CD8+ T Cell Imaging During Pre-surgery Immunotherapy in People with Melanoma, C-IT Neo Study

Status: closed to accrual

This phase II trial tests whether pre-surgery immunotherapy with nivolumab and ipilimumab before surgery may help reduce tumor size in patients with skin cancer (melanoma) and whether imaging using 89Zr-Df-crefmirlimab is an effective way to identify CD8+ T cells, immune system cells that play an important role in the body’s response to disease. Nivolumab is an antibody, like the proteins made by the immune system to protect the body from harm. Nivolumab blocks the protein PD-1 (programmed cell death receptor 1) that usually acts as a “brake” on the immune system. Blocking this protein is like releasing the brakes, so that the immune system can target cancer cells and destroy them. Ipilimumab is another antibody treatment that targets and blocks the protein receptor CTLA-4. When CTLA-4 is not blocked, cancer cells can produce substances that make it difficult for the immune system to recognize these diseased cells. Ipilimumab prevents the production of the substances that mask the appearance of cancer cells, allowing the immune system to recognize and attack the cancer. 89Zr-Df-crefmirlimab is an experimental imaging agent/radiotracer made from two different parts. One part is an antibody called crefmirlimab that attaches to CD8+ T cells. The other part (89Zr) gives off a small amount of radiation, which “lights up” the CD8+ T cells and makes them easy to see on an imaging scan. Tracking the amount and location of CD8+ T cells may help to learn more about the cancer and the body’s response to cancer immunotherapy treatments.

Inclusion Criteria

Patient is capable of understanding and complying with the protocol requirements and has signed the informed consent document
Adults at least 18 years of age
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
Cytologically or histologically confirmed stage IIIB, IIIC, IIID melanoma that can be surgically removed. * Notes: ** In-transit melanoma is acceptable ** Patients can enroll regardless of their BRAF mutational status
1cm of tumor needs to be visible on standard imaging (i.e. FDG PET or CT scan)
White blood cell (WBC) >= 2.0 x 10^9/L
Neutrophils >= 1.5 x 10^9/L
Platelets >= 100 x 10^9/L
Hemoglobin >= 5.5 mmol/L
Creatinine =< 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST) =< 1.5 x ULN and alanine aminotransferase (ALT) =< 1.5 x ULN
Bilirubin =< 1.5 X ULN
Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of study treatment (ipilimumab/nivolumab)
Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of ipilimumab + nivolumab
Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of study treatment (ipilimumab/nivolumab) * Note: Women who are not of childbearing potential (i.e., who are postmenopausal), or surgically sterile as well as azoospermic men do not require contraception

Exclusion Criteria

Subjects with any active autoimmune disease (current symptoms or requirement for immunosuppression at the time of study start).
Positive active hepatitis B viral infection (+viral load by polymerase chain reaction [PCR])
Prior immunotherapy targeting CTLA-4 and/or PD-1/PD-L1 for any disease
Potentially unresectable melanoma
History of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
History of severe hypersensitivity reaction to any monoclonal antibody
Underlying medical conditions that, in the Investigator's opinion, will make the administration of treatment hazardous or obscure the interpretation of toxicity
Patients who have undergone splenectomy or have other splenic disorders. The normal spleen usually has CD8+ cell activity and serves as a positive control to enable proper imaging technique
Use of other investigational drugs before study drug administration 30 days and 5 halftimes before study inclusion
Pregnant or nursing

PRIMARY OBJECTIVE:

I. Estimate the major pathologic response rate (pathologic complete response [0% viable tumor] and pathologic near complete response [=< 10% of viable tumor]) following one dose of neoadjuvant nivolumab 1 mg/kg + ipilimumab 3 mg/kg.

SECONDARY OBJECTIVES:

I. Evaluate the association between absolute values and percent change in zirconium Zr 89-desferrioxamine (Df)-crefmirlimab (89Zr-Df-crefmirlimab) imaging quantitative measurements (e.g. maximum standardized uptake value [SUV]max, SUVpeak, SUVmean, CD8 tumor volume) before and after nivolumab + ipilimumab with major pathologic responses (as defined in primary endpoint).

II. Estimate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 from diagnostic computed tomography (CT) scans at baseline and 4 weeks.

III. Estimate recurrence free survival (RFS) from surgery.

IV. Evaluate safety as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

V. Estimate the proportion of patients who have delayed surgery due to toxicity.

EXPLORATORY OBJECTIVES:

I. Explore the association between 89Zr-Df-crefmirlimab imaging quantitative positron emission tomography (PET) measurements as above to other pathologic response categories using standard reporting definitions of pathological response:

Ia. Pathologic Partial Response (pPR) >=10 but =< 50% viable tumor;

Ib. Pathologic Non-Response >=50% viable tumor.

II. Explore the pattern of 89Zr-Df-crefmirlimab uptake within a tumor on PET scan and see whether this pattern resembles the spatial pattern of 89Zr-Df-crefmirlimab uptake by autoradiography within a tumor following resection.

III. Explore the spatial pattern uptake of 89Zr-Df-crefmirlimab by autoradiography and see how this generally aligns with CD8 T cell presence by immunohistochemistry (IHC) in resected tissues.

IV. Assess whether 89Zr-Df-crefmirlimab uptake on-treatment (pre-surgical scan) and change in 89Zr-Df-crefmirlimab uptake from baseline are associated with RFS.

V. Describe associations between RECIST response rates and CD8 PET scan imaging.

VI. Evaluate the use of 89Zr-Df-crefmirlimab PET scans to visualize organ inflammation which may arise due to immune related adverse events.

VII. Investigate immunologic changes in the peripheral blood and whether these are associated with response and/or toxicity.

VII. Explore levels of circulating tumor deoxyribonucleic acid (DNA) in the peripheral blood and assess whether these are associated with response.

OUTLINE:

Patients may optionally receive zirconium Zr 89-Df-crefmirlimab intravenously (IV) and then undergo a PET/CT scan over 5-10 minutes after 24 hours. Within 2 weeks after the scan and 4 weeks before scheduled surgery, patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes. Within 1 to 2 days before the scheduled surgery, patients may optionally receive 89Zr-Df-crefmirlimab IV, followed by a PET/CT scan 24 hours later. Patients then undergo surgical resection per standard of care. Additionally, patients undergo blood sample collection, PET/CT and CT of the chest, abdomen, and pelvis throughout the study.

After study treatment, patients are followed up at 1 and 3 months and then every 3 months for 2 years.

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CD8+ T Cell Imaging During Pre-surgery Immunotherapy in People with Melanoma, C-IT Neo Study

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