Abstract P047

Trial in Progress: Evaluating Combination of Nivolumab and Axatilimab in Patients With Relapsed/Refractory Classical Hodgkin Lymphoma (NAHL)

Background: Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) who have progression on anti-PD-1 therapy have 1-year median overall survival of 60% (Armand JCO 2018). Tumor Associated Macrophages (TAMs) expressing CSF1-R receptor have been implicated in resistance to anti-PD-1 therapy through (i) direct inhibition of cytotoxic T lymphocytes and (ii) phagocytosis of the anti-PD-1 antibody. Pre-clinical studies suggest that combination of anti-PD-1 and anti-CSF1-R blockade can result in upregulation of cytotoxic T lymphocytes and increased PD-L1 expression, resulting in Th1 type of type of tumor microenvironment.

Methods: We have designed a phase 2 dose de-escalation trial (Figure 1) using combination of nivolumab and axatilimab (anti-CSF1-R monoclonal antibody) in pts with R/R cHL who have sub-optimal response to anti-PD-1 therapy to determine the efficacy and safety of the drug combination (NCT05723055). Included patients must have progression on anti-PD-1 based therapy or have SD or PR after at least 4 months of treatment with anti-PD-1 based therapy. Key exclusion criteria include: (A) History of grade ≥ 3 immune-related adverse events (irAE) other than endocrinopathies, (B) prior exposure to anti-CSF1-R inhibitor. For the phase 2 portion, the planned sample size is 9 response-evaluable pts. The null hypothesis is a response rate of 10% and the alternative hypothesis is a response rate of 45%. The null hypothesis will be rejected if three (3) or more objective responses are observed in nine pts. Nine evaluable pts will be enrolled and receive axatilimab 3mg/kg Q4 weeks in combination with nivolumab 480mg Q4 weeks. If more than one DLT is observed during the DLT period (first two cycles) in the first 6 pts, the study drug dose will be reduced to 2mg/kg and additional pts (up to 6 at 2mg/kg dose) may be included in the study. This could result in maximum 12 pts for the entire study. The above combination will be continued until unacceptable toxicity or progression of disease (whichever comes first) for maximum of 12 months. Primary endpoint is ORR as defined by Lugano Criteria. Key secondary endpoints include frequency of AEs and serious adverse events (SAEs), PFS and ORR as measured by LYRIC criteria. Exploratory endpoints include: i) pre-treatment and on-treatment lymph node biopsy to examine changes in tumor microenvironment, ii) serial blood analysis including cytokine profile, circulating tumor DNA testing, and flow cytometry.

Authors

Harsh Shah, Boyu Hu, Ken Boucher, Deborah Stephens