Clinical trial NCT04669899: Study of JTX-8064, as Monotherapy and in Combination With a PD-1 Inhibitor, in Adult Subjects With Advanced Refractory Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Cancer
Keywords: JTX-8064
LILRB2
ILT4
PD-1
JTX-4014
Immunotherapy
Immuno-oncology
Solid tumor Malignancies
Dose escalation
INNATE
Monotherapy
Combination Therapy
Antineoplastic Agents
Immunological
Lead sponsor: Jounce Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2020-12-17
Enrollment: 190
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 (RP2D) of JTX-8064 alone and in combination with a PD-1 inhibitor (PD-1i).

Detailed description: 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, maximum tolerated dose (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.

Eligibility criteria: Inclusion Criteria:

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: Subjects 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 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;
      * 2L/3L platinum-experienced HNSCC. Subjects must have progressed on or after treatment with an anti-PD-(L)1-agent in their most recent prior line of therapy;
      * 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 undifferentiated pleomorphic sarcoma (UPS) and liposarcoma (LPS);
      * 2L/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) in the metastatic setting and must have PD-(L)1 inhibitor resistance. Subjects with FGFR and IDH1 mutations must have progressed on or after targeted therapies for these mutations;
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 (ECOG) performance status 0 or 1;
6. Predicted life expectancy of ≥3 months;
7. Have specified laboratory values (obtained ≤28 days prior to planned Cycle 1, Day 1 \[C1D1\]) 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 or ongoing toxicity attributed to prior therapy that was \>Grade 1 according to the NCI CTCAE, version 5.0. Exceptions: \>Grade 1 toxicities that, in the opinion of the Investigator, should not exclude the subject (e.g., alopecia, Grade 2 neuropathy, hypo- or hyperthyroidism, or other endocrinopathies that are well controlled with hormone replacement) and are approved by the Medical Monitor:

   1. Major surgery (excluding minor procedures, for example, placement of vascular access, gastrointestinal/biliary stent, biopsy) \<4 weeks prior to planned C1D1;
   2. Immunotherapy or biologic therapy \<28 days prior to planned C1D1 or 5 half-lives, whichever is shorter;
   3. Chemotherapy \<21 days prior to planned C1D1, or \<42 days for mitomycin or nitrosoureas or 5 half-lives, whichever is shorter;
   4. Targeted small molecule therapy \<14 days or 5 half-lives, whichever is shorter, prior to planned C1D1;
   5. Hormonal or other adjunctive therapy for cancers other than the cancer under evaluation in this study that started \<14 days prior to planned C1D1 are not permitted; however, antiestrogen therapy, bisphosphonates, somatostatin analogues, leuprolide, and denosumab are permitted if started ≥14 days prior to C1D1. Other hormonal treatments and/or treatment for stable cancers (other than the cancer being treated on-study) may also be permitted 1) if these therapies would not be expected to have any positive or negative effect on the cancer being treated and 2) if discussed with and approved by the Medical Monitor;
   6. 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;
   7. Any prior organ transplantation, including allogeneic or autologous stem cell transplantation;
4. History of intolerance, hypersensitivity, or treatment discontinuation due to Grade 3 or greater irAEs (related to prior immunotherapy);
5. Diagnosis of immunodeficiency, either primary or acquired, or treatment with immunosuppressive levels of systemic corticosteroids (equivalent to ≥10 mg prednisone per day) or any other form of immunosuppressive therapy within 7 days prior to planned C1D1. Exception: Inhaled, intra-articular, topical, or systemic corticosteroids (systemic only at doses intended for adrenal replacement) and doses of immunosuppressive agents used prophylactically for contrast allergies are permitted in the absence of active autoimmune disease;
6. Known severe intolerance or life-threatening hypersensitivity reactions to humanized mAbs or IV immunoglobulin preparations; any history of anaphylaxis; known allergy to any of the study medications, their analogues, or excipients (sodium acetate, sucrose, sodium chloride and polysorbate 80) in the various formulations of any agent;
7. 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);
8. Active and clinically relevant bacterial, fungal, or viral infection, including known hepatitis A, B, or C, or HIV (testing not required);
9. 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;
10. History of pneumonitis requiring treatment with corticosteroids, interstitial lung disease, or severe (≥Grade 3) radiation pneumonitis (excluding localized radiation pneumonitis);
11. History in the last 3 months of acute diverticulitis, intra-abdominal abscess, or gastrointestinal obstruction, unless approved by Medical Monitor;
12. Symptomatic cardiac or cerebrovascular disease that is unresponsive to surgical or medical management;
13. Medical or social condition that, in the opinion of the Investigator, might place the subject at increased risk, adversely affect compliance, or confound safety or other clinical study data interpretation;
14. Active disease requiring systemic immunosuppressive therapy;
15. Live vaccines ≤30 days of C1D1;
16. Deep vein thrombosis, pulmonary embolism (including asymptomatic pulmonary embolism identified on imaging), or other thromboembolic event within the 6 months preceding C1D1 for JTX-8064 monotherapy cohorts only.

