Dose Escalation and Expansion of JTX-2011 Alone or in Combination With Anti-PD-1 in Subjects With Advanced Solid Tumors (ICONIC)

Study Description

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Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Cancer	Drug: JTX-2011; Drug: nivolumab	Phase 1; Phase 2

Detailed Description:

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 or in combination with a fixed dose of nivolumab in adult subjects with advanced refractory solid tumors. The study will be conducted in four parts: single agent (Part A) and combination therapy (Part B) dose escalation, and expansion cohorts of single agent (Part C) and combination therapy (Part D).

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	282 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase 1/2 Multicenter Trial of ICOS Agonist Monoclonal Antibody (mAb) JTX-2011 Alone or in Combination With Nivolumab in Adult Subjects With Advanced Refractory Solid Tumor Malignancies
Study Start Date :	August 2016
Estimated Primary Completion Date :	October 2018
Estimated Study Completion Date :	April 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Part A (JTX-2011); Phase 1 dose escalation and expansion of JTX-2011 by intravenous (IV) infusion every 21 days in subjects with advanced refractory solid tumors	Drug: JTX-2011; JTX-2011 administered as a one hour IV infusion every 21 days; Other Name: ICOS agonist monoclonal antibody
Experimental: Part B (JTX-2011 + nivolumab); Phase 1 dose escalation and expansion of JTX-2011 by IV infusion in combination with a fixed dose of nivolumab by IV infusion every 21 days in subjects with advanced refractory solid tumors	Drug: JTX-2011; JTX-2011 administered as a one hour IV infusion every 21 days; Other Name: ICOS agonist monoclonal antibody; Drug: nivolumab; Nivolumab 240 mg administered as a one hour IV infusion every 21 days; Other Name: OPDIVO
Experimental: Part C (JTX-2011); Phase 2 expansion of JTX-2011 by IV infusion every 21 days in subjects with advanced refractory solid tumors	Drug: JTX-2011; JTX-2011 administered as a one hour IV infusion every 21 days; Other Name: ICOS agonist monoclonal antibody
Experimental: Part D (JTX-2011 + nivolumab); Phase 2 expansion of JTX-2011 by IV infusion in combination with a fixed dose of nivolumab by IV infusion every 21 days in subjects with specific advanced refractory solid tumors	Drug: JTX-2011; JTX-2011 administered as a one hour IV infusion every 21 days; Other Name: ICOS agonist monoclonal antibody; Drug: nivolumab; Nivolumab 240 mg administered as a one hour IV infusion every 21 days; Other Name: OPDIVO

Outcome Measures

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Primary Outcome Measures :

1. % subjects with adverse events (AEs) [ Time Frame: 26 months ]
2. % subjects with serious adverse events (SAEs) [ Time Frame: 26 months ]
3. % subjects with dose-limiting toxicities (DLTs) [ Time Frame: 20 months ]
4. % subjects with changes from baseline in pro-inflammatory cytokines [ Time Frame: 26 months ]
5. % subjects with anti-drug antibodies (ADA) to JTX-2011 [ Time Frame: 26 months ]
6. % subjects with ADA to nivolumab [ Time Frame: 26 months ]
7. % subjects with clinically significant change from baseline in clinical laboratory tests [ Time Frame: 26 months ]
8. Maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of JTX-2011 [ Time Frame: 26 months ]
9. % subjects with overall response (OR) [ Time Frame: 26 months ]
10. % subjects with complete response (CR) [ Time Frame: 26 months ]
11. Median duration of response (DOR) [ Time Frame: 26 months ]
12. Median progression free survival (PFS) [ Time Frame: 26 months ]
13. Median overall survival (OS) [ Time Frame: 26 months ]
14. Landmark overall survival (OS) [ Time Frame: 26 months ]

Secondary Outcome Measures :

