MC# 19-09 - A Phase I, Open-Label, Multiple-Ascending Dose Study of the Safety and Tolerability of CTX-471 Administered Either as a Monotherapy or in Combination with Pembrolizumab in Patients with Inadequate Responses to PD-1/PD-L1 Checkpoint Inhibitors in Metastatic or Locally Advanced Malignancies
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Agent(s): CTX-471
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Disease Type(s): Bladder, Gastric, Head and Neck, Lymphoma, Melanoma, Solid Tumor, Renal, Lung-NSCLC, Lung-SCLC, Breast- Triple Negative, Gastroesophageal Junction
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Phase(s): I
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Drug Classification(s): Targeted Therapy, Immunotherapy, Monoclonal Antibody
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Molecular Target(s): CD137, 4-1BB
Mechanism of Action
CTX-471 is a fully humanized IgG4 agonist antibody for CD137, also known as 4-1BB, a costimulatory factor for T cells and NK cells.
Purpose
In this study, the sponsor and investigators want to learn:
- How much of CTX-471 can be given with an acceptable level of side effects
- About the safety and tolerability of CTX-471
- How much of CTX-471 is absorbed into the blood and how fast it is removed
- How proteins that indicate the status of your disease are affected with use of CTX-471
- If your body develops proteins that work against CTX-471
- If research tests can be used in the future to predict who will benefit from CTX-471
Inclusion Criteria
- Age 18 years or older
- Histologically confirmed diagnosis of metastatic or locally advanced malignancies
- Measurable disease per RECIST 1.1
- Disease progression after at least 12 weeks and at least 2 doses of a commercially available PD-1 or PD-L1 inhibitor per the approved prescriber’s information
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
- Life expectancy > 12 weeks
- Adequate bone marrow function defined by ANC of ≥ 1.5×109/L, platelet count of
- ≥100.0×109/L, and hemoglobin of ≥ 9.0 g/dL
- Adequate hepatic function defined as serum total bilirubin < 2 mg/dL,
- AST/ALT ≤ 2.5 × upper limit of normal (ULN) (or ≤ 5 × ULN in patients with liver metastases)
- Adequate renal function defined as serum creatinine < 1.5 × ULN or creatinine clearance > 60 mL/min as determined by the Cockcroft-Gault equation
- Female patients must be surgically sterile (or have a monogamous partner who is surgically sterile), or be at least 2 years postmenopausal, or commit to use 2 acceptable forms of birth control (defined as the use of an intrauterine device (IUD), a barrier method with spermicide, condoms, any form of hormonal contraceptives, or abstinence) for the duration of the study and for 3 months following the last dose of study treatment. Male patients must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control (condoms with spermicide) for the duration of the study
- Female patients who are women of childbearing potential (WCBP) must have a negative serum pregnancy test at Screening within 7 days of dosing with CTX-471
- Last dose of previous PD-1 or PD-L1 therapy ≥ 28 days, other anticancer therapy
- 21 days (or 2 half-lives for proteins, whichever is longer), radiotherapy > 21 days (concurrent localized palliative radiotherapy is allowed during CTX-471 treatment), or surgical intervention > 21 days prior to the first dose of CTX-471
- Resolution of all prior anti-cancer therapy toxicities ≤ Grade 1
- Willingness to provide pre- and post-treatment fresh tumor biopsies
- Capable of understanding and complying with protocol requirements
- Signed and dated institutional review board (IRB)/independent ethics committee (IEC)-approved informed consent form (ICF) before any protocol-directed screening procedures are performed
Exclusion Criteria
- Developed clinically significant adverse reaction to PD-1 or PD-L1 therapy, including immune-related adverse reactions that led to discontinuation of treatment
- Prior treatment with other immune-oncology therapies (eg, oncolytic virus, cellular therapies)
- Systemic therapy with immunosuppressive agents within 7 days before the start of CTX-471 treatment. Topical, intranasal, intraocular, or inhaled corticosteroids and physiologic replacement for patients with adrenal insufficiency are allowed.
- Patient is a pregnant or lactating WCBP
- Prior organ transplantation
- Active hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infection or a positive serological test at Screening within 7 days of dosing with CTX-471
- Active autoimmune disease or medical conditions requiring chronic steroid
- (ie, > 10 mg/day prednisone or equivalent) or immunosuppressive therapy. Patients with a prior history of autoimmune disease may be eligible following discussion with the Medical Monitor.
- History of or current central nervous system metastases
- History of seizure disorders
- Congestive heart failure (> New York Heart Association Class II), active coronary artery disease, unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest) or clinically significant cardiac arrhythmias
- Clinically significant baseline QT interval corrected with Fridericia’s method (QTcF), including QTcF > 480 msec
- Other systemic conditions or organ abnormalities that in the opinion of the Investigator may interfere with the conduct and/or interpretation of the current study
Location
- Dallas, TX - Mary Crowley Cancer Research - Medical City
