Testing RG1-VLP Vaccine to Prevent HPV-related Cancers

Study Overview
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Brief Summary
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This phase I trial tests the safety, side effects, and best dose of RG1-virus-like particle (VLP) in preventing human papillomavirus (HPV)-related cancers in women. RG1-VLP is a vaccine that aims to protect against rare HPV types not targeted by currently approved HPV vaccines. HPV is a common sexually-transmitted infection that can cause certain genital and oral cancers. RG1-VLP contains a protein of HPV type 16 (HPV16) with a slightly different structure than the licensed Gardasil-9 vaccine. Gardasil-9 is approved by the Federal Drug Administration to help protect against diseases caused by some types of HPV. Gardasil-9 also contains 9 different HPV proteins. Both vaccines contain alum to stimulate the immune system. The usual approach for the prevention of HPV-related cancers for patients who are at increased risk is to consider the currently approved HPV vaccine like Gardasil-9, as well as to be followed closely by their doctor to watch for the development of cancer via routine pap smears. This trial may allow researchers to find out whether the RG1-VLP vaccine can safely trigger an immune response against HPV in healthy women and if it is better or worse than the usual approach for the prevention of HPV-related cancers.

Detailed Description
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PRIMARY OBJECTIVE: I. Assess the safety of RG1-virus-like particles (VLP) in healthy 18-45 years old women at 3 escalating doses. SECONDARY OBJECTIVES: I. Determine the immunogenicity of RG1-VLP in healthy 18-45 year old women at 3 escalating doses via the following assays: Ia. Determine serum antibody responses induced by RG1-VLP vaccination by both human papillomavirus (HPV) 16 L1 VLP and HPV16 L2 RG1-peptide enzyme-linked immunosorbent assay (ELISA); Ib. Determine whether vaccination-induced serum antibody response neutralizes HPV16. EXPLORATORY OBJECTIVES: I. Determine whether vaccination-induced serum antibody response broadly neutralizes high risk (hr) HPV other than HPV16. II. Determine whether vaccination induces a cell-mediated immune (CMI) response. III. Determine whether vaccination-induced serum antibody response upon passive transfer to naive animals, protects mice against hrHPV pseudovirion (PsV) challenge. IV. Determine whether vaccination results in changes in local antibody titers in vaginal and oral secretions (via oral rinse) and the effects of vaccination on HPV types in optionally-collected vaginal and oral secretions and eyebrow hair samples between months 0, 7 and 12. V. Assess the safety of recombinant human papillomavirus nonavalent vaccine (Gardasil-9) in healthy women post-administration of RG1-VLP. OUTLINE: This is a dose-escalation study of RG1-VLP. Patients are randomized to 1 of 2 arms. ARM I: Patients receive RG1-VLP intramuscularly (IM) for 3 doses at months 0, 2, and 6 in the absence of disease progression or unacceptable toxicity. Patients may also receive Gardasil-9 via injection for 3 doses at 6 months after the 3rd study vaccination (month 12), then at months 14 and 18 in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection on study and may undergo vaginal swab collection on study. ARM II: Patients receive saline placebo IM for 3 doses at months 0, 2, and 6 in the absence of disease progression or unacceptable toxicity. Patients may also receive Gardasil-9 via injection for 3 doses at 6 months after the 3rd saline injection (month 12), then at months 14 and 18 in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection on study and may undergo vaginal swab collection on study. Upon completion of study treatment, patients are followed up to 6 months post-3rd RG1-VLP vaccination/saline injection or up to 14 days post-3rd Gardasil-9 vaccination.

Official Title
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A Dose Escalation Phase I Trial of the Safety and Immunogenicity of RG1-VLP, a Candidate Broadly Protective Vaccine for the Prevention of HPV-Associated Cancer

Conditions
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Human Papillomavirus-Related Carcinoma

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Biological: HPV16 RG1 VLP Vaccine
* Other: Questionnaire Administration
* Biological: Recombinant Human Papillomavirus Nonavalent Vaccine
* Other: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women, age 18 - 45 years. Because no dosing or adverse event (AE) data is currently available for the use of RG1-VLP in humans, children and adolescents are excluded from this study White blood cell (WBC) between 3000/mm^3-institutional upper limit of normal Hemoglobin (Hgb) between 10 g/dl-institutional upper limit of normal Platelets >= 100,000/mm^3 Serum creatinine within institutional normal limits Bilirubin =< 2x institutional upper limit of normal Alanine aminotransferase (ALT) =< 2x institutional upper limit of normal Aspartate aminotransferase (AST) =< 2x institutional upper limit of normal Human immunodeficiency virus (HIV)-1/HIV-2 negative Hepatitis B and hepatitis C negative The effects of RG1-VLP vaccination on the developing human fetus at the proposed doses are unknown. For this reason, all women of childbearing potential will have a pregnancy test and all heterosexually active women must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and 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 study physician immediately The following persons are not considered to be able to bear children and are therefore eligible to participate without the use of concurrent birth control: Female with bilateral oophorectomy and/or hysterectomy Female with fallopian tubes cut, tied or sealed Female with sterilization implant (e.g. Adiana, Essure) placed > 3 months prior to randomization Female post-menopausal (> 1 year since last menses or prior laboratory follicle stimulating hormone (FSH) value per institutional range indicating post-menopausal) Eastern Cooperative Oncology Group (ECOG) performance status of =< 1 Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: History of any of the following: Prior or current genital warts For women 25 and older: any abnormal Pap smear and positive HPV deoxyribonucleic acid (DNA) test (if co-testing), or positive HPV DNA test (if primary HPV screening) Treatment for anogenital intraepithelial neoplasia (cervical intraepithelial neoplasia [CIN], anal intraepithelial neoplasia [AIN], vaginal intraepithelial neoplasia [VAIN], vulvar intraepithelial neoplasia [VIN]) Treatment for any cancer History of anaphylaxis to vaccines or fever > 100 degrees Fahrenheit (F) within 72 hours of vaccination Any prior vaccination with Gardasil, Gardasil-9, or Cervarix or other HPV vaccine Receipt of blood products within 3 months of enrollment, or continuing plasma donation Participants receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to the adjuvant or to RG1-VLP Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women or actively lactating women are excluded from this study because RG1-VLP is a vaccine with the potential for teratogenic or abortifacient effects Planned receipt of any inactivated vaccine in the 2 weeks preceding and the 2 weeks following any trial vaccination Planned receipt of any live attenuated vaccine in the 4 weeks preceding and the 4 weeks following any trial vaccination Women with a history of bleeding disorders or use of anticoagulants (aspirin is acceptable) Had prior medical conditions: Rheumatoid arthritis or other auto-immune disease Congenital or acquired immunodeficiency Collagen vascular disease Following medical treatments: Current use of immunosuppressive drugs including corticosteroid use (inhaled or topical steroids are permitted)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (RG1-VLP, Gardasil-9)<br>Patients receive RG1-VLP IM for 3 doses at months 0, 2, and 6 in the absence of disease progression or unacceptable toxicity. Patients may also receive Gardasil-9 via injection for 3 doses at 6 months after the 3rd study vaccination (month 12), then at months 14 and 18 in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection on study and may undergo vaginal swab collection on study. | Procedure: Biospecimen Collection<br>* Undergo blood sample and vaginal swab collection<br>* Other names: Specimen Collection;Biological: HPV16 RG1 VLP Vaccine<br>* Given IM<br>* Other names: RG1-VLPs;Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Recombinant Human Papillomavirus Nonavalent Vaccine<br>* Given via injection<br>* Other names: Recombinant Human Papillomavirus 9-valent Vaccine;|
| Placebo Comparator: Arm II (saline placebo, Gardasil-9)<br>Patients receive saline placebo IM for 3 doses at months 0, 2, and 6 in the absence of disease progression or unacceptable toxicity. Patients may also receive Gardasil-9 via injection for 3 doses at 6 months after the 3rd saline injection (month 12), then at months 14 and 18 in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection on study and may undergo vaginal swab collection on study. | Procedure: Biospecimen Collection<br>* Undergo blood sample and vaginal swab collection<br>* Other names: Specimen Collection;Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Recombinant Human Papillomavirus Nonavalent Vaccine<br>* Given via injection<br>* Other names: Recombinant Human Papillomavirus 9-valent Vaccine;Other: Saline<br>* Given IM<br>* Other names: Sodium Chloride 0.9%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Safety of the three escalating doses of RG1-VLP will be assessed by adverse events in terms of severity grade and attribution to vaccination as ordinal outcomes. All toxicities will be tabulated and frequencies and percentages of events will be presented for each vaccine dose cohort. The severity of the adverse events will be assessed using the Common Terminology Criteria for Adverse Events 5.0 and supplemented by Food and Drug Administration Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials. | Up to 6 months post-3rd RG1-virus-like particle (VLP) vaccination/saline injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of serum antibody responses to both human papillomavirus (HPV)16 L1 VLP and to HPV16 L2 | Will be tested for IgG against HPV16 L1 using a VLP-based enzyme-linked immunosorbent assay (ELISA). The HPV16 L2 17-36 peptide will be synthesized and used for an L2 ELISA. A dose response relationship for log antibody response will be tested with a linear mixed model. Will be summarized with frequency and relative frequencies along with 95% confidence intervals by time, vaccine dose group, and visit. As appropriate, Jonckheere-Terpstra or Cochran-Armitage tests will be used to test for dose-response relationships. | At months 0, 1, 2, 3, 6, 7, and 12 | 
| Determination of whether vaccination-induced serum antibody response neutralizes HPV16 | In vitro HPV pseudovirion (PsV) neutralization assays will be performed for HPV16 and HPV18 and additional PsV types requested by the National Cancer Institute, using an assay specifically developed for sensitivity to L2-specific as well as L1-specific neutralizing antibodies. A dose response relationship with serum neutralizing antibody titer will be tested with linear mixed models or Jonckheere-Terpstra tests as appropriate. Will be summarized with frequency and relative frequencies along with 95% confidence intervals by time, vaccine dose group, and visit. As appropriate, Cochran-Armitage tests will be used to test for dose-response relationships. | At months 0, 1, 2, 3, 6, 7, and 12 |