Study of JTX 8064, as Monotherapy and in Combination With a PD-1 Inhibitor, in Adult Subjects With Advanced Refractory Solid Tumors

Study Overview
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Brief Summary
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JTX-8064-101 is a Phase 1/2, open label, dose escalation and dose expansion clinical study to determine the safety, tolerability, and recommended Phase 2 dose of JTX-8064 alone and in combination with a PD-1 inhibitor (PD-1i).

Detailed Description
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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 1/2, 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.

Official Title
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Phase 1/2 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

Conditions
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Cancer

Intervention / Treatment
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* Drug: JTX-8064
* Drug: pimivalimab


Participation Criteria
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Eligibility Criteria
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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; Histologically or cytologically confirmed advanced/metastatic extracranial solid tumor malignancy. 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 Stage 3: This stage may enroll subjects with the following cancers: • 3L/4L PD-(L)1-naïve, platinum-resistant ovarian cancer 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 2L/3L HNSCC. 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. 2/3L biliary tract cancer (BTC), including intra-and extra-hepatic biliary duct cancer and cancer of the gallbladder. Subjects must have progressed on or after gemcitabine/cisplatin (Gem/Cis) and an anti-PD-(L)1 therapy in the metastatic setting. Must have PD-(L)1 inhibitor resistance. Subjects with FGFR and IDH1 mutations must have progressed on or after targeted therapies for these mutations. Measurable disease, according to the RECIST version 1.1, that has objectively progressed since (or on) previous treatment as assessed by the Investigator; ≥ 18 years of age; Eastern Cooperative Oncology Group performance status 0 or 1; Predicted life expectancy of ≥ 3 months; Have specified laboratory values (obtained ≤ 28 days prior to first dose) in accordance with the study protocol; 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 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: 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 Prior infusion of JTX-8064, LILRB2, or ILT4-directed therapy; The therapies listed below within the specified timeframe: Immunotherapy or biologic therapy < 28 days prior to planned C1D1 or 5 half-lives, whichever is shorter Chemotherapy < 21 days prior to planned C1D1, or < 42 days for mitomycin or nitrosoureas or 5 half-lives, whichever is shorter Targeted small molecule therapy < 14 days or 5 half-lives, whichever is shorter, prior to planned C1D1 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 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); 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 Live vaccines ≤ 30 days of C1D1

