Original Study
High-dose Vincristine Sulfate Liposome Injection (Marqibo) Is Not Associated With Clinically Meaningful Hematologic Toxicity Olivia R. Deitcher,1 John Glaspy,2 Rene Gonzalez,3 Takami Sato,4 Agop Y. Bedikian,5 Karen Segarini,1 Jeffrey Silverman,1 Steven R. Deitcher1 Abstract Hematologic toxicity of vincristine sulfate liposome injection (VSLI) was assessed in 54 patients with metastatic cancer not known to involve bone marrow. VSLI was not associated with clinically meaningful blood count changes when dosed at 2.25 mg/m2 every 14 or 7 days. VSLI could be well suited for combination drug therapy and use in patients unable to tolerate blood cytopenias. 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/m2 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. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. 3, 197-202 ª 2014 Elsevier Inc. All rights reserved. Keywords: Anemia, Liposome, Neutropenia, Thrombocytopenia, Vincristine
Introduction The treatment of patients with heavily pretreated, advanced, relapsed, and refractory hematologic malignancies, such as Philadelphia chromosomeenegative (Ph) acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), sometimes requires the 1
Talon Therapeutics, Inc, South San Francisco, CA University of California, Los Angeles, CA University of Colorado Denver, Aurora, CO 4 Thomas Jefferson University, Philadelphia, PA 5 University of Texas MD Anderson Cancer Center, Houston, TX 2 3
Submitted: Jun 24, 2013; Revised: Oct 17, 2013; Accepted: Oct 21, 2013; Epub: Nov 15, 2013 Address for correspondence: Steven R. Deitcher, MD, Talon Therapeutics, Inc, 400 Oyster Point Boulevard, South San Francisco, CA 94080 E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.10.012
use of therapies with limited hematologic toxicity and associated peripheral blood cytopenia. The same requirement might also apply to patients with cancer and advanced age, active infection, cardiovascular disease, recent surgery, or poor performance status. Because of the near-universal, disease-related, and concomitant chemotherapyrelated anemia, neutropenia, and thrombocytopenia, it has been difficult to specifically assess for, and isolate, related hematologic toxicity during the evaluation of new agents in ALL and NHL clinical trials. Vincristine sulfate liposome injection (VSLI) is sphingomyelinand cholesterol-based nanoparticle-encapsulated vincristine (VCR) designed to overcome the dosing and pharmacokinetic limitations of nonliposomal VCR.1-4 In nonclinical experiments, VSLI enhanced VCR penetration and concentration in tissues and organs with fenestrated vasculature or involved in the mononuclear phagocyte system, including ALL and NHL target tissues (eg, bone marrow,
Clinical Lymphoma, Myeloma & Leukemia June 2014
- 197
Liposomal Vincristine Lacks Hematologic Toxicity lymph nodes, spleen) and implanted tumors.2-6 VSLI exhibited greater milligram per milligram anticancer activity and a larger maximum tolerated dose than nonliposomal VCR. In phase 1 dose-finding studies, VSLI was generally well tolerated and active at dose levels up to and including 2.25 mg/m2/wk in adults and children with relapsed and refractory ALL.7,8 All VSLI doses reflected the amount of VCR delivered and were determined by the actual patient body surface area (BSA) without dose capping at any level. Compared with the labeled dose of nonliposomal VCR of 1.4 mg/m2, each weight-based dose of VSLI delivered 61% more VCR. The dose intensification facilitated by the VSLI formulation was even greater compared with the standard, fixed, “capped” 2-mg dose of nonliposomal VCR. In phase 2 studies, VSLI dosed at 2.0 mg/m2 every 2 weeks was effective at inducing complete and partial responses as both monotherapy and combined with rituximab in patients with advanced, relapsed, and refractory aggressive NHL.9,10 The same dose of VSLI, combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHMP, where M ¼ VSLI), produced remarkable response rates and long progression-free and overall survival in patients with untreated diffuse large B-cell lymphoma.11 Weekly single-agent VSLI 2.25 mg/m2 was approved in the United States for adults with relapsed and refractory Ph ALL.12 Because previous and current VSLI development programs have focused on NHL and ALL, a different cancer patient population was required to enable assessment of the hematologic toxicity profile of the drug. Uveal melanoma almost exclusively metastasizes to the liver, lungs, and lymph nodes and is not known to directly invade the bone marrow.13 VSLI has been reported to be active in this rare cancer.14 In our report, we present an assessment of the hematologic toxicity profile of VSLI 2.25 mg/m2 in patients with metastatic uveal melanoma.
Patients and Methods
The institutional review board at the participating centers approved the present study. This study was conducted in accordance with the principles of the World Medical Association’s Declaration of Helsinki and the International Conference on Harmonisation Guideline for Good Clinical Practice. All patients provided written informed consent.
Study Design The data for the present analysis were collected as part of a phase 2, multicenter, single-arm, open-label study (NCT00506142). The patients in cohort 1 were treated with VSLI (Marqibo, Talon Therapeutics, Inc, South San Francisco, CA) 2.25 mg/m2, intravenously (I.V.) by way of a peripheral or central venous catheter within 60 10 minutes every 14 3 days on study day 1 of each 14-day cycle. The patients in cohort 2 were treated with VSLI 2.25 mg/m2 I.V. by way of a peripheral or central venous catheter within 60 10 minutes every 7 3 days on study day 1 and day 8 of each 14-day cycle. The dose calculations were determined from the BSA calculated from the actual body weight obtained at the onset of each cycle and the height obtained at study screening. No VSLI dose capping was used. The patients were treated until the appearance of unacceptable toxicity or an investigator determined that the patient was no longer benefitting from treatment. The duration of VSLI exposure was calculated from the date of the first dose plus 1 day until the date of the last dose plus 6 days to account for the extended release characteristics of the VSLI liposome.1 VSLI dosing modifications for hematologic toxicity were based on the ANC and platelet count assessments on the days of infusion. If the ANC was < 0.5 109/L or the platelet count was < 50.0 109/L, the VSLI dose was delayed for 7 days, and the counts were reassessed. If this grade 3 toxicity persisted, the VSLI was delayed for another 7 days. If the criteria for VSLI treatment were not met after 14 days of delay, the patient was removed from treatment.
