Phase 1 First-in-Human (FIH) Study of Leukocyte Immunoglobulin-Like Receptor B2 (LILRB2) Inhibitor Monoclonal Antibody (mAb) JTX-8064, as Monotherapy and in Combination With a Programmed Cell Death Receptor-1 (PD-1) Inhibitor, in Adult Subjects With Advanced Refractory Solid Tumor Malignancies

JTX-8064 is a humanized mAb designed to block the interaction of LILRB2 with its known ligands, endogenous major histocompatibility complex class I (MHC I) molecules. This is a Phase 1, first in human, open label, multicenter, dose escalation and dose expansion clinical trial to determine the safety, tolerability, MTD and RP2D of JTX-8064 when administered as a single agent and in combination with a PD-1i in adult subjects with advanced refractory solid tumor malignancies. Additionally, the study will seek to evaluate the pharmacokinetics and immunogenicity of JTX-8064, and preliminary efficacy of JTX-8064 as a monotherapy and in combination with a PD-1i.

1. Able and willing to participate and comply with all study requirements and provide signed and dated informed consent prior to initiation of any study procedures;
2. Histologically or cytologically confirmed advanced/metastatic extracranial solid tumor malignancy.
   1. Stages 1 and 2: Subject must have received, have been intolerant to, have been ineligible for, or have declined all treatment known to confer clinical benefit with the exception of subjects enrolled in combination cohorts with a PD-1i, where a PD-1i is approved by the local regulatory agencies
   2. Stage 3: This stage may enroll subjects with the following cancers:

      • 3L/4L PD-(L)1-naïve, platinum-resistant ovarian cancer

   3. Stage 4: This stage may enroll subjects with the following cancers:
      • 2L/3L ccRCC. Subjects must have progressed on or after treatment with an anti-PD-(L)1 agent in their most recent prior line of therapy
      • 2L-4L TNBC. Subjects must have progressed on or after treatment with a prior anti-PD-(L)1 therapy
      • 1L, PD-(L)1-naïve, PD-L1+; combined positive score (CPS) ≥ 1% HNSCC
      • 3L/4L, PD-(L)1-naïve, platinum-resistant ovarian cancer
      • 2L/3L NSCLC; Subjects must have progressed on or after treatment with platinum-based chemotherapy and an anti-PD-(L)1-containing therapy. The anti-PD-(L)1 agent must have been a part of the most recent prior line of therapy. Subjects with EGFR mutations and ALK rearrangements will be excluded. Subjects with other targetable genomic aberrations for which FDA approved therapies exist must have received appropriate FDA-approved targeted therapy
      • 2L/3L cSCC; Subjects must have progressed on or after treatment with an anti-PD-(L)1 agent in their most recent prior line of therapy
      • 2L-4L PD-(L)1-naïve UPS and LPS
3. Measurable disease, according to the RECIST version 1.1, that has objectively progressed since (or on) previous treatment as assessed by the Investigator;
4. ≥ 18 years of age;
5. Eastern Cooperative Oncology Group performance status 0 or 1;
6. Predicted life expectancy of ≥ 3 months;
7. Have specified laboratory values (obtained ≤ 28 days prior to first dose) in accordance with the study protocol;
8. For women of childbearing potential (WOCBP): negative serum pregnancy test during the Screening period and a negative urine pregnancy test up to 24 hours in advance of C1D1
9. WOCBP and males whose partners are WOCBP must agree to use a highly effective method of birth control throughout their participation and for 5 months following the last study drug administration.

Exclusion Criteria:

1. Concurrent anticancer treatment, either FDA approved or investigational, for the cancer being evaluated in this study or for prior malignancies. A past history of other malignancies is allowed as long as the subject is not receiving treatment other than hormonal therapy and, in the judgment of the Investigator, is unlikely to have a recurrence. Of note, concurrent malignancies that do not require treatment and are clinically stable are allowed
2. Prior infusion of JTX-8064, LILRB2, or ILT4-directed therapy;
3. The therapies listed below within the specified timeframe:
   1. Immunotherapy or biologic therapy < 28 days prior to planned C1D1 or 5 half-lives, whichever is shorter
   2. Chemotherapy < 21 days prior to planned C1D1, or < 42 days for mitomycin or nitrosoureas or 5 half-lives, whichever is shorter
   3. Targeted small molecule therapy < 14 days or 5 half-lives, whichever is shorter, prior to planned C1D1
   4. Radiation therapy < 21 days prior to planned C1D1. Exception: Limited (e.g., pain palliation) radiation therapy is allowed prior to and during study drug administration as long as there are no acute toxicities, any AE due to prior radiation therapy has recovered to < Grade 2, and the radiation is not administered to a target lesion
4. Symptomatic or uncontrolled brain metastases, leptomeningeal disease, or spinal cord compression not definitively treated with surgery or radiation (brain metastases that are stable and asymptomatic after prior treatment will be allowed);
5. Women who are pregnant or breastfeeding or who plan to become pregnant/breastfeed while on study; men who plan to father children during the study
6. Live vaccines ≤ 30 days of C1D1