1. Maximum measured concentration in serum (Cmax) [ Time Frame: 26 months ]
2. Minimum measured concentration in serum (Cmin) [ Time Frame: 26 months ]
3. Time from dosing to maximum measured concentration (tmax) [ Time Frame: 26 months ]
4. Area under the serum concentration-time curve (AUC) [ Time Frame: 26 months ]
5. Terminal half-life (t1/2) [ Time Frame: 26 months ]
6. Mean residence time (MRT) [ Time Frame: 26 months ]
7. Total clearance of the analyte in serum (CL) [ Time Frame: 26 months ]
8. Apparent volume of distribution during specific time points [ Time Frame: 26 months ]
9. % target engagement [ Time Frame: 26 months ]
10. Area under the effect-time curve (AUEC) of the pharmacodynamics marker in serum [ Time Frame: 26 months ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. 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;
2. Have histologically or cytologically confirmed cancer that is recurrent, metastatic, or persistent after at least one line of therapy and with no further standard treatment options; evaluable or measurable disease, according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria, with at least one measurable lesion that has objectively progressed since (or on) previous treatment (unless subject has refused standard of care treatment), as assessed by enrolling physician; and meet the requirements for the intended study cohort
3. All subjects in Parts A and B must have available and consent to provide archival tumor tissue
4. All subjects in Parts A and B Expansion must have a tumor lesion that can be biopsied at acceptable risk and must agree to both a fresh biopsy between screening and Cycle 1 Day 1 (C1D1) and a second biopsy after completion of two cycles of study treatment
5. All subjects in Parts C and D must have available and consent to provide archival tumor tissue, have a lesion that can be biopsied at acceptable clinical risk (as judged by the investigator), and agree to a fresh biopsy between screening and C1D1. If the tumor site to be biopsied was previously irradiated or is the target lesion for response assessment, it must be at least 2 cm and have progressed
6. Male or Female ≥ 18 years of age
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. Subjects with PS 2 may be considered for enrollment in Parts C and D, if approved by medical monitor
8. Have a predicted life expectancy of ≥ 3 months

9. Have the following laboratory values (obtained ≤ 28 days prior to first infusion day):

   1. Serum creatinine <1.5 × ULN or if higher than normal range, calculated creatinine clearance (CrCl) must be ≥ 50 mL/min/1.73 m2 (e.g., by Cockroft-Gault formula); actual body weight must be used for CrCl unless BMI >30 kg/m2 then lean body weight must be used
   2. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) unless prior history of Gilbert's syndrome
   3. Aspartate transaminase and alanine transaminase ≤ 2.5 × ULN, or ≤ 5 × ULN if due to liver involvement by tumor
   4. Hemoglobin ≥ 9.0 g/dL
   5. Platelets ≥ 100 × 109 cells/L
   6. Absolute neutrophil count (ANC) ≥ 1.5 ×109 cells/L (without the use of hematopoietic growth factors). Subjects with lower ANC may be enrolled if not the result of prior therapy, if approved by medical monitor
10. Have a corrected QT interval (QTc) < 470ms for females and < 450ms for males (as calculated by the Fridericia correction formula)
11. 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
12. Women of child-bearing potential (WOCBP) and males with partners of child-bearing potential must agree to use adequate birth control throughout their participation and for 3 months following the last study treatment

Exclusion Criteria:

1. Receiving concurrent anticancer treatment (including radiation therapy), either approved or investigational
2. Have refused standard therapy

3. Have received the 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 patient (e.g. alopecia, Grade 2 neuropathy, hypo- or hyper-thyroidism or other endocrinopathies that are well-controlled with hormone replacement) and are approved by the medical monitor. Major surgery (excluding minor procedures, e.g. placement of vascular access) < 6 months prior to the first day of study treatment, C1D1

   1. Have undergone a major surgery (excluding minor procedures, e.g. placement of vascular access) < 6 months prior to the first day of study treatment, C1D1
   2. Have received biologic therapy, including immunotherapy, < 28 days prior to C1D1
   3. Have received chemotherapy < 21 days prior to C1D1, or < 42 days for mitomycin or nitrosoureas
   4. Have received targeted small molecule therapy < 14 days prior to C1D1
   5. Have received hormonal therapy < 14 days prior to C1D1 (Bisphosphonates are permitted provided treatment was initiated ≥ 14 days prior to C1D1)
   6. Have received radiation therapy < 21 days prior to C1D1
   7. Have undergone organ transplantation including allogeneic or autologous stem-cell transplantation, at any time
4. 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 (Parts B and D). Subjects who discontinued prior immunotherapies for immune related adverse events that are well-controlled with appropriate treatment, and, in the opinion of the investigator, may be enrolled if approved by the medical monitor
5. 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
6. Have an active or prior history of autoimmune disease. Exception: subjects with type 1 diabetes, vitiligo, hypo- or hyperthyroid disease, or autoimmune alopecia not requiring immunosuppressive treatment
7. Have known severe intolerance to or hypersensitivity reactions to 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
8. 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)
9. Have current second malignancy at other sites (exceptions: adequately treated in situ carcinoma (e.g., cervical), non-melanoma skin cancer, bilateral synchronous discordant breast cancer, or indolent prostate cancer under observation). A past history of other malignancies is allowed as long as subject has been free of recurrence for ≥ 2 years, or if the subject has been treated with curative intent within the past 2 years and, in the opinion of the investigator, is unlikely to have a recurrence
10. 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)
11. Have received live vaccines within past 30 days (inactivated vaccines are allowed; seasonal vaccines should be up to date prior to first infusion day)
12. Women who are pregnant or breastfeeding
13. Have experienced the occurrence of any of the following within 1 year prior to C1D1: myocardial infarction, uncontrolled angina, coronary artery bypass graft, symptomatic congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, cardiac amyloidosis, cerebrovascular accident, or transient ischemic attack
14. 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

