JTX-2011 Alone and in Combination With Anti-PD-1 or Anti-CTLA-4 in Subjects With Advanced and/or Refractory Solid Tumors

Study Overview
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Brief Summary
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JTX-2011-101 is a Phase 1/2, open label, dose escalation and expansion clinical study of JTX-2011 alone and in combination with nivolumab, ipilimumab, or pembrolizumab in adult subjects with advanced and/or refractory solid tumors, to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), as well as to evaluate preliminary efficacy.

Detailed Description
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JTX-2011 is an agonist monoclonal antibody that specifically binds to the Inducible CO-Stimulator of T cells (ICOS) to generate an anti-tumor immune response. This is a Phase 1/2, open label, multicenter, dose escalation and expansion, first-in-human (FIH) clinical study to evaluate the safety and tolerability, PK, PD, and preliminary efficacy of the ICOS agonist monoclonal antibody JTX-2011 alone and in combination with nivolumab, ipilimumab, or pembrolizumab in adult subjects with advanced and/or refractory solid tumors. The study will include a dose escalation phase for single agent and the combination therapies, followed by an expansion phase in specified tumor types for single agent and the combination therapies.

Official Title
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Phase 1/2 Multicenter Trial of ICOS Agonist Monoclonal Antibody (mAb) JTX-2011 Alone and in Combination With Nivolumab, Ipilimumab, or Pembrolizumab in Adult Subjects With Advanced and/or Refractory Solid Tumor Malignancies

Conditions
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Cancer

Intervention / Treatment
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* Drug: JTX-2011
* Drug: Nivolumab
* Drug: Ipilimumab
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be willing and able to participate and comply with all trial requirements and able to provide signed and dated informed consent prior to initiation of any trial procedures Evaluable or measurable disease, according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria, and meet the requirements for the intended study cohort Male or Female ≥ 18 years of age Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. Subjects with ECOG 2 may be considered for enrollment in Parts C, D, F, and H if approved by Medical Monitor Have a predicted life expectancy of ≥ 3 months Have laboratory values (obtained ≤ 28 days prior to first infusion day) in accordance with the study protocol If medical history of the following, case should be reviewed by the Medical Monitor: prior biliary tract disorders (as based on Hepatobiliary SOC high level terms of: obstructive bile duct disorders, hepatic vascular disorders, structural and other bile duct disorders) or portal hypertension and/or hepatic vascular disorders Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to administration of each dose of JTX-2011 WOCBP and males with partners of child-bearing potential must agree to use adequate birth control throughout their participation and for 5 months following the last study treatment Exclusion Criteria: Receiving concurrent anti-cancer treatment (excluding radiation therapy), either approved or investigational Have refused standard therapy Have received anti-cancer therapies listed below within the specified timeframe, or who have ongoing toxicity from prior therapy > Grade 1 according to the Common Terminology for Adverse Events (CTCAE). Exceptions to this are: > Grade 1 toxicities which 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. Have received biologic therapy, including immunotherapy, < 28 days prior to C1D1; Have received CAR-T therapy; Have received chemotherapy < 21 days prior to C1D1, or < 42 days for mitomycin or nitrosoureas; Have received targeted small molecule therapy < 14 days prior to C1D1; Have undergone organ transplantation including allogeneic or autologous stem-cell transplantation, at any time; Have undergone a major surgery (excluding minor procedures, e.g. placement of vascular access, biopsy, etc.) < 6 months prior to the first day of study treatment, C1D1 Have a history of intolerance, hypersensitivity, or treatment discontinuation due to severe immune adverse events on prior immunotherapy, or documented presence of neutralizing anti-drug antibody to nivolumab, ipilimumab, or pembrolizumab. Subjects who discontinued prior immunotherapies for immune-related adverse events that are well-controlled with appropriate treatment may be enrolled if approved by the Medical Monitor. Have a diagnosis of immunodeficiency, either primary or acquired, or treatment with systemic steroids or any other form of immunosuppressive therapy within 7 days prior to C1D1. Exception: inhaled or topical steroids and adrenal replacement doses are permitted in the absence of active autoimmune disease as well as a one-time dose of immunosuppressive agents used prophylactically for contrast allergies Have any active disease requiring systemic immunosuppressive treatment Have known severe intolerance to or life-threatening hypersensitivity reactions to humanized monoclonal antibodies or intravenous immunoglobulin preparations; any history of anaphylaxis; prior history of human anti-human antibody response; known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent Are symptomatic or have uncontrolled brain metastases, leptomeningeal disease, or spinal cord compression not definitively treated with surgery or radiation (brain metastases that are stable and asymptomatic, either treated or untreated, will be allowed) Have current second malignancy at other sites, which requires treatment, or in the judgement of the Investigator, may require treatment within the next year. Concurrent malignancies that do not require treatment and are clinically stable are allowed. A past history of other malignancies is allowed as long as the subject is not receiving specific treatment other than hormonal therapy, and, in the judgement of the Investigator, is unlikely to have a recurrence. Have active and clinically relevant bacterial, fungal, or viral infection, including known Hepatitis A, B, or C or human immunodeficiency virus (HIV) (testing not required) Have received live vaccines within past 30 days (inactivated vaccines are allowed; seasonal vaccines should be up to date prior to first infusion day) Women who are pregnant or breastfeeding Have experienced symptomatic cardiac disease that is unresponsive to surgical or medical management Have any medical or social condition that, in the opinion of the Investigator, might place a subject at increased risk, affect compliance, or confound safety or other clinical trial data interpretation

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: Part A (JTX-2011)<br>Phase 1 dose escalation and expansion of JTX-2011 by intravenous (IV) infusion | Drug: JTX-2011<br>* Specified dose on specified days<br>* Other names: ICOS agonist monoclonal antibody;|
| Experimental: Part B (JTX-2011 + nivolumab)<br>Phase 1 dose escalation and expansion of JTX-2011 by IV infusion in combination with nivolumab by IV infusion | Drug: JTX-2011<br>* Specified dose on specified days<br>* Other names: ICOS agonist monoclonal antibody;Drug: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;|
| Experimental: Part C (JTX-2011)<br>Phase 2 expansion of JTX-2011 by IV infusion | Drug: JTX-2011<br>* Specified dose on specified days<br>* Other names: ICOS agonist monoclonal antibody;|
| Experimental: Part D (JTX-2011 + nivolumab)<br>Phase 2 expansion of JTX-2011 by IV infusion in combination with nivolumab by IV infusion | Drug: JTX-2011<br>* Specified dose on specified days<br>* Other names: ICOS agonist monoclonal antibody;Drug: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;|
| Experimental: Part E (JTX-2011 + ipilimumab)<br>Phase 1 dose escalation of JTX-2011 by IV infusion in combination with ipilimumab by IV infusion | Drug: JTX-2011<br>* Specified dose on specified days<br>* Other names: ICOS agonist monoclonal antibody;Drug: Ipilimumab<br>* Specified dose on specified days<br>* Other names: Yervoy;|
| Experimental: Part F (JTX-2011 + ipilimumab)<br>Phase 2 expansion of JTX-2011 by IV infusion in combination with ipilimumab by IV infusion | Drug: JTX-2011<br>* Specified dose on specified days<br>* Other names: ICOS agonist monoclonal antibody;Drug: Ipilimumab<br>* Specified dose on specified days<br>* Other names: Yervoy;|
| Experimental: Part G (JTX-2011 + pembrolizumab)<br>Phase 1 dose escalation of JTX-2011 by IV infusion in combination with pembrolizumab by IV infusion | Drug: JTX-2011<br>* Specified dose on specified days<br>* Other names: ICOS agonist monoclonal antibody;Drug: Pembrolizumab<br>* Specified dose on specified days<br>* Other names: Keytruda;|
| Experimental: Part H (JTX-2011 + pembrolizumab)<br>Phase 2 expansion of JTX-2011 by IV infusion in combination with pembrolizumab by IV infusion | Drug: JTX-2011<br>* Specified dose on specified days<br>* Other names: ICOS agonist monoclonal antibody;Drug: Pembrolizumab<br>* Specified dose on specified days<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAE) | Number of participants with an adverse event occurring from the time of informed consent until resolution or new therapy initiated or for 28 days post final dose if no new therapy is initiated | 46.3 months | 
| Number of Participants With Grade 5 (Fatal) Treatment Emergent Adverse Events (TEAE) | Number of participants with Grade 5 (fatal) treatment emergent adverse events (TEAE) assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. | 46.3 months | 
| Number of Participants With Grade 4 (Life Threatening) Treatment Emergent Adverse Events (TEAE) | Number of participants with Grade 4 (life threatening) treatment emergent adverse events (TEAE) assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. | 46.3 months | 
| Number of Participants With Grade 3 (Sever) Treatment Emergent Adverse Events (TEAE) | Number of participants with Grade 3 (severe) treatment emergent adverse events (TEAE) assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. | 46.3 months | 
