The Experts below are selected from a list of 564 Experts worldwide ranked by ideXlab platform

Steven R Deitcher - One of the best experts on this subject based on the ideXlab platform.

  • high dose Vincristine Sulfate liposome injection marqibo is not associated with clinically meaningful hematologic toxicity
    Clinical Lymphoma Myeloma & Leukemia, 2013
    Co-Authors: Olivia R Deitcher, Agop Y Bedikian, Jeffrey A Silverman, Takami Sato, John A Glaspy, Rene Gonzalez, Karen Segarini, Steven R Deitcher
    Abstract:

    Abstract Background Vincristine Sulfate liposome injection (VSLI) facilitates Vincristine dose intensification and densification, is active in untreated and relapsed lymphoma, and has been approved in the United States for relapsed and refractory acute lymphoblastic leukemia. Cancer- and concomitant chemotherapy-related anemia, neutropenia, and thrombocytopenia in patients with hematologic malignancy have complicated the evaluation of hematologic toxicity related to new drugs. Patients and Methods We assessed the hematologic toxicity of VSLI 2.25 mg/m 2 administered every 14 (cohort 1) or 7 (cohort 2) days in 54 patients with metastatic uveal melanoma, a cancer not known to involve the bone marrow. Results Cohort 2 received a greater median number of VSLI doses (6 vs. 4) within a shorter median period (5.7 vs. 8.7 weeks), resulting in a larger median cumulative exposure (22.6 vs. 17.7 mg) and near doubling of the median dose density (2.2 vs. 4.0 mg/wk) compared with cohort 1. Despite greater VSLI exposure and dose density, cohort 2 had a lower median decrease from baseline in the neutrophil count and a greater increase from baseline in the platelet count compared with cohort 1. Hematologic adverse events (AEs) were uncommon and mostly grade 1 or 2 in severity. No grade 4 hematologic AEs developed. Conclusion VSLI at its approved dose resulted in a low incidence of clinically meaningful hematologic toxicity. A near doubling of the median dose density did not have an identifiable effect on the reported incidence and severity of hematologic AEs. VSLI could be well suited for use combined with myelosuppresive drugs and for patients unable to tolerate peripheral blood cytopenia.

  • pharmacokinetics and pharmacodynamics of Vincristine Sulfate liposome injection vsli in adults with acute lymphoblastic leukemia
    The Journal of Clinical Pharmacology, 2013
    Co-Authors: Jeffrey A Silverman, Laurie Reynolds, Steven R Deitcher
    Abstract:

    Vincristine Sulfate liposome injection (VSLI,) is a sphingomyelin and cholesterol nanoparticle formulation of Vincristine Sulfate (VCR) that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR. In contrast to the rapid CL and wide tissue distribution of non-liposomal VCR, VSLI circulates in plasma for a prolonged period of time, with a slow CL of 345 mL/h and relatively small Vd of 3,570 mL. This facilitates enhanced and prolonged tumor-tissue delivery of VCR. The maximum tolerated dose of VSLI, 2.25 mg/m(2) once per week without a dose cap, enables individual and cumulative VCR exposure unachievable with non-liposomal VCR at its labeled dose of 1.4 mg/m(2) . VSLI is associated with a dose-dependent peripheral neurotoxicity albeit at doses that are two to three times that of standard VCR. VCR dose intensification with VSLI correlated with an increased probability of overall response and a strong trend towards increased complete response in adults with relapsed and/or refractory acute lymphoblastic leukemia. Overall, VSLI improves the therapeutic index by facilitating increased dose intensification while maintaining a predictable and manageable safety profile.

  • long term results of a phase 2 study of Vincristine Sulfate liposome injection marqibo substituted for non liposomal Vincristine in cyclophosphamide doxorubicin Vincristine prednisone with or without rituximab for patients with untreated aggressive n
    British Journal of Haematology, 2013
    Co-Authors: Fredrick B Hagemeister, Steven R Deitcher, Maria Alma Rodriguez, Anas Younes, Luis Fayad, Andre Goy, Nam H Dang, Arthur D Forman, Peter Mclaughlin, L J Medeiros
    Abstract:

    Vincristine Sulfate liposome injection (VSLI; Marqibo(®) ; M) is active in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory adult acute lymphocytic leukaemia. We evaluated VSLI (2·0 mg/m(2) without dose cap) substituted for non-liposomal Vincristine (VCR) in a cyclophosphamide, doxorubicin, Vincristine, prednisone ± ritiximab (CHOP±R) regimen, creating CHMP±R in 72 untreated, aggressive non-Hodgkin lymphoma patients, including 60 with diffuse large B-cell lymphoma (DLBCL). The overall response rate was 96% (69/72) including complete response (CR) in 65 (90%) and unconfirmed CR in 2 (3%). Median progression-free survival (PFS) and overall survival (OS) were not reached at median follow-up of 8 and 10·2 years, respectively. The 5- and 10-year PFS and OS were 75%, 63%, 87%, and 77%, respectively. Despite VSLI exposure of up to 35 mg, the safety profile of CHMP±R was comparable to that reported for CHOP±R. Grade 3 peripheral neuropathy was reported in 2 (3%) patients; there was no reported Grade 3/4 constipation. CHMP±R was highly active, generally well tolerated, and compared favourably to historical trials with R-CHOP in DLBCL. This enhanced activity probably reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A Phase 3 trial of R-CHMP versus R-CHOP in elderly patients with untreated DLBCL is ongoing.

  • Marqibo^® (Vincristine Sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of Vincristine
    Cancer Chemotherapy and Pharmacology, 2013
    Co-Authors: Jeffrey A Silverman, Steven R Deitcher
    Abstract:

    Vincristine (VCR) is a mainstay of treatment of hematologic malignancies and solid tumors due to its well-defined mechanism of action, demonstrated anticancer activity and its ability to be combined with other agents. VCR is an M-phase cell cycle-specific anticancer drug with activity that is concentration and exposure duration dependent. The pharmacokinetic profile of standard VCR is described by a bi-exponential elimination pattern with a very fast initial distribution half-life followed by a longer elimination half-life. VCR also has a large volume of distribution, suggesting diffuse distribution and tissue binding. These properties may limit optimal drug exposure and delivery to target tissues as well as clinical utility as a single agent or as an effective component of multi-agent regimens. Vincristine Sulfate liposome injection (VSLI), Marqibo^®, is a sphingomyelin and cholesterol-based nanoparticle formulation of VCR that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR. VSLI was developed to increase the circulation time, optimize delivery to target tissues and facilitate dose intensification without increasing toxicity. In xenograft studies in mice, VSLI had a higher maximum tolerated dose, superior antitumor activity and delivered higher amounts of active drug to target tissues compared to standard VCR. VSLI recently received accelerated FDA approval for use in adults with advanced, relapsed and refractory Philadelphia chromosome-negative ALL and is in development for untreated adult ALL, pediatric ALL and untreated aggressive NHL. Here, we summarize the nonclinical data for VSLI that support its continued clinical development and recent approval for use in adult ALL.

  • Vincristine Sulfate liposome injection vsli marqibo facilitates increased delivery of Vincristine Sulfate to target cancer tissues
    Blood, 2012
    Co-Authors: Jeffrey A Silverman, Steven R Deitcher
    Abstract:

    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. | | AUCinf, ng eq*hr/g | |:---- | ------------------ | ------ | | | Spleen | Liver | Lymph node | Bone marrow | | VSLI | 381,154 | 28,202 | 66,333 | 40,936 | | VCR | 30,765 | 6,496 | 6,420 | 17,767 | 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.

Dan Douer - One of the best experts on this subject based on the ideXlab platform.

  • high dose Vincristine Sulfate liposome injection for advanced relapsed or refractory philadelphia chromosome negative acute lymphoblastic leukemia in an adolescent and young adult subgroup of a phase 2 clinical trial
    Journal of adolescent and young adult oncology, 2018
    Co-Authors: Gary J Schiller, Lloyd E Damon, Steven Coutre, Pamela Hsu, Gajanan Bhat, Dan Douer
    Abstract:

    Purpose: A study of Vincristine Sulfate (VCR) liposome injection (VSLI) was conducted in patients with advanced, relapsed, or refractory, Philadelphia chromosome-negative acute lymphoblastic/lympho...

  • efficacy and safety of Vincristine Sulfate liposome injection in the treatment of adult acute lymphocytic leukemia
    Oncologist, 2016
    Co-Authors: Dan Douer
    Abstract:

    UNLABELLED : Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies that arise from clonal proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs. The vinca alkaloid Vincristine is a standard component of chemotherapy regimens used to treat ALL, because of its well-defined mechanism of action, demonstrated anticancer activity, and ability to be combined with other agents. However, the dosage of Vincristine is frequently capped because of neurotoxicity concerns, and patients with large body surface areas are, therefore, almost always underdosed. Liposomal formulations have the ability to "passively" accumulate at sites of increased vasculature permeability and reduce the adverse effects of encapsulated relative to free drug. Vincristine Sulfate liposome injection (VSLI) is a sphingomyelin/cholesterol-based liposome-encapsulated formulation that is delivered weekly in a 1-hour infusion. Based on the pharmacokinetics of the liposomal delivery system, Vincristine is slowly released from the liposome and delivered into the tissues more efficiently than with the standard preparation, allowing a higher dose. This increase in therapeutic index from reduced toxicity is a valuable difference between the two formulations. VSLI is indicated for the treatment of adults with second or greater relapse and clinically advanced Philadelphia chromosome-negative ALL. For the first time, studies will be able to exploit the delivery of higher and uncapped doses of Vincristine in randomized studies comparing first-line chemotherapy with standard Vincristine versus VSLI in both ALL and lymphoma to determine whether VSLI is superior to conventional Vincristine. IMPLICATIONS FOR PRACTICE This review summarizes the development of Vincristine Sulfate liposome injection, a new formulation of Vincristine. The pharmacokinetics of liposomal drug delivery are examined, the limitations and advantages of conventional and liposomal Vincristine are compared, and the use of Vincristine Sulfate liposome injection in clinical trials and case studies is included. Clinicians will be informed of a new chemotherapy agent that is indicated for the treatment of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia, whose disease has relapsed two or more times or whose leukemia has progressed after two or more regimens of antileukemia therapy.

