CELL INTELLIGENCE · 肿瘤细胞治疗研究

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

1. 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.
2. 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.
3. 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.
4. The patient must have at least one tumor site appropriate for intratumoral injection.
5. The patient must have radiographically measurable disease as per RECIST 1.1.
6. Life expectancy more than 12 weeks.
7. The patient is ≥ 18 years of age, able to understand and give informed consent to study related procedures and treatments.

Procurement Exclusion Criteria

1. 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).
2. Evidence of significant immunosuppressive conditions, such as the following:

   * Post organ transplant.
   * Diagnosis of HIV or other immunodeficiency disorders.
3. Diagnosis of other malignancies within 5 years except for cutaneous basal cell or squamous cell carcinoma, well-differentiated thyroid cancer, or localized prostate cancer.
4. Patients with known active hepatitis B or C infection.
5. Patient has had acute myocardial infarction within 6 months prior to consent for procurement.
6. 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.
7. 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:

1. 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).
2. 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.
3. 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.
4. The patient must have at least one tumor site appropriate for intratumoral injection.
5. The patient must have radiographically measurable disease as per RECIST 1.1.
6. 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.
7. Prior HER2 targeted therapy is allowed if delivered at least 4 weeks prior to the enrollment. (Excluding DL1 and DL2)
8. Eastern Cooperative Oncology Group (ECOG) performance status 2 or less (Appendix I).
9. 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.
10. 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.
11. The patient is ≥ 18 years of age, and able to understand and give informed consent to study related procedures and treatments.

Treatment Exclusion Criteria:

1. 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.
2. 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.
3. History or evidence of active autoimmune disease requiring continuous systemic corticosteroids, immunosuppressants or other disease modifying agents.
4. Evidence of significant immunosuppressive conditions, such as the following:

   * Post organ transplant.
   * Diagnosis of HIV or other immunodeficiency disorders.
5. 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.
6. Patients with known active infectious disease, such as hepatitis B or C infection.
7. Patient has had acute myocardial infarction within 6 months prior to enrollment for treatment.
8. Patients with abnormal left ventricular function (LVEF \<55%).
9. 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).
10. Pregnant or breastfeeding females.
11. 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.

主要终点：Number of patients with dose limiting toxicity (DLT) by CTCAE 5.0 · Incidence of dose limiting toxicities (DLT) of CAdVEC intratumoral injection in combination with HER2.CAR AdVST cells in patients with advanced refractory HER2 positive solid tumors. · 4 weeks after the HER2.CAR AdVST infusion or 4 weeks + 3 days after the CAdVEC injection.
次要终点：Overall Response Rate (ORR) according to RECIST1.1 criteria；Disease Control Rate (DCR)；Progression Free Survival (PFS)；Overall Survival (OS)；Number of treatment related adverse events with grade 3 or greater severity by CTCAE 5.0

• Treatment Phase · EXPERIMENTAL · Five dose levels will be evaluated using the BOIN design. Cohorts of size 3 will be enrolled at each dose level until 9 evaluable patients have been studied at a single dose. Each patient will receive an intratumoral injection of CAdVEC alone on Day 1 or combined with an injection of HER2.CAR.T cells on Day 4, according to the following dose levels: Dose Level 1 CAdVEC = 5.00E+9 HER2 specific CAR-T cells = 0 Dose Level 2 CAdVEC = 1.00E+10 HER2 specific CAR-T cells = 0 Dose Level 3 CAdVEC = 1.00E+10 HER2 specific CAR-T cells = 1.00E+06 Dose Level 4 CAdVEC = 1.00E+10 HER2 specific CAR-T cells = 1.00E+07 Dose Level 5 CAdVEC = 1.00E+10 HER2 specific CAR-T cells = 1.00E+08

This study is a first in human Phase 1 study that involves patients with a type of cancer called HER2 (Human Epidermal Growth Factor Receptor 2) positive cancer. This study asks patients to volunteer to take part in a research study investigating the safety and efficacy of using special immune cells called HER2 chimeric antigen receptor specific cytotoxic T lymphocytes (HER2 specific CAR T cells), in combination with intra-tumor injection of CAdVEC, an oncolytic adenovirus that is designed to help the immune system including HER2 specific CAR T cell react to the tumor. The study is looking at combining these two treatments together, because we think that the combination of treatments will work better than each treatment alone. We also hope to learn the best dose level of the treatments and whether or not it is safe to use them together. In this study, CAdVEC will be injected into participants tumor at one tumor site which is most easiest to reach. Once it infects the cancer cells, activation of the immune response will occur so it can attack and kill cancer cells. (This approach may have limited effects on the other tumor sites that have not received the oncolytic virus injection, so, patients will also receive specific T cells following the intratumor CAdVEC injection.) These T cells are special infection-fighting blood cells that can kill cells infected with viruses and tumor cells. Investigators want to see if these cells can survive in the blood and affect the tumor. Both CAdVEC and HER2-specific autologous CAR T are investigational products. They are not approved by the FDA.