Abstract
Abstract 2465
The immunosuppressive molecule CD200 is upregulated on B-CLL and MM cells which may contribute to tumor immune evasion. Samalizumab is a novel first-in-class recombinant humanized monoclonal antibody that specifically binds CD200 and blocks CD200-CD200R interactions. Preclinical data suggest that CD200 blockade may inhibit CD200-dependent immune suppression, enabling a more efficient immune response against CD200+ tumor cells. A first-in-human phase I/II trial was initiated to evaluate safety, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamic (PD) activity of samalizumab.
In this 3+3 design, dose-escalation trial, pts with advanced stage B-CLL or MM (with or without prior therapy) received a single IV dose of samalizumab. Pts could receive additional 28-day cycles (1 dose/cycle) if first dose was tolerated and pts exhibited at least stable disease (SD). Assessments performed throughout cycle 1 and then every 2 wks included standard safety measures, HAHA, PK, PD, CBC, and CT scans (at cycle 4 and every other cycle thereafter).
Results are reported as of 20-Jun-10. Enrollment is complete with 26 pts (18M; median age 67 yrs, range 41–87) including 3 MM pts (2 at 500 mg/m2, 1 at 600 mg/m2) and 1 pt with SLL (500 mg/m2). Four pts had no prior chemotherapy; the other 22 had received a median of 2 regimens (range 1–9). Twenty pts (1 MM) received multiple (2–14+) cycles of samalizumab (86+ cycles in total); safety and efficacy data are available for 25 pts through the 500 mg/m2 cohort. Adverse events were mostly mild or moderate and manageable; the most common events were fatigue (48%), fever (20%) and rash (20%). Grade 3–5 events included neutropenia (12%) and infections (12%); no events were indicative of a cytokine storm. One non-drug-, non-CLL-related death occurred. Three pts developed HAHA. Although preliminary PK analyses (Table 1) indicate high variability due to the limited number of pts and differences in tumor burden, the median AUC of serum drug levels after the first dose (300–500 mg/m2) are consistent with a linear relationship between dose and AUC. AUC in the low dose cohorts (50–200 mg/m2) is unreliable as most PK values were below the level of quantification. PD effects consistent with inhibition of CD200-dependent immune suppression by samalizumab were observed. Out of 21 pts with sufficient peripheral immune cells to evaluate, 18 (86%) showed 81–98% reductions in peripheral CD200+CD4+ T cells and 14 (67%) demonstrated 64–75% CD200 loss on B-CLL cells following the first dose. These responses were transient at lower doses (50–200 mg/m2) and sustained at higher doses (300–500 mg/m2), indicating a dose-dependent immunoregulatory effect. Eight of 21 evaluable pts (38%) showed an increase in CD200R+ CD4+ T cells. Regulatory T cell (Treg) levels decreased 20–57% (median = 38%) in 4/7 (57%) pts whose clinical disease stabilized or improved, whereas only 5/17 (29%) pts whose disease progressed clinically showed a similar decrease (13–62%; median = 18%). Modest first-dose Th1 cytokine responses were noted in 10/25 pts. Two pts who received ≥ 9 cycles showed reduction in tumor burden by CT scan (including 1 pt with a 58% reduction and near normalization of absolute lymphocyte cell count), associated with a reduction in Tregs and increase in activated T cells over time. No MTD was identified.
Samalizumab appears to be well tolerated and exhibits a dose-dependent linear increase in serum AUC, dose-dependent changes in CD200+ B-CLL and CD4+ T cells, and modest Th1 cytokine responses. These PD effects are consistent with the predicted immunomodulatory mechanism of action. Anti-tumor activity is evident in some pts receiving multiple cycles. Treatment is ongoing with plans for additional studies of samalizumab to explore other dosing regimens.
Dosing, Safety, PK & PD Parameters by Cohort
| Samalizumab Dose (mg/m2) . | No. pts (n = 25) . | PK . | ||||||
|---|---|---|---|---|---|---|---|---|
| Enrolled . | Dosed ≥4 cycles . | AE grade ≥3 . | HAHA . | 1st-dose Th1 Cytokines . | Systemic Clearance L/h median (range) . | Distributional Clearance L/h median (range) . | AUC mg h/mL median (range) . | |
| 50 | 4 | 1 | 3 | 1 | 2 | 0.01 (0.006–0.27) | 0.03 (0.0008–2.5) | – |
| 100 | 5 | 5 | 2 | 0 | 0 | 0.04 (0.005–0.11) | 0.002 (0.001–0.003) | – |
| 200 | 3 | 1 | 0 | 2 | 2 | 0.03 (0.007–0.06) | 0.02 (0.002–6.13) | – |
| 300 | 3 | 2 | 2 | 0 | 1 | 0.01 (0.01–0.01) | 0.05 (0.02–0.6) | 28.13 (19–36) |
| 400 | 3 | 2 | 1 | 0 | 0 | 0.02 (0.01–0.02) | 0.13 (0.12–22.2) | 35.64 (30–38) |
| 500 | 7 | 0 | 1 | 0 | 5 | 0.02 (0.01–0.04) | 0.04 (0.02–0.41) | 45.09 (25–74) |
| Samalizumab Dose (mg/m2) . | No. pts (n = 25) . | PK . | ||||||
|---|---|---|---|---|---|---|---|---|
| Enrolled . | Dosed ≥4 cycles . | AE grade ≥3 . | HAHA . | 1st-dose Th1 Cytokines . | Systemic Clearance L/h median (range) . | Distributional Clearance L/h median (range) . | AUC mg h/mL median (range) . | |
| 50 | 4 | 1 | 3 | 1 | 2 | 0.01 (0.006–0.27) | 0.03 (0.0008–2.5) | – |
| 100 | 5 | 5 | 2 | 0 | 0 | 0.04 (0.005–0.11) | 0.002 (0.001–0.003) | – |
| 200 | 3 | 1 | 0 | 2 | 2 | 0.03 (0.007–0.06) | 0.02 (0.002–6.13) | – |
| 300 | 3 | 2 | 2 | 0 | 1 | 0.01 (0.01–0.01) | 0.05 (0.02–0.6) | 28.13 (19–36) |
| 400 | 3 | 2 | 1 | 0 | 0 | 0.02 (0.01–0.02) | 0.13 (0.12–22.2) | 35.64 (30–38) |
| 500 | 7 | 0 | 1 | 0 | 5 | 0.02 (0.01–0.04) | 0.04 (0.02–0.41) | 45.09 (25–74) |
Mahadevan: Alexion Pharmaceuticals, Inc: Honoraria, Speakers Bureau. Whelden: Alexion Pharmaceuticals, Inc: Employment, Equity Ownership. Faas: Alexion Pharmaceuticals, Inc: Employment, Equity Ownership. Ulery: Alexion Pharmaceuticals, Inc: Employment, Equity Ownership. Kukreja: Alexion Pharmaceuticals, Inc: Employment, Equity Ownership. Li: Alexion Pharmaceuticals, Inc: Employment, Equity Ownership. Bedrosian: Alexion Pharmaceuticals, Inc: Employment, Equity Ownership. Heffner: Alexion Pharmaceuticals, Inc: Research Funding.
Author notes
Asterisk with author names denotes non-ASH members.