  • marqibo Vincristine Sulfate liposome injection for the treatment of advanced relapsed or refractory philadelphia chromosome negative ph acute lymphoblastic leukemia all in an adolescent young adult aya population
    Blood, 2015
    Co-Authors: Gary J Schiller, Lloyd E Damon, Steven Coutre, Pamela Hsu, Wendy Stock, Lucy Prasad, Dan Douer
    Abstract:

    Background : Patients aged 15 to 39 years old constitute the Adolescent Young Adult (AYA) population. In the US, leukemias represent ~6% of all cancers in this population with the incidence of Acute Lymphoblastic Leukemia (ALL) gradually decreasing with age as the incidence of acute and chronic myeloid leukemias (AML, CML, respectively) increase; ALL occurs at approximately twice the rate of AML in 15- to 19-year olds. Further studies are needed to define the unique features of leukemia in AYA patients, and to better assess and optimize treatment regimens. Marqibo®, Vincristine Sulfate liposome injection, uses a novel sphingomyelin and cholesterol nanoparticle that facilitates Vincristine dose intensification without exacerbation of its toxicity, i.e., it has a wider therapeutic index than standard formulation Vincristine. This formulation has also been shown to enhance the penetration and concentration of Vincristine into tumors, and prolong plasma circulation time in non-clinical experiments. Marqibo is approved in the US for the treatment of adult patients with Philadelphia chromosome negative (Ph-) ALL in second or greater relapse, whose disease has progressed following two or more previous lines of therapy. We performed a retrospective analysis of data from the Phase 2 RALLY clinical trial (n=65) to examine the effects of Marqibo in the subgroup of the AYA population. The Phase 2 study results of the entire study demonstrated that treatment with single-agent Marqibo resulted in an Overall Response Rate (ORR) of 35%, with 20% of patients achieving a Complete Response (CR) or CR with Incomplete Blood Count Recovery (CRi) (O'Brien, S., 2012 J Clin Oncol). Methods : Data from the RALLY Phase 2 study of Marqibo were analyzed retrospectively to examine only the relapsed or refractory Ph- ALL patients 39 years of age and younger (n=44). In this study, Marqibo (2.25mg/m2) was administered via IV over 60 minutes without dose capping, once per week until response, progression, toxicity or hematopoietic transplant. Results : The median age of the 44 patients was 27 (range: 19-39), 57% were male, 82% had B-cell ALL and 18% had T-cell ALL. 84% had ECOG performance status of 0 or 1. The number of previous treatments ranged from 2-6. 41% had 2 prior lines of treatment, 41% had 3 prior lines of treatment, 16% had 4 prior lines of treatment and 2% had 6 prior lines of treatment. In addition, 59% of patients had previously received a hematopoietic cell transplant. The ORR in the AYA population was 39%, with 25% of patients achieving a CR or CRi. Overall, the safety profile of Marqibo was similar to that in the older adult population, with 35 (79.5%) patients having a treatment-related adverse event, of any grade, on study. The most common treatment-related adverse events, of any grade, in the AYA population were constipation (34%) and peripheral neuropathy (32%). Conclusions : Marqibo (Vincristine Sulfate liposome injection) was shown to have clinical benefit in AYA patients with relapsed or refractory Ph- ALL with similar safety and efficacy profiles compared to the entire adult population (range: 19-83). Disclosures Schiller: Sunesis: Honoraria, Research Funding. Damon: Atara: Consultancy; Sunesis: Research Funding; McGraw Hill: Other: Chapter Royalties; Sigms Tau: Research Funding. Stock: Gilead: Membership on an entity's Board of Directors or advisory committees. Coutre: Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Douer: Gilead: Consultancy.

  • high dose Vincristine Sulfate liposome injection for advanced relapsed and refractory adult philadelphia chromosome negative acute lymphoblastic leukemia
    Journal of Clinical Oncology, 2013
    Co-Authors: Susan Obrien, Gary J Schiller, Lloyd E Damon, Steven Coutre, Wendy Stock, John Lister, Stuart L Goldberg, Walter E Aulitzky, Dina Benyehuda, Dan Douer
    Abstract:

    Purpose Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine Sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle Vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) –negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Patients and Methods Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m2, without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete respon...

  • pivotal phase 2 study of weekly Vincristine Sulfate liposomes injection vsli marqibo in adults with philadelphia chromosome negative acute lymphoblastic leukemia all in second relapse or progressing following two anti leukemia treatment lines
    Blood, 2009
    Co-Authors: Susan Obrien, Dan Douer, Gary J Schiller, Lloyd E Damon, John Lister, Dina Benyehuda, Farhad Ravandi, Aisha Masood, Jacob M Rowe, Nicola Gokbuget
    Abstract:

