HER2 FPBMC in Patients With Metastatic Breast and Prostate Cancer (AM006)

Phase I/II Study of Anti-CD3 x Anti-HER2 Bispecific Antibody (HER2Bi) Armed Fresh Peripheral Blood Mononuclear Cells (HER2 FPBMC) in Metastatic Castrate Resistant Prostate Cancer (mCRPC) and Metastatic Breast Cancer (MBC)

The purpose of this study is to understand the safety and estimate the efficacy of anti-CD3 x anti-HER2 bispecific antibody (HER2Bi) armed fresh peripheral blood mononuclear cells (HER2 FPBMC) for patients with metastatic breast or prostate cancer. Participants receive 5 weekly doses of CD33 FPBMC by intravenous infusion followed by 4 infusions every other week.

Once subjects are determined to be eligible, white blood cells (lymphocytes) are collected via leukapheresis procedure. The T cells in the mononuclear cells are coated with bispecific antibody to activate the T cells and the mononuclear cells are re-infused into the patients so the T cells can multiply and kill cancer cells. At least 72 hours after the leukapheresis procedure, study treatment will start. After 5 HER2 FPBMC infusions, participants will have another leukapheresis procedure. Before, throughout and following study treatment, research blood will be collected to better understand immune response. Disease status will be checked regularly during and after study treatment.

Inclusion Criteria:

1. Provision of signed and dated informed consent form

2. Stated willingness to comply with all study procedures and availability for the duration of the study

3. Age ≥ 18 years at the time of signing informed consent

4. Expected survival ≥ 3 months in the judgment of the investigator

5. ECOG PS 0-1

6. Adequate Organ Function per the following criteria (within 10 days of study registration):

   • Absolute lymphocyte count ≥ 400/mm3
   • Absolute neutrophil count ≥ 1000/mm3
   • Platelets ≥ 75,000/mm3
   • Hemoglobin ≥ 9g/dL
   • Serum creatinine < 2.0 mg/dL OR measured or calculated creatinine clearance ≥ 50 ml/mm
   • Total bilirubin ≤ mg/dL
   • Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) < 5.0 times normal

7. Agreement to adhere to Lifestyle Considerations throughout study duration

8. A diagnosis of either of the following:

   a. Prostate Cancer: i. Histological and/or cytological confirmation of prostate adenocarcinoma. ii. Participants must have progressive mCRPC at screening iii. Serum testosterone levels <50 ng/dL during screening. iv. Must have progressed on at least one prior ARPI (abiraterone acetate, enzalutamide, apalutamide, or darolutamide).

   v. Participants must have ≥1 metastatic lesion that is present on baseline CT, MRI, or bone scan obtained ≤28 days prior to registration.

   b. Breast Cancer i. Histological and/or cytological confirmation of invasive breast cancer. ii. Participants must have previously treated metastatic breast cancer at screening. Metastatic breast cancer must be evaluable by RECIST 1.1 criteria.

iii. Must have progressed on at least two prior endocrine or targeted therapies or at least two lines of cytotoxic chemotherapy. If HER2 positive, then must have progressed on or been intolerant of at least one HER2 targeted therapy.

iv. Participants must have ≥1 metastatic lesion that is present on baseline CT, MRI, or bone scan obtained ≤28 days prior to registration.

Exclusion Criteria:

1. Pregnancy (must have negative pregnancy test within 7 days prior to study registration) or lactation

2. History of a recent myocardial infarction (within one year) or a past myocardial infarction (more than one year prior to enrollment) who are actively requiring nitroglycerine more than once per week

3. Inadequate cardiac function, as defined as any of the following:

   • Uncontrolled angina or severe ventricular arrhythmias
   • Clinically significant pericardial disease
   • History of myocardial infarction (MI) in the last year before registration
   • Class 3 or higher New York Heart Association Congestive Heart Failure

4. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study registration. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

5. Serious non-healing wound, ulcer, bone fracture, major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to registration

6. Active liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis

7. Is HIV positive or has evidence of active Hepatitis C virus or active Hepatitis B virus.

8. Active bleeding or a pathological condition that is associated with a high risk of bleeding (therapeutic anticoagulation is allowed)

9. Has an active infection requiring systemic therapy

10. A serious uncontrolled medical disorder that in the opinion of the Investigator may be jeopardized by the treatment with protocol therapy

11. Has a known history of active TB (Bacillus Tuberculosis)

12. Has received a live vaccine within 30 days of study registration.

13. Treatment with any investigational agent within 3 weeks prior to study registration

14. Active second malignancy requiring systemic treatment. Exceptions include basal cell carcinoma of the skin, treated cervical cancer, and squamous cell carcinoma of the skin

15. Has active autoimmune disease that has required systemic treatment in the 2 years prior to registration (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.

17. Patient may be excluded if, in the opinion of the PI and investigator team, the patient is not capable of being compliant

Additional Exclusion Criteria for Patients with Prostate Cancer:

1. Has small cell neuroendocrine carcinoma (pure or mixed) on prior or current histologic evaluation of primary or metastatic lesions
2. Has an actionable BRCA1 or BRCA2 alteration, for which approved therapies are available, e.g., PARP inhibitors, unless these therapies are not appropriate for the participant as determined by the investigator or the participant refuses such therapy. Participants with one of these mutations and who have progressed on targeted therapy are eligible.

Additional Exclusion Criteria for Patients with Breast Cancer:

1. Has an actionable BRCA1 or BRCA2 alteration, for which approved therapies are available, e.g., PARP inhibitors, unless these therapies are not appropriate for the participant as determined by the investigator or the participant refuses such therapy. Participants with one of these mutations and who have progressed on targeted therapy are eligible.
2. Participants in visceral crisis at risk of immediately life-threatening complications in the short term, including participants with massive uncontrolled effusions (pleural, pericardial, and peritoneal), pulmonary lymphangitis, or liver involvement > 50%.