Vincristine Sulfate Liposome Injection (VSLI) with Bendamustine and Rituximab As First-Line Therapy for Indolent B-Cell Lymphomas: A Phase 1 Study

Background: The combination of bendamustine and rituximab (BR) is frequently used as treatment for indolent B-cell lymphomas (iBCL; Rummel et al, Lancet 2013; Olszewski et al, Am J Hematol 2019). Its relatively low adverse effect profile and lack of overlapping toxicities suggest the potential for adding vincristine - another highly active anti-lymphoma agent. However, a prior trial found high rates of thrombocytopenia when standard vincristine was combined with full-dose bendamustine (Herold M, et al. J Cancer Res Clin Oncol. 2006). VSLI is a liposome-encapsulated formulation of vincristine designed to improve its activity, therapeutic index, and pharmacokinetic profile. VSLI at an uncapped dose of 2.0 mg/m² has been successfully combined with cyclophosphamide, doxorubicin, and prednisone (Hagemeister et al., Br J Haematol 2013). The objective of this phase 1 study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of VSLI in combination with standard doses of BR for treatment of iBCL.

Methods: Patients with iBCL otherwise appropriate for BR therapy were eligible for this phase 1 study. Bendamustine was given at 90 mg/m2 on Day 1, 2, and rituximab at 375 mg/m2 on Day 1 of each 28-day cycle, for 6 cycles. VSLI was given on Day 2 of each cycle at a patient-specific dose ranging from 1.8 mg/m2 up to maximum 2.3 mg/m2, as determined by the Escalation with Overdose Control (EWOC) model-based design (Babb et al., Stat Med, 2001). EWOC allows for rapid identification of the MTD using a small sample size and single-subject dose cohorts. Model parameters for this study included target probability of DLT (q) of 0.33 and starting probability of exceeding MTD (a) of 0.25. There was no intra-patient dose escalation. Simulations indicated that n=10 subjects would be sufficient to determine the MTD, and this sample size was set for the study by design. MTD was defined as median of the Bayesian 95% confidence interval (CI) for the VSLI dose, calculated from the model at the end of the study. DLT was defined during cycle 1 only, as grade (G) 4 neutropenia lasting >7 days (or G3 with fever / infection), G4 thrombocytopenia (or G3 requiring transfusion), or any G3/4 non-hematologic toxicity. Secondary objectives included cumulative rates of adverse effects (AE, particularly VSLI-related neuropathy), completion rate of 6 cycles of therapy, overall response rate (ORR), and complete response (CR) rate. This study (BrUOG-326) was conducted by Brown University Oncology Research Group (BrUOG) and registered on clinicaltrials.gov as NCT02257242.

Results: Ten patients received BR+VSLI as first-line therapy. The VSLI dose was escalated from 1.80 to 2.24 mg/m² (see Table). Median age was 59.5 years; there were 6 (60%) women. Patients had follicular (n=4), marginal zone (n=3), mantle cell (n=2), and small lymphocytic lymphoma (n=1). There was 1 observed DLT (G3 ileus) at VSLI dose 2.04 mg/m². So far, six patients have completed 6 cycles of BR+VSLI, while two discontinued VSLI and continued on 6 cycles with BR alone (one for DLT in cycle 1, and one for G2 neuropathy after cycle 3). The most common AE included lymphopenia (100%), constipation (60%), nausea, infusion reaction, neutropenia (each 50%), and peripheral neuropathy (40%). The only G3/4 AE were lymphopenia (90%), neutropenia (20%) and ileus (10%). Four patients developed neuropathy: two G1 and two G2. Only one patient (10%) had treatment-related rash (G2 during cycle 5). Using data from all 10 subjects, the MTD for VSLI in combination with BR was estimated to be 2.25 mg/m² (Bayesian 95% CI, 2.00-2.40 mg/m²).

All patients who completed therapy (n=8) achieved a response, with 50% achieving CR at the end of therapy (i.e. after 6 cycles of BR+VSLI or BR if VSLI was discontinued early). With median follow-up 18 months (range, 2-29), one patient experienced recurrence of a blastoid mantle cell lymphoma, while others remain in remission (see Figure). Estimated 2-year progression-free survival is 80.0% (95% CI, 20.4-96.9%), and all patients remain alive.

Conclusions: VSLI at 2.25 mg/m² can be safely combined with BR as first-line treatment for iBCL. In this study, the efficient phase 1 EWOC design enabled MTD determination for VSLI in a small cohort. Considering low rate of G3/4 toxicity, BR+VSLI may provide a platform for further combinations in treatment of B-cell lymphomas (including with an anthracycline for aggressive NHL).

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