    Abstract 3088 Poster Board III-25 Adult ALL is a disease of primarily young and middle-aged adults that is associated with a high relapse rate following initial remission induction and a short overall survival following relapse. Patients in second relapse must deal with the lingering toxicities of prior therapies, organ dysfunction secondary to extramedullary disease, and the absence of fully approved and standard of care therapies for this advanced disease setting. Realistic goals of treatment in second relapse include eradication of leukemia, bridging to stem cell transplant, and prolongation of survival. Vincristine is active against leukemia and is typically used as part of multi-agent regimens to treat relapsed disease, but the pharmacokinetic profile and dosing cap are suboptimal and contribute to poor disease control and abysmal overall survival. VSLI is a nanoparticle formulation of Vincristine Sulfate USP encapsulated in sphingomyelin/cholesterol liposomes called Optisomes™. The Optisomal formulation permits dose intensification beyond that attainable with conventional Vincristine Sulfate injection, USP (VSI). VSLI provides a long circulation time and slow release of encapsulated Vincristine Sulfate resulting in enhanced tumor penetration and concentration. Preclinical studies of VSLI showed enhanced efficacy versus VSI in a variety of solid and hematologic malignancies. VSLI has a maximum tolerated dose of 2.25 mg/m2 weekly with no dose cap, while conventional Vincristine Sulfate is dosed at 1.4 mg/m2 with a 2 mg dose cap. A previous study involving VSLI in relapsed ALL showed a complete response rate of 19%, suggesting activity in the relapsed setting and prompting further study. This international, multicenter, single-arm study has completed enrollment of its target 56 subjects at 21 centers in 4 countries over 27 months. Major endpoints include response rate (CR/CRi) and overall survival (OS). 56 adult subjects received single agent intravenous VSLI at a dose of 2.25 mg/m2 weekly with no dose cap. The highest single dose of VSLI given to date in this study was 5.22 mg contrasted to the 2 mg dose this subject would have received with conventional Vincristine. Subjects were monitored for disease response every 4 weeks and could be treated until disease progression. Of the demographic data available for 48 subjects, 24 were female and 24 male with a mean age of 38.7 years (range 19.3-79.6). All subjects received at least one prior Vincristine-containing regimen and 21 subjects (44%) received Vincristine Sulfate in two prior regimens. 18 subjects (37%) had a prior stem cell transplant and 2 subjects (4%) had 2 prior stem cell transplants before receiving single agent VSLI. 71% of subjects had an ECOG Performance Status of 1 or greater, with 21% ECOG 2 or 3. Seven subjects (15%) had evidence of extramedullary disease at study entry. At interim analysis, treatment with single agent VSLI produced morphologic and cytogenetic CR in several of these heavily pretreated subjects, suggesting significant activity of VSLI in second relapsed leukemia. Of investigator-reported responses on 48 subjects with data available to date, 71% have evidence of either disease response or disease stabilization and 29% have reported disease progression. Of the subjects experiencing CR/CRi, at least 5 subjects subsequently underwent allogeneic stem cell transplant after receiving VSLI. At the time of this abstract the median OS is estimated to be 4.7 months (Q1-Q3: 3.4-10.5) using Kaplan-Meier methodology. The 5 most frequently reported adverse event are peripheral neuropathy, 14.6% Grade 3 or 4 (100% attributed to study drug); constipation, 2.4% Grade 3 (100% attributed to study drug); nausea, no Grade 3 or higher; pyrexia, 9.8% Grade 3 (2.4% attributed to study drug); and febrile neutropenia, 34.2% Grade 3 or 4 (7.3% attributed to study drug). VSLI is a promising new agent for the treatment of acute lymphoblastic leukemia in second relapse, a situation where there is high unmet need and no approved therapies exist. VSLI may be used as a single agent as a bridge to transplant in these heavily pretreated, multiply-relapsed subjects, or considered as a substitute for conventional Vincristine Sulfate. The ability to complete enrollment rapidly internationally with compelling evidence of objective responses in this study underscores the enthusiasm for and importance of developing VSLI for the treatment of this orphan leukemia indication. Efficacy data and preliminary PK results from the target 56 subjects will be presented. Disclosures O9Brien:Hana Biosciences, Inc.: Consultancy. Hagey:Hana Biosciences, Inc.: Employment. Deitcher:Hana Biosciences, Inc.: Employment. Kantarjian:Hana Biosciences, Inc.: Consultancy.

Lloyd E Damon - One of the best experts on this subject based on the ideXlab platform.

  • high dose Vincristine Sulfate liposome injection for advanced relapsed or refractory philadelphia chromosome negative acute lymphoblastic leukemia in an adolescent and young adult subgroup of a phase 2 clinical trial
    Journal of adolescent and young adult oncology, 2018
    Co-Authors: Gary J Schiller, Lloyd E Damon, Steven Coutre, Pamela Hsu, Gajanan Bhat, Dan Douer
    Abstract:

    Purpose: A study of Vincristine Sulfate (VCR) liposome injection (VSLI) was conducted in patients with advanced, relapsed, or refractory, Philadelphia chromosome-negative acute lymphoblastic/lympho...

  • marqibo Vincristine Sulfate liposome injection for the treatment of advanced relapsed or refractory philadelphia chromosome negative ph acute lymphoblastic leukemia all in an adolescent young adult aya population
    Blood, 2015
    Co-Authors: Gary J Schiller, Lloyd E Damon, Steven Coutre, Pamela Hsu, Wendy Stock, Lucy Prasad, Dan Douer
    Abstract:

    Background : Patients aged 15 to 39 years old constitute the Adolescent Young Adult (AYA) population. In the US, leukemias represent ~6% of all cancers in this population with the incidence of Acute Lymphoblastic Leukemia (ALL) gradually decreasing with age as the incidence of acute and chronic myeloid leukemias (AML, CML, respectively) increase; ALL occurs at approximately twice the rate of AML in 15- to 19-year olds. Further studies are needed to define the unique features of leukemia in AYA patients, and to better assess and optimize treatment regimens. Marqibo®, Vincristine Sulfate liposome injection, uses a novel sphingomyelin and cholesterol nanoparticle that facilitates Vincristine dose intensification without exacerbation of its toxicity, i.e., it has a wider therapeutic index than standard formulation Vincristine. This formulation has also been shown to enhance the penetration and concentration of Vincristine into tumors, and prolong plasma circulation time in non-clinical experiments. Marqibo is approved in the US for the treatment of adult patients with Philadelphia chromosome negative (Ph-) ALL in second or greater relapse, whose disease has progressed following two or more previous lines of therapy. We performed a retrospective analysis of data from the Phase 2 RALLY clinical trial (n=65) to examine the effects of Marqibo in the subgroup of the AYA population. The Phase 2 study results of the entire study demonstrated that treatment with single-agent Marqibo resulted in an Overall Response Rate (ORR) of 35%, with 20% of patients achieving a Complete Response (CR) or CR with Incomplete Blood Count Recovery (CRi) (O'Brien, S., 2012 J Clin Oncol). Methods : Data from the RALLY Phase 2 study of Marqibo were analyzed retrospectively to examine only the relapsed or refractory Ph- ALL patients 39 years of age and younger (n=44). In this study, Marqibo (2.25mg/m2) was administered via IV over 60 minutes without dose capping, once per week until response, progression, toxicity or hematopoietic transplant. Results : The median age of the 44 patients was 27 (range: 19-39), 57% were male, 82% had B-cell ALL and 18% had T-cell ALL. 84% had ECOG performance status of 0 or 1. The number of previous treatments ranged from 2-6. 41% had 2 prior lines of treatment, 41% had 3 prior lines of treatment, 16% had 4 prior lines of treatment and 2% had 6 prior lines of treatment. In addition, 59% of patients had previously received a hematopoietic cell transplant. The ORR in the AYA population was 39%, with 25% of patients achieving a CR or CRi. Overall, the safety profile of Marqibo was similar to that in the older adult population, with 35 (79.5%) patients having a treatment-related adverse event, of any grade, on study. The most common treatment-related adverse events, of any grade, in the AYA population were constipation (34%) and peripheral neuropathy (32%). Conclusions : Marqibo (Vincristine Sulfate liposome injection) was shown to have clinical benefit in AYA patients with relapsed or refractory Ph- ALL with similar safety and efficacy profiles compared to the entire adult population (range: 19-83). Disclosures Schiller: Sunesis: Honoraria, Research Funding. Damon: Atara: Consultancy; Sunesis: Research Funding; McGraw Hill: Other: Chapter Royalties; Sigms Tau: Research Funding. Stock: Gilead: Membership on an entity's Board of Directors or advisory committees. Coutre: Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Douer: Gilead: Consultancy.

  • high dose Vincristine Sulfate liposome injection for advanced relapsed and refractory adult philadelphia chromosome negative acute lymphoblastic leukemia
    Journal of Clinical Oncology, 2013
    Co-Authors: Susan Obrien, Gary J Schiller, Lloyd E Damon, Steven Coutre, Wendy Stock, John Lister, Stuart L Goldberg, Walter E Aulitzky, Dina Benyehuda, Dan Douer
    Abstract:

    Purpose Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine Sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle Vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) –negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Patients and Methods Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m2, without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete respon...

  • 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
    Blood, 2011
    Co-Authors: Lloyd E Damon, Gary J Schiller, Leonard T Heffner, John Lister, Stuart L Goldberg, Steven R Deitcher
    Abstract:

    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-naive 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-naive 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 entity9s Board of Directors or advisory committees.

  • 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
    Blood, 2011
    Co-Authors: Gary J Schiller, Jeffrey A Silverman, Lloyd E Damon, Leonard T Heffner, John Lister, Stuart L Goldberg, Steven R Deitcher
    Abstract:

    Abstract 4235 A 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][1]) clinical trial and a multi-national, Phase 2 (HBS407; [NCT00495079][2]) 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. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00144963&atom=%2Fbloodjournal%2F118%2F21%2F4235.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00495079&atom=%2Fbloodjournal%2F118%2F21%2F4235.atom

Susan Obrien - One of the best experts on this subject based on the ideXlab platform.

  • high dose Vincristine Sulfate liposome injection for advanced relapsed and refractory adult philadelphia chromosome negative acute lymphoblastic leukemia
    Journal of Clinical Oncology, 2013
    Co-Authors: Susan Obrien, Gary J Schiller, Lloyd E Damon, Steven Coutre, Wendy Stock, John Lister, Stuart L Goldberg, Walter E Aulitzky, Dina Benyehuda, Dan Douer
    Abstract:

    Purpose Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine Sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle Vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) –negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Patients and Methods Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m2, without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete respon...