Patients
198
-
Adults ( 18 years old) with histologically or cytologically confirmed metastatic uveal melanoma were study eligible. The patients were enrolled in 2 serial cohorts. Cohort 1 patients could have received 1 previous systemic therapy. Previous treatment with immunotherapy or a cancer vaccine was allowed, provided documentation was available of disease progression. Previous treatment with hepatic arterial chemotherapy infusion or perfusion or chemoembolization of liver metastasis was allowed as long as extrahepatic disease or progression of the liver metastasis was present after regional therapy. Cohort 1 patients must not have been previously treated with a vinca alkaloid. Cohort 2 patients must not have received any previous systemic chemotherapy, immunotherapy, cancer vaccine, or hepatic arterial chemotherapy for metastatic disease. Study eligibility required adequate liver and kidney function, as defined by a serum total bilirubin at or less than the institution’s upper normal limit and a serum creatinine level of 2.0 mg/dL. Patients had to have adequate bone marrow function, as defined by an absolute neutrophil count (ANC) 1.0 109/L and platelet count 100 109/L. The patients had to have a Zubrod performance status of 0 to 2. Patients with known positive human immunodeficiency virus status, symptomatic central nervous system metastasis, and active serious infection not controlled by systemic antimicrobial agents were excluded.
Clinical Lymphoma, Myeloma & Leukemia June 2014
Hematology Assessment The hematologic toxicity evaluation was based on serial peripheral blood assessments and hematologic adverse event (AE) reporting using Medical Dictionary for Regulatory Activities, version 12.1 (MedDRA, McLean, VA). AE severity was graded according to the National Cancer Institute’s “Common Terminology Criteria for Adverse Events, version 3.0.” Bone marrow assessments were not mandated.
Statistical Analysis Descriptive and inferential analyses were used to summarize the study data on a per cohort basis. All patients who had received 1 dose of VSLI (safety population) were included in this analysis. No attempt was made to combine the data from cohorts 1 and 2, because the 2 cohorts had different dosing schedules. The median, minimum, and maximum are reported for continuous variables. For qualitative outcomes, descriptive analyses were based on the distribution of these discrete outcomes and are reported as patient counts and percentages.
Results Patient and Disease Characteristics The baseline patient demographics and disease characteristics are listed in Table 1. A total of 54 patients, 35 in cohort 1 and 19 in
Olivia R. Deitcher et al Table 1 Baseline Patient and Disease Characteristics Characteristic
Table 2 Exposure to Vincristine Sulfate Liposome Injection
Cohort 1 Cohort 2 Total (n [ 35) (n [ 19) (n [ 54)
Gender Female
Cohort 1 (n [ 35)
Variable
Cohort 2 (n [ 19)
Duration of exposure (wk) 27 (77)
9 (47)
36 (67)
Median
8.7
5.7
8 (23)
10 (53)
18 (33)
Range
0.7-29.7
0.7-13.6
Median
65
65
65
Median
4
6
Range
35-79
53-81
35-81
Range
1-15
1-14
Male Age (years)
Number of treatment infusions started
Age group (years)
Total dose (mg) per infusion
18-29
0
0
0
Median
3.8
3.8
30-59
14 (40)
3 (16)
17 (31)
Range
2.8-5.9
1.8-6.5
60
21 (60)
16 (84)
37 (69)
Median
1.8
1.8
1.8
Range
1.4-2.6
1.5-2.7
1.4-2.7
1.43 m2
1 (3)
0
1 (2)
>1.43 m2
34 (97)
19 (100)
53 (98)
BSA (m2)
BSA group
Baseline performance status
Cumulative total dose (mg) Median
17.7
22.6
Range
4.1-51.7
5.0-57.9
Dose density (mg/wk) Median
2.2
4.0
Range
1.3-6.3
2.2-7.0
Median
1.2
2.2
Range
0.8-3.2
1.2-4.1
Dose density (mg/m2/wk)
0
21 (60)
14 (74)
35 (65)
1
12 (34)
5 (26)
17 (31)
Number of patients with missed doses (%)
1 (3)
7 (37)
2
2 (6)
0
2 (4)
Number of patients with reduced doses (%)
13 (37)
7 (37)
35 (100)
19 (100)
54 (100)
Number of patients with delayed doses (%)
0
0
Number of patients with study drug discontinuation (%)
AJCC stage IV at screening Documented metastasis site Liver
28 (80)
18 (95)
46 (85)
Lung
13 (37)
14 (74)
27 (50)
New health condition Disease progression/new therapy
1 (3)
1 (5)
22 (63)
7 (37)
Lymph node
6 (17)
5 (26)
11 (20)
Soft tissue
7 (20)
2 (11)
9 (17)
Adverse event
7 (20)
5 (26)
Bone
7 (20)
1 (5)
8 (15)
Patient/investigator judgment
5 (14)
6 (32)
Adrenal gland
2 (6)
2 (11)
4 (7)
Kidney
2 (6)
0
2 (4)
Heart
1 (3)
0
1 (2)
Study Drug Exposure
Brain
1 (3)
0
1 (2)
0
0
0
A summary of patient VSLI exposure is listed in Table 2. The patients in cohort 1 (VSLI 2.25 mg/m2 every 14 days) received a median of 4 doses (range, 1-15) of VSLI, with a median individual dose size of 3.8 mg (range, 2.8-5.9 mg) within a median of 8.7 weeks (range, 0.7-29.7 weeks). The patients in cohort 1 received a median cumulative VSLI exposure of 17.7 mg (range, 4.1-51.7 mg), for a median dose density of 1.2 mg/m2/wk (range, 0.8-3.2 mg/m2/wk). The patients in cohort 2 (VSLI 2.25 mg/m2 every 7 days) received a median of 6 doses (range, 1-14) of VSLI, with a median individual dose size of 3.8 mg (range, 1.8-6.5 mg) within a median of 5.7 weeks (range, 0.713.6 weeks). The patients in cohort 2 received a median cumulative VSLI exposure of 22.6 mg (range, 5.0-57.9 mg), for a median dose density of 2.2 mg/m2/wk (range, 1.2-4.1 mg/m2/wk). Cohort 2 received a greater median number of VSLI doses within a shorter median period, for a larger median cumulative VSLI exposure and a near doubling of the median VSLI dose density compared with cohort 1. No VSLI dose reductions, dose delays, or missed doses were related to hematologic AEs. A greater percentage of patients in cohort 1 than in cohort 2 discontinued the study drug because of disease progression, and more patients in cohort 2
Bone marrow Previous therapy Systemic therapy
8 (23)
0
8 (15)
Hepatic catheter-directed therapy
2 (6)
0
2 (4)
Data presented as numbers of patients (%), unless otherwise noted. Abbreviations: AJCC ¼ American Joint Committee on Cancer; BSA ¼ body surface area.
