doses of alfimeprase (0.3 mg; 1.0 mg; and 3.0 mg) and Cathflo® Activase® (Genentech) 2.0 mg in reestablishing patency to occluded central venous access devices (CVADs). This report describes an interim analysis of 48 patients with CVAD withdrawal occlusion who were enrolled and randomized to treatment. Catheter patency was assessed at 5, 15, 30, and 120 minutes after each dose of study drug. Adverse events including bleeding events were assessed for a 30-day period after exposure to study drug. Cumulative patency rates are shown in the table. All study arms had similar patency rates at 120 minutes after the first dose. The alfimeprase 3.0 mg dose produced the highest patency rate at 120 minutes after the second dose. All three alfimeprase doses were more effective than Cathflo® Activase® during the first 30 minutes of treatment. The alfimeprase 1.0 mg and 3.0 mg doses resulted in ≥ 50% patency restoration rates at 15 minutes compared to 0% for Cathflo® Activase®. No intracranial hemorrhage, major hemorrhagic, or embolic events were reported in any treated patients at 5 days. Efficacy and safety results of this study support further evaluation of alfimeprase doses ranging from 1.0 mg to 3.0 mg for treatment of occluded CVADs. Cumulative Patency Rate (%) Alfimeprase 0.3 Alfimeprase 1 Alfimeprase 3 Cathflo Activase N=13 N=14 N=9 N=12 D=dose; min=minutes after dose Baseline 0 0 0 0 D 1; 5 min 15 14 44 0 D 1; 15 min 15 50 57 0 D 1; 30 min 30 50 57 25 D 1; 120 min 46 50 57 50 D 2; 5 min 46 50 57 58 D 2; 15 min 46 50 57 67 D 2; 30 min 46 50 57 67 D 2; 120 min 46 50 78 67

Description: Background Despite 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. Methods Twenty-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. Results The 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. Conclusion High 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.