  • minimal residual disease in adults with advanced relapsed philadelphia chromosome negative acute lymphoblastic leukemia treated with marqibo Vincristine Sulfate liposome injection
    Blood, 2012
    Co-Authors: Olivia R Deitcher, Jeffrey A Silverman, Steven R Deitcher, Gary J Schiller, Wendy Stock, John Lister, Stuart L Goldberg, Susan Obrien
    Abstract:

    Abstract 4805 Minimal 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/m 2 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 2 nd 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 table 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.

  • 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
    Blood, 2011
    Co-Authors: Olivia R Deitcher, Steven R Deitcher, Susan Obrien, Deborah A Thomas, Hagop M Kantarjian
    Abstract:

    Abstract Abstract 2592 There 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 0 Prior HSCT, N (%) 31 (47.7) 0 Prior 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.

  • pivotal phase 2 study of weekly Vincristine Sulfate liposomes injection vsli marqibo in adults with philadelphia chromosome negative acute lymphoblastic leukemia all in second relapse or progressing following two anti leukemia treatment lines
    Blood, 2009
    Co-Authors: Susan Obrien, Dan Douer, Gary J Schiller, Lloyd E Damon, John Lister, Dina Benyehuda, Farhad Ravandi, Aisha Masood, Jacob M Rowe, Nicola Gokbuget
    Abstract:

    Abstract 3088 Poster Board III-25 Adult ALL is a disease of primarily young and middle-aged adults that is associated with a high relapse rate following initial remission induction and a short overall survival following relapse. Patients in second relapse must deal with the lingering toxicities of prior therapies, organ dysfunction secondary to extramedullary disease, and the absence of fully approved and standard of care therapies for this advanced disease setting. Realistic goals of treatment in second relapse include eradication of leukemia, bridging to stem cell transplant, and prolongation of survival. Vincristine is active against leukemia and is typically used as part of multi-agent regimens to treat relapsed disease, but the pharmacokinetic profile and dosing cap are suboptimal and contribute to poor disease control and abysmal overall survival. VSLI is a nanoparticle formulation of Vincristine Sulfate USP encapsulated in sphingomyelin/cholesterol liposomes called Optisomes™. The Optisomal formulation permits dose intensification beyond that attainable with conventional Vincristine Sulfate injection, USP (VSI). VSLI provides a long circulation time and slow release of encapsulated Vincristine Sulfate resulting in enhanced tumor penetration and concentration. Preclinical studies of VSLI showed enhanced efficacy versus VSI in a variety of solid and hematologic malignancies. VSLI has a maximum tolerated dose of 2.25 mg/m2 weekly with no dose cap, while conventional Vincristine Sulfate is dosed at 1.4 mg/m2 with a 2 mg dose cap. A previous study involving VSLI in relapsed ALL showed a complete response rate of 19%, suggesting activity in the relapsed setting and prompting further study. This international, multicenter, single-arm study has completed enrollment of its target 56 subjects at 21 centers in 4 countries over 27 months. Major endpoints include response rate (CR/CRi) and overall survival (OS). 56 adult subjects received single agent intravenous VSLI at a dose of 2.25 mg/m2 weekly with no dose cap. The highest single dose of VSLI given to date in this study was 5.22 mg contrasted to the 2 mg dose this subject would have received with conventional Vincristine. Subjects were monitored for disease response every 4 weeks and could be treated until disease progression. Of the demographic data available for 48 subjects, 24 were female and 24 male with a mean age of 38.7 years (range 19.3-79.6). All subjects received at least one prior Vincristine-containing regimen and 21 subjects (44%) received Vincristine Sulfate in two prior regimens. 18 subjects (37%) had a prior stem cell transplant and 2 subjects (4%) had 2 prior stem cell transplants before receiving single agent VSLI. 71% of subjects had an ECOG Performance Status of 1 or greater, with 21% ECOG 2 or 3. Seven subjects (15%) had evidence of extramedullary disease at study entry. At interim analysis, treatment with single agent VSLI produced morphologic and cytogenetic CR in several of these heavily pretreated subjects, suggesting significant activity of VSLI in second relapsed leukemia. Of investigator-reported responses on 48 subjects with data available to date, 71% have evidence of either disease response or disease stabilization and 29% have reported disease progression. Of the subjects experiencing CR/CRi, at least 5 subjects subsequently underwent allogeneic stem cell transplant after receiving VSLI. At the time of this abstract the median OS is estimated to be 4.7 months (Q1-Q3: 3.4-10.5) using Kaplan-Meier methodology. The 5 most frequently reported adverse event are peripheral neuropathy, 14.6% Grade 3 or 4 (100% attributed to study drug); constipation, 2.4% Grade 3 (100% attributed to study drug); nausea, no Grade 3 or higher; pyrexia, 9.8% Grade 3 (2.4% attributed to study drug); and febrile neutropenia, 34.2% Grade 3 or 4 (7.3% attributed to study drug). VSLI is a promising new agent for the treatment of acute lymphoblastic leukemia in second relapse, a situation where there is high unmet need and no approved therapies exist. VSLI may be used as a single agent as a bridge to transplant in these heavily pretreated, multiply-relapsed subjects, or considered as a substitute for conventional Vincristine Sulfate. The ability to complete enrollment rapidly internationally with compelling evidence of objective responses in this study underscores the enthusiasm for and importance of developing VSLI for the treatment of this orphan leukemia indication. Efficacy data and preliminary PK results from the target 56 subjects will be presented. Disclosures O9Brien:Hana Biosciences, Inc.: Consultancy. Hagey:Hana Biosciences, Inc.: Employment. Deitcher:Hana Biosciences, Inc.: Employment. Kantarjian:Hana Biosciences, Inc.: Consultancy.

