Immunotherapy Combination: Irradiated PD-L1 CAR-NK Cells Plus Pembrolizumab Plus N-803 for Subjects With Recurrent/Metastatic Gastric or Head and Neck Cancer

Study Overview
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Brief Summary
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Background: Immunotherapy is a powerful tool in the fight against cancer. It uses the body s own immune system to fight the cancer. Unfortunately, cancer cells can find ways to escape from destruction by the body s immune system, even when immunotherapy is used. Natural killer (NK) cells are an important part of the body s immune system and can help fight cancer. In combination with immunotherapy, researchers are using engineered NK cells that recognize and kill cancer cells trying to escape destruction by the immune system. Objective: To test the effectiveness of irradiated PD-L1 CAR-NK cells, combined with pembrolizumab and N-803, in people with advanced forms of gastric or head and neck cancer. Eligibility: Adults ages 18 and older with advanced gastric or head and neck cancer who have already had standard cancer treatment. Design: Participants will be screened with a medical history and physical exam. Their symptoms and ability to do normal activities will be assessed. They will have blood and urine tests. They will have imaging scans of the chest, abdomen, and pelvis. Participants will get PD-L1 CAR-NK cells by intravenous (IV) infusion. They will get the cells once a week for 6 weeks. Then they will get the cells once every 2 weeks. Before each infusion, an IV catheter will be placed in a large arm vein for infusion of these treatments. Participants will get pembrolizumab by IV every 6 weeks. They will get N-803 under the skin every 4 weeks. Participants will get the study drugs for up to 2 years. They will have study visits every 1-2 weeks during treatment. They will have a safety visit 28 days after treatment ends. After treatment ends, participants will be contacted for follow-up every 2 months for a year. Then they will be contacted every 6 months. They will have tumor scans every 6-12 weeks until their cancer gets worse.

Detailed Description
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Background: Natural killer (NK) cells are an important component of an anti-tumor immune response. PD-L1 CAR-NK (PD-L1 t-haNKs) is an off the shelf, irradiated human, allogeneic, NK cell line that is frozen, shipped, thawed and then infused. PD-L1 CAR-NK cells have been engineered to have 3 adaptive modifications: Expression of a chimeric antigen receptor (CAR) targeting the tumor-associated antigen PD-L1 Expression of the high-affinity variant (158V) of the human Fc >= receptor (Fc >=RIIIa/CD16a) An endoplasmic reticulum-retained version of the human interleukin-2 (ERIL-2) cytokine. To improve the safety profile, PD-L1 CAR-NK cells are irradiated, thus inhibiting proliferation while maintaining cytotoxicity. Irradiated PD-L1 CAR-NK cells are highly effective at lysing PD-L1 expressing tumor cells as well as PD-L1 null tumor cells (via expression of native NK cell receptors). Preliminary clinical data from 10 participants treated with PD-L1 CAR-NK cells (NCT04050709) suggest PD-L1 CAR-NK are well tolerated at a dose of 2x109 cells intravenous (IV) twice per week. An additional 8 participants have received irradiated PD-L1 CAR-NK under single patient INDs. PD-L1 CAR-NK