cohort 2, were enrolled and treated at 4 institutions between November 2007 and September 2012 and were included in the present hematologic toxicity analysis. The median age was 65 years (range, 35-81 years), and 69% of the patients were aged 60 years at study entry. All study patients had metastatic uveal melanoma, with documented metastases most commonly involving the liver (85%), lungs (50%), and lymph nodes (20%). Of cohort 1, 23% had received previous systemic melanoma therapy; all patients in cohort 2 were treatment naive. The median BSA was 1.8 m2, and all but 1 patient had a baseline BSA > 1.43 m2. Except for the receipt of previous treatment, cohorts 1 and 2 were generally comparable.
Clinical Lymphoma, Myeloma & Leukemia June 2014
- 199
Liposomal Vincristine Lacks Hematologic Toxicity Table 3 Hematology Laboratory Values During Study Period Cohort 1 (n [ 35)
Cohort 2 (n [ 19)
Median
13.5
13.3
Range
9.8 to 16.0
10.8 to 17.5
Variable Hemoglobin concentration (g/dL) Baseline
End of therapy Median
12.4
11.3
Range
8.5 to 14.9
9.1 to 16.1
Change from baseline Median
1.1
1.7
Range
4.1 to 1.2
5.2 to -0.2
Absolute neutrophil count ( 109/L) Baseline Median Range
Range
All study patients experienced 1 treatment-emergent AE during the study period. Twenty-five patients in cohort 1 experienced a grade 3 AE. Seventeen patients in cohort 2 experienced a grade 3 AE. The 5 most common AEs experienced by the entire study population were constipation (72%), fatigue (70%), decreased appetite (59%), nausea (57%), and vomiting (46%). The most common AEs for the patients in cohort 1 were fatigue (74%), constipation (71%), decreased appetite (63%), nausea (60%), and vomiting (49%). The most common AEs for the patients in cohort 2 were constipation (74%), fatigue (63%), decreased appetite (53%), nausea (53%), and peripheral sensory neuropathy (47%). Regardless of the cohort, all AEs resulting in study drug discontinuation (n ¼ 12) involved peripheral sensory or motor neuropathy. No deaths were attributed to any form of neuropathy.
Hematologic AEs 5.02 2.82 to 12.97
4.60 1.4 to 16.6
End of therapy Median
Summary of AEs
4.18
5.65
1.8 to 20.0
2.79 to 13.97
Median
0.4
2.0
Range
4.7 to 15.7
2.0 to 5.87
Change from baseline
Platelet count ( 109/L)
All hematologic AEs, regardless of investigator attribution to VSLI, are presented according to the preferred term for both cohorts in Table 4. Grade 3 anemia was reported in 1 patient in cohort 2 and overall. One grade 3 neutropenia was reported in each cohort. The grade 3 neutropenia event in cohort 1 was in a patient with concomitant chronic lymphocytic leukemia and fluctuating ANCs. No grade 4 anemia or neutropenia AEs and no grade 3 or 4 thrombocytopenia AEs were reported.
Discussion
Baseline Median
308
275
Range
158 to 950
164 to 458
End of therapy Median
321
366
Range
126 to 699
83 to 556
VSLI, at the 2.25 mg/m2 dose approved for relapsed and refractory adult ALL, was associated with mostly noneclinically significant hematologic toxicity when administered to patients with an advanced nonhematologic malignancy. This finding was consistent with that for nonliposomal VCR at its approved dose of 1.4 mg/m2 and suggests a small, if any, effect of VSLI on normal hematopoietic
Change from baseline Median
69
99
Range
565 to 295
81 to 222
than in cohort 1 discontinued the study drug because of a patient or investigator decision to stop.
200
-
Table 4 Hematologic Adverse Events by Preferred Term Variable Any AE
Cohort 1 Cohort 2 Total (n [ 35) (n [ 19) (n [ 54) 35 (100)
19 (100)
54 (100)
Hematologic Laboratory Assessments
Any grade 3 AE
25 (71)
17 (89)
42 (78)
The baseline and end of therapy hematology laboratory values for both cohorts are listed in Table 3. Figures 1 to 3 present the mean SD for hemoglobin, ANC, and platelet counts by study visit for each cohort. Although both cohorts showed a decrease over time in the median hemoglobin concentration (Fig. 1), the decrease from baseline at the end of therapy was greater for cohort 2 (1.7-g/dL decrease) than for cohort 1 (1.1-g/dL decrease). The median decrease from baseline at the end of therapy in the ANC was greater for cohort 1 (0.4 109/L decrease) than for cohort 2 (2.0 109/L increase). Although both cohorts showed an increase in the median platelet count during the study period, the increase from baseline at the end of therapy was greater for cohort 2 (99 109/L) than for cohort 1 (69 109/L). Figure 3 demonstrates a possible study drug effect on the platelet count for cohort 1 on study day 8 of each therapy cycle. In contrast, a near doubling of VSLI dose density in cohort 2 resulted in no such effect.
Any blood and lymphatic system AE
10 (29)
6 (32)
16 (30)
9 (26)
4 (21)
13 (24)
Grade 3
0
1 (5)
1 (2)
Grade 4
0
0
0
All grades
1 (3)
1 (5)
2 (4)
Grade 3
1 (3)
1 (5)
2 (4)
Grade 4
0
0
0
Clinical Lymphoma, Myeloma & Leukemia June 2014
Anemia NOS All grades
Neutropenia
Thrombocytopenia NOS All grades
2 (6)
2 (11)
4 (7)
Grade 3
0
0
0
Grade 4
0
0
0
Data presented as numbers of patients (%). Abbreviations: AE ¼ adverse event; NOS ¼ not otherwise specified.