  • marqibo Vincristine Sulfate liposomes injection optisome concentrates Vincristine in tumor tissue and lymphoid malignancy oriented tissues in tumor bearing mice
    Blood, 2007
    Co-Authors: Pieter R Cullis, Hagop M Kantarjian, Susan Obrien, May Wong, Frederick R Appelbaum, Gavin S Choy, Steven R Deitcher
    Abstract:

    Background: Vincristine Sulfate (VCR) is a cell-cycle specific, lipophilic, anti-cancer drug that inhibits cell division by binding to tubulin in mitotic spindles. Marqibo is a proprietary sphingomyelin/cholesterol liposome (OPTISOME) encapsulated formulation of VCR with an extended circulating half-life and the potential for preferential malignancy targeting, exposure, and anti-cancer activity. This report evaluates the concentration and accumulation of VCR in solid tumor tissue as well as tissues frequently involved with lymphoid malignancies in tumor-bearing mice following equivalent doses of Marqibo or conventional VCR. Methods: Mice were implanted subcutaneously with MX-1 human breast tumor tissue. When the tumor volume reached 162–485 mm3, mice received a single intravenous dose of Marqibo, containing 1.5 mg/kg of [14C]-VCR, or 1.5 mg/kg of non-liposomal [14C]-VCR. The total radioactivity from parent compound and metabolites in tissue, VCReq, was analyzed by Quantitative Whole Body Autoradioluminography (QWBA) and tissue digestion (TD). QWBA analysis of bone marrow (BM), tumor tissue, lymph nodes, liver, and spleen required 1 flash-frozen mouse per group at various time intervals. Sagittal sections were examined histologically for radioactivity. For TD, all tissues except bone marrow were obtained from 3 mice per group prior to infusion and at selected time points. The samples were chemically digested and analyzed for radioactivity by liquid scintillation counting. Results: QWBA analysis revealed at least two-fold higher VCReq tissue concentrations in the Marqibo-injected mice compared to the conventional VCR-injected mice. | | VCReq Tissue Concentration (mcg/g) at 48 hours Post-Injection | |:-----------------:| ------------------------------------------------------------- | ----- | | | BM | Tumor | Lymph | Liver | Spleen | | Marqibo | 0.99 | 1.35 | 1.98 | 0.47 | 6.08 | | VCR | 0.36 | 0.31 | -- | 0.13 | 0.76 | | Marqibo/VCR ratio | 2.75 | 4.35 | -- | 3.61 | 8 | The TD results are consistent with the QWBA results shown in the table. Marqibo-injected mice demonstrated a minimum 5-fold increase in VCR exposure over a 96 hour period (VCReq AUC analysis) compared to VCR-injected mice over a 48 hour period, as defined in the parameters of the study, in the implanted tumor (123 vs. 21 hr*μg/g), lymph nodes (121 vs. 16.5 hr*μg/g), liver (68.8 vs. 12 hr*μg/g), and spleen (512 vs. 68.9 hr*μg/g). Though the parameters for the AUC values may favor Marqibo, the Tmax of all specified tissues are at least 16 times greater in Marqibo-injected mice than in VCR-injected mice (16 hrs vs. 1hr in tumor, spleen, and lymph; 4 hrs vs. 15 min. in liver; 16 hrs. vs. 15 min. in the kidney). The greatest increase in VCR exposure produced by Marqibo was observed in the spleen and lymph nodes (7.4- and 7.3-fold). Conclusions: Marqibo resulted in targeted delivery of VCR; concentration of VCR in tumor tissue, BM, lymph nodes, liver, and spleen; and maintenance of significant tissue drug concentrations for an extended period of time compared to conventional VCR. The ability of Marqibo to target drug to these tissues and organs makes it particularly attractive as a treatment for hematologic malignancies like myeloma, lymphoma, and acute lymphoblastic leukemia (ALL). Late-stage clinical development of Marqibo in adult ALL is underway.

Jeffrey A Silverman - One of the best experts on this subject based on the ideXlab platform.