cell treatment combined with PD-1 blockade and cytokine therapy may synergistically activate the T-cell and NK cell arms of the immune system and enhance anti-tumor activity. The combination of N-803 + PD-1/PD-L1 interaction blockade has a manageable safety profile Objectives: Determine the clinical response rate (CR+PR) with irradiated PD-L1 CAR-NK cells in combination with N-803 plus pembrolizumab in participants with Head and neck squamous cell carcinoma and gastric/GEJ cancer. Eligibility: Gastric/GEJ Cancer Cohort Participants must have metastatic or unresectable locally advanced Gastric/GEJ cancer. Participants must have measurable disease by RECISTv1.1. If the participant is one of the first six participants enrolled on study and is part of the safety-lead in, either measurable or evaluable (e.g. ascites, elevated tumor marker, or lesion visualized on imaging) disease will be permitted. Participants must have completed, had disease progression on, or been ineligible to receive first-line systemic chemotherapy for advanced/metastatic disease. Participants with HER2 positive disease must have received HER2-targeted systemic therapy. Head and neck squamous cell carcinoma Cohort Participants must have metastatic or unresectable locally advanced HNSCC. Participants must have measurable disease by RECISTv1.1. If the participant is one of the first six participants enrolled on study and is part of the safety-lead in, either measurable or evaluable (e.g. ascites, elevated tumor marker, or lesion visualized on imaging) disease will be permitted. Participants must have received or been ineligible to receive first-line systemic chemotherapy and must have received systemic anti-PD-1 therapy (in the first-line or subsequent-line setting). Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Men or women, Age >= 18 years Design: This is an open-label, single-center, phase II trial using a safety lead-in to assess the safety and tolerability of irradiated PD-L1 CAR-NK cells in combination with N-803 plus pembrolizumab in participants with head and neck squamous cell carcinoma and/or gastric/GEJ cancer The phase II objective of this study is to determine the clinical response rate (CR+PR) with irradiated PD-L1 CAR-NK cells in combination with N-803 plus pembrolizumab in participants with head and neck squamous cell carcinoma and gastric/GEJ cancer. Cohorts 1 and 2 enroll simultaneously. Initially, up to 12 participants from Cohort 1 and/or Cohort 2 will enroll and receive 1 dose of PD-L1 CAR-NK cell monotherapy (week -1) for PK/PD studies before starting the combined treatment of Pembrolizumab and N-803 one week later (week 0). PD-L1 CAR-NK cells (2x109) will be given intravenously every week until week 6 and then every two weeks from 6 weeks onward. Administration of pembrolizumab will be at the fixed dose of 400 mg intravenous every 6 weeks starting at week 0. Administration of N-803 will be at 15mcg/kg subcutaneously every 4 weeks starting at week 0. Participants will receive treatments in cycles (1 week=1 cycle) consisting of 7 (+/- 2) days with a minimum of 5 days between treatments. It is expected that 1-2 participants per month may be enrolled on this trial; thus, an accrual of 50 evaluable participants is expected to be completed within 3-4 years. To allow for a small number of inevaluable participants, the accrual ceiling will be set at 55 participants.