Olivia R. Deitcher et al Figure 1 Mean ± SD Hemoglobin Values Stratified by Time. C#D#, Cycle #, day #
Figure 3 Mean ± SD Platelet Counts Stratified by Time. C#D#, Cycle #, day #
elements. Hematologic AEs were uncommon and were mostly grade 1 or 2 in severity at this clinically relevant dose intensity. In contrast, the peripheral neuropathy and constipation AE rates were meaningful and as expected. No grade 4 hematologic AEs occurred. Most hematologic laboratory values remained within the normal ranges. The decreases in hemoglobin over time in both cohorts were believed to reflect progressive anemia secondary to the malignancy and frequent blood draws related to sampling for pharmacokinetic analysis. The cumulative VSLI exposure in the present study was comparable to that reported for the treatment of relapsed and refractory adult ALL and mostly greater than the maximum (12 mg) nonliposomal VCR exposure provided by 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone)ebased NHL therapy.12 As expected, the greater median cumulative VSLI dose and dose density in cohort 2 in the present study were associated with a greater incidence of grade 3 AEs, more reported peripheral sensory neuropathy events, and more patient requests for study drug discontinuation. However, no obvious differences were found in the reported or measured hematologic toxicities between cohorts 1 and 2, despite the near doubling in the median dose density. No new or unexpected incidence of hematologic toxicity was observed for VSLI at individual doses 6.5 mg compared with that reported for nonliposomal
VCR at doses no greater than 2 mg. Although the efficacy outcomes of the present study are pending, more patients in cohort 1 than in cohort 2 discontinued VSLI because of disease progression. VSLI at doses 2.25 mg/m2 administered as frequently as once every 7 days and because of a favorable hematologic toxicity profile in a solid tumor population might combine well with myelosuppressive cancer chemotherapeutic agents. In addition, VSLI might be an ideal agent alone or combined with other drugs lacking significant hematologic toxicity for patients unable to tolerate peripheral blood cytopenia. VSLI facilitated VCR dose intensification, and dose densification might be particularly important for patients with rapidly progressive cancer such as aggressive NHL and ALL. Ongoing phase 3 combination chemotherapy clinical trials of untreated diffuse large B-cell lymphoma and untreated adult Ph ALL are addressing this very extrapolation.
Figure 2 Mean ± SD Absolute Neutrophil Counts Stratified by Time. C#D#, Cycle #, day #
Clinical Practice Points NHL and ALL treatment options that do not cause or exacerbate
anemia, neutropenia, and thrombocytopenia are desirable. Assessment of new drugs for hematologic toxicity is difficult in
patients with active hematologic malignancy. VSLI facilitates dose intensification and densification of VCR
without inducing hematologic toxicity in patients with a solid tumor that does not metastasize to the bone marrow. VSLI might combine well with myelosuppressive chemotherapy and could be a treatment option for patients unable to tolerate peripheral blood cytopenia.
Acknowledgments The present study was supported by Talon Therapeutics, Inc.
Disclosure Drs Deitcher and Silverman and Ms Segarini were employed by Talon Therapeutics, Inc. The remaining authors have stated that they have no conflicts of interest.
References 1. Silverman JA, Deitcher SR. Marqibo (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine. Cancer Chemother Pharmacol 2013; 71:555-64.
Clinical Lymphoma, Myeloma & Leukemia June 2014
- 201
Liposomal Vincristine Lacks Hematologic Toxicity 2. Balis FM, Holcenberg JS, Bleyer WA. Clinical pharmacokinetics of commonly used anticancer drugs. Clin Pharmacokinet 1983; 8:202-32. 3. Gidding CE, Kellie SJ, Kamps WA, et al. Vincristine revisited. Crit Rev Oncol Hematol 1999; 29:267-87. 4. Webb MS, Harasym TO, Masin D, et al. Sphingomyelin-cholesterol liposomes significantly enhance the pharmacokinetic and therapeutic properties of vincristine in murine and human tumour models. Br J Cancer 1995; 72:896-904. 5. Krishna R, Webb MS, St Onge G, et al. Liposomal and nonliposomal drug pharmacokinetics after administration of liposome-encapsulated vincristine and their contribution to drug tissue distribution properties. J Pharmacol Exp Ther 2001; 298:1206-12. 6. Webb MS, Logan P, Kanter PM, et al. Preclinical pharmacology, toxicology and efficacy of sphingomyelin/cholesterol liposomal vincristine for therapeutic treatment of cancer. Cancer Chemother Pharmacol 1998; 42:461-70. 7. Thomas DA, Sarris AH, Cortes J, et al. Phase II study of sphingosomal vincristine in patients with recurrent or refractory adult acute lymphocytic leukemia. Cancer 2006; 106:120-7. 8. Shah NN, Merchant M, Cole D, et al. Vincristine sulfate liposomes injection (VSLI, Marqibo): interim results from a phase I study in children and adolescents with refractory cancer. Blood (ASH Annual Meeting Abstracts) 2012; 120:1497.
202
-
Clinical Lymphoma, Myeloma & Leukemia June 2014
9. Rodriguez MA, Pytlik R, Kozak T, et al. Vincristine sulfate liposomes injection (Marqibo) in heavily pretreated patients with refractory aggressive nonHodgkin lymphoma: report of the pivotal phase 2 study. Cancer 2009; 115: 3475-82. 10. Kaplan LD, Deitcher SR, Silverman JA, et al. Phase II study of vincristine sulfate liposome injection (Marqibo) and rituximab for patients with relapsed and refractory diffuse large B-cell lymphoma or mantle cell lymphoma [e-pub ahead of print]. Clin Lymphoma Myeloma Leuk doi:10.1016/j.clml.2013.09.009, accessed . 11. Hagemeister F, Rodriguez MA, Deitcher SR, et al. Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo) substituted for non-liposomal vincristine in CHOP with or without rituximab for patients with untreated aggressive non-Hodgkin’s lymphomas. Br J Haematol 2013; 162:631-8. 12. O’Brien S, Schiller G, Lister J, et al. High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosomenegative acute lymphoblastic leukemia. J Clin Oncol 2013; 31:676-83. 13. Woll E, Bedikian A, Legha SS. Uveal melanoma: natural history and treatment options for metastatic disease. Melanoma Res 1999; 9:575-81. 14. Bedikian AY, Papadopoulos NE, Kim KB, et al. A pilot study with vincristine sulfate liposome infusion in patients with metastatic melanoma. Melanoma Res 2008; 18:400-4.