Primary outcomes:
measure: Incidence and severity of 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
timeFrame: up to 24 months
measure: Determination of a RP2D for JTX-8064 monotherapy and in combination with a PD-1i
timeFrame: up to 24 months
Secondary outcomes:
measure: Cmax (the maximum observed concentration) for JTX-8064 monotherapy and in combination with a PD-1i
timeFrame: Cycles 1 through 12 (each cycle is 21 days)
measure: Tmax (time of maximum observed concentration) for JTX-8064 monotherapy and in combination with a PD-1i
timeFrame: Cycles 1 through 12 (each cycle is 21 days)
measure: Cmin for JTX-8064 monotherapy and in combination with a PD-1i
timeFrame: Cycles 1 through 12 (each cycle is 21 days)
measure: AUClast (area under the concentration-time curve from time 0 to the last measurable concentration) for JTX-8064 monotherapy and in combination with a PD-1i
timeFrame: Cycles 1 and 3 (each cycle is 21 days)
measure: Cmax for PD-1i in combination with JTX-8064
timeFrame: Cycles 1 through 12 (each cycle is 21 days)
measure: Tmax for PD-1i in combination with JTX-8064
timeFrame: Cycles 1 through 12 (each cycle is 21 days)
measure: Cmin for PD-1i in combination with JTX-8064
timeFrame: Cycles 1 through 12 (each cycle is 21 days)
measure: Incidence of anti-drug antibodies (ADAs) to JTX-8064 and, as appropriate, to PD-1i
timeFrame: Baseline through Cycle 12 (each cycle is 21 days)
measure: Incidence of neutralizing antibodies (Nabs) to JTX-8064 and, as appropriate, to PD-1i
timeFrame: Baseline through Cycle 12 (each cycle is 21 days)
measure: For Stages 1 and 2: Receptor occupancy for LILRB2 on monocytes in whole blood
timeFrame: Baseline through Cycle 6 (each cycle is 21 days)
measure: For Stages 3 and 4: Preliminary efficacy endpoints: Objective response rate (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
timeFrame: up to 36 months
measure: For Stages 3 and 4: Preliminary efficacy endpoints: Disease control rate (DCR; the proportion of subjects who have a PR, CR, or stable disease [SD]), as per RECIST version 1.1
timeFrame: up to 36 months
measure: For Stages 3 and 4: Preliminary efficacy endpoints: Progression-free survival (PFS; the interval from start of treatment to the earlier of first documentation of disease progression or death from any cause)
timeFrame: up to 36 months
measure: For Stages 3 and 4: Preliminary efficacy endpoints: Overall survival (OS; the interval from start of treatment to death of any cause)
timeFrame: up to 36 months
measure: 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)
timeFrame: up to 36 months
measure: For Stages 3 and 4: Preliminary efficacy endpoints: Percentage of subjects with tumor reduction at any time
timeFrame: up to 36 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Tucson
country: United States
facility: Arizona Clinical Research Center
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas Medical Sciences
state: Arkansas
city: Duarte
country: United States
facility: City of Hope
state: California
city: La Jolla
country: United States
facility: California Cancer Associates for Research & Excellence, Inc.
state: California
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai
state: California
city: Orange
country: United States
facility: UC Irvine Medical Center
state: California
city: Sacramento
country: United States
facility: University of California, Davis
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami - Sylvester Comprehensive Cancer Center
state: Florida
city: Orlando
country: United States
facility: Adventist Health System/Sunbelt, Inc.
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Augusta
country: United States
facility: Augusta Oncology Associates - Wheeler Road
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Decatur
country: United States
facility: Cancer Care Center of Decatur
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky Chandler Medical Center (UKCMC)
state: Kentucky
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Grand Rapids
country: United States
facility: START Midwest -Cancer & Hematology Center of Western Michigan
state: Michigan
city: Minneapolis
country: United States
facility: Regents of the University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Weill Cornell
state: New York
city: New York
country: United States
facility: Mount Sinai
state: New York
city: New York
country: United States
facility: Montefiore Medical Center PRIME
state: New York
city: Huntersville
country: United States
facility: Carolina BioOncology
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Cincinnati
country: United States
facility: UC Health, LLC
state: Ohio
city: Cleveland
country: United States
facility: Case Comprehensive Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Providence Portland Cancer Center
state: Oregon
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Greenville
country: United States
facility: Prisma Health
state: South Carolina
city: Dallas
country: United States
facility: Mary Crowley Cancer Research
state: Texas
city: Houston
country: United States
facility: Oncology Consultants, P.A.
state: Texas
city: Houston
country: United States
facility: MD Anderson
state: Texas
city: Lubbock
country: United States
facility: Joe Arrington Cancer Research & Treatment Center
state: Texas
city: San Antonio
country: United States
facility: START Texas Accelerated Research Therapeutics
state: Texas
city: West Valley City
country: United States
facility: START Mountain Region
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Madison
country: United States
facility: The Board of Regents of the University of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Jounce Therapeutics, Inc.
name: Stew Kroll
role: STUDY_DIRECTOR
References: