This phase I trial studies the side effects and best dose of M5A-IL2 immunocytokine (M5A-ICK) combined with stereotactic body radiation therapy (SBRT) and to see how well they work in treating patients with colorectal cancer or xarcinoembryonic antigen (CEA) positive breast cancer that cannot be removed by surgery (unresectable) or has spread from where it first started (primary site) to other places in the body (metastatic). Carcinoembryonic Antigen (CEA) is a protein that is present in most colorectal cancers and in many other cancers, such as breast cancer, as well. SBRT uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Cytokines are signaling proteins that help control inflammation in the body. They allow the immune system to mount a defense if germs or cancer or other substances that can make people sick enter the body. Interleukin-2 (IL-2) is a powerful cytokine able to regulate the immune responses that are important for anticancer immunity. Immunocytokines (also called antibody-cytokine fusion proteins) are small proteins that regulate the activity of immune cells. The M5A-IL2 immunocytokine (M5A-ICK) combines the cancer targeting features of the M5A antibody with the immune system regulation properties of the cytokine IL-2. Giving M5A-ICK in combination with standard of care (SOC) SBRT may work better in treating patients with unresectable metastatic colorectal cancer or CEA positive metastatic breast cancer.
PRIMARY OBJECTIVE: I. Identify the maximum tolerated dose (MTD) and recommend phase 2 dose (RP2D) and characterize toxicities associated with administration of the M5A-IL2 after fractionated SBRT. SECONDARY OBJECTIVES: I. Describe the therapeutic response to treatment of irradiated and unirradiated tumors per Criteria in Solid Tumors version 1.1 (RECIST v 1.1) guidelines. II. Describe AEs by M5A-IL2 dose level, per Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0. III. Describe the pharmacokinetics of M5A-IL2. IV. Describe the frequency of auto-antibody formation, overall and by dose of M5A-IL2. EXPLORATORY OBJECTIVE: I. If medically feasible, tumors targeted for SBRT will be biopsied pre-SBRT and 1-2 weeks post 3rd dose of M5A-IL2. OUTLINE: This is a dose-escalation study of M5A-ICK. Patients undergo SOC SBRT over 3 fractions on days 1, 3, and 5, followed by M5A-ICK subcutaneously (SC) on days 8, 9, and 10 once daily for a single cycle on study. Patients undergo computed tomography (CT) or positron emission tomography (PET)/CT as well as blood sample collection throughout the trial. Patients may undergo magnetic resonance imaging or bone scan as clinically indicated on the trial. Additionally, patients may optionally undergo tissue biopsy during screening and on study. After completion of study treatment, patients are followed-up at 3 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Undergo tissue biopsy
Undergo blood sample collection
Undergo bone scan
Undergo CT or PET/CT
Receive M5A-IL2 ICK SC
Undergo MRI
Undergo PET/CT
Undergo SBRT
City of Hope Medical Center
Duarte, California, United States
RECRUITINGMaximum tolerated dose (MTD) of the M5A-IL2 immunocytokine (M5A-ICK)
Will be assessed following accelerated titration design 3, single patient cohorts will be used with dose doubling between cohorts until either a dose limiting toxicity (DLT) is observed, or 2 patients experience a moderate (grade 2) M5A-ICK related adverse event. At dose level 5, the design reverts to 3 patient cohorts (following the traditional 3+3 design) with 40% increments between dose levels. In the traditional 3+3 design, once 3 patients at a dose level are evaluable, if none has experienced a DLT, the dose can be escalated.
Time frame: At the end of cycle 1 (each cycle is 28 days)
Recommended phase 2 dose
Will either be the MTD, or below, based on the full consideration of late adverse events, sub-DLT toxicities, clinical activity, and biological correlatives.
Time frame: At the end of cycle 1 (each cycle is 28 days)
Therapeutic response to treatment
Will be reported according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Time frame: Up to 2 years
Incidence of adverse events
All adverse events, including allergic reactions, hypertension, hypotension, and infusion reactions will be summarized in terms of dose level, type and frequency, data of onset and duration (where relevant) using Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0.
Time frame: Up to 3 months after last M5A-ICK injection
Number of participants with treatment-related auto-antibody formation
Frequency of participants with auto-antibody formation, overall and by dose of M5A-IL2.
Time frame: Screening, days 8 and 36, and 3 months
Pharmacokinetics of M5A-IL2 (M5A-ICK blood clearance )
Blood samples up to 4 days (based on the predicted ICK half life of 10 hours) will be used to determine M5A-ICK blood clearance by ELISA analysis using human CEA for capture and reporting with anti-IL2-HRP.
Time frame: Pre-injection, approximately 1, 4 and 6 hours post injection on each day, and one sample done 1 and 2 days following the 3rd subcutaneous dose of M5A-IL2
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