High-dose Vincristine Sulfate Liposome Injection (Marqibo) Is Not Associated With Clinically Meaningful Hematologic Toxicity Olivia R. Deitcher,1 John Glaspy,2 Rene Gonzalez,3 Takami Sato,4 Agop Y. Bedikian,5 Karen Segarini,1 Jeffrey Silverman,1 Steven R. Deitcher1 Abstract Hematologic toxicity of vincristine sulfate liposome injection (VSLI) was assessed in 54 patients with metastatic cancer not known to involve bone marrow. VSLI was not associated with clinically meaningful blood count changes when dosed at 2.25 mg/m2 every 14 or 7 days. VSLI could be well suited for combination drug therapy and use in patients unable to tolerate blood cytopenias. 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/m2 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. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. 3, 197-202 ª 2014 Elsevier Inc. All rights reserved. Keywords: Anemia, Liposome, Neutropenia, Thrombocytopenia, Vincristine
Introduction The treatment of patients with heavily pretreated, advanced, relapsed, and refractory hematologic malignancies, such as Philadelphia chromosomeenegative (Ph) acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), sometimes requires the 1
Talon Therapeutics, Inc, South San Francisco, CA University of California, Los Angeles, CA University of Colorado Denver, Aurora, CO 4 Thomas Jefferson University, Philadelphia, PA 5 University of Texas MD Anderson Cancer Center, Houston, TX 2 3
Submitted: Jun 24, 2013; Revised: Oct 17, 2013; Accepted: Oct 21, 2013; Epub: Nov 15, 2013 Address for correspondence: Steven R. Deitcher, MD, Talon Therapeutics, Inc, 400 Oyster Point Boulevard, South San Francisco, CA 94080 E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.10.012
use of therapies with limited hematologic toxicity and associated peripheral blood cytopenia. The same requirement might also apply to patients with cancer and advanced age, active infection, cardiovascular disease, recent surgery, or poor performance status. Because of the near-universal, disease-related, and concomitant chemotherapyrelated anemia, neutropenia, and thrombocytopenia, it has been difficult to specifically assess for, and isolate, related hematologic toxicity during the evaluation of new agents in ALL and NHL clinical trials. Vincristine sulfate liposome injection (VSLI) is sphingomyelinand cholesterol-based nanoparticle-encapsulated vincristine (VCR) designed to overcome the dosing and pharmacokinetic limitations of nonliposomal VCR.1-4 In nonclinical experiments, VSLI enhanced VCR penetration and concentration in tissues and organs with fenestrated vasculature or involved in the mononuclear phagocyte system, including ALL and NHL target tissues (eg, bone marrow,
Clinical Lymphoma, Myeloma & Leukemia June 2014
- 197
Liposomal Vincristine Lacks Hematologic Toxicity lymph nodes, spleen) and implanted tumors.2-6 VSLI exhibited greater milligram per milligram anticancer activity and a larger maximum tolerated dose than nonliposomal VCR. In phase 1 dose-finding studies, VSLI was generally well tolerated and active at dose levels up to and including 2.25 mg/m2/wk in adults and children with relapsed and refractory ALL.7,8 All VSLI doses reflected the amount of VCR delivered and were determined by the actual patient body surface area (BSA) without dose capping at any level. Compared with the labeled dose of nonliposomal VCR of 1.4 mg/m2, each weight-based dose of VSLI delivered 61% more VCR. The dose intensification facilitated by the VSLI formulation was even greater compared with the standard, fixed, “capped” 2-mg dose of nonliposomal VCR. In phase 2 studies, VSLI dosed at 2.0 mg/m2 every 2 weeks was effective at inducing complete and partial responses as both monotherapy and combined with rituximab in patients with advanced, relapsed, and refractory aggressive NHL.9,10 The same dose of VSLI, combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHMP, where M ¼ VSLI), produced remarkable response rates and long progression-free and overall survival in patients with untreated diffuse large B-cell lymphoma.11 Weekly single-agent VSLI 2.25 mg/m2 was approved in the United States for adults with relapsed and refractory Ph ALL.12 Because previous and current VSLI development programs have focused on NHL and ALL, a different cancer patient population was required to enable assessment of the hematologic toxicity profile of the drug. Uveal melanoma almost exclusively metastasizes to the liver, lungs, and lymph nodes and is not known to directly invade the bone marrow.13 VSLI has been reported to be active in this rare cancer.14 In our report, we present an assessment of the hematologic toxicity profile of VSLI 2.25 mg/m2 in patients with metastatic uveal melanoma.
Patients and Methods
The institutional review board at the participating centers approved the present study. This study was conducted in accordance with the principles of the World Medical Association’s Declaration of Helsinki and the International Conference on Harmonisation Guideline for Good Clinical Practice. All patients provided written informed consent.
Study Design The data for the present analysis were collected as part of a phase 2, multicenter, single-arm, open-label study (NCT00506142). The patients in cohort 1 were treated with VSLI (Marqibo, Talon Therapeutics, Inc, South San Francisco, CA) 2.25 mg/m2, intravenously (I.V.) by way of a peripheral or central venous catheter within 60 10 minutes every 14 3 days on study day 1 of each 14-day cycle. The patients in cohort 2 were treated with VSLI 2.25 mg/m2 I.V. by way of a peripheral or central venous catheter within 60 10 minutes every 7 3 days on study day 1 and day 8 of each 14-day cycle. The dose calculations were determined from the BSA calculated from the actual body weight obtained at the onset of each cycle and the height obtained at study screening. No VSLI dose capping was used. The patients were treated until the appearance of unacceptable toxicity or an investigator determined that the patient was no longer benefitting from treatment. The duration of VSLI exposure was calculated from the date of the first dose plus 1 day until the date of the last dose plus 6 days to account for the extended release characteristics of the VSLI liposome.1 VSLI dosing modifications for hematologic toxicity were based on the ANC and platelet count assessments on the days of infusion. If the ANC was < 0.5 109/L or the platelet count was < 50.0 109/L, the VSLI dose was delayed for 7 days, and the counts were reassessed. If this grade 3 toxicity persisted, the VSLI was delayed for another 7 days. If the criteria for VSLI treatment were not met after 14 days of delay, the patient was removed from treatment.
