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History of Changes for Study: NCT02002182
Window of Opportunity Trial of ADXS 11-001 Vaccination Prior to Robotic Surgery of HPV-Positive Oropharyngeal Cancer
Latest version (submitted September 9, 2022) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 December 4, 2013 None (earliest Version on record)
2 January 16, 2014 Recruitment Status, Study Status, Contacts/Locations and Outcome Measures
3 November 7, 2014 Contacts/Locations, Study Status, Study Identification, Arms and Interventions, Study Design and Sponsor/Collaborators
4 June 19, 2015 Recruitment Status, Study Status, Contacts/Locations, Arms and Interventions and Study Identification
5 November 10, 2015 Recruitment Status, Study Status and Contacts/Locations
6 April 20, 2016 Study Status, Study Description and Eligibility
7 September 16, 2016 Study Status and Contacts/Locations
8 December 15, 2016 Contacts/Locations and Study Status
9 November 7, 2017 Recruitment Status, Study Status, Contacts/Locations, Arms and Interventions, Conditions, Study Description and Sponsor/Collaborators
10 April 23, 2018 Recruitment Status, Study Status, Contacts/Locations, Arms and Interventions and Conditions
11 November 27, 2018 Outcome Measures, Contacts/Locations and Study Status
12 March 20, 2019 Study Status
13 March 27, 2020 Recruitment Status, Study Status, Contacts/Locations, Study Design
Show
Results Submission Events
14 July 1, 2020 Outcome Measures, Study Status, Document Section and Results
15 July 1, 2021 Study Status and Study Identification
16 September 9, 2022 Recruitment Status and Study Status
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Study NCT02002182
Submitted Date:  December 4, 2013 (v1)

Open or close this module Study Identification
Unique Protocol ID: GCO 13-1411
Brief Title: Window of Opportunity Trial of ADXS 11-001 Vaccination Prior to Robotic Surgery of HPV-Positive Oropharyngeal Cancer
Official Title: Window of Opportunity Trial of Neoadjuvant ADXS 11-001 Vaccination Prior to Robot -Assisted Resection of HPV-Positive Oropharyngeal Squamous Cell Carcinoma
Secondary IDs:
Open or close this module Study Status
Record Verification: November 2013
Overall Status: Not yet recruiting
Study Start: December 2013
Primary Completion: January 2015 [Anticipated]
Study Completion: January 2015 [Anticipated]
First Submitted: November 29, 2013
First Submitted that
Met QC Criteria:
December 4, 2013
First Posted: December 5, 2013 [Estimate]
Last Update Submitted that
Met QC Criteria:
December 4, 2013
Last Update Posted: December 5, 2013 [Estimate]
Open or close this module Sponsor/Collaborators
Sponsor: Andrew Sikora
Responsible Party: Sponsor-Investigator
Investigator: Andrew Sikora
Official Title: Assistant Professor
Affiliation: Icahn School of Medicine at Mount Sinai
Collaborators: Advaxis, Inc.
Open or close this module Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary:

Squamous cell carcinoma is the most frequently occurring malignant tumor of the head and neck and is a major cause of morbidity and mortality worldwide. More than 90% of HNSCCs originate from the mucosal linings of the oral cavity, pharynx, or larynx.

Currently 60-80% of oropharyngeal cancer is caused by the human papillomavirus (HPV), particularly the so-called "high-risk" oncogenic HPV16 and HPV18 genotypes. While patients with HPV+ tumors typically have an excellent response to surgical or radiation-based therapy6,7, treatment can be associated with significant short- and long-term toxicity, and it is not yet known whether patients with HPV+ OPSCCA have better long-term control. Thus, approaches which target the unique biology of HPV-infected cancer cells, such as therapeutic vaccination, are attractive strategies for potentially de-escalating XRT and chemo/XRT regimens (and thus decreasing toxicity) and enhancing long-term disease control.

Preventive and therapeutic vaccines targeting HPV have been developed in an effort to tip the immunologic balance towards beneficial immune activation. This is an investigator-initiated prospective clinical study of patients with stage II-IV squamous cell carcinoma of the oropharynx (OPSCC) who are to undergo ablative transoral robotic surgery (TORS). We propose to test the hypothesis that the listeria-based HPV vaccine ADX11-001 induces circulating and tumor-infiltrating antigen-specific T cells in HPV16+ oropharyngeal cancer patients undergoing TORS resection. The results of this trial will assess the ability of ADX11-001 vaccination to induce a robust HPV-specific cytotoxic lymphocyte (CTL) response in the blood and tumor.