Official Title
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A Phase II Study of Immunotherapy Combination: Irradiated PD-L1 CAR-NK Cells Plus Pembrolizumab Plus N-803 for Subjects With Recurrent/Metastatic Gastric or Head and Neck Cancer

Conditions
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Gastroesophageal Junction (GEJ) Cancers, Advanced HNSCC

Intervention / Treatment
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* Drug: N-803
* Drug: Pembrolizumab
* Biological: PD-L1 t-haNK


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Gastric/GEJ cancer Cohort: Participants must have metastatic or unresectable locally advanced Gastric/GEJ cancer that has been histologically confirmed. Participants must have measurable disease by RECISTv1.1. If the participant is one of the first six participants enrolled on study and is part of the safety-lead in, either measurable or evaluable (e.g. ascites, elevated tumor marker, or lesion visualized on imaging) disease will be permitted. Participants must have received or been ineligible to receive first line systemic chemotherapy for Gastric/GEJ cancer. Participants with HER2 positive disease must have received HER2-targeted therapy. Head and neck squamous cell carcinoma Cohort Participants must have metastatic or unresectable locally advanced HNSCC that has been histologically confirmed. Participants must have measurable disease by RECISTv1.1. If the participant is one of the first six participants enrolled on study and is part of the safety-lead in, either measurable or evaluable (e.g. ascites, elevated tumor marker, or lesion visualized on imaging) disease will be permitted. Participants must have received or been ineligible to receive first-line systemic chemotherapy and must have received systemic anti-PD-1 therapy (in the first-line or subsequent-line setting). Age >=18 years. Because no dosing or adverse event data are currently available on the use of this investigation combination therapy in participants <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. ECOG performance status <2 Participants must have adequate organ and marrow function as defined below: leukocytes greater than or equal to 3,000/mcL absolute neutrophil count greater than or equal to 1,500/mcL platelets greater than or equal to 100,000/mcL total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal creatinine Creatinine within 1.5X upper limit of normal institutional limits Participants with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. Participants with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first 7 weeks of therapy. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Participants on therapeutic anticoagulation with warfarin must have an international normalized ratio (INR) that is within target range for their condition at the time of enrollment. The effects of PD-L1 t-haNKs with N-803 and pembrolizumab on the developing human fetus are unknown. For this reason and because these investigational agents teratogenicity is unknown, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry for the duration of study participation and for at least 4 months after last dose of study drug pembrolizumab. -Ability of subject to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: Participants who are receiving any other investigational agents or concurrent anticancer treatment. Palliative radiotherapy is allowed. Participants with concurrent use of systemic steroids (within 10 days of enrollment), except for physiologic doses of systemic steroid replacement or local (topical, nasal, intraarticular or inhaled) steroid use. Participants with active systemic autoimmune disease (e.g., lupus erythematosus, rheumatoid arthritis, Addison s disease, autoimmune disease associated with lymphoma, inflammatory bowel disease). Participants with autoimmune endocrine disorders controlled with medical management (e.g. thyroid disorders, type 1 diabetes, or adrenal insufficiency) will not be excluded Participants with a history of grade 3 or higher immune-related adverse events attributed to pembrolizumab or other anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy. This exclusion does not apply to participants with permanent endocrine insufficiencies (e.g. adrenal insufficiency or hypothyroidism) under satisfactory medical management. Additionally, participants with grade 2 adverse events attributed to these classes of agents will be excluded with the exception of rash, transient hyperthyroidism, transient liver enzyme abnormalities or other transient events that resolved without steroids or immunomodulatory agents. HIV or HBV infection due to unknown effect of PD-L1 targeting via a CAR or N-803 in these chronic viral infections. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled serious cardiac arrhythmia, clinically significant coagulopathy or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study because PD-L1 targeting via a CAR has unknown potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with PD-L1 targeting via a CAR and N-803, breastfeeding should be discontinued if the mother is treated on this study for the duration of study participation and for at least 4 months after last dose of any study drug.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Arm 1<br>1-week lead in for PD-L1 CAR NK cell monotherapy followed by combination therapy of Pembrolizumab plus N-803 | Drug: N-803<br>* N-803 will be given via subcutaneous injection at a dose of 15 mcg/kg every 4 weeks (1 week after starting treatment with the PDL-1 CAR-NK cells).<br>Drug: Pembrolizumab<br>* Pembrolizumab 400 mg will be administered as a 30-minute IV infusion every 6 weeks. Pembrolizumab will be administered on the same day as the PD-L1 CAR-NK cells.<br>Biological: PD-L1 t-haNK<br>* PD-L1 CAR NK cells (2x109) will be administered by IV infusion over approximately 30 minutes every week. After the week 6 treatment, these cells will be given every 2 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the clinical response rate (CR+PR) with irradiated PD-L1 CAR-NK cells in combination with N-803 plus pembrolizumab in patients with head and neck squamous cell carcinoma and gastric/GEJ cancer. | Clinical response rate (CR+PR) | every 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the progression free survival (PFS) in patients with HNSCC and/or gastric/GEJ cancer treated with irradiated PD-L1 CAR-NK cells in combination with N-803 plus pembrolizumab | The proportion of patients that have progressive disease after 18 months | Until progression or death | 
| To assess the safety and tolerability of irradiated PD-L1 CAR-NK cells in combination with N-803 plus pembrolizumab in patients with head and neck squamous cell carcinoma and/or gastric/GEJ cancer | List of adverse event frequency | 28 days after treatment (Study Calendar-Last AE evaluation) | 
| To assess duration of response in patients with HNSCC and/or gastric/GEJ cancer treated with irradiated PD-L1 CAR-NK cells in combination with N-803 plus pembrolizumab | The time when the proportion of patient's tumors shrunk after therapy | Until progression or death | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Keytruda, PD-L1 t-haNK cells, GEJ cancer, Advanced HNSCC, Cellular Therapy