CD40 Agonistic Antibody APX005M Research Articles

EPCT-02. PBTC-051: FIRST IN PEDIATRICS PHASE 1 STUDY OF CD40 AGONISTIC MONOCLONAL ANTIBODY APX005M IN PEDIATRIC SUBJECTS WITH RECURRENT/REFRACTORY BRAIN TUMORS

BACKGROUNDCD40 is a co-stimulatory molecule expressed on antigen presenting cells (APCs). APX005M is a CD40 agonist monoclonal antibody which stimulates innate and adaptive anti-tumor immunity through activation of APCs, macrophages, and antigen-specific CD8+T-cells. Pediatric Brain Tumor Consortium study PBTC-051 is the first investigation of APX005M in pediatric patients and is evaluating the safety, recommended phase 2 dose (RP2D), pharmacokinetics, and preliminary efficacy of APX005M in children with central nervous system (CNS) tumors.RESULTSAccrual of patients with recurrent/refractory primary malignant CNS tumors (stratum 1) began in March 2018. 16 patients (2 ineligible) have enrolled on this stratum; 14 were treated. Dose escalation through 3 planned dose levels of APX005M was completed without excessive or unanticipated toxicities. The highest dose level (0.6 mg/kg q3 weeks) is the presumptive RP2D, and an expansion cohort is currently enrolling at this dose. 2 patients at dose level 3 have received >12 cycles of therapy. Grade 3 or higher adverse events at least possibly attributable to APX005M include 11 lymphopenia, 5 neutropenia, 5 leukopenia, 3 ALT elevations, 1 AST elevation, 1 thrombocytopenia, and 1 hypoalbuminemia. PK data will be available March 2020. Stratum 2 is now enrolling patients with post-radiation/pre-progression DIPG beginning at dose level 2, with 1 patient currently enrolled.CONCLUSIONThe CD40 agonistic antibody APX005M has demonstrated preliminary safety in pediatric patients with recurrent/refractory primary malignant CNS tumors and has a likely RP2D of 0.6 mg/kg q3 weeks in this population. Preliminary efficacy data are pending.

Abstract CT089: Phase Ib/II of CD40 agonistic antibody APX005M in combination with nivolumab (nivo) in subjects with metastatic melanoma (M) or non-small cell lung cancer (NSCLC)

Abstract Background: Despite recent success with checkpoint inhibitors, the majority of patients with M or NSCLC have a transient response or no response to checkpoint blockade. Preclinical data suggest that activation of CD40 can be combined with PD-1 blockade to trigger effective T cell immunity. We are conducting a multi-center, open label Phase Ib/II clinical trial to evaluate the combination of APX005M with nivo in subjects with M or NSCLC. We report safety and efficacy from the completed Phase Ib portion of the study and the 1st stage of the Phase II M cohort. Methods: Phase Ib followed a 3+3 design and enrolled adult subjects with M and disease progression (PD) while receiving anti-PD-1 therapy (anti-CTLA-4 more than 3 months prior to study entry was allowed) and subjects with immunotherapy naïve NSCLC, in 3 dose levels of APX005M (0.03, 0.1 and 0.3 mg/kg) combined with a fixed dose of nivo (360mg) every 3 weeks. Primary objectives in Phase Ib were to evaluate safety and determine the Phase II dose (P2D) of APX005M. Phase II is enrolling subjects with M or NSCLC in two parallel Phase II cohorts, each following a Simon 2-stage design. Primary objective in Phase II is to evaluate the tumor response in each cohort. Phase Ib analyses were performed on dose limiting toxicity (DLT)-evaluable subjects. Phase II analyses were performed on all treated subjects. Results: Phase Ib: No DLTs were observed in the 9 subjects enrolled in Phase Ib and the P2D for APX005M is 0.3 mg/kg. Four subjects experienced Grade 3 AEs considered related to study drugs (non-DLTs, including transaminitis, hyperbilirubinemia, anemia, pneumonitis, 1 subject each) with no grade 4 AEs reported. Of the 5 subjects with M, 1 had a confirmed PR, 2 had prolonged SD (>8 months) and 2 had PD as best overall response. Of the 4 subjects with NSCLC, 1 had a robust confirmed PR, 2 had SD (on study lesion biopsies histology negative) and 1 had PD as best overall response. Phase II: The 1st stage of the M cohort enrolled 10 additional subjects. One subject experienced a Grade 3 AE considered related to study drugs with no grade 4 AEs reported. Of these 10 subjects, 2 had confirmed PR, 2 had SD, and 6 had PD as best overall response. The overall toxicity profile of the combination is consistent with the profiles of individual agents. NanoString analysis of paired tumor biopsies revealed high tumor-infiltrating lymphocytes, and increased expression of IFNγ inducible cytokines (CXCL9 and CXCL10) while on treatment. Increased tumor T cell infiltration was further confirmed by immunohistochemistry. Conclusions: APX005M + nivo demonstrated a good safety profile and promising antitumor activity in M subjects with PD while receiving anti-PD-1 therapy and potential activity in NSCLC. The study is currently enrolling subjects in the 2nd stage of the Phase II M cohort and the 1st stage of the Phase II NSCLC cohort. Clinical trial information: NCT03123783. Citation Format: Harriet Kluger, Sarah A. Weiss, Anthony J. Olszanski, Lynn Schuchter, Gerald P. Linette, Linda Garland, Nicholas O. Iannotti, Melissa Johnson, Emin Avsar, Minu K. Srivastava, Ovid C. Trifan, Martin J. Edelman. Phase Ib/II of CD40 agonistic antibody APX005M in combination with nivolumab (nivo) in subjects with metastatic melanoma (M) or non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT089.

Abstract 4867: The CD40 agonistic antibody APX005M ‘licenses’ antigen presenting cells to promote tumor-specific T-cell responses

Abstract Modulation of co-stimulatory and co-inhibitory molecules on immune cells has become a promising approach for cancer immunotherapy. CD40 engagement on antigen presenting cells (APCs) by its ligand CD154 leads to maturation and expression of co-stimulatory molecules such as CD80, CD86, OX-40L, and 4-1BBL that are requisite for optimal antigen-specific T-cell activation, an essential component of the anti-tumor immune response. To evaluate the therapeutic potential of targeting the CD40-CD154 pathway, Apexigen has developed APX005M - a humanized IgG1 CD40 agonistic antibody that binds with high affinity to human CD40. APX005M mimics CD154, has potent CD40 agonistic activity and promotes activation of APCs. Monocyte-derived dendritic cells treated with APX005M display a mature phenotype characterized by upregulation of CD80, CD86 and HLA-DR and increased secretion of IL-12. In mixed lymphocyte reaction and viral antigen recall assays, APX005M significantly enhances proliferation of and IFN-ã secretion from both naïve and memory T cells. Since CD40-CD154 signaling is involved in the priming phase of T cell activation and acts upstream of many critical costimulatory pathways, CD40 agonistic antibodies may represent an essential component of combination immunotherapy. In support of this, we show that APX005M synergizes with checkpoint inhibitors to promote antigen-specific T-cell responses. Importantly, in an ex vivo tumor assay APX005M induces T-cell proliferation and cytokine secretion. These data demonstrate that APX005M binds to APCs and induces their activation and maturation to ultimately drive a potent tumor-specific T-cell response. T cell activation in cancer patients receiving APX005M will be assessed in current and future clinical studies. Citation Format: Erin L. Filbert, Pia Björck, Xiaodong Yang, Ovidiu C. Trifan. The CD40 agonistic antibody APX005M ‘licenses’ antigen presenting cells to promote tumor-specific T-cell responses. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4867.