| Number of Participants With Grade 2 (Moderate) Treatment Emergent Adverse Events (TEAE) | Number of participants with Grade 2 (moderate) treatment emergent adverse events (TEAE) assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 | 46.3 months | 
| Number of Participants With Grade 1 (Mild) Treatment Emergent Adverse Events (TEAE) | Number of participants with Grade 1 (mild) treatment emergent adverse events (TEAE) assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 | 46.3 months | 
| Number of Participants With Dose Limiting Toxicities | Number of participants with at least one dose limiting toxicity (DLT) | 33 months | 
| Overall Response Rate | Overall response rate (ORR) is defined as the proportion of subjects with a Best Overall Response characterized as either a Complete Response (CR) or Partial Response (PR) as defined by RECISTv1.1 guidelines based on investigator's review | 46.5 months | 
| Disease Control Rate | Disease Control Rate: Percent Subjects with confirmed Complete Response + confirmed Partial Response + BoR of SD (or unconfirmed complete response or partial response lasting at least 53 days from the date of first dose) | 46.5 months | 
| Progression Free Survival | Progression free survival, as determined by the Investigator using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 46.5 months | 
| 6 Month Landmark Progression Free Survival | Percentage of patients that are progression free at 6 months, estimated by the Kaplan Meier method as the probability of being event-free at 6 months out of the entire 45.5-month primary study period. This method generates survival probability estimates across the Time Frame of the study using all data throughout the course of the trial. | 46.5 months | 
| 12 Month Landmark Progression Free Survival | Percentage of patients that are progression free at 12 month, estimated by the Kaplan Meier method as the probability of being event-free at 12 months out of the entire 45.5-month primary study period. This method generates survival probability estimates across the Time Frame of the study using all data throughout the course of the trial. | 46.5 months | 
| Landmark Overall Survival at 6 Months | Percentage of patients that are alive at 6 month, estimated by the Kaplan Meier method as the probability of being event-free at 6 months out of the entire 45.5-month primary study period. This method generates survival probability estimates across the Time Frame of the study using all data throughout the course of the trial. | 46.5 months | 
| Landmark Overall Survival at 12 Months | Percentage of patients that are alive at 12 month, estimated by the Kaplan Meier method as the probability of being event-free at 12 months out of the entire 45.5-month primary study period. This method generates survival probability estimates across the Time Frame of the study using all data throughout the course of the trial. | 46.5 months | 
| Overall Survival | The time from first dose date to the date of death for any cause | 46.5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ICOS, ICOS agonist monoclonal antibody, JTX-2011, Anti-PD-1, Nivolumab, ICONIC, Immunotherapy, Immuno-oncology, Cancer, Solid Tumor, Dose Escalation, Dose Expansion, Anti-CTLA-4, Ipilimumab, Pembrolizumab