Detailed Description:

This is an investigator-initiated prospective clinical study of patients with stage I-IV squamous cell carcinoma of the oropharynx (OPSCC) who are to undergo ablative transoral robotic surgery (TORS). The investigators propose to test the hypothesis that the listeria-based HPV vaccine ADX11-001 induces circulating and tumor-infiltrating antigen-specific T cells in HPV16+ oropharyngeal cancer patients undergoing TORS resection. The results of this trial will assess the ability of ADX11-001 vaccination to induce a robust HPV-specific cytotoxic lymphocyte (CTL) response in the blood and tumor.

ADXS11-001 (ADXS-HPV) is a live attenuated Listeria monocytogenes (Lm)-LLO immunotherapy developed for the treatment of HPV-associated dysplasia and malignancy. ADXS11-001 is bioengineered to secrete an antigen-adjuvant fusion (tLLO-E7) protein consisting of a truncated fragment of the listeriolysin (tLLO) fused to HPV16 E7. The proposed mechanism of action for ADXS11-001 is stimulation of the immune system to specifically target tumors or dysplastic cells that express the tumor associated antigen (HPV 16-E7) or homologous antigens (such as HPV18 E7).

The use of live attenuated, bioengineered, bacteria is a different way to approach cancer immunotherapy than those based upon synthetic chemistry, cellular therapy, or antibody based agents. Using this novel platform technology, the activation of an immune response to live bacteria appears to be more complex and comprehensive. Lm-LLO immunotherapies generate a strong innate and adaptive cellular immune response and invoke pathogen associated immune mechanisms [7-10]. Advaxis Lm-LLO immunotherapies are comprised of highly attenuated strains of Lm bioengineered to secrete tumor associated antigen(s) of interest fused to a truncated and inactive fragment of the Lm protein listeriolysin O (tLLO). ADXS11-001 exhibits an estimated 4 log reduction in virulence when compared to wt-Lm.

The mechanism of attenuation for ADXS-HPV is partly due to incorporation of a defective prfA virulence gene transcription activator, with allogeneic complementation and potential metabolic burden due to the expression of fusion protein tLLO-E7. LLO appears to have evolved as an innate target of the immune system, stimulates many potentially therapeutic immune responses by itself and can act as an adjuvant independent of the microbe. By using truncated LLO as part of the fusion protein along with an antigen, the bioengineered Lm construct secretes combined antigen-adjuvant directly within the phagolysosome and cytoplasm of APC.

Lm is actively phagocytosed by APCs, and unlike other intracellular bacteria, can escape into the cytoplasm of the host cell by disrupting the phagosomal membrane via LLO (Figure 1). Since Lm is a Gram-positive organism it does not contain/express LPS endotoxin. Humoral immunity does not play a major role in combating Lm infections as Lm quickly leaves the circulation and becomes an intracellular infection. Consequently, Lm predominantly stimulates a cellular immune response, and does not stimulate much antibody formation. Peptides derived from Lm in the phagolysosome and the cytosol can be presented by both the MHC Class I and Class II pathways, inducing both CD4+ and CD8+ T-cell responses. Further details about the design and production of ADXS11-001 are found in the Investigator's Brochure.

ADXS11-001 is currently being evaluated in a number of HPV-induced cancers and precancers, including: cervical intraepithelial neoplasia (CIN) 2/3, recurrent/refractory cervical cancer, anal cancer, and HPV-positive oropharyngeal cancer. In nonclinical studies, ADXS11-001 was found to cause the therapeutic regression of tumors that express the HPV16-E7 antigen. The reduction in tumor growth with ADXS11-001 treatment was directly associated with the induction of E7 specific immune responses. Both CD4 and CD8 T cell responses elicited by ADXS11-001 treatment were found to be essential for tumor regression. Additional mechanistic studies show that treatment with Lm-LLO immunotherapies cause both an infiltration of T cells and a reduction in suppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) in the tumor microenvironment. These effects are localized to the tumor as there is no effect on immune suppressive cells in the peripheral organs such as spleen or lymph nodes.

TRANSORAL ROBOTIC SURGERY (TORS) - A UNIQUE OPPORTUNITY TO PROFILE THE TUMOR IMMUNE MICROENVIRONMENT (TIME) Increasing evidence suggests that the tumor immune microenvironment (TIME) of head and neck cancer is immunosuppressive, and that tumor-mediated immunosuppression may play a unique role in HPV-associated head and neck cancer. The TIME includes both anti-tumor effector cells (CD8+ cytotoxic T lymphocytes, CD4+ helper T cells, natural killer [NK] cells) and regulatory/suppressive immunocytes such as regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). Other factors, such as local concentrations of cytokines and chemokines also play a role in determining the TIME. The balance of effector and regulatory cells determines whether an individual TIME is associated with productive anti-tumor immunity or localized immunosuppression and unrestrained tumor growth. While the majority of tumor vaccine studies examine circulating antigen-specific T cell responses, these responses do not always correlate with infiltration of antigen-specific T cells into the tumor and objective tumor responses,

Robotic resection of oropharyngeal cancer is a treatment modality, pioneered at the Mount Sinai School of Medicine and other institutions. Transoral robotic surgery (TORS) is intended to minimize or avoid morbidity of radiation therapy or chemo-radiation by completely removing the tumor in three dimensions with negative histological margins, thus allowing de-escalation of adjuvant therapy in some patients and sparing adjuvant therapy altogether in others. When clinically indicated, a neck dissection is performed simultaneously. TORS is FDA approved for head and neck cancer, and considered standard of care therapy of OPSCC in appropriate patients.

