HPV Vaccine, Imiquimod, and Metformin Combination Trial

Официальное название

A Phase 2 Study of HPV L1 Vaccine in Combination With Imiquimod and Metformin in Cervical, Vaginal, and Vulvar Cancers

Обзор

The goal of this clinical trial is to explore whether additional treatments can help strengthen the participant's immune system to fight cancer caused by the Human Papillomavirus (HPV), a virus spread through intimate skin-to-skin contact. The trial will also monitor the safety of these treatments. The main questions it aims to answer are: Does the combination of treatments help the participant's body fight the cancer more effectively when used alongside standard therapy? What side effects or medical issues arise when using these experimental treatments? Researchers will use three experimental therapies along with the participant's standard treatment to find out if these therapies work better together than standard treatment alone. Participants will: Receive HPV vaccinations during the 2nd and 4th week of radiation, and again at weeks 8, 10, 12, and 16 after completing radiation. Have blood samples taken, tumor cells brushed from the surface, and imiquimod cream applied during each visit. Take a daily metformin pill and apply an imiquimod suppository three times a week for two weeks after each visit.

Подробное описание

The goal of this clinical trial is to determine whether stimulating tumor immunity through sequential, targeted intratumoral vaccinations using the FDA-approved quadrivalent HPV-L1 antigen vaccine, in combination with chemotherapy, radiotherapy, pembrolizumab, imiquimod, and metformin, improves outcomes for patients with locally advanced cervical, vaginal, or vulvar carcinoma. The primary objective is to assess the impact of this approach on 24-month progression-free survival when used alongside whole pelvic radiotherapy, chemotherapy, and brachytherapy.

The trial will also monitor the safety and potential side effects of combining intratumoral HPV vaccination with topical imiquimod and oral metformin during and after chemoradiation. Additionally, researchers aim to evaluate specific immune markers to understand how these treatments boost the immune system and enhance the effects of standard care.

Participants will:

Receive intratumoral HPV vaccinations during the 2nd and 4th week of radiation, and after completing radiation at weeks 8, 10, 12, and 16.

Have blood samples taken, tumor cells brushed, and imiquimod cream applied during each visit.

Take a daily metformin pill and apply an imiquimod suppository three times a week for two weeks after each visit.

Throughout the trial, immune biomarker assays will be conducted at the beginning, middle, and end of treatment to measure markers such as CD4, CD8, NK, TNF alpha and beta, IL2, HPV viral load, TGF Beta, Ki67, and IgG. Blood tests will also be done for IgG L1 and L2, E6 and E7, and a CBC, to track immune changes across the three treatment groups.

Вмешательства

• Препарат HPV vaccine, Imiquimod, and metformin combination therapy
  Participants in the treatment arm will have visits during the 2nd and 4th weeks of radiation, and then at weeks 8, 10, 12, and 16 after radiation. At each visit, a blood sample will be taken, and tumor cells collected using a cytobrush (or directly from the tumor for vulvar cancer). An HPV vaccine will be injected into the tumor, imiquimod cream will be applied topically, and participants will receive a subcutaneous vaccine shot. They will also take metformin tablets twice daily for two weeks an

Первичные конечные точки

• Progression free survival [Срок оценки: 24 months]

Вторичные конечные точки (2)

• Common Toxicity Criteria (CTC) [Срок оценки: 24 months]
• Identify Immune changes [Срок оценки: 24 months]

Критерии участия

Критерии включения

• Participants must have histologically confirmed locally advanced or metastatic cervical carcinoma (Stage IB2-IVB), vaginal, or vulvar carcinoma (Stage II-IVB), AND not be considered a primary surgical candidate. Patients offered neoadjuvant therapy may be enrolled if they respond and receive chemoradiation.
• Participants must have measurable disease, per Recist criteria. See Section 12 (Measurement of Effect) for the evaluation of measurable disease. Radiological evaluation shall occur within approximately 30 days prior to enrollment initiation and start of radiation.
• Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Participants must be ≥ 18 years of age
• Participants must have adequate organ function within 28 days of registration, defined as follows: - Absolute neutrophil count ≥ 1,500/µL - Platelets ≥ 100,000/µL - Hemoglobin ≥ 9 g/dL - Serum creatinine ≤ 1.5 x upper limit of normal (ULN) - Total bilirubin ≤ 1.5 x ULN (≤2.0 in patients with known Gilberts syndrome) OR direct bilirubin ≤ 1 x ULN - Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN unless liver metastases are present, in which case they must be ≤ 5 x ULN
• Participants receiving corticosteroids may continue as long as their dose is stable for at least 4 weeks prior to initiating protocol therapy.
• Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.
• Female participants of childbearing potential must have a negative serum pregnancy test within 14 days prior to registration. Females of non-childbearing potential is defined as follows (by other than medical reasons): - ≥45 years of age and has not had menses for \>1 year, post-hysterectomy, post-bilateral oophorectomy, post external beam radiation of 6 Gy to the pelvis, or post-tubal ligation.
• Participants must agree to not breastfeed during the study.
• Participants must be able to understand the study procedures and agree to participate in the study by providing written informed consent
• Participants must be eligible for chemoradiation treatment in the opinion of the treating investigator.
• Participants who are HIV+ must have CD4 counts \>200/dL and demonstrate documented Highly active antiretroviral therapy (HAART) compliance m. Participant must have CT (chest/abdomen/pelvis) or PET-CT, within 56 days of registration.
• Participants must be newly diagnosed.
• Standard chemoradiation using external beam radiation therapy (EBRT) and brachytherapy is permitted for cervical or vaginal carcinoma, and chemoradiation with EBRT for vulvar carcinoma. A lesion must be readily accessible for intratumoral tumor injection.
• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

Критерии исключения

• Patients who are receiving any other investigational agents.
• Patients who have untreated, new or progressive brain metastases or leptomeningeal disease.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in study.
• Patients with uncontrolled intercurrent illness.
• Patients with psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because cervical carcinoma or vulva carcinoma patients have undergone treatment rendering the patient infertile. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cervical carcinoma or vulva carcinoma, breastfeeding should be discontinued.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 2 центра

• Baylor St. Luke's Medical Center- Dan L. Duncan Comprehensive Cancer Center — Houston
• Harris Health Smith Clinic — Houston

Публикации

• Tantipalakorn C, Robertson G, Marsden DE, Gebski V, Hacker NF. Outcome and patterns of recurrence for International Federation of Gynecology and Obstetrics (FIGO) stages I and II squamous cell vulvar cancer. Obstet Gynecol. 2009 Apr;113(4):895-901. doi: 10.1097/AOG.0b013e31819b413f. PMID 19305336
• Reedy M, Jonnalagadda S, Palle K. Case Report: Intra-Tumoral Vaccinations of Quadrivalent HPV-L1 Peptide Vaccine With Topical TLR-7 Agonist Following Recurrence: Complete Resolution of HPV-HR-Associated Gynecologic Squamous Cell Carcinomas in Two Patients. Pathol Oncol Res. 2021 Dec 20;27:1609922. doi: 10.3389/pore.2021.1609922. eCollection 2021. PMID 34987310
• Mondini M, Nizard M, Tran T, Mauge L, Loi M, Clemenson C, Dugue D, Maroun P, Louvet E, Adam J, Badoual C, Helley D, Dransart E, Johannes L, Vozenin MC, Perfettini JL, Tartour E, Deutsch E. Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer. Mol Cancer Ther. 2015 Jun;14(6):1336-45. doi: 10.1158/1535-7163.MCT-14-1015. Epub 2015 Apr 1. PMID 25833837
• Mu J, Lei L, Zheng Y, Li D, Li J, Fu Y, Wang G, Liu Y. Comparative study of subcutaneous, intramuscular, and oral administration of bovine pathogenic Escherichia coli bacterial ghost vaccine in mice. Front Immunol. 2022 Nov 14;13:1008131. doi: 10.3389/fimmu.2022.1008131. eCollection 2022. PMID 36451816
• Afzal MZ, Mercado RR, Shirai K. Efficacy of metformin in combination with immune checkpoint inhibitors (anti-PD-1/anti-CTLA-4) in metastatic malignant melanoma. J Immunother Cancer. 2018 Jul 2;6(1):64. doi: 10.1186/s40425-018-0375-1. PMID 29966520
• Wu Z, Zhang C, Najafi M. Targeting of the tumor immune microenvironment by metformin. J Cell Commun Signal. 2022 Sep;16(3):333-348. doi: 10.1007/s12079-021-00648-w. Epub 2021 Oct 5. PMID 34611852
• Ma R, Yi B, Riker AI, Xi Y. Metformin and cancer immunity. Acta Pharmacol Sin. 2020 Nov;41(11):1403-1409. doi: 10.1038/s41401-020-00508-0. Epub 2020 Aug 31. PMID 32868904
• Tselikas L, Dardenne A, de Baere T, Faron M, Ammari S, Farhane S, Suzzoni S, Danlos FX, Raoult T, Susini S, Al Shatti N, Mouraud S, Deschamps F, Kobe A, Delpla A, Roux C, Baldini C, Soria JC, Barlesi F, Massard C, Robert C, Champiat S, Marabelle A. Feasibility, safety and efficacy of human intra-tumoral immuno-therapy. Gustave Roussy's initial experience with its first 100 patients. Eur J Cancer. PMID 35724442

Идентификаторы

NCT: NCT06686043 · H-54674

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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