A Phase 1 Study of ALX148, a CD47 Blocker, in Combination with Rituximab in Patients with Non-Hodgkin Lymphoma

Background:

CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host's immune response. ALX148 is a fusion protein comprised of a high affinity CD47 blocker linked to an inactive human immunoglobulin Fc region. In combination with anti-tumor antibodies, ALX148 enhances the innate and adaptive immune response against cancer. ALX148 has previously been shown to be well tolerated both as a single agent and in combination with pembrolizumab or trastuzumab in a range of solid tumors with no maximum tolerated dose (MTD) identified (SITC 2018 #P335, ASCO 2019 #2514). Characterization of ALX148's safety profile and antitumor activity in combination with rituximab are reported in patients (pts) with both aggressive and indolent histologies of non-Hodgkin Lymphoma (NHL).

Methods:

Patients with relapsed or refractory CD20-positive B-cell NHL for which no curative therapy was available received ALX148 (10 mg/kg QW) in combination with rituximab (375 mg/m2 weekly for 4 doses followed by once monthly for 8 doses). The primary endpoint for the safety confirmation population was first cycle dose limiting toxicity (DLT). Tumor response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed in all pts. Preliminary clinical data from the fully enrolled cohort is reported as of July 15, 2019.

Results:

Twenty pts (15 males, 5 females) with NHL were administered ALX148 in combination with rituximab (DLBCL, n=11; mantle cell lymphoma, n=4; follicular lymphoma, n=3; and marginal zone lymphoma, n=2). The pts median age was 66 years (range 32-80) and ECOG PS 0/1 was 7/13. Patients had a median of 3 prior lines of therapy (range 1-7) with 50% having rituximab-refractory tumors. There were no dose limiting toxicities reported and the MTD of ALX148 in combination with rituximab was not reached. The maximum administered dose was 10 mg/kg QW. Sixteen pts experienced any AE, while 11 pts reported mostly low grade treatment-related adverse events (TRAE). The most common TRAEs were rash (20%, n=4); anemia, fatigue, nausea, neutropenia and decreased platelets (10%, n=2 each). One TRAE ≥ G3 of neutropenia occurred in more than 1 patient (1G3, 1G4). As of the data cut off with a median follow-up time of 3 (0.3-14) months, preliminary tumor response was assessed in 17 evaluable pts using the Lugano Classification, 2014. The ORR was 35% across all tumor histologies, with a 50% ORR reported in indolent (FL+MZL), and 31% ORR reported in aggressive (DLBCL+MCL) histologies. The overall DCR was 41%. Six pts achieved partial response [(2) follicular, (2) DLBCL, (2) mantle cell]. Four pts achieved SD [(1) each of follicular, marginal zone, DLBCL(>1yr), and mantle cell]. Preliminary results indicate favorable ALX148 PK and near complete CD47 receptor occupancy across the dosing interval. Results will be updated at time of presentation.

Conclusions:

ALX148 demonstrates excellent tolerability with favorable PK/PD characteristics in combination with rituximab in patients with relapsed/refractory NHL. The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity in combination with rituximab was observed with objective responses reported in heavily pretreated and rituximab-refractory patients.

Clinical trial information: NCT03013218