  • high dose Vincristine Sulfate liposome injection marqibo is not associated with clinically meaningful hematologic toxicity
    Clinical Lymphoma Myeloma & Leukemia, 2013
    Co-Authors: Olivia R Deitcher, Agop Y Bedikian, Jeffrey A Silverman, Takami Sato, John A Glaspy, Rene Gonzalez, Karen Segarini, Steven R Deitcher
    Abstract:

    Abstract Background Vincristine Sulfate liposome injection (VSLI) facilitates Vincristine dose intensification and densification, is active in untreated and relapsed lymphoma, and has been approved in the United States for relapsed and refractory acute lymphoblastic leukemia. Cancer- and concomitant chemotherapy-related anemia, neutropenia, and thrombocytopenia in patients with hematologic malignancy have complicated the evaluation of hematologic toxicity related to new drugs. Patients and Methods We assessed the hematologic toxicity of VSLI 2.25 mg/m 2 administered every 14 (cohort 1) or 7 (cohort 2) days in 54 patients with metastatic uveal melanoma, a cancer not known to involve the bone marrow. Results Cohort 2 received a greater median number of VSLI doses (6 vs. 4) within a shorter median period (5.7 vs. 8.7 weeks), resulting in a larger median cumulative exposure (22.6 vs. 17.7 mg) and near doubling of the median dose density (2.2 vs. 4.0 mg/wk) compared with cohort 1. Despite greater VSLI exposure and dose density, cohort 2 had a lower median decrease from baseline in the neutrophil count and a greater increase from baseline in the platelet count compared with cohort 1. Hematologic adverse events (AEs) were uncommon and mostly grade 1 or 2 in severity. No grade 4 hematologic AEs developed. Conclusion VSLI at its approved dose resulted in a low incidence of clinically meaningful hematologic toxicity. A near doubling of the median dose density did not have an identifiable effect on the reported incidence and severity of hematologic AEs. VSLI could be well suited for use combined with myelosuppresive drugs and for patients unable to tolerate peripheral blood cytopenia.

  • pharmacokinetics and pharmacodynamics of Vincristine Sulfate liposome injection vsli in adults with acute lymphoblastic leukemia
    The Journal of Clinical Pharmacology, 2013
    Co-Authors: Jeffrey A Silverman, Laurie Reynolds, Steven R Deitcher
    Abstract:

    Vincristine Sulfate liposome injection (VSLI,) is a sphingomyelin and cholesterol nanoparticle formulation of Vincristine Sulfate (VCR) that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR. In contrast to the rapid CL and wide tissue distribution of non-liposomal VCR, VSLI circulates in plasma for a prolonged period of time, with a slow CL of 345 mL/h and relatively small Vd of 3,570 mL. This facilitates enhanced and prolonged tumor-tissue delivery of VCR. The maximum tolerated dose of VSLI, 2.25 mg/m(2) once per week without a dose cap, enables individual and cumulative VCR exposure unachievable with non-liposomal VCR at its labeled dose of 1.4 mg/m(2) . VSLI is associated with a dose-dependent peripheral neurotoxicity albeit at doses that are two to three times that of standard VCR. VCR dose intensification with VSLI correlated with an increased probability of overall response and a strong trend towards increased complete response in adults with relapsed and/or refractory acute lymphoblastic leukemia. Overall, VSLI improves the therapeutic index by facilitating increased dose intensification while maintaining a predictable and manageable safety profile.

  • Marqibo^® (Vincristine Sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of Vincristine
    Cancer Chemotherapy and Pharmacology, 2013
    Co-Authors: Jeffrey A Silverman, Steven R Deitcher
    Abstract:

    Vincristine (VCR) is a mainstay of treatment of hematologic malignancies and solid tumors due to its well-defined mechanism of action, demonstrated anticancer activity and its ability to be combined with other agents. VCR is an M-phase cell cycle-specific anticancer drug with activity that is concentration and exposure duration dependent. The pharmacokinetic profile of standard VCR is described by a bi-exponential elimination pattern with a very fast initial distribution half-life followed by a longer elimination half-life. VCR also has a large volume of distribution, suggesting diffuse distribution and tissue binding. These properties may limit optimal drug exposure and delivery to target tissues as well as clinical utility as a single agent or as an effective component of multi-agent regimens. Vincristine Sulfate liposome injection (VSLI), Marqibo^®, is a sphingomyelin and cholesterol-based nanoparticle formulation of VCR that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR. VSLI was developed to increase the circulation time, optimize delivery to target tissues and facilitate dose intensification without increasing toxicity. In xenograft studies in mice, VSLI had a higher maximum tolerated dose, superior antitumor activity and delivered higher amounts of active drug to target tissues compared to standard VCR. VSLI recently received accelerated FDA approval for use in adults with advanced, relapsed and refractory Philadelphia chromosome-negative ALL and is in development for untreated adult ALL, pediatric ALL and untreated aggressive NHL. Here, we summarize the nonclinical data for VSLI that support its continued clinical development and recent approval for use in adult ALL.

  • Vincristine Sulfate liposome injection vsli marqibo facilitates increased delivery of Vincristine Sulfate to target cancer tissues
    Blood, 2012
    Co-Authors: Jeffrey A Silverman, Steven R Deitcher
    Abstract:

    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. | | AUCinf, ng eq*hr/g | |:---- | ------------------ | ------ | | | Spleen | Liver | Lymph node | Bone marrow | | VSLI | 381,154 | 28,202 | 66,333 | 40,936 | | VCR | 30,765 | 6,496 | 6,420 | 17,767 | 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.

  • neurotoxicity profile of Vincristine Sulfate liposome injection vsli marqibo monotherapy in adults with relapsed acute lymphoblastic leukemia and universal prior standard Vincristine exposure
    Blood, 2012
    Co-Authors: Steven R Deitcher, Jeffrey A Silverman
    Abstract:

    Abstract 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. 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.