mipletamig (APVO436)

P1, N=39, Not yet recruiting, Aptevo Therapeutics

The expansion phase is evaluating the safety and tolerability of APVO436 at the RP2D level when it is used as an adjunct to the standard of care to obtain a preliminary assessment of the anti-leukemia activity of APVO436-containing experimental monotherapy (Cohorts 3 and 5) and combination therapy modalities (Cohort 1 with MEC chemotherapy, Cohort 2 with venetoclax and azacitidine, and Cohort 4 with oral azacitidine). Conclusions Preliminary results from the dose-expansion phase indicate that APVO436 is well tolerated and safe as single agent and in combination across cohorts with different underlying leukemic conditions. Furthermore, anti-leukemic activity has been observed.

This article discusses the clinical impact potential of bispecific antibodies (BiAB) capable of redirecting host T-cell cytotoxicity in an MHC-independent manner to malignant clones as well as immunosuppressive myeloid-derived suppressor cells (MDSC) as a new class of anti-MDS drug candidates. T-cell engaging BiAB targeting the CD123 antigen may help delay disease progression in high-risk adult MDS and potentially reduce the risk of transformation to secondary AML.

The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.

APVO436-associated CRS was generally manageable with tocilizumab with or without dexamethasone. Notably, the development of CRS after APVO436 therapy did not appear to be associated with a response. The prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS, as well as patients who did not experience CRS after APVO436 infusions.

Seven of 8 had failed 2-4 prior lines of anti-AML therapy and one patient had relapsed after achieving a remission on frontline venetoclax plus decitabine therapy. Three of these 6 patients had marrow CRs. In conclusion, the safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential.

APVO436-associated CRS was generally manageable with standard of care and in most cases it resolved rapidly with the administration of tocilizumab at standard doses combined with dexamethasone. APVO436-related CRS was not required for clinically meaningful responses in R/R AML patients, and it did not affect the survival outcome. Prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS as well as patients who did not experience CRS after APVO436 infusions.

Three of six evaluable MDS patients had marrow CRs. The safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential.

P1b, N=136, Recruiting, Aptevo Research and Development LLC | Active, not recruiting --> Recruiting

P1b, N=136, Active, not recruiting, Aptevo Research and Development LLC | Recruiting --> Active, not recruiting | Phase classification: P1 --> P1b

Pre-medication with diphenhydramine, acetaminophen, and dexamethasone was administered starting with dose 1 to mitigate infusion related reactions (IRR) and cytokine release syndrome (CRS). Conclusions Preliminary results indicate that APVO436 is tolerated in patients with R/R AML and MDS at the doses and schedules tested to date, with a manageable safety profile. Dose escalation continues and the results will be updated for this ongoing study.