CF33-hNIS-antiPDL1 for the Treatment of Metastatic Triple Negative Breast Cancer

Study Overview
=================
Brief Summary
-----------------
This phase I trial tests the safety, side effects, and best dose of CF33-hNIS-antiPDL1 in treating patients with triple negative breast cancer that has spread to other places in the body (metastatic). CF33-hNIS-antiPDL1 is an oncolytic virus. This is a virus that is designed to infect tumor cells and break them down.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. To determine the safety and tolerability of a novel chimeric oncolytic orthopoxvirus, oncolytic virus CF33-expressing hNIS/Anti-PD-L1 antibody (CF33-hNIS-antiPDL1), by the evaluation of toxicities including: type, frequency, severity, attribution, time course, reversibility and duration according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0 criteria. SECONDARY OBJECTIVES: I. To determine the optimal biologic dose (OBD) (defined as a safe dose that induces an immune response in tumors [increase checkpoint target PD-L1 by at least 5% and/or increase T cell infiltration by at least 10%]) and the recommended phase II dose (RP2D) for future expansion trial. II. To determine tumor response rates by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (primary) and immune-modified (i)RECIST (secondary). III. To document possible therapeutic efficacy and evaluate progression-free survival, overall survival and response. EXPLORATORY OBJECTIVE: I. To determine the immune and genomic profiles of tumors before and after CF33-hNIS-antiPDL1 therapy. OUTLINE: This is a dose-escalation study. Patients receive CF33-hNIS-antiPDL1 intratumorally (IT) on days 1 and 15. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, then every 3 months for 1 year.

Official Title
-----------------
A Phase I, First-in-Human Study of Intratumoral Administration of CF33-hNIS-antiPDL1, A Novel Chimeric Oncolytic Poxvirus Encoding Human Sodium Iodide Symporter (HNIS) in Patients With Metastatic Triple Negative Breast Cancer

Conditions
-----------------
Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Triple-Negative Breast Carcinoma, Prognostic Stage IV Breast Cancer AJCC v8

Intervention / Treatment
-----------------
* Biological: Oncolytic Virus CF33-expressing hNIS/Anti-PD-L1 Antibody


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Documented informed consent of the participant and/or legally authorized representative Assent, when appropriate, will be obtained per institutional guidelines Agreement to research biopsies on study, once during study and end of study, exceptions may be granted with study principal investigator (PI) approval >= 18 years Eastern Cooperative Oncology Group (ECOG) =< 2 Histologically confirmed metastatic triple negative breast cancer. Triple negative status will be defined as estrogen receptor (ER) and progesterone receptor (PR) =< 10% by immunohistochemistry (IHC) and HER2 negative, per American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines Measurable disease by RECIST 1.1 Patients must have progressed on or been intolerant of at least 2 prior lines of therapy for advanced/metastatic disease. Patients that qualify for immunotherapy and/or PARP inhibitors must have progressed on or been intolerant of these agents Fully recovered from the acute toxic effects (except alopecia) to =< grade 2 to prior anti-cancer therapy Must have a superficial tumor (cutaneous, subcutaneous), breast lesion or nodal metastases amenable to safe repeated intratumoral injections per treating physician and interventional radiologist review Absolute neutrophil count (ANC) >= 1,500/mm^3 NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement Platelets >= 100,000/mm^3 NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement Total bilirubin =< 1.5 X upper limit of normal (ULN) Aspartate aminotransferase (AST) =< 2.5 x ULN If liver metastases are present: AST =< 5 x ULN Alanine aminotransferase (ALT) =< 2.5 x ULN If liver metastases are present: ALT =< 5 x ULN Serum creatinine =< 1.5 mg/dL or creatinine clearance of >= 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula Prothrombin (PT) =< 1.5 x ULN Activated partial thromboplastin time (aPTT) =< 1.5 x ULN Women of childbearing potential (WOCBP): negative serum pregnancy test Agreement by females and males of childbearing potential* and their partners to use an effective method of birth control (defined as a hormonal or barrier method) or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only) Exclusion Criteria: Chemotherapy, biological therapy, immunotherapy or investigational therapy within 14 days prior to day 1 of protocol therapy Major surgery or radiation therapy within 28 days of study therapy Has received a vaccination within 30 days of first study injection History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent Clinically significant uncontrolled illness Active infection requiring antibiotics Known history of immunodeficiency virus (HIV) Patients with a known history of hepatitis B or hepatitis C infection who have active disease as evidenced by hepatitis (Hep) B surface antigen status or Hep C polymerase chain reaction (PCR) status obtained within 14 days of cycle 1, day 1 Another malignancy within 3 years, except non-melanomatous skin cancer Females only: Pregnant or breastfeeding Patients may not have clinically unstable brain metastases. Patients may be enrolled with a history of treated brain metastases that are clinically stable for >= 4 weeks prior to start of study treatment Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (CF33-hNIS-antiPDL1)<br>Patients receive CF33-hNIS-antiPDL1 IT on days 1 and 15. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. | Biological: Oncolytic Virus CF33-expressing hNIS/Anti-PD-L1 Antibody<br>* Given IT<br>* Other names: CF33-hNIS-antiPDL1;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Toxicity will be graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0. Observed toxicities/adverse events will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome. | Up to 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune Biomarker Expression | Changes (%) in PD1 expression compared to baseline by immunohistochemistry Changes (%) in PD-L1 expression compared to baseline by immunohistochemistry Changes (%) CTLA-4 expression compared to baseline by immunohistochemistry Changes (%) CD8 cell quantification compared to baseline by Immunohistochemistry | Up to 6 months | 
| Optimal biologic dose | Defined as safe dose that induces an immune response in tumors (increase checkpoint target PD-L1 by at least 5% and/or increase T cell infiltration by at least 10%). | Up to 3 months | 
| Response rate based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Will estimate the response rate by the percent of evaluable patients and its 95% confidence interval (C.I.) by the exact method. | Up to 6 months | 
| Response rate based on immune related iRECIST | Will estimate the response rate by the percent of evaluable patients and its 95% C.I. by the exact method. | Up to 6 months | 
| Progression free survival | Will be estimated using the Kaplan-Meier product-limit method. | Up to 1 year | 
| Clinical benefit rate | Percentage of patients who achieved Partial Response/ Complete Response/ Stable disease at 6 months | Up to 6 months | 
| Event-free survival | Event-free survival (EFS): defined as the duration of time from start of protocol treatment to time of disease relapse/progression or death due to any cause, whichever occurs earlier. | Up to 3 years | 
| Duration of response | Duration of response (DOR): defined as the time from the first achievement of PR and CR to time of PD. | Up to 3 years | 
| Overall survival | Will be estimated using the Kaplan-Meier product-limit method. | Up to 3 years |