Preliminary Results From A Phase I Dose Escalation Study to Determine the Maximum Tolerated Dose of Plerixafor In Combination with Rituximab In Patients with Relapsed Chronic Lymphocytic Leukemia
Authors: Andritsos Leslie , Byrd John C. , Jones Jeffrey A. , Hewes Becker , Kipps Thomas J. , Hsu Frank J , Burger Jan A. 
Published: October 2019

Abstract
Abstract 2450

Background:
Dose intense rituximab in previously-treated patients (pts) with CLL has demonstrated modest activity. Preclinical data indicate that the CXCR4/CXCL12 axis plays a key role in CLL cell homing and retention in tissue microenvironments, such as the bone marrow. Disruption of this axis using the small-molecule CXCR4-antagonist, plerixafor, may abrogate stroma-mediated drug resistance, and enhance sensitivity of CLL cells to rituximab. To test this hypothesis, we initiated a phase 1 trial of plerixafor + rituximab in previously-treated pts with CLL.

Aims:
The primary objective was to determine the maximum tolerated dose (MTD) and safety of plerixafor when combined with rituximab.

Methods:
Adult pts with WBC≤ 50×109/L, intermediate/high risk CLL not refractory to rituximab, and with active disease by NCI criteria were eligible in this ongoing study. Pts were treated with 3x/week rituximab, as a 100mg flat dose on Day 1, and subsequently 375mg/m2 IV for 12 total doses (i.e. for 4 weeks). Plerixafor was given SC prior to rituximab starting at the 4th rituximab dose (Day 8) for 9 total doses. Cohorts of pts were treated at 1 of 4 dose levels with plerixafor (0.08mg/kg, 0.16mg/kg, 0.24mg/kg and 0.32mg/kg). Pts were observed for dose-limiting toxicities (DLT) from the first plerixafor dose (Day 8) through Day 29 and cohort advancement followed dose escalation rules using a 3+3 design. Peripheral blood (PB) CD34+ and CLL cells were enumerated on Days 8 and 26 by flow cytometry; PB samples were obtained at baseline pre-plerixafor treatment and at 2, 4, 6, 10, and 24 hours post-plerixafor. Responses were assessed as defined by Cheson et al (Blood, 1996).

Results:
17 pts (median age 64 years; 88% male; Rai Stage IV: 53%) were enrolled, 3 pts each in the 0.08 and 0.24 mg/kg cohorts, 4 pts in the 0.16mg/kg cohort and 7 pts in the 0.32mg/kg cohort (Table 1). No DLTs were reported. Of 14 evaluable pts, 5 (36%) had partial response, 3 (21%) had stable disease for ≥2 months and 6 (43%) had progressive disease. Treatment-emergent, plerixafor-related adverse events (AEs) were seen in 5 pts and included diarrhea, vomiting, nausea, appetite loss, headache, hypoaesthesia and paraesthesia. All AEs were grade 1 except nausea (n=1) that was grade 2. Treatment-emergent serious AEs were seen in 2 pts (0.16mg/kg dose; grade 3 EBV infection, grade 2 gastrointestinal reflux disease and grade 2 dyspnea); all unrelated to plerixafor. On Day 8, there was a median 3.8-fold increase in PB CLL cells (range: 1.2 –15.0-fold), indicating CLL cell mobilization. On Day 26 fewer PB CLL cells were detected with a median fold increase of 1.5 (range, 0.9–8.0).

Conclusions:
The combination of plerixafor + rituximab in CLL pts with WBC < 50×109/L was well tolerated. CLL cells were mobilized following plerixafor, and partial remissions were seen in a proportion of pts. In some cases, maximum responses were seen several months after completion of rituximab, consistent with single agent therapy. This suggests that continued follow up may show additional responses in recently treated pts.

Disclosures:
Andritsos: Genzyme Corporation: Research Funding. Off Label Use: Plerixafor (Mozobil®), a hematopoietic stem cell mobilizer, is approved by the US FDA in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. Byrd: Genzyme Corporation: Research Funding. Jones: Genzyme Corporation: Research Funding. Hewes: Genzyme Corporation: Employment. Kipps: Genzyme Corporation: Research Funding. Hsu: Genzyme Corporation: Employment, Equity Ownership. Burger: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.