Intensive Locoregional Chemoimmunotherapy, Intradermal Autologous Alpha-DC1 Vaccines, and Systemic Pembrolizumab for Advanced-Stage Ovarian Cancer

Официальное название

A Phase 2 Efficacy Trial of Intensive Locoregional Chemoimmunotherapy, Intradermal Autologous Alpha-DC1 Vaccines, and Systemic Pembrolizumab for Advanced-Stage Ovarian Cancer

Обзор

This trial proposes to evaluate the immunologic and potential clinical effectiveness of intensive locoregional sequential intraperitoneal (IP) cisplatin (IPC) with intravenous (iv) paclitaxel followed by peritoneal infusion of a chemokine modulatory (CKM) regimen composed of a cocktail of IP rintatolimod and interferon-alpha (IFNα) for patients with advanced stage ovarian cancer (III-IV) in the primary neoadjuvant setting. It was previously determined the tolerable dose of IPC-CKM. This study will add intradermal (ID) autologous αDC1 vaccines (known to be nontoxic) to the tolerable IPC-CKM regimen and systemic Keytruda (pembrolizumab). To optimize the pattern of immunity, all patients will also receive oral celecoxib (COX2 inhibitor).

Подробное описание

In addition to its typically late detection, the difficulty in treating OvCa results from its particular adeptness at avoiding immune elimination. Several vaccine trials targeting ovarian cancer have recently reported a lack of efficacy with vaccine only approaches. OvCa cells have been reported to display numerous defects in their MHC class I antigen-presenting capacity, involving loss of HLA alleles and loss of the molecules involved in the generation of antigenic peptides. In addition to these passive mechanisms of immune subversion, OvCa employs a series of active suppressive mechanisms, involving the suppression of endogenous immune cells and innate immune response pathways, and a particularly high ability to attract regulatory T cells (Tregs), mediated by elevated expression of CXCL12 and CCL22 2. It is suspected that massive chemotherapy-induced apoptosis may further promote this modulation by enhancing local immunity. These considerations suggest that effective immunotherapies of OvCa may need to involve countermeasures to both these modes (passive and active) of immune subversion. Since αDC1-induced CD8+ T cells express particularly high levels of the typical CTL-associated chemokine receptors (CXCR3 and CCR5), the therapeutic benefit of αDC1 vaccination is likely to be enhanced by the CKM therapies, able of selectively enhancing CXCL10 (and other CXCR3 ligands) as well as CCR5 ligands, such as CCL5/RANTES, in order to promote the entry of the vaccination-induced effector cells to tumor tissue.

Вмешательства

• Препарат Paclitaxel
  A chemotherapy for cancer patients that interferes structures that help move chromosomes during cell division, thus stabilizing these structures to prevents cancer cells from dividing and ultimately causing them to die. Dose: 175 mg/m\^2 IV on D1 each cycle during neoadjuvant and adjuvant periods.
• Препарат Cisplatin
  An alkylating agent that contains platinum, which binds to DNA in cancer cells, causing cross-links that prevent DNA replication and repair, leading to cell death, particularly in rapidly dividing cancer cells. Dose: 75 mg/m\^2 IP / 1 hour on D1 of each cycle during neoadjuvant and adjuvant treatment periods.
• Препарат Bioferon
  Inhibits replication of a wide range of RNA and DNA viruses and exerts antiproliferative effects on malignant cells. It suppresses antibody formation through an effect on B-lymphocytes and inhibits onset of delayed hypersensitivity. Dose:6 milli on units/100 mL IP over 30-60 minutes on D2 of each cycle during neoadjuvant and adjuvant treatment. D1 during maintenance treatment periods.
• Препарат Rintatolimod
  A synthetic double-stranded RNA that selectively activates Toll-like Receptor 3 (TLR3), triggering antiviral and immunomodulatory responses, priming the immune system without causing excessive inflammation. Dose: 200 mg IP over 1-2 hours on D2 of each cycle during the neoadjuvant and adjuvant treatment periods. D1 during maintenance treatment periods
• Биопрепарат αDC1 Vaccine
  Autologous tumor-loaded alpha-DC1 vaccine is the new type of dendritic cell vaccine developed by our group, are the serum-free, clinically-applicable version of type-1 polarized DCs, combining a fully-mature phenotype and high expression of co-stimulatory molecules with an elevated, rather than exhausted, ability to produce IL-12p70. Dose: 6 million dendritic cells (reduced or omitted if insufficient vaccine material), ID injection on rotating sides of lower extremities on D2 each cycle during
• Препарат Pembrolizumab
  Humanized monoclonal antibody and a PD-1 inhibitor used in cancer immunotherapy that differs from chemotherapy as it does not directly kill cancer cells but stimulates the immune system, particularly T-cells, to recognize and attack cancer cells more effectively. Dose: 200 mg IV / 30 minutes on D2 of each cycle during neoadjuvant treatment period (none last neoadjuvant cycle), then optional on D2 for adjuvant treatment cycles, and on D1 of maintenance cycles
• Препарат Celecoxib
  A COX-2 inhibitor in the class of nonsteroidal anti-inflammatory drugs (NSAIDs) that specifically target the cyclooxygenase-2 (COX-2) enzyme, which plays a key role in inflammation Dose: 200mg/day, orally twice a day for days 1-5 and once a day for days 6-21 of neoadjuvant and adjuvant treatment cycles, and then twice a day on D1 and once a day for days 2-21 for maintenance cycles
• Процедура Debulking Procedure
  A surgical procedure designed to remove the majority of cancerous tumors when complete removal may not be feasible, with the goal of reducing tumor burden, making follow-up treatments like chemotherapy or radiation more effective. Surgery occurs in between the neoadjuvant and adjuvant treatment periods.