An important distinction between TORS and definitive chemoradiation as treatment for oropharyngeal tumors is that only TORS yields a pathological specimen which can be used to provide postoperative risk-stratification and guide the use of adjuvant therapy. The pathological specimen also permits evaluation of the response of tumor biomarkers and the TIME following a course of preoperative (also described as "neoadjuvant") treatment. TORS resection of oropharyngeal cancer provides a unique opportunity to evaluate the ability of vaccination to induce an immune response in the tumor and draining lymph nodes.

Open or close this module Conditions
Conditions: Head and Neck Cancer
Squamous Cell Carcinoma of the Head and Neck
Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinoma
Keywords: HPV
0ropharynx
squamous cell carcinoma
head and neck cancer
transoral robotic surgery
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Not Applicable
Interventional Study Model: Parallel Assignment
Number of Arms: 2
Masking: None (Open Label)
Allocation: Non-Randomized
Enrollment: 30 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: Treatment-Vaccine Group
Two vaccinations with ADXS11-001 will be given at a dose of 1x109 cfu intravenously. The drug will be given as an 500ml infusion over 30 minutes.
Biological: ADXS11-001 (ADXS-HPV)
ADXS11-001 (ADXS-HPV) is a live attenuated Listeria monocytogenes (Lm)-LLO immunotherapy developed for the treatment of HPV-associated dysplasia and malignancy.
Other Names:
  • ADXS11-001
  • ADXS-HPV
No Intervention: Control Group
Observational control group treated with standard of care therapy only
Open or close this module Outcome Measures
Primary Outcome Measures:
1. change in HPV E6/E7-specific CD8+ cytotoxic lymphocyte (CTL) responses
[ Time Frame: baseline and Day 15 ]

The primary endpoint will be the change in HPV E6/E7-specific CD8+ cytotoxic lymphocyte (CTL) responses in the peripheral blood at time of surgery, with respect to baseline.
2. change in HPV E6/E7-specific CD8+ cytotoxic lymphocyte (CTL) responses
[ Time Frame: baseline and Day 25 ]

The primary endpoint will be the change in HPV E6/E7-specific CD8+ cytotoxic lymphocyte (CTL) responses in the peripheral blood at time of surgery, with respect to baseline.
3. change in HPV E6/E7-specific CD8+ cytotoxic lymphocyte (CTL) responses
[ Time Frame: baseline and week 2 ]

The primary endpoint will be the change in HPV E6/E7-specific CD8+ cytotoxic lymphocyte (CTL) responses in the peripheral blood at time of surgery, with respect to baseline.
4. change in HPV E6/E7-specific CD8+ cytotoxic lymphocyte (CTL) responses
[ Time Frame: baseline and 3 months ]

The primary endpoint will be the change in HPV E6/E7-specific CD8+ cytotoxic lymphocyte (CTL) responses in the peripheral blood at time of surgery, with respect to baseline.
5. change in HPV E6/E7-specific CD8+ cytotoxic lymphocyte (CTL) responses
[ Time Frame: baseline and 6 months ]

The primary endpoint will be the change in HPV E6/E7-specific CD8+ cytotoxic lymphocyte (CTL) responses in the peripheral blood at time of surgery, with respect to baseline.
6. change in HPV E6/E7-specific CD8+ cytotoxic lymphocyte (CTL) responses
[ Time Frame: baseline and 12 months ]

The primary endpoint will be the change in HPV E6/E7-specific CD8+ cytotoxic lymphocyte (CTL) responses in the peripheral blood at time of surgery, with respect to baseline.
Secondary Outcome Measures:
1. Toxicity
[ Time Frame: Baseline ]

To evaluate the tolerability, safety, and nature and degree of toxicity of ADX11001 by the numbers of patients with dose limiting toxicities (DLTs) and adverse events as assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0)
2. Toxicity
[ Time Frame: Day 15 ]

To evaluate the tolerability, safety, and nature and degree of toxicity of ADX11001 by the numbers of patients with dose limiting toxicities (DLTs) and adverse events as assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0)
3. Toxicity
[ Time Frame: Day 25 ]

