Phase 1b/2 study of axatilimab in combination with azacitidine in advanced Phase MPN, MDS/ MPN overlap and high-risk CMML Free

Background & Significance: Effective management strategies are urgently needed for patients (pts) with MDS/MPN overlap syndromes. Current therapies are limited to hydroxyurea for pts with proliferative phenotypes and hypomethylating agents for pts with dysplastic phenotype with complete response (CR) rates <20% and second-line options lacking. Prognosis is poor for pts with high-risk CMML and other MDS/MPN overlap syndromes with a median overall survival (OS) <3 yrs and dismal for accelerated phase disease with OS <1 yr. The only curative treatment is an allogeneic stem cell transplant which is not feasible in many pts due to age, comorbidities, poor performance status, or inability to achieve adequate pre-transplant disease control. 

Axatilimab (Axa) is a first-in-class humanized IgG4 monoclonal antibody with high affinity against colony stimulating factor-1 receptor (CSF-1R). CSF-1R is expressed on cells in the mononuclear phagocyte lineage. In vitro studies have demonstrated that Axa binds to human CSF-1R and completely inhibits macrophage viability during CSF1–mediated differentiation. Axa has demonstrated adequate tolerability and encouraging response rates in the treatment of chronic graft vs host disease (cGVHD) through inhibition of donor-derived monocytes and macrophages and is FDA approved for refractory cGVHD. Inhibition of CSF-1R–mediated signaling has shown anti-tumor activity in AML models by targeting supportive cells in the microenvironment (Edwards DK et al.Blood 2019) and may therefore represent a therapeutic strategy in other myeloid malignancies as well. 

Study Design & Methods: We have designed a multicenter phase 1b/2 study (NCT06523556) to assess the tolerability & preliminary efficacy of Axa in combination with Azacitidine (AZA) in pts with advanced phase MPN, CMML (intermediate-2 or high risk per CPSS molecular model), and other MDS/MPN overlap syndromes as per 2016 WHO criteria including atypical CML, MDS/MPN with ring sideroblasts and thrombocytosis and MDS/MPN unclassifiable (MDS/MPN-U). 

In phase 1b, Axa monotherapy will be examined in the relapsed/refractory setting using a standard 3+3 design for 2 dose levels (0.15 mg/kg and 0.3 mg/kg administered on D1 and 15 of Cycle 1). Dose limiting toxicity (DLT) will be evaluated for each 3-patient cohort at the end of cycle 1. Upon completion of phase 1b, enrollment will be paused for a safety review. Once the RP2D of Axa monotherapy is identified, we will proceed with phase 2. The dose utilized in phase 2 will be one dose level below the RP2D in combination with AZA 75 mg/m2 daily SQ/IV administered on Days 1-7. Cycles will be 28 days. Pts may receive up to 4 cycles of combination treatment with bone marrow (BM) aspirate and biopsy after cycle 1, 2, and 4 for response assessment. Pts who achieve less than a partial response (PR) by cycle 4 can receive 2 additional cycles with BM assessment after cycle 6. If PR or better response is achieved, pts continue on combination for up to 24 cycles total in the absence of progression or intolerable toxicity.  

The study plans to enroll 9 to 12 pts during phase 1b dose escalation and a maximum of 35 pts during phase 2. The phase 2 portion of the study will utilize a Simon Optimal 2-stage design with early stopping rules if the combination is deemed futile after evaluation of the first 11 pts. The null hypothesis that the true response rate (that includes CR and PR achieved by cycle 4) is 15% based on published experience with single-agent AZA will be tested against a one-sided alternative hypothesis of a CR rate of 40%. Only if significant efficacy is observed for pts accrued to the first stage, the second stage will proceed to a total enrollment of 35 pts. The study is currently open and has enrolled 3 pts (ages 78-81; 2 males/1 female; all white) including 2 with CMML and 1 with MDS/MPN-U.  

The primary objective of phase 2 is to evaluate the overall response rate of Axa + AZA in newly diagnosed pts using Savona response criteria (Savona MR et al. Blood 2015). The secondary objectives include evaluation of safety and tolerability of the combination with a focus on immune-related side effects from Axa and QoL assessment using the MPNSAF scores. Correlative studies will evaluate markers of myeloid differentiation, mechanisms of intrinsic and acquired resistance to the regimen by tracking morphologic, signaling and epigenetic changes over time, and biomarkers specific to CSF-1R biology.