Patients
198
-
Adults ( 18 years old) with histologically or cytologically confirmed metastatic uveal melanoma were study eligible. The patients were enrolled in 2 serial cohorts. Cohort 1 patients could have received 1 previous systemic therapy. Previous treatment with immunotherapy or a cancer vaccine was allowed, provided documentation was available of disease progression. Previous treatment with hepatic arterial chemotherapy infusion or perfusion or chemoembolization of liver metastasis was allowed as long as extrahepatic disease or progression of the liver metastasis was present after regional therapy. Cohort 1 patients must not have been previously treated with a vinca alkaloid. Cohort 2 patients must not have received any previous systemic chemotherapy, immunotherapy, cancer vaccine, or hepatic arterial chemotherapy for metastatic disease. Study eligibility required adequate liver and kidney function, as defined by a serum total bilirubin at or less than the institution’s upper normal limit and a serum creatinine level of 2.0 mg/dL. Patients had to have adequate bone marrow function, as defined by an absolute neutrophil count (ANC) 1.0 109/L and platelet count 100 109/L. The patients had to have a Zubrod performance status of 0 to 2. Patients with known positive human immunodeficiency virus status, symptomatic central nervous system metastasis, and active serious infection not controlled by systemic antimicrobial agents were excluded.
Clinical Lymphoma, Myeloma & Leukemia June 2014
Hematology Assessment The hematologic toxicity evaluation was based on serial peripheral blood assessments and hematologic adverse event (AE) reporting using Medical Dictionary for Regulatory Activities, version 12.1 (MedDRA, McLean, VA). AE severity was graded according to the National Cancer Institute’s “Common Terminology Criteria for Adverse Events, version 3.0.” Bone marrow assessments were not mandated.
Statistical Analysis Descriptive and inferential analyses were used to summarize the study data on a per cohort basis. All patients who had received 1 dose of VSLI (safety population) were included in this analysis. No attempt was made to combine the data from cohorts 1 and 2, because the 2 cohorts had different dosing schedules. The median, minimum, and maximum are reported for continuous variables. For qualitative outcomes, descriptive analyses were based on the distribution of these discrete outcomes and are reported as patient counts and percentages.
Results Patient and Disease Characteristics The baseline patient demographics and disease characteristics are listed in Table 1. A total of 54 patients, 35 in cohort 1 and 19 in
Olivia R. Deitcher et al Table 1 Baseline Patient and Disease Characteristics Characteristic
Table 2 Exposure to Vincristine Sulfate Liposome Injection
Cohort 1 Cohort 2 Total (n [ 35) (n [ 19) (n [ 54)
Gender Female
Cohort 1 (n [ 35)
Variable
Cohort 2 (n [ 19)
Duration of exposure (wk) 27 (77)
9 (47)
36 (67)
Median
8.7
5.7
8 (23)
10 (53)
18 (33)
Range
0.7-29.7
0.7-13.6
Median
65
65
65
Median
4
6
Range
35-79
53-81
35-81
Range
1-15
1-14
Male Age (years)
Number of treatment infusions started
Age group (years)
Total dose (mg) per infusion
18-29
0
0
0
Median
3.8
3.8
30-59
14 (40)
3 (16)
17 (31)
Range
2.8-5.9
1.8-6.5
60
21 (60)
16 (84)
37 (69)
Median
1.8
1.8
1.8
Range
1.4-2.6
1.5-2.7
1.4-2.7
1.43 m2
1 (3)
0
1 (2)
>1.43 m2
34 (97)
19 (100)
53 (98)
BSA (m2)
BSA group
Baseline performance status
Cumulative total dose (mg) Median
17.7
22.6
Range
4.1-51.7
5.0-57.9
Dose density (mg/wk) Median
2.2
4.0
Range
1.3-6.3
2.2-7.0
Median
1.2
2.2
Range
0.8-3.2
1.2-4.1
Dose density (mg/m2/wk)
0
21 (60)
14 (74)
35 (65)
1
12 (34)
5 (26)
17 (31)
Number of patients with missed doses (%)
1 (3)
7 (37)
2
2 (6)
0
2 (4)
Number of patients with reduced doses (%)
13 (37)
7 (37)
35 (100)
19 (100)
54 (100)
Number of patients with delayed doses (%)
0
0
Number of patients with study drug discontinuation (%)
AJCC stage IV at screening Documented metastasis site Liver
28 (80)
18 (95)
46 (85)
Lung
13 (37)
14 (74)
27 (50)
New health condition Disease progression/new therapy
1 (3)
1 (5)
22 (63)
7 (37)
Lymph node
6 (17)
5 (26)
11 (20)
Soft tissue
7 (20)
2 (11)
9 (17)
Adverse event
7 (20)
5 (26)
Bone
7 (20)
1 (5)
8 (15)
Patient/investigator judgment
5 (14)
6 (32)
Adrenal gland
2 (6)
2 (11)
4 (7)
Kidney
2 (6)
0
2 (4)
Heart
1 (3)
0
1 (2)
Study Drug Exposure
Brain
1 (3)
0
1 (2)
0
0
0
A summary of patient VSLI exposure is listed in Table 2. The patients in cohort 1 (VSLI 2.25 mg/m2 every 14 days) received a median of 4 doses (range, 1-15) of VSLI, with a median individual dose size of 3.8 mg (range, 2.8-5.9 mg) within a median of 8.7 weeks (range, 0.7-29.7 weeks). The patients in cohort 1 received a median cumulative VSLI exposure of 17.7 mg (range, 4.1-51.7 mg), for a median dose density of 1.2 mg/m2/wk (range, 0.8-3.2 mg/m2/wk). The patients in cohort 2 (VSLI 2.25 mg/m2 every 7 days) received a median of 6 doses (range, 1-14) of VSLI, with a median individual dose size of 3.8 mg (range, 1.8-6.5 mg) within a median of 5.7 weeks (range, 0.713.6 weeks). The patients in cohort 2 received a median cumulative VSLI exposure of 22.6 mg (range, 5.0-57.9 mg), for a median dose density of 2.2 mg/m2/wk (range, 1.2-4.1 mg/m2/wk). Cohort 2 received a greater median number of VSLI doses within a shorter median period, for a larger median cumulative VSLI exposure and a near doubling of the median VSLI dose density compared with cohort 1. No VSLI dose reductions, dose delays, or missed doses were related to hematologic AEs. A greater percentage of patients in cohort 1 than in cohort 2 discontinued the study drug because of disease progression, and more patients in cohort 2
Bone marrow Previous therapy Systemic therapy
8 (23)
0
8 (15)
Hepatic catheter-directed therapy
2 (6)
0
2 (4)
Data presented as numbers of patients (%), unless otherwise noted. Abbreviations: AJCC ¼ American Joint Committee on Cancer; BSA ¼ body surface area.
cohort 2, were enrolled and treated at 4 institutions between November 2007 and September 2012 and were included in the present hematologic toxicity analysis. The median age was 65 years (range, 35-81 years), and 69% of the patients were aged 60 years at study entry. All study patients had metastatic uveal melanoma, with documented metastases most commonly involving the liver (85%), lungs (50%), and lymph nodes (20%). Of cohort 1, 23% had received previous systemic melanoma therapy; all patients in cohort 2 were treatment naive. The median BSA was 1.8 m2, and all but 1 patient had a baseline BSA > 1.43 m2. Except for the receipt of previous treatment, cohorts 1 and 2 were generally comparable.
Clinical Lymphoma, Myeloma & Leukemia June 2014
- 199
Liposomal Vincristine Lacks Hematologic Toxicity Table 3 Hematology Laboratory Values During Study Period Cohort 1 (n [ 35)
Cohort 2 (n [ 19)
Median
13.5
13.3
Range
9.8 to 16.0
10.8 to 17.5
Variable Hemoglobin concentration (g/dL) Baseline
End of therapy Median
12.4
11.3
Range
8.5 to 14.9
9.1 to 16.1
Change from baseline Median
1.1
1.7
Range
4.1 to 1.2
5.2 to -0.2
Absolute neutrophil count ( 109/L) Baseline Median Range
Range
All study patients experienced 1 treatment-emergent AE during the study period. Twenty-five patients in cohort 1 experienced a grade 3 AE. Seventeen patients in cohort 2 experienced a grade 3 AE. The 5 most common AEs experienced by the entire study population were constipation (72%), fatigue (70%), decreased appetite (59%), nausea (57%), and vomiting (46%). The most common AEs for the patients in cohort 1 were fatigue (74%), constipation (71%), decreased appetite (63%), nausea (60%), and vomiting (49%). The most common AEs for the patients in cohort 2 were constipation (74%), fatigue (63%), decreased appetite (53%), nausea (53%), and peripheral sensory neuropathy (47%). Regardless of the cohort, all AEs resulting in study drug discontinuation (n ¼ 12) involved peripheral sensory or motor neuropathy. No deaths were attributed to any form of neuropathy.
Hematologic AEs 5.02 2.82 to 12.97
4.60 1.4 to 16.6
End of therapy Median
Summary of AEs
4.18
5.65
1.8 to 20.0
2.79 to 13.97
Median
0.4
2.0
Range
4.7 to 15.7
2.0 to 5.87
Change from baseline
Platelet count ( 109/L)
All hematologic AEs, regardless of investigator attribution to VSLI, are presented according to the preferred term for both cohorts in Table 4. Grade 3 anemia was reported in 1 patient in cohort 2 and overall. One grade 3 neutropenia was reported in each cohort. The grade 3 neutropenia event in cohort 1 was in a patient with concomitant chronic lymphocytic leukemia and fluctuating ANCs. No grade 4 anemia or neutropenia AEs and no grade 3 or 4 thrombocytopenia AEs were reported.
Discussion
Baseline Median
308
275
Range
158 to 950
164 to 458
End of therapy Median
321
366
Range
126 to 699
83 to 556
VSLI, at the 2.25 mg/m2 dose approved for relapsed and refractory adult ALL, was associated with mostly noneclinically significant hematologic toxicity when administered to patients with an advanced nonhematologic malignancy. This finding was consistent with that for nonliposomal VCR at its approved dose of 1.4 mg/m2 and suggests a small, if any, effect of VSLI on normal hematopoietic
Change from baseline Median
69
99
Range
565 to 295
81 to 222
than in cohort 1 discontinued the study drug because of a patient or investigator decision to stop.
200
-
Table 4 Hematologic Adverse Events by Preferred Term Variable Any AE
Cohort 1 Cohort 2 Total (n [ 35) (n [ 19) (n [ 54) 35 (100)
19 (100)
54 (100)
Hematologic Laboratory Assessments
Any grade 3 AE
25 (71)
17 (89)
42 (78)
The baseline and end of therapy hematology laboratory values for both cohorts are listed in Table 3. Figures 1 to 3 present the mean SD for hemoglobin, ANC, and platelet counts by study visit for each cohort. Although both cohorts showed a decrease over time in the median hemoglobin concentration (Fig. 1), the decrease from baseline at the end of therapy was greater for cohort 2 (1.7-g/dL decrease) than for cohort 1 (1.1-g/dL decrease). The median decrease from baseline at the end of therapy in the ANC was greater for cohort 1 (0.4 109/L decrease) than for cohort 2 (2.0 109/L increase). Although both cohorts showed an increase in the median platelet count during the study period, the increase from baseline at the end of therapy was greater for cohort 2 (99 109/L) than for cohort 1 (69 109/L). Figure 3 demonstrates a possible study drug effect on the platelet count for cohort 1 on study day 8 of each therapy cycle. In contrast, a near doubling of VSLI dose density in cohort 2 resulted in no such effect.
Any blood and lymphatic system AE
10 (29)
6 (32)
16 (30)
9 (26)
4 (21)
13 (24)
Grade 3
0
1 (5)
1 (2)
Grade 4
0
0
0
All grades
1 (3)
1 (5)
2 (4)
Grade 3
1 (3)
1 (5)
2 (4)
Grade 4
0
0
0
Clinical Lymphoma, Myeloma & Leukemia June 2014
Anemia NOS All grades
Neutropenia
Thrombocytopenia NOS All grades
2 (6)
2 (11)
4 (7)
Grade 3
0
0
0
Grade 4
0
0
0
Data presented as numbers of patients (%). Abbreviations: AE ¼ adverse event; NOS ¼ not otherwise specified.