Contacts and Locations

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Contacts

Contact: Manny Lazaro		ICONIC@jouncetx.com

Locations

United States, California
Stanford University School of Medicine	Recruiting
Palo Alto, California, United States, 94304
Contact: Feriel Buchholz 650-721-4090
United States, Colorado
Sarah Cannon Research Institute at HealthONE	Recruiting
Denver, Colorado, United States, 80218
Contact: Kelly Mozzetta 720-754-2610
United States, Connecticut
Yale New Haven Hospital	Recruiting
New Haven, Connecticut, United States, 06510
Contact: Caroline Hotchkiss, MPH, CCRP 203-737-5228
United States, District of Columbia
Georgetown Lombardi Comprehensive Cancer Center	Recruiting
Washington, District of Columbia, United States, 20007
Contact: Laura Macke, RN 202-687-2111
United States, Illinois
The University of Chicago Medicine Comprehensive Cancer Center	Recruiting
Chicago, Illinois, United States, 60637
Contact: Sara Kochanny 773-702-2336
United States, Massachusetts
Massachusetts General Hospital	Recruiting
Boston, Massachusetts, United States, 02114
Contact: Justin Gainor 617-724-4000
Beth Israel Deaconess Medical Center	Recruiting
Boston, Massachusetts, United States, 02215
Contact: Sue Gotthardt 617-975-7452
Dana Farber Cancer Institute	Recruiting
Boston, Massachusetts, United States, 02215
Contact: Kristina Kelley, RN 617-632-4876
United States, Missouri
Washington University School of Medicine	Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Sarah Larson 314-747-1864
United States, New York
Memorial Sloan Kettering Westchester	Recruiting
Harrison, New York, United States, 10604
Contact: Margaret Callahan, MD, PhD 646-888-4593
Memorial Sloan Kettering Cancer Center	Recruiting
New York, New York, United States, 10065
Contact: Margaret Callahan, MD, PhD 646-888-4593
United States, Tennessee
Sarah Cannon Research Institute at TriStar Health	Recruiting
Nashville, Tennessee, United States, 37203
Contact: askSARAH 615-514-2401
United States, Texas
The University of Texas - MD Anderson Cancer Center	Recruiting
Houston, Texas, United States, 77030
Contact: Timothy Yap 877-632-6789
South Texas Accelerated Research Therapeutics, LLC	Recruiting
San Antonio, Texas, United States, 78229
Contact: Isabel Jimenez, RN, MSN 210-593-5256
United States, Washington
University of Washington	Recruiting
Seattle, Washington, United States, 98109
Contact: Heather Johnson, CCRC 206-606-7551

Sponsors and Collaborators

Jounce Therapeutics, Inc.

Investigators

Study Director:	Elizabeth Trehu, MD, FACP	Jounce Therapeutics, Inc.

More Information

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Responsible Party:	Jounce Therapeutics, Inc.
ClinicalTrials.gov Identifier:	NCT02904226 History of Changes
Other Study ID Numbers:	JTX-2011-101
First Posted:	September 16, 2016
Last Update Posted:	January 12, 2018
Last Verified:	January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Jounce Therapeutics, Inc.:

JTX-2011; ICOS; ICOS agonist monoclonal antibody; Anti-PD-1; Nivolumab; ICONIC	Immunotherapy; Immuno-oncology; Cancer; Solid Tumor; Dose Escalation; Dose Expansion

Additional relevant MeSH terms:

Antibodies; Immunoglobulins; Antibodies, Monoclonal; Nivolumab	Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents