A Vaccine (PDS0101) and Chemoradiation for the Treatment of Stage IB3-IVA Cervical Cancer, the IMMUNOCERV Trial

Study Overview
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Brief Summary
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This phase IIA trial studies the effect of a vaccine (PDS0101) when given together with chemotherapy and radiation therapy (chemoradiation) in treating patients with stage IB3-IVA cervical cancer. Chemotherapy drugs, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. PDS0101 is a type of vaccine that is intended to help the immune system respond to human papillomavirus (HPV16)-infected cervical tumor cells. PDS0101 contains two active components: the first is called R-DOTAP (Versamune) and is included in the vaccine to boost the immune system's response against the HPV viral proteins and the second group of active components are selected small pieces of proteins (called peptides) taken from the HPV virus. Giving PDS0101 in combination with chemoradiation may work help to control cervical cancer.

Detailed Description
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PRIMARY OBJECTIVE: I. Evaluate the safety and toxicity profile of delivering the immune nanoparticle liposomal HPV-16 E6/E7 multipeptide vaccine PDS0101 (PDS0101) with standard-of-care chemoradiation (chemoRT) in patients with locally advanced cervical cancer. SECONDARY OBJECTIVES: I. Rate of complete metabolic response on day 170 (+/- 14 days) positron emission tomography computed tomography (PET CT). II. Rate of >= 90% gross tumor volume reduction day 35 magnetic resonance imaging (MRI) (+/- 5 days). III. Report rates of local control (LC), progression-free survival (PFS), and overall survival (OS) at 12 and 18 months following chemoRT completion. IV. Long-term safety: rate of grade >= 3 chronic toxicity (from day 81 to completion of trial). EXPLORATORY HPV-SPECIFIC IMMUNE RESPONSE OBJECTIVES: I. Enzyme-linked immunosorbent spot (ELISpot) assays on interferon-gamma and granzyme B levels in E6/7-specific T cells isolated from peripheral blood mononuclear cells (PBMCs). II. Compare intratumoral T-cell receptor (TCR) clonality at baseline and end of treatment by TCR sequencing. III. Measure CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) from cervical brush samples by using markers of T-cell exhaustion (PD1, CTLA4) and T cell-activation (granzyme B, CD69+). IV. Assess the intestinal and cervical microbiome by analyzing rectal and cervical swab samples with 16s ribosomal ribonucleic acid (rRNA) sequencing. V. Additional assays such as circulating tumor cells, circulating cell-free tumor deoxyribonucleic acid (DNA) (ccfDNA), and other assays will be performed at the discretion of the principal investigator. OUTLINE: Patients undergo radiation therapy over 1 hour 5 days per week (Monday-Friday) for 5-7 weeks and receive cisplatin intravenously (IV) over 4 hours once per week (QW) during the 5 weeks of radiation therapy in the absence of disease progression and unacceptable toxicity. Patients also receive PDS0101 subcutaneously (SC) on days -10, 7, 28, 49, and 170 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, 1, 4, 6, 12, and 18 weeks, and 18 months.

Official Title
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IMMUNOCERV: Evaluating the Safety of Chemoradiation Combined With PDS0101 Immunotherapy in Treating Locally Advanced Cervical Cancer

Conditions
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Locally Advanced Cervical Squamous Cell Carcinoma, Not Otherwise Specified, Stage IB3 Cervical Cancer FIGO 2018, Stage II Cervical Cancer FIGO 2018, Stage IIA Cervical Cancer FIGO 2018, Stage IIA1 Cervical Cancer FIGO 2018, Stage IIA2 Cervical Cancer FIGO 2018, Stage IIB Cervical Cancer FIGO 2018, Stage III Cervical Cancer FIGO 2018, Stage IIIA Cervical Cancer FIGO 2018, Stage IIIB Cervical Cancer FIGO 2018, Stage IIIC Cervical Cancer FIGO 2018, Stage IIIC1 Cervical Cancer FIGO 2018, Stage IIIC2 Cervical Cancer FIGO 2018, Stage IVA Cervical Cancer FIGO 2018

Intervention / Treatment
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* Drug: Cisplatin
* Biological: Liposomal HPV-16 E6/E7 Multipeptide Vaccine PDS0101
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed locally advanced squamous cell carcinoma of cervix (Federation of Gynecology and Obstetrics [FIGO] 2018 stage IB3-IVA with primary tumor >= 5 cm and/or positive pelvic or periaortic nodal disease assessed by imaging) Histologic diagnosis of squamous cell carcinoma of the cervix Written informed consent before initiation of any study-related procedures World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Alanine aminotransferase (ALT) =< 2-fold the upper limit of normal Aspartate aminotransferase (AST) =< 2-fold the upper limit of normal Alkaline phosphatase (alk phos) =< 2-fold the upper limit of normal Total bilirubin (total bili) =< 2-fold the upper limit of normal Creatinine =< 1.5 Electrocardiogram (ECG) with no clinically significant findings (as assessed by the investigator) performed within 30 days of signing the informed consent form Absence of current malignancies at other sites, except for adequately treated basal or squamous cell carcinoma of the skin. Cancer survivors who have undergone potentially curative therapy for a prior malignancy who have no evidence of that disease for 5 years and who are deemed at low risk for recurrence are eligible for the study Exclusion Criteria: Human immunodeficiency virus (HIV) infection, cellular immune deficiencies, hypogammaglobulinemia or dysgammaglobulinemia, or hereditary or congenital immunodeficiencies Prior diagnosis of hepatitis B or C (unless anti-hepatitis C therapy has produced a sustained virologic response) History of clinically significant autoimmune disease, Crohn's disease, or ulcerative colitis Serious concomitant disorder, including active systemic infection requiring treatment, as judged by the investigator Receipt of immunotherapy (e.g., interferons [IFNs], check-point inhibitors, tumor necrosis factor, interleukins, etc.) or biological response modifiers (granulocyte-macrophage colony-stimulating factor [GM-CSF], granulocyte colony-stimulating factor, macrophage colony-stimulating factor) within 4 weeks before the first study vaccination Receipt of chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug Current or recent use of physiologic doses of intra-articular, topical, or inhaled corticosteroids is acceptable History of previous therapeutic HPV vaccination (individuals who have been immunized with licensed prophylactic HPV vaccines [e.g., Silgard, Cervarix, Gardasil are not excluded) Known or suspected hypersensitivity to any component of the investigational product or contraindications to cisplatin (e.g., peripheral neuropathy grade =< 2 or ototoxicity =< grade 2 per Common Terminology Criteria for Adverse Events [CTCAE] version [v]5.0) Previous pelvic radiation therapy (RT) Previous chemotherapy for the cervix tumor Previous hysterectomy or will have a hysterectomy as part of their initial cervical cancer therapy Prior major surgery within 4 weeks of enrollment from which the patient has not recovered Other condition or prior therapy that, in the opinion of the Investigator, compromises the subject's welfare or may confound study results Concurrent participation in another therapeutic investigational study or use of another investigational drug within 6 months before the first study vaccination Previous enrollment in this study HPV genotyping is to be done from cervical swab samples. Enrollment will not require HPV testing Pregnancy: a female subject defined as a women of childbearing potential (WOCBP) who has a positive urine pregnancy test (e.g. within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (radiation therapy, cisplatin, PDS0101)<br>Patients undergo radiation therapy over 1 hour 5 days per week (Monday-Friday) for 5-7 weeks and receive cisplatin IV over 4 hours QW during the 5 weeks of radiation therapy in the absence of disease progression and unacceptable toxicity. Patients also receive PDS0101 SC on days -10, 7, 28, 49, and 170 in the absence of disease progression or unacceptable toxicity. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Biological: Liposomal HPV-16 E6/E7 Multipeptide Vaccine PDS0101<br>* Given SC<br>* Other names: PDS0101;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of grade >= 3 acute toxicity | Measured from first vaccine injection up to 30 days following completion of chemoradiotherapy (chemoRT). Adverse events (AEs) will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Any AE that occurs between the first day of PDS0101 injection and up to 30 days following completion of chemoRT ( Day 80) will be considered as acute toxicity (AT). | Day -10 to day 80 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complete metabolic response | Measured by positron emission tomography computed tomography (PET CT). | Day 170 | 
| Rate of >= 90% gross tumor volume reduction | Measured by magnetic resonance imaging (MRI). | Day 35 | 
| Rates of local control | Will be represented by Kaplan-Meier curves. | At 12 and 18 months | 
| Rates of progression-free survival | Will be represented by Kaplan-Meier curves. | At 12 and 18 months | 
| Rates of overall survival | Will be represented by Kaplan-Meier curves. | At 12 and 18 months | 
| Rate of grade >= 3 chronic toxicity | AEs will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Chronic toxicity (CT) is any toxicity that occurs outside of the AT window (between Days 81 and study completion of the study). | Day 81 to completion of trial |