Binary Oncolytic Adenovirus in Combination With HER2-Specific Autologous CAR VST, Advanced HER2 Positive Solid Tumors

Inclusion criteria

• This study will look at solid tumors (as a basket trial for any solid cancer) with HER2 positivity based on IHC Procurement Inclusion Criteria
• The patient has a histologically confirmed advanced refractory HER2 positive solid tumor, including but not limited to: head and neck squamous cell carcinoma; cancer of the salivary glands; lung cancer; breast cancer; bladder cancer; gastric cancer; esophageal cancer; colorectal cancer; and pancreatic adenocarcinoma. HER2 positivity is defined as ≥2+ staining by IHC with either the FDA-approved CB11 antibody (Leica) or anti HER2/neu (4B5) (VENTANA), which refers to greater than weak-to-moderate staining intensity in \>10% tumor cells.
• The disease must be deemed unsuitable for curative treatments including surgery, radiotherapy, systemic therapy, including checkpoint inhibitors, or any combination of the above modalities by the referring oncology physician and confirmed by the senior oncologists leading the protocol.
• Disease must have progressed after standard first line therapy, or without available effective treatment options. Patients are still eligible if they have failed more than one line of therapy.
• The patient must have at least one tumor site appropriate for intratumoral injection.
• The patient must have radiographically measurable disease as per RECIST 1.1.
• Life expectancy more than 12 weeks.
• The patient is ≥ 18 years of age, able to understand and give informed consent to study related procedures and treatments. Procurement

Exclusion criteria

• History or evidence of active autoimmune disease requiring continuous systemic corticosteroids (with more than 10mg/day prednisone or equivalent dose), immunosuppressants or other disease modifying agents (except palliative radiation).
• Evidence of significant immunosuppressive conditions, such as the following:
• Post organ transplant.
• Diagnosis of HIV or other immunodeficiency disorders.
• Diagnosis of other malignancies within 5 years except for cutaneous basal cell or squamous cell carcinoma, well-differentiated thyroid cancer, or localized prostate cancer.
• Patients with known active hepatitis B or C infection.
• Patient has had acute myocardial infarction within 6 months prior to consent for procurement.
• Injectable tumor site is considered to incur a significant risk of major hemorrhage (e.g. located in the CNS (brain), and proximal to critical neurovascular structures) per investigator's review.
• Uncontrolled intercurrent illness including but not limited to psychiatric illness and or social situations that in the opinion of the investigator would compromise compliance of study requirements or put the patient at unacceptable risk. Treatment Inclusion Criteria:
• Histologically confirmed advanced refractory HER2 positive solid tumors, including but not limited to: head and neck squamous cell carcinoma; cancer of the salivary glands; lung cancer; breast cancer; bladder cancer; gastric cancer; esophageal cancer; colorectal cancer; and pancreatic adenocarcinoma. HER2 positivity is defined as ≥2+ staining by IHC with either the FDA-approved CB11 antibody (Leica) or anti HER2/neu (4B5) (VENTANA), which refers to greater than weak-to-moderate staining intensity in \>10% tumor cells (HER2 positivity requirement is excluded in DL1 and DL2 as HER2 targeted agents are not used).
• The disease must be deemed unsuitable for curative treatments including surgery, radiotherapy, systemic therapy, including checkpoint inhibitors, or any combination of the above modalities by the referring oncology physician and confirmed by the senior oncologists leading the protocol.
• Disease must have progressed after standard first line therapy, or without available effective treatment options. Patients are still eligible if they have failed more than one line of therapy.
• The patient must have at least one tumor site appropriate for intratumoral injection.
• The patient must have radiographically measurable disease as per RECIST 1.1.
• The patient must have adequate organ function within 7 days prior to treatment as indicated by following measures:
• Hematologic: Absolute neutrophil count (ANC) ≥1.0 x 10\^9/l; Hemoglobin ≥7 g/dl; Platelet count ≥ 100 x 10\^9/l; PT or PTT ≤ 1.5 x ULN unless the subject is receiving anticoagulation.
• Hepatic function: bilirubin \< 2 x ULN, and AST and ALT \< 3 x ULN
• Renal Function: serum creatinine \<2 x the ULN or creatinine clearance \>60 mL/min.
• Prior HER2 targeted therapy is allowed if delivered at least 4 weeks prior to the enrollment. (Excluding DL1 and DL2)
• Eastern Cooperative Oncology Group (ECOG) performance status 2 or less (Appendix I).
• Females of childbearing potential must have a negative pregnancy test and agree to use contraception during on-study protocol therapy, or deemed to be not able to get pregnant.
• Male subjects with pregnant partner/female partner of childbearing potential agree to use barrier contraceptive during the study to minimize the risk of embryo-fetal exposure.
• The patient is ≥ 18 years of age, and able to understand and give informed consent to study related procedures and treatments. Treatment Exclusion Criteria:
• Patients with any concurrent treatment that would compromise the study including but not limited to continuous high dose corticosteroids (more than 10mg/day prednisone or equivalent dose), lympho-depleting antibodies, immunotherapy, targeted therapies or cytotoxic agents, CNS metastasis requiring continuous high-dose steroids (more than 10mg/day prednisone or equivalent dose) or other active therapeutic intervention. This does not include stable, previously-treated brain metastases. Patients on DL1 and DL2 can continue prior checkpoint inhibitors and HER2 targeted agents during the DLT evaluation period.
• Patients at significant risk of airway compromise or other critical obstruction (e.g. bowel, ureter, etc.) in the event of possible post injection tumor inflammation based on the investigative team's judgement.
• History or evidence of active autoimmune disease requiring continuous systemic corticosteroids, immunosuppressants or other disease modifying agents.
• Evidence of significant immunosuppressive conditions, such as the following:
• Post organ transplant.
• Diagnosis of HIV or other immunodeficiency disorders.
• Diagnosis of other malignancies within 5 years except for cutaneous basal cell or squamous cell carcinoma, well-differentiated thyroid cancer, or localized prostate or cervical cancer.
• Patients with known active infectious disease, such as hepatitis B or C infection.
• Patient has had acute myocardial infarction within 6 months prior to enrollment for treatment.
• Patients with abnormal left ventricular function (LVEF \<55%).
• Injectable tumor site is considered to incur a significant risk of major hemorrhage (e.g. located in the CNS (brain), pulmonary parenchyma, and proximal to critical neurovascular structures).
• Pregnant or breastfeeding females.
• Uncontrolled intercurrent illness including but not limited to psychiatric illness and or social situations that in the opinion of the investigator would compromise compliance of study requirements or put the patient at unacceptable risk.