Первичные конечные точки

• Dose Limiting Toxicities (DLT) [Срок оценки: Up to 2 months]
• Complete Pathologic Response (pCR) [Срок оценки: Up to 5 years]

Вторичные конечные точки (5)

• Treatment-related Adverse Events (AEs) and Serious Adverse Events (SAEs) [Срок оценки: Up to 14 months]
• 12-month Progression-free Survival (PFS) [Срок оценки: At 12 months]
• 18-month Progression-free Survival (PFS) [Срок оценки: At 18 months]
• Progression-free Survival (PFS) [Срок оценки: Up to 5 years]
• Overall Survival (OS) [Срок оценки: Up to 7 years]

Критерии участия

Критерии включения

• Patients must have advanced stage (III-IV) epithelial carcinoma or carcinosarcoma of ovarian, tubal or peritoneal origin.

a. Histologic documentation of the original primary tumor is required via a pathology report.

• Patients must be eligible for cancer-related definitive therapy with neoadjuvant chemotherapy.
• Patients must be chemo-naive and receiving therapy in primary first-line neoadjuvant setting.
• Patients must have ECOG performance of 0-1.
• Patients must be reasonable candidate for interval debulking surgery as well as for IP platinum-based combination chemotherapy regimen, with no prior evidence of clinically significant intra-abdominal adhesions, persistent abdominal wall infections, renal disease or bowel obstruction.
• At least one lesion must be considered to be large enough for biopsy and resection to yield greater than 2 grams of tumor for tumor loading of αDC1's and immunoassays at the discretion of the treating investigator and/or surgeon.
• Patients must have measurable disease per iRECIST criteria.
• Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception prior to study entry, during the course of the study, and for the following durations after the last dose of treatment (whichever is later). An additional contraceptive method, such as a barrier method (e.g., condom), is required. In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods.
• Female subjects of childbearing potential must not be pregnant or breastfeeding at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met:

a. Permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other biological or physiological causes). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff.

• Patients must be willing to undergo leukapheresis.
• Patients must be willing to adhere to protocol requirements.
• Patients must have adequate:

• Bone marrow function:

• Absolute neutrophil count (ANC) greater than or equal to 1,500/μL
• Platelets greater than or equal to 100,000/μL
• Hemoglobin greater than or equal to 8.0 g/dL
• Renal function:

\- Creatinine less than or equal to 1.5 x institutional upper limit normal (ULN)

• Hepatic function:

• Bilirubin less than or equal to 1.5 x ULN
• SGOT and alkaline phosphatase less than or equal to 2.5 x ULN
• Patients who have signed informed consent and authorization permitting release of personal health information.
• Patients must be ≥ 18 years of age.
• Patient must be able to swallow oral medication and have no absorption related medical concern as deemed by the investigator.

Критерии исключения

• Patients with sarcoma.
• Patients who have an active autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's Disease, multiple sclerosis (MS), ankylosing spondylitis).
• Patients with a known allergy to cisplatin or taxane chemotherapy. Patients with carboplatin allergy may be included if they tolerate a test dose of IV cisplatin given in monitored floor conditions. Patients who are allergic to paclitaxel can be alternatively treated with abraxane.
• Patients being chronically treated with immunosuppressive drugs such as cyclosporin, adrenocorticotropic hormone (ACTH), or systemic corticosteroids.

a. Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Principal Investigator confirmation has been obtained.

• Patients with a recognized immunodeficiency disease including cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia; patients who have acquired, hereditary, or congenital immunodeficiencies.
• Patients with uncontrolled diseases other than cancer will be excluded.
• Patients who have contraindications to the use of NSAID's like chronic renal failure, coronary artery disease, or bleeding ulcers.
• Patients who have contraindications to the use of interferon α-2b (Bioferon), including hypersensitivity to interferon-α or any component of the product, autoimmune hepatitis, and decompensated liver disease.
• Patients with tumors of low malignant potential, except ovarian pseudomyxoma or with no peritoneal disease.
• Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the last five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol therapy.
• Patients with previous pelvic radiation therapy.

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• UMPC Hillman Cancer Center — Pittsburgh

Идентификаторы

NCT: NCT07634094 · HCC 25-166

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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