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1, Dose Escalation: JTX-8064 monotherapy dose escalation<br>Dose Escalation, Stage 1 JTX-8064 Monotherapy. Cohorts will enroll subjects with histologically or cytologically confirmed advanced/metastatic extracranial solid tumor malignancies | Drug: JTX-8064<br>* Specified dose on specified days<br>* Other names: Anti-ILT4;|
| Experimental: Stage 2, Dose Escalation: JTX-8064 in combination with pimivalimab<br>Dose Escalation, Stage 2: JTX-8064 in combination with pimivalimab. Cohorts will enroll subjects with histologically or cytologically confirmed advanced/metastatic extracranial solid tumor malignancies | Drug: JTX-8064<br>* Specified dose on specified days<br>* Other names: Anti-ILT4;Drug: pimivalimab<br>* Specified dose on specified days<br>* Other names: Anti-PD-1;|
| Experimental: Stage 3 Expansion: JTX-8064 monotherapy (Ovarian)<br>Cohort will enroll subjects with advanced/metastatic PD-1/PD-L1 (PD-(L)1)-naïve, platinum-resistant ovarian cancer | Drug: JTX-8064<br>* Specified dose on specified days<br>* Other names: Anti-ILT4;|
| Experimental: Stage 4, Expansion: JTX-8064 in combination with pimivalimab (ccRCC)<br>JTX-8064 in combination with pimivalimab. Cohort will enroll subjects with advanced/metastatic PD-(L)1i-experienced clear cell renal cell carcinoma (ccRCC) | Drug: JTX-8064<br>* Specified dose on specified days<br>* Other names: Anti-ILT4;Drug: pimivalimab<br>* Specified dose on specified days<br>* Other names: Anti-PD-1;|
| Experimental: Stage 4, Expansion: JTX-8064 in combination with pimivalimab (TNBC)<br>JTX-8064 in combination with pimivalimab. Cohort will enroll subjects with advanced/metastatic PD-(L)1i-experienced triple negative breast cancer (TNBC) | Drug: JTX-8064<br>* Specified dose on specified days<br>* Other names: Anti-ILT4;Drug: pimivalimab<br>* Specified dose on specified days<br>* Other names: Anti-PD-1;|
| Experimental: Stage 4, Expansion: JTX-8064 in combination with pimivalimab (HNSCC)<br>JTX-8064 in combination with pimivalimab. Cohort will enroll subjects with advanced/metastatic PD-(L)1-naïve, PD-L1+ head and neck squamous cell carcinoma (HNSCC) | Drug: JTX-8064<br>* Specified dose on specified days<br>* Other names: Anti-ILT4;Drug: pimivalimab<br>* Specified dose on specified days<br>* Other names: Anti-PD-1;|
| Experimental: Stage 4, Expansion: JTX-8064 in combination with pimivalimab (Ovarian)<br>JTX-8064 in combination with pimivalimab. Cohort will enroll subjects with advanced/metastatic PD-(L)1-naïve, platinum resistant ovarian cancer | Drug: JTX-8064<br>* Specified dose on specified days<br>* Other names: Anti-ILT4;Drug: pimivalimab<br>* Specified dose on specified days<br>* Other names: Anti-PD-1;|
| Experimental: Stage 4, Expansion: JTX-8064 in combination with pimivalimab (NSCLC)<br>JTX-8064 in combination with pimivalimab. Cohort will enroll subjects with advanced/metastatic PD-(L)1-experienced non-small cell lung cancer (NSCLC) | Drug: JTX-8064<br>* Specified dose on specified days<br>* Other names: Anti-ILT4;Drug: pimivalimab<br>* Specified dose on specified days<br>* Other names: Anti-PD-1;|
| Experimental: Stage 4, Expansion: JTX-8064 in combination with pimivalimab (cSCC)<br>JTX-8064 in combination with pimivalimab. Cohort will enroll subjects with advanced/metastatic PD-(L)1-experienced cutaneous squamous cell carcinoma (cSCC) | Drug: JTX-8064<br>* Specified dose on specified days<br>* Other names: Anti-ILT4;Drug: pimivalimab<br>* Specified dose on specified days<br>* Other names: Anti-PD-1;|
| Experimental: Stage 4, Expansion: JTX-8064 in combination with pimivalimab (UPS & LPS)<br>JTX-8064 in combination with pimivalimab. Cohort will enroll subjects with advanced/metastatic PD-(L)1-naïve undifferentiated pleomorphic sarcoma (UPS) and liposarcoma (LPS) | Drug: JTX-8064<br>* Specified dose on specified days<br>* Other names: Anti-ILT4;Drug: pimivalimab<br>* Specified dose on specified days<br>* Other names: Anti-PD-1;|
| Experimental: Stage 4, Expansion: JTX-8064 in combination with pimivalimab (PD-(L)1i-experienced HNSCC)<br>JTX-8064 in combination with pimivalimab. Cohort will enroll subjects with PD-(L)1i-experienced HNSCC | Drug: JTX-8064<br>* Specified dose on specified days<br>* Other names: Anti-ILT4;Drug: pimivalimab<br>* Specified dose on specified days<br>* Other names: Anti-PD-1;|
| Experimental: Stage 4, Expansion: JTX-8064 in combination with pimivalimab (BTC)<br>JTX-8064 in combination with pimivalimab. Cohort will enroll subjects with biliary tract cancer (BTC), including intra-and extra-hepatic biliary duct cancer and cancer of the gallbladder. All subjects must have progressed on or after gemcitabine/cisplatin (Gem/Cis) in the metastatic setting, must have PD-(L)1 inhibitor resistance. | Drug: JTX-8064<br>* Specified dose on specified days<br>* Other names: Anti-ILT4;Drug: pimivalimab<br>* Specified dose on specified days<br>* Other names: Anti-PD-1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuation due to adverse events (AEs). | Evaluated using National Cancer Institute (NCI) Common Technology Criteria for Adverse Events (CTCAE) version 5.0 | up to 18 months | 
| Determination of a RP2D for JTX-8064 monotherapy and in combination with JTX-4014 or pembrolizumab |  | up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax (the maximum observed concentration) for JTX-8064 when administered as monotherapy or in combination with a PD-1i |  | Cycle 1 through 12 (each cycle is 21 days) | 
| Tmax (time of maximum observed concentration) for JTX-8064 when administered as monotherapy or in combination with a PD-1i |  | Cycle 1 through 12 (each cycle is 21 days) | 
| Cmin for JTX-8064 when administered as monotherapy or in combination with a PD-1i |  | Cycle 1 through 12 (each cycle is 21 days) | 
| AUClast (area under the concentration-time curve from time 0 to the last measurable concentration) for JTX-8064 when administered as monotherapy or in combination with a PD-1i |  | Cycle 1 and 3 (each cycle is 21 days) | 
| Cmax for PD-1i in combination with JTX-8064 |  | Cycles 1 through 12 (each cycle is 21 days) | 
| Tmax for PD-1i in combination with JTX-8064 |  | Cycles 1 through 12 (each cycle is 21 days) | 
| Cmin for PD-1i in combination with JTX-8064 |  | Cycles 1 through 12 (each cycle is 21 days) | 
| Incidence of ADAs to JTX-8064 and, as appropriate, to PD-1i |  | Baseline through Cycle 12 (each cycle is 21 days)] | 
| Incidence of neutralizing antibodies (Nabs) to JTX-8064 and, as appropriate, to PD-1i |  | Baseline through Cycle 12 (each cycle is 21 days)] | 
| For Stages 1 and 2: Receptor occupancy for LILRB2 on monocytes in whole blood |  | Baseline through Cycle 6 (each cycle is 21 days)] | 
| For Stages 3 and 4: Preliminary efficacy endpoints: ORR (the proportion of subjects who have had a partial response, PR or complete response CR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 |  | up to 36 months | 
| For Stages 3 and 4: Preliminary efficacy endpoints: DCR (the proportion of subjects who have a PR, CR or stable disease SD), as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 |  | up to 36 months | 
| For Stages 3 and 4: Preliminary efficacy endpoints: Duration of response (DOR) (the time from documentation of tumor progression or death due to any cause, whichever comes first) |  | up to 36 months | 
| For Stages 3 and 4: Preliminary efficacy endpoints: Percentage of subjects with tumor reduction at any time |  | up to 36 months | 
| For Stages 3 and 4: Preliminary efficacy endpoints: Progression-free survival (PFS) (interval from start of treatment to the earlier of first documentation of disease progression or death from any cause) |  | up to 36 months | 
| For Stages 3 and 4: Preliminary efficacy endpoints: Overall survival (OS) (the interval from start of treatment to death of any cause) |  | up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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JTX-8064, LILRB2, ILT-4, PD-1, JTX-4014, Immunotherapy, Immuno-oncology, Solid tumor Malignancies, Dose escalation, INNATE, Monotherapy, Combination Therapy, Antineoplastic Agents, Immunological