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).
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
28
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.
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.
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.
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
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 the neoadjuvant (not C1) and adjuvant treatment periods. D1 of each cycle during maintenance period.
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
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
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.
UMPC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States
Dose Limiting Toxicities (DLT)
Proportion of patients in the safety cohort (chemoimmunotherapy combined with the αDC1 vaccine) experiencing a dose-limiting toxicity (DLT). A DLT will be any adverse event that is at least possibly related to the study treatment and prevents surgery or delays surgery by more than 4 weeks, or that prevents the initiation of the next cycle of treatment on schedule due to toxicity in the prior cycle. The DLT period will be 2 cycles of treatment.
Time frame: Up to 2 months
Complete Pathologic Response (pCR)
Percentage of patients who show no detectable cancer (cells) in tissue samples after neoadjuvant treatment as assessed at the time of the interval debulking procedure. Per RECIST v1.1, Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in SLD compared to baseline, confirmed on a follow-up scan.
Time frame: Up to 5 years
Treatment-related Adverse Events (AEs) and Serious Adverse Events (SAEs)
Number of patients who experience Adverse Events (AEs) and Serious Adverse Events (SAEs) least possibly related to treatment per CTCAE v 5.0.
Time frame: Up to 14 months
12-month Progression-free Survival (PFS)
Percentage of patients without disease progression per iRECIST at 12 months post treatment initiation. Per iRECIST, Progressive Disease (PD): At least a 20% increase in SLD from the nadir, with an absolute increase of ≥5 mm, or the appearance of any new lesion.
Time frame: At 12 months
18-month Progression-free Survival (PFS)
Percentage of patients without disease progression per iRECIST at 18 months post treatment initiation. Per iRECIST, Progressive Disease (PD): At least a 20% increase in SLD from the nadir, with an absolute increase of ≥5 mm, or the appearance of any new lesion.
Time frame: At 18 months
Progression-free Survival (PFS)
Median time from treatment initiation when 50% of patients have disease progression (per RECIST v1.1) or have died from any cause, whichever occurs first. Per RECIST v1.1, Progressive Disease (PD): At least a 20% increase in SLD from the nadir, with an absolute increase of ≥5 mm, or the appearance of any new lesion
Time frame: Up to 5 years
Overall Survival (OS)
Median time from treatment initiation when 50% of patients have died from any cause.
Time frame: Up to 7 years
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