Vaccine Therapy in Treating Patients With Persistent or Recurrent Cervical Cancer

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies the side effects and how well vaccine therapy works in treating patients with cervical cancer that does not go to remission despite treatment (persistent) or has come back (recurrent). Vaccines therapy may help the body build an effective immune response to kill tumor cells.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To evaluate the tolerability, safety, and nature and degree of toxicity of ADXS11-001 (live-attenuated Listeria monocytogenes cancer vaccine ADXS11-001) by the numbers of patients with dose-limiting toxicities (DLTs) and adverse events as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0. II. To assess the activity of ADXS11-001 for patients with persistent or recurrent carcinoma of the cervix with the frequency of patients who survive for at least 12 months after initiating therapy. SECONDARY OBJECTIVES: I. To characterize the distribution of progression-free survival and overall survival. II. To examine the proportion of patients with objective tumor response. TERTIARY OBJECTIVES: I. To assess changes in clinical immunology based upon serum cytokines and to correlate any observed changes with clinical response including progression-free survival, overall survival, tumor response, DLTs, and adverse effects. II. To examine associations between presence and type of high-risk human papillomavirus (H-HPV) and measures of clinical response and serum cytokine levels. OUTLINE: Patients receive live-attenuated Listeria monocytogenes cancer vaccine ADXS11-001 intravenously (IV) over 30 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Official Title
-----------------
A Phase II Evaluation of ADXS11-001 (NSC 752718) in the Treatment of Persistent or Recurrent Squamous or Non-Squamous Cell Carcinoma of the Cervix

Conditions
-----------------
Cervical Adenocarcinoma, Cervical Adenosquamous Carcinoma, Cervical Squamous Cell Carcinoma, Not Otherwise Specified, Recurrent Cervical Carcinoma

Intervention / Treatment
-----------------
* Biological: Attenuated Live Listeria Encoding HPV 16 E7 Vaccine ADXS11-001
* Other: Laboratory Biomarker Analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have persistent or recurrent squamous or non-squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix with documented disease progression (disease not amenable to curative therapy); histologic confirmation of the original primary tumor is required via the pathology report Patient must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded) Each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI), or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray Lymph nodes must be >= 15 mm in short axis when measured by CT or MRI Patient must have at least one ?target lesion? to be used to assess response on this protocol as defined by RECIST 1.1 Tumors within a previously irradiated field will be designated as ?non-target? lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy Patients must not be eligible for a higher priority Gynecologic Oncology Group (GOG) protocol, if one exists In general, this would refer to any active GOG phase III or rare tumor protocol for the same patient population Patients must have a GOG performance status of 0 or 1 Recovered from effects of recent surgery, radiotherapy, or chemotherapy Patients should be free of active infection requiring antibiotics Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration Continuation of hormone replacement therapy is permitted Any other prior therapy directed at the malignant tumor, including chemotherapy, biologic/targeted (non-cytotoxic) agents and immunologic agents, must be discontinued at least three weeks prior to registration Any prior radiation therapy must be completed at least 4 weeks prior to registration Patients must have had one prior systemic chemotherapeutic regimen for management of advanced, metastatic, or recurrent carcinoma of the cervix Chemotherapy administered concurrent with primary radiation (e.g.; weekly cisplatin) is not counted as a systemic chemotherapy regimen for management of advanced, metastatic, or recurrent disease; adjuvant chemotherapy given following the completion of radiation therapy (or concurrent chemotherapy and radiation therapy) is not counted as a systemic chemotherapy regimen for management of advanced, metastatic, or recurrent disease (e.g.; paclitaxel and carboplatin for up to 4 cycles) Patients are allowed to receive, but are not required to receive, biologic/targeted (non-cytotoxic) therapy as part of their primary therapy and/or as part of their therapy for advanced, metastatic, or recurrent disease (e.g., bevacizumab) Platelet count greater than or equal to 75,000/mcL Absolute neutrophil count (ANC) count greater than or equal to 1,000/mcL Lymphocyte count greater than or equal to 700/mcL Hemoglobin count greater than or equal to 9 g/dL or greater than or equal to 5.6 mmol/L Note: ANC, platelets, hemoglobin requirement cannot be met by the use of recent transfusions, or growth factor support (granulocyte colony-stimulating factor [G-CSF], erythropoietin, etc.) within 2 weeks prior to treatment initiation Creatinine less than or equal to 1.5 x institutional upper limit of normal (ULN) or measured or calculated creatinine clearance greater than or equal to 50 mL/min for subject with creatinine levels greater than 1.5 x institutional ULN; (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) (creatinine clearance should be calculated per institutional standard) Total bilirubin less than or equal to 1.5 x ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x ULN Alkaline phosphatase less than or equal to 2.5 x ULN International normalized ratio (INR) or prothrombin time (PT) and activated partial thromboplastin time (aPTT) less than or equal to 1.5 x ULN, unless patient is receiving anticoagulant therapy as long as PT or INR is within therapeutic range of intended use of anticoagulants Neuropathy (sensory and motor) less than or equal to grade 1 Patients must have signed an approved informed consent and authorization permitting release of personal health information Patients must meet pre-entry requirements as specified Patients of childbearing potential must have a negative serum pregnancy test prior to the study entry and must agree to ongoing use of 2 methods of study doctor approved birth control or abstain from heterosexual activity for the course of the study from screening through 120 days after the last dose of study medication; patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year Patients cannot be lactating Patients must be able to swallow pills Exclusion Criteria: Patients who have received prior therapy with ADXS11-001 Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer and other specific malignancies as noted below are excluded if there is any evidence of other malignancy being present within the last three years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis OTHER THAN for the treatment of cervical cancer within the last three years are excluded Prior radiation for localized cancer of the breast, head and neck, or skin is permitted provided that it was completed more than three years prior to registration and the patient remains free of recurrent or metastatic disease Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER THAN for the treatment of cervical cancer within the last three years are excluded; patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease Patients with a contraindication (e.g. sensitivity/allergy) to trimethoprim/sulfamethoxazole or ampicillin Patients allergic to nonsteroidal antiinflammatory drug (NSAID) Patients with active infection requiring systemic therapy or who are dependent on or currently receiving antibiotics that cannot be discontinued before dosing; (Note: subjects who discontinue an antibiotic prior to dosing must wait at least 5 half-lives after the last dose of antibiotic before receiving any ADXS11-001 infusion) Patients with a diagnosis of immunodeficiency, or who are dependent on or have received systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment with the exception of topical corticosteroids and occasional inhaled corticosteroids, as indicated Patients with uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia or Psychiatric illness/social situations that would limit compliance with study requirements Patients with liver cirrhosis or any other impaired hepatic function as determined by serum enzymes Patients known to be seropositive for human immunodeficiency virus (HIV) and/or active hepatitis, even if liver function studies are in the eligible range Patients with a prior history of a splenectomy and/or sickle cell trait/disease Patient has implanted medical device(s) that pose a high risk for colonization and/or cannot be easily removed (e.g., prosthetic joints, artificial heart valves, pacemakers, orthopedic screw(s), metal plate(s), bone graft(s), or other exogenous implant(s)); NOTE: more common devices and prosthetics which include arterial and venous stents, dental and breast implants and venous access devices (e.g., Port-a-Cath or Mediport) are permitted; sponsor must be contacted prior to consenting any subject who has any other device and/or implant Any patient currently requiring or anticipated to require tumor necrosis factor (TNF) blocking agent (e.g., infliximab) therapy for diagnosis of rheumatologic disease or inflammatory bowel disease (e.g., ankylosing spondylitis, Crohn disease, plaque psoriasis, psoriatic arthritis, rheumatoid arthritis or ulcerative colitis) Patient has undergone a major surgery, including surgery for a new artificial implant and/or device, within 6 weeks prior to the initiation of ADXS11-001 treatment; NOTE: all toxicities and/or complications must have recovered to baseline or grade 1 prior to the initiation of ADXS11-001 study therapy; sponsor must be consulted prior to enrolling patients on the study who recently had a major surgery or have new artificial implant, and/or devices Patient has a known allergy to any component of the study treatment formulations Patient has a history of listeriosis or prior ADXS11-001 therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ADXS11-001)<br>Patients receive live-attenuated Listeria monocytogenes cancer vaccine ADXS11-001 IV over 30 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Biological: Attenuated Live Listeria Encoding HPV 16 E7 Vaccine ADXS11-001<br>* Given IV<br>* Other names: Lovaxin-C;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Dose-limiting Toxicities, as Assessed by CTCAE v 4.0 | Number of patients with dose-limiting toxicities, as assessed by CTCAE v 4.0 | 28 days | 
| Incidence of Adverse Effects as Assessed by CTCAE v 4.0 | Incidence of adverse effects as assessed by CTCAE v 4.0 (i.e. the number of patients experiencing at least one grade 3 adverse event) | Adverse events were collected an average of 4 years 7 months | 
| Number of Patients Who Survive for at Least 12 Months | The number of patients (and percentage) who survive for at least 12 months. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distribution of Overall Survival | Characterized with Kaplan-Meier plots and estimates of the median time until death. | Patients will be followed (physical exams and histories) every three months for the first three years, then every six months for the next two years. Patients will be monitored for delayed toxicity and survival for 5-year period, unless consent withdrawn. | 
| Distribution of Progression-free Survival | Characterized with Kaplan-Meier plots and estimates of the median time until progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Patients will be followed (physical exams and histories) every three months for the first three years, then every six months for the next two years. Patients will be monitored for delayed toxicity and survival for 5-year period, unless consent withdrawn. | 
| Number of Patients Who Have Objective Tumor Response (Complete or Partial) | The number of patients who have objective tumor response (complete response or partial response). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Patients will be followed (physical exams and histories) every three months for the first three years, then every six months for the next two years. Patients will be monitored for delayed toxicity and survival for 5-year period, unless consent withdrawn. |