To evaluate the tolerability, safety, and nature and degree of toxicity of ADX11001 by the numbers of patients with dose limiting toxicities (DLTs) and adverse events as assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0)
4. Vaccine induced HPV E6/E7specific CD8+ CTL responses
[ Time Frame: baseline and 2 weeks ]

Vaccine induced HPV E6/E7specific CD8+ CTL responses in the blood at 2, 4, and 6 weeks and 3, 6, and 12 months after surgery, with respect to baseline levels, in vaccinated patients and unvaccinated controls.
5. Vaccine induced HPV E6/E7specific CD8+ CTL responses
[ Time Frame: baseline and 4 weeks ]

Vaccine induced HPV E6/E7specific CD8+ CTL responses in the blood at 2, 4, and 6 weeks and 3, 6, and 12 months after surgery, with respect to baseline levels, in vaccinated patients and unvaccinated controls.
6. Vaccine induced HPV E6/E7specific CD8+ CTL responses
[ Time Frame: baseline and 6 weeks ]

Vaccine induced HPV E6/E7specific CD8+ CTL responses in the blood at 2, 4, and 6 weeks and 3, 6, and 12 months after surgery, with respect to baseline levels, in vaccinated patients and unvaccinated controls.
7. Vaccine induced HPV E6/E7specific CD8+ CTL responses
[ Time Frame: baseline and 3 months ]

Vaccine induced HPV E6/E7specific CD8+ CTL responses in the blood at 2, 4, and 6 weeks and 3, 6, and 12 months after surgery, with respect to baseline levels, in vaccinated patients and unvaccinated controls.
8. Vaccine induced HPV E6/E7specific CD8+ CTL responses
[ Time Frame: baseline and 12 months ]

Vaccine induced HPV E6/E7specific CD8+ CTL responses in the blood at 2, 4, and 6 weeks and 3, 6, and 12 months after surgery, with respect to baseline levels, in vaccinated patients and unvaccinated controls.
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  • The patient has newly-diagnosed, biopsy proven squamous cell carcinoma of Stage I-IV (T1-3, N0-2b) of the oropharynx.
  • The patient's tumor is HPV positive by PCR or ISH assay of tumor biopsy.
  • The patient is able/eligible to undergo treatment with transoral robotic surgery (TORS) with or without neck dissection.
  • The patient may or may not receive adjuvant radiation therapy or chemoradiation.
  • The patient is able to understand and give informed consent.
  • The patient is at least 18 years old.
  • The patient's ECOG performance status is </= 2.

Exclusion Criteria:

  • The patient has had prior head and neck squamous cell carcinoma (HNSCC), with the exception of superficial cutaneous basal cell or squamous cell carcinomas.
  • The patient has active cancer in another part of the body, with the exception of superficial cutaneous basal cell or squamous cell carcinomas
  • If a cancer survivor, the disease free interval is less than 3 years, with the exception of superficial cutaneous basal cell or squamous cell carcinomas.
  • If a cancer survivor the patient received prior systemic chemotherapy or radiotherapy
  • If prior standard-of-care pre-treatment biopsy is inadequate for analysis by immunohistochemistry, and the patient is unwilling to undergo an additional biopsy procedure.
  • The patient is a minor.
  • The patient is a prisoner.
  • The patient has a psychiatric illness or developmental delay which would interfere with understanding of the study and provision of informed consent.
  • The patient has previously received definitive surgical, radiation, or chemoradiation treatment for HNSCC.
  • The patient has a history of HIV or other known cause of immunosuppression, or is actively taking immunosuppressive medications due to organ transplantation, rheumatoid disease, or other medical conditions.
  • Patient is allergic to naproxen or Ibuprofen.
  • The patient has a history of liver disease.
  • Pregnancy. The effects of this vaccine on the developing human fetus are unknown. For this reason women of child-bearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation, Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
Open or close this module Contacts/Locations
Central Contact Person: Alexis Patsias, MD
Telephone: 212-241-4282
Email: alexis.patsias@mssm.edu
Central Contact Backup: Andrew Sikora, MD PhD
Telephone: 212-241-5951
Email: andrew.sikora@mssm.edu
Study Officials: Andrew G Sikora, MD PhD
Principal Investigator
Icahn School of Medicine at Mount Sinai
Marshall Posner, MD
Principal Investigator
Icahn School of Medicine at Mount Sinai
Locations: United States, New York
Icahn School of Medicine at Mount Sinai
New York, New York, United States, 10029
Contact:Contact: Andrew G Sikora, MD PhD 212-241-4282 andrew.sikora@mountsinai.org
Contact:Contact: Alexis Patsias, MD 212-241-4282 alexis.patsias@mssm.edu
Contact:Principal Investigator: Andrew G Sikora, MD PhD
Open or close this module IPDSharing
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