Olivia R. Deitcher et al Figure 1 Mean ± SD Hemoglobin Values Stratified by Time. C#D#, Cycle #, day #
Figure 3 Mean ± SD Platelet Counts Stratified by Time. C#D#, Cycle #, day #
elements. Hematologic AEs were uncommon and were mostly grade 1 or 2 in severity at this clinically relevant dose intensity. In contrast, the peripheral neuropathy and constipation AE rates were meaningful and as expected. No grade 4 hematologic AEs occurred. Most hematologic laboratory values remained within the normal ranges. The decreases in hemoglobin over time in both cohorts were believed to reflect progressive anemia secondary to the malignancy and frequent blood draws related to sampling for pharmacokinetic analysis. The cumulative VSLI exposure in the present study was comparable to that reported for the treatment of relapsed and refractory adult ALL and mostly greater than the maximum (12 mg) nonliposomal VCR exposure provided by 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone)ebased NHL therapy.12 As expected, the greater median cumulative VSLI dose and dose density in cohort 2 in the present study were associated with a greater incidence of grade 3 AEs, more reported peripheral sensory neuropathy events, and more patient requests for study drug discontinuation. However, no obvious differences were found in the reported or measured hematologic toxicities between cohorts 1 and 2, despite the near doubling in the median dose density. No new or unexpected incidence of hematologic toxicity was observed for VSLI at individual doses 6.5 mg compared with that reported for nonliposomal
VCR at doses no greater than 2 mg. Although the efficacy outcomes of the present study are pending, more patients in cohort 1 than in cohort 2 discontinued VSLI because of disease progression. VSLI at doses 2.25 mg/m2 administered as frequently as once every 7 days and because of a favorable hematologic toxicity profile in a solid tumor population might combine well with myelosuppressive cancer chemotherapeutic agents. In addition, VSLI might be an ideal agent alone or combined with other drugs lacking significant hematologic toxicity for patients unable to tolerate peripheral blood cytopenia. VSLI facilitated VCR dose intensification, and dose densification might be particularly important for patients with rapidly progressive cancer such as aggressive NHL and ALL. Ongoing phase 3 combination chemotherapy clinical trials of untreated diffuse large B-cell lymphoma and untreated adult Ph ALL are addressing this very extrapolation.
Figure 2 Mean ± SD Absolute Neutrophil Counts Stratified by Time. C#D#, Cycle #, day #
Clinical Practice Points NHL and ALL treatment options that do not cause or exacerbate
anemia, neutropenia, and thrombocytopenia are desirable. Assessment of new drugs for hematologic toxicity is difficult in
patients with active hematologic malignancy. VSLI facilitates dose intensification and densification of VCR
without inducing hematologic toxicity in patients with a solid tumor that does not metastasize to the bone marrow. VSLI might combine well with myelosuppressive chemotherapy and could be a treatment option for patients unable to tolerate peripheral blood cytopenia.
Acknowledgments The present study was supported by Talon Therapeutics, Inc.
Disclosure Drs Deitcher and Silverman and Ms Segarini were employed by Talon Therapeutics, Inc. The remaining authors have stated that they have no conflicts of interest.
References 1. Silverman JA, Deitcher SR. Marqibo (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine. Cancer Chemother Pharmacol 2013; 71:555-64.
Clinical Lymphoma, Myeloma & Leukemia June 2014
- 201
Liposomal Vincristine Lacks Hematologic Toxicity 2. Balis FM, Holcenberg JS, Bleyer WA. Clinical pharmacokinetics of commonly used anticancer drugs. Clin Pharmacokinet 1983; 8:202-32. 3. Gidding CE, Kellie SJ, Kamps WA, et al. Vincristine revisited. Crit Rev Oncol Hematol 1999; 29:267-87. 4. Webb MS, Harasym TO, Masin D, et al. Sphingomyelin-cholesterol liposomes significantly enhance the pharmacokinetic and therapeutic properties of vincristine in murine and human tumour models. Br J Cancer 1995; 72:896-904. 5. Krishna R, Webb MS, St Onge G, et al. Liposomal and nonliposomal drug pharmacokinetics after administration of liposome-encapsulated vincristine and their contribution to drug tissue distribution properties. J Pharmacol Exp Ther 2001; 298:1206-12. 6. Webb MS, Logan P, Kanter PM, et al. Preclinical pharmacology, toxicology and efficacy of sphingomyelin/cholesterol liposomal vincristine for therapeutic treatment of cancer. Cancer Chemother Pharmacol 1998; 42:461-70. 7. Thomas DA, Sarris AH, Cortes J, et al. Phase II study of sphingosomal vincristine in patients with recurrent or refractory adult acute lymphocytic leukemia. Cancer 2006; 106:120-7. 8. Shah NN, Merchant M, Cole D, et al. Vincristine sulfate liposomes injection (VSLI, Marqibo): interim results from a phase I study in children and adolescents with refractory cancer. Blood (ASH Annual Meeting Abstracts) 2012; 120:1497.
202
-
Clinical Lymphoma, Myeloma & Leukemia June 2014
9. Rodriguez MA, Pytlik R, Kozak T, et al. Vincristine sulfate liposomes injection (Marqibo) in heavily pretreated patients with refractory aggressive nonHodgkin lymphoma: report of the pivotal phase 2 study. Cancer 2009; 115: 3475-82. 10. Kaplan LD, Deitcher SR, Silverman JA, et al. Phase II study of vincristine sulfate liposome injection (Marqibo) and rituximab for patients with relapsed and refractory diffuse large B-cell lymphoma or mantle cell lymphoma [e-pub ahead of print]. Clin Lymphoma Myeloma Leuk doi:10.1016/j.clml.2013.09.009, accessed . 11. Hagemeister F, Rodriguez MA, Deitcher SR, et al. Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo) substituted for non-liposomal vincristine in CHOP with or without rituximab for patients with untreated aggressive non-Hodgkin’s lymphomas. Br J Haematol 2013; 162:631-8. 12. O’Brien S, Schiller G, Lister J, et al. High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosomenegative acute lymphoblastic leukemia. J Clin Oncol 2013; 31:676-83. 13. Woll E, Bedikian A, Legha SS. Uveal melanoma: natural history and treatment options for metastatic disease. Melanoma Res 1999; 9:575-81. 14. Bedikian AY, Papadopoulos NE, Kim KB, et al. A pilot study with vincristine sulfate liposome infusion in patients with metastatic melanoma. Melanoma Res 2008; 18:400-4.
