Plasma Vincristine Levels Are 100-Fold Higher with Marqibo® (Vincristine Sulfate LIPOSOME Injection) in Place of Standard Vincristine in Combination Chemotherapy of Patients ≥ 60 Years Old with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)

Background: Marqibo® (vincristine sulfate LIPOSOME injection, VSLI) is currently approved in the US for treatment of adults with Philadelphia negative (Ph-) relapsed or refractory acute lymphoblastic leukemia (ALL). VSLI allows for greater dose intensification compared to standard vincristine sulfate (VCR) because unlike VCR, VSLI is dosed at 2.25 mg/m² rather than 1.4mg/m², and is not capped at 2 mg. To date, VSLI exposure has not been directly compared with VCR for the upfront treatment of adult patients with ALL.

Methods: This was a phase 3, multicenter, open-label randomized clinical trial for newly diagnosed Ph- ALL patients ≥ 60 years of age. The primary objective compared the safety and efficacy of VSLI to VCR as part of multi-component chemotherapy (induction, intensification and maintenance). The secondary objectives included Objective Response Rate (ORR), safety and pharmacokinetics (PK). The chemotherapy backbone was based on the Cancer and Leukemia Group B (CALGB) Study 8811 (Larson et al, Blood 1995), with vincristine provided as either VCR or VSLI. VCR was dosed at 1.4 mg/m² with a 2 mg dose cap over 10 minutes, and VSLI at 2.25 mg/m² dose infused over 60 minutes with no dose cap. Patients with neuropathy or CNS disease were excluded. PK samples, consisting of 5 mL of blood, were collected at Course 1, Day 1 at the following time-points: prior to VSLI/VCR infusion, 15 minutes to 4 hours at the end of the VSLI/VCR infusion, and 24 -48 hours at the end of the VSLI/VCR infusion. Blood samples were processed within one hour by centrifugation at 2,000 rpm for 10 minutes at 2-8°C. PK samples were processed for 13 and 7 patients in the VSLI and VCR Treatment Groups respectively.

Results: 26 patients were enrolled from May 2012 to June 2014 (13 randomized to each group). Median age was 67 (range 60-77) years and median study duration was 50 days. 8 patients died during induction therapy, 5 in the VSLI Treatment Group and 3 in the VCR Treatment Group. Treatment-related deaths was 3 (12%): 2 (15%) in the VSLI Treatment Group and 1 (8%) in the VCR Treatment Group. 7 (54%) patients experienced treatment-related serious adverse events in the VSLI Treatment Group compared to 5 (38%) patients in the VCR Treatment Group. 1 patient (8%) in each group had ≥ grade 3 constipation. No patients in the VCR Treatment Group had ≥ grade 3 neuropathy, whereas 4 (31%) patients in the VSLI Treatment Group did. ORR was the same in both treatment groups with 8 (62%) patients in both treatment groups achieving CR/CRi. PK analysis demonstrated a median plasma vincristine level within 4 hours of infusion of 866 ng/mL for VSLI-treated patients, 100-fold higher than the 6 ng/mL for VCR-treated patients. A higher mean plasma vincristine levels of 877.2 ng/mL for VSLI and only 8.8 ng/mL for VCR immediately after infusion (15 minutes - 4 hours), and 153.5 ng/ml for VSLI patients and only 0.5 ng/ml for VCR 12-48 hours after infusion (Table 1).

Conclusion: Liposomal vincristine (Marqibo) was successfully administered as part of the CALGB 8811 regimen in newly diagnosed ALL patients as a substitute for standard vincristine. The study was terminated prematurely due to poor enrollment, limiting conclusions that can be made regarding the safety or efficacy of VSLI versus VCR in combination with chemotherapy for older ALL patients. However of note, median plasma levels of vincristine were 100-fold higher in the patients treated with VSLI as compared to VCR.