CAR-macrophages for the Treatment of HER2 Overexpressing Solid Tumors

Study Overview
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Brief Summary
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Phase 1, first-in-human, open label study of CAR macrophages in HER2 overexpressing solid tumors.

Detailed Description
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A Phase 1, First in Human Study of Adenovirally Transduced Autologous Macrophages Engineered to Contain an Anti-HER2 Chimeric Antigen Receptor in Subjects with HER2 Overexpressing Solid Tumors Main Study - Group 1 and Group 2 all HER2 overexpressing solid tumors Intraperitoneal Substudy - HER2 overexpressing peritoneal disease 89[Zr] radiolabeled CT-0508 Substudy - All HER2 overexpressing solid tumors (Univ of Penn, Abramson Cancer Center only) CT-0508 Combination with Pembrolizumab Substudy - All HER2 overexpressing solid tumors

Official Title
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A Phase 1, First in Human Study of Adenovirally Transduced Autologous Macrophages Engineered to Contain an Anti-HER2 Chimeric Antigen Receptor in Subjects With HER2 Overexpressing Solid Tumors

Conditions
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HER2-positive, Adenocarcinoma, Bile Duct Cancer, Biliary Tract Cancer, Bladder Cancer, Breast Cancer, Breast Neoplasm, Carcinoma, Ductal, Carcinoma, Hepatocellular, Cancer, Lung Cancer, Non-Small-Cell, Carcinoma, Ovarian Epithelial, Carcinoma, Small Cell, Carcinoma, Squamous, Carcinoma, Transitional Cell, Colorectal Cancer, Esophagogastric Junction Neoplasms, Inflammatory Breast Cancer, Stomach Neoplasms, Malignant Neoplasms, Ovarian Neoplasms, Pancreatic Cancer, HER2-positive Solid Tumors, HER2-positive Breast Cancer, HER2-positive Gastric Cancer, HER-2 Protein Overexpression, HER-2 Gene Amplification, Prostate Cancer, Head and Neck Cancer, Endometrial Cancer, Lung Cancer, Small Cell

Intervention / Treatment
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* Biological: CT-0508
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HER2-positive recurrent or metastatic solid tumors for which there are no available curative treatment options. Breast cancer and gastric/gastroesophageal junction cancers must have failed approved HER2-targeted agents. Other HER2-positive tumor types must have failed standard of care therapies, while prior therapy with anti-HER2 drugs is not required. Subject must be willing and able to undergo tumor tissue biopsy procedures Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Subject has adequate bone marrow and organ function Exclusion Criteria: HIV, active hepatitis B or hepatitis C infection. Diagnosis of immunodeficiency or chronic exposure to systemic corticosteroid therapy or any other form of immunosuppressive therapy Untreated or symptomatic central nervous system (CNS) metastases or cytology proven carcinomatous meningitis. o Subjects with small, asymptomatic CNS metastases that do not require treatment are permitted to enroll. Left ventricular ejection fraction (LVEF) <50% as determined by ECHO or multiple gated acquisition scan (MUGA) Other protocol-defined Inclusion/Exclusion may apply. CT-0508 in Combination with Pembrolizumab Substudy Only: Exclusion Criteria: Subjects with severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients Subjects with an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Subjects who have a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease Subjects who have had an allogeneic tissue/solid organ transplant

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 and Group 2<br>Both groups will receive the full dose manufactured per patient. Group 1 will undergo intra subject dose escalation of IV administrations of up to 500 million total cells on Day 1, up to 1.5 billion total cells on Day 3, and up to 3.0 billion total cells on Day 5. Group 2 will receive the full dose IV on Day 1 of up to 5 billion cells total. | Biological: CT-0508<br>* anti-HER2 CAR macrophages<br>|
| Experimental: Intraperitoneal Administration<br>All cohorts will receive the full dose manufactured per patient. Cohorts 1-3 will undergo intrasubject dose escalations of IP administration as follows: Cohort 1 up to 500 million total cells on Day 1, up to 1 billion total cells on Day 3 and up to 1.5 billion total cells on Day 5. Cohort 2 up to 1.5 billion total cells on Day 1, up to 2 billion total cells on Day 3 and any remaining cells on Day 5. Cohort 3 up to 2.5 billion total cells on Day 1 and up to 2.5 billion total cells on Day 3. Cohort 4 will 1 dose on Day 1 of up to 5 billion total cells. | Biological: CT-0508<br>* anti-HER2 CAR macrophages<br>|
| Experimental: 89[Zr]radiolabeled CT-0508<br>89[Zr] radiolabeled group will receive a full dose IV on Day 1 of up to 500 million total cells of 89[Zr] radiolabeled CT-0508 and non-radiolabeled CT-0508 of up to 4.5 billion total cells (Univ of Penn Abramson Cancer Center only). | Biological: CT-0508<br>* anti-HER2 CAR macrophages<br>|
| Experimental: CT-0508 in Combination with Pembrolizumab<br>All regimen levels will receive the full dose manufactured per patient up to 5 billion total cells. Regimen Levels 1 and 2 will undergo intrasubject dose escalations of IV administration as follows: Regimen Level 1: up to 500 million total cells on Day 1, up to 1.5 billion total cells on Day 3, and up to 3.0 billion total cells on Day 5 plus pembrolizumab 200 mg q3w starting on Day 8. Regimen Level 2: up to 500 million total cells on Day 1, up to 1.5 billion total cells on Day 3, and up to 3.0 billion total cells on Day 5 plus pembrolizumab 200 mg q3w starting on Day 1. Regimen Level 3 will receive the full dose IV on Day 1 of up to 5 billion total cells plus pembrolizumab 200 mg q3w starting on Day 1. | Biological: CT-0508<br>* anti-HER2 CAR macrophages<br>Biological: Pembrolizumab<br>* anti-PD antibody<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the safety and tolerability of CT-0508 by estimating the frequency and severity of adverse events in subjects with HER2 overexpressing solid tumors. | Frequency and severity of adverse events including, but not limited to, estimating frequency and severity of Cytokine Release Syndrome (CRS) | 14 months | 
| Assess the feasibility of manufacturing CT-0508 by describing the percentage of products passing release criteria. | Percentage of products that pass release criteria among all manufactured products. | 12 months | 
| Assess the safety and tolerability of CT-0508 in combination with pembrolizumab by estimating the frequency and severity of adverse events in subjects with HER2 overexpressing solid tumors (CT-0508 and pembrolizumab substudy only) | Frequency and severity of adverse events including, but not limited to, estimating frequency and severity of Cytokine Release Syndrome (CRS) | 14 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate the objective response rate (ORR), according to RECIST v1.1, of at least 1 dose of CT-0508 among subjects with HER2 overexpressing solid tumors. | Proportion of subjects with an objective response (either a complete response [CR] or partial response [PR]) in subjects who received at least 1 dose of CT-0508 and at least the 8-week tumor evaluation as determined by the investigator using RECIST v1.1. | 24 months | 
| Estimate progression-free survival (PFS). | Defined as the time between the date of first dose and the date of first documented disease progression as determined by the investigator using RECIST v1.1 or death due to any cause, whichever occurs first. Defined as the time between the date of first dose and the date of first documented disease progression as determined by the investigator using RECIST v1.1 or death due to any cause, whichever occurs first. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-positive solid tumors, Phase 1, cell therapy, CAR-macrophage, immunotherapy, advanced cancer, post menopausal, premenopausal, metastatic cancer, Prostate Cancer, Head and Neck Cancer, Lung Cancer, Small Cell, Endometrial Cancer, Lung Cancer, Non-Small Cell