Results from Ongoing Phase 1/2 Trial of SL-401 As Consolidation Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission with Minimal Residual Disease (MRD)

Background: SL-401 is a novel targeted therapy, comprised of recombinant IL-3 genetically fused to a truncated diphtheria toxin payload, directed to the interleukin-3 receptor α (CD123), a target expressed on acute myeloid leukemia (AML) blasts, AML stem cells (LSCs), and on cells from a variety of additional hematologic malignancies. While conventional chemotherapy can induce remission in a majority of AML patients, relapse rates remain high and durability of remissions are short. Outcomes are particularly poor when minimal/measurable residual disease (MRD) is detected by molecular and/or flow cytometric analyses after therapy; even when consolidation with allogeneic stem cell transplant is used. A therapy directed at lowering MRD may improve long-term outcomes. Accordingly, SL-401 is being evaluated in patients with AML in first or second complete remission (CR1 or CR2, respectively) with MRD with the intent to potentially lessen MRD thereby improving clinical outcomes. Preliminary results from this ongoing trial are reported here.

Methods: This multicenter, single-arm Phase 1/2 trial of AML patients in CR1 or CR2 with high risk of relapse, including with MRD, includes a standard 3x3 dose escalation stage (Stage 1) and an expansion stage (Stage 2). In Stage 1, AML patients in remission, either MRD⁺ or MRD^-, received SL-401 as a daily IV infusion at 7, 9, or 12 mcg/kg/day for days 1-5 of a 28-day cycle. In Stage 2, AML patients in remission, who are MRD⁺, receive SL-401 at the dose determined in Stage 1 (12 mcg/kg). Objectives include characterization of SL-401 safety with determination of the maximum tolerated or tested dose, and preliminary assessment of efficacy including changes in MRD burden and disease-free survival. In Stage 1, MRD assessment methods included multiparameter flow cytometry (MFC) or alternative analyses (cytogenetics, FISH, PCR, or next-generation sequencing of AML-associated mutations) per each participating institution standard. In Stage 2, MRD assessment methods for eligibility are per each institution standard; for baseline and subsequent MRD assessments, MFC analyses are conducted at a central laboratory.

Results: In Stage 1 (enrollment completed), 9 patients (5 MRD^-) received SL-401 (7 mcg/kg, n=3; 9 mcg/kg, n=3; 12 mcg/kg, n=3); no MTD was identified in Stage 1, and the 12 mcg/kg dose was selected for Stage 2. In Stage 2 (enrollment ongoing), 7 patients received SL-401 (12 mcg/kg). The median age across both stages was 64 years (range: 45-82 years); 12 males and 4 females were enrolled. Median number of treatment cycles was 2 (range: 1-6). The most common treatment-related adverse events (TRAEs), all grades, were thrombocytopenia, hypoalbuminemia, and AST and ALT elevations, all at 38% (6/16). The most common ≥ grade 3 TRAEs were ALT elevation (5/16; 31%), AST elevation (4/16; 25%), and thrombocytopenia (3/16; 19%). Two patients had grade 3 capillary leak syndrome (CLS) at the 12mcg/kg dose that resolved. MRD assessments per institution demonstrated baseline MRD in the range of 0.4-4%. Central analysis available for 6 of 7 stage 2 patients detected CD123 expression (quantification pending) at baseline on the MRD cells; central analysis of MRD is in progress. Of 7 MRD⁺ patients who received SL-401 (12 mcg/kg), one patient subsequently went on to stem cell transplant (SCT), 3 patients relapsed within 2 months of study entry, 1 patient discontinued due to TRAE of grade 1 hypoalbuminemia, and 2 patients receiving SL-401 remain in remission at 3⁺ and 4⁺ months, ongoing. MRD analyses are underway and Stage 2 enrollment continues.

Conclusions: In this Phase 1/2 trial, Stage 1 is complete without DLT or MTD, and enrollment in Stage 2 is ongoing. The SL-401 safety profile has been similar to that observed in other SL-401 clinical studies, with no unexpected TRAEs. Targeting MRD with SL-401 has the potential to reduce the presumptively chemo-resistant cell population remaining after conventional therapy to offer improved outcomes for AML patients in remission with high risk of relapse. MRD and disease-free-survival analysis is ongoing and enrollment continues in Stage 2 of this Phase 1/2 trial. Clinical trial information: NCT02270463.