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

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ClinicalTrials.gov Identifier: NCT03740256
Recruitment Status : Not yet recruiting
First Posted : November 14, 2018
Last Update Posted : January 23, 2020
Sponsor:
Collaborator:
The Methodist Hospital System
Information provided by (Responsible Party):
Andrew Sikora, Baylor College of Medicine

Brief Summary:

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. Because there is no standard treatment for this cancer at this time or because the currently used treatments do not work fully, 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-modified Adenovirus-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.

This research study combines two different ways of fighting cancer: oncolytic adenovirus (CAdVEC) and (HER2- specific autologous CAR T).

CAdVEC is an oncolytic adenovirus that has been modified to include additional immune system stimulators. Specifically, genes that stimulate the immune system have been added to the oncolytic adenovirus. Oncolytic adenoviruses are viruses that are made to target and kill cancer cells without killing normal cells. In this study, CAdVEC will be injected into participants tumor at one tumor site which is most easiest to reach. Once the oncolytic adenovirus 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 have found from previous research that they can put a new gene into T cells and make them specifically recognize and kill cancer cells expressing HER2. Only patients that have already signed a consent form that allowed us to put on their T cells the HER2 chimeric receptor with viral antigen receptor on their T cells will be able to be in this study.

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.


Condition or disease Intervention/treatment Phase
Bladder Cancer Head and Neck Squamous Cell Carcinoma Cancer of the Salivary Gland Lung Cancer Breast Cancer Gastric Cancer Esophageal Cancer Colorectal Cancer Pancreatic Adenocarcinoma Biological: CAdVEC Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 39 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A First in Human Phase I Trial of Binary Oncolytic Adenovirus in Combination With HER2-Specific Autologous CAR T Cells in Patients With Advanced HER2 Positive Solid Tumors
Estimated Study Start Date : June 1, 2020
Estimated Primary Completion Date : January 1, 2024
Estimated Study Completion Date : January 1, 2038


Arm Intervention/treatment
Experimental: Treatment Phase

Six 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 or combined with an injection of HER2.CAR.T cells 3 days later (Day 4), according to the following dose levels.

Dose Level 1 CAdVEC = 1.00E+10 HER2-specific-CAR- T = 0

Dose Level 2 CAdVEC = 1.00E+10 HER2-specific-CAR- T = 1.00E+06

Dose Level 3 CAdVEC = 1.00E+11 HER2-specific-CAR- T = 1.00E+06

Dose Level 4 CAdVEC = 1.00E+11 HER2-specific-CAR- T= 1.00E+07

Dose Level 5 CAdVEC = 1.00E+12 HER2-specific-CAR- T = 1.00E+07

Dose Level 6 CAdVEC = 1.00E+12 HER2-specific-CAR- T = 1.00E+08

Biological: CAdVEC
The intratumoral administration of CAdVEC will create a pro-inflammatory tumor microenvironment and will promote the recruitment and expansion of adoptively transferred HER2 specific CAR T cells via CAR (tumor antigen). We expect HER2 CAR T cells expanded at primary tumor sites will re-circulate and target metastasized tumors. The combination we propose to test has the potential to overcome each of the established individual limitations of oncolytic viruses and of CAR T-cells. Testing each element separately would not be beneficial or informative, since the combination therapy is anticipated to have unique profiles of both therapeutic benefit and potential toxicities.
Other Name: HER2-specificCAR- T




Primary Outcome Measures :
  1. Number of patients with dose limiting toxicity (DLT) by CTCAE 5.0 [ Time Frame: 6 weeks after the HER2.CAR AdVST infusion or 6 weeks + 3 days after the CAdVEC injection. ]
    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.


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) according to RECIST1.1 criteria [ Time Frame: 13 weeks ]
    Overall response rate is defined as the number of patients experiencing PR or better (i.e. PR + CR) divided by the number evaluable for efficacy. Tumor regression or progression will be evaluated accordingly with RECIST 1.1 criteria.

  2. Disease Control Rate (DCR) [ Time Frame: 13 weeks ]
    Disease Control Rate is defined as as the number of patients experiencing SD or better (i.e. SD+PR+CR) divided by the number evaluable for efficacy. Tumor regression or progression will be evaluated accordingly with RECIST 1.1 criteria.

  3. Progression Free Survival (PFS) [ Time Frame: 15 years ]
    Progression-Free Survival is defined as the time from start of treatment to disease progression or death.

  4. Overall Survival (OS) [ Time Frame: 15 years ]
    Overall survival is defined as the time from the start of treatment to death due to any cause.

  5. Number of treatment related adverse events with grade 3 or greater severity by CTCAE 5.0 [ Time Frame: 30 days ]
    Treatment related adverse events with grade 3 or greater severity by CTCAE 5.0



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed 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 the FDA-approved CB11 antibody (Leica), which refers to greater than weak-to-moderate staining intensity in >10% tumor cells.
  2. The disease must be deemed by the appropriate multidisciplinary tumor board unsuitable for curative surgery, radiotherapy, systemic therapy or any combination of the above modalities.
  3. Disease must have progressed after standard first line therapy, or without available effective treatment options.
  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 consent for treatment as indicated by following measures:

    • Hematologic: Absolute neutrophil count (ANC) ≥1.0 x 109/l; Hemoglobin ≥9 g/dl; Platelet count ≥ 100 x 109/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.
    • Cardiac function: LVEF ≥ 55%.
  7. Prior HER2 targeted therapy is allowed if delivered at least 4 weeks prior to the enrollment.
  8. Prior immunotherapy is allowed if it was delivered at least 4 weeks prior to the enrollment.
  9. Eastern Cooperative Oncology Group (ECOG) performance status 2 or less.
  10. Females of childbearing potential must have a negative pregnancy test and agree to use contraception during on-study protocol therapy.
  11. 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.
  12. The patient is ≥ 18 years of age, and able to understand and give informed consent to study related procedures and treatments.

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 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.
  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 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. HNSCC encasing a major blood vessel).
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03740256


Contacts
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Contact: Andrew Sikora, MD 713-798-3909 Andrew.Sikora@bcm.edu

Sponsors and Collaborators
Baylor College of Medicine
The Methodist Hospital System
Investigators
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Principal Investigator: Andrew Sikora, MD Baylor College of Medicine

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Responsible Party: Andrew Sikora, Assistant Professor, Center for Cell and Gene Therapy, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT03740256    
Other Study ID Numbers: H-43405 VISTA
First Posted: November 14, 2018    Key Record Dates
Last Update Posted: January 23, 2020
Last Verified: January 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Andrew Sikora, Baylor College of Medicine:
HER2
Human Epidermal Growth Factor Receptor 2
Bladder
Squamous Cell Carcinoma
Salivary Gland
Lung
Breast
Gastric
Esophageal
Colorectal
Pancreatic
Additional relevant MeSH terms:
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Carcinoma, Squamous Cell
Adenocarcinoma
Squamous Cell Carcinoma of Head and Neck
Salivary Gland Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Mouth Neoplasms
Mouth Diseases
Stomatognathic Diseases
Salivary Gland Diseases