Phase I/II Study to Test the Immunogenicity, Feasibility, and Safety of Autologous PEP-DC Vaccine vs. Autologous OC-DC Vaccine Followed by PEP-DC Vaccine, in Combination With Low-dose Cyclophosphamide, in Patients With Advanced HGSOC
Overview
- Phase
- Phase 1
- Intervention
- PEP-DC1
- Conditions
- Ovarian Carcinoma
- Sponsor
- Centre Hospitalier Universitaire Vaudois
- Enrollment
- 16
- Primary Endpoint
- Immunogenicity of OC-DC + PEP-DC vaccine vs. PEP-DC vaccine
- Status
- Withdrawn
- Last Updated
- last year
Overview
Brief Summary
Single center, phase I/II randomized 2-arm study, evaluating two different vaccination regimens combined with low-dose cyclophosphamide in patients with advanced high grade serous ovarian carcinoma (HGSOC):
- Arm A patients will be vaccinated with a personalized peptide vaccine comprised of autologous monocyte-derived dendritic cells (moDC) loaded with patient-specific peptides (PEP-DC1 vaccine) identified a priori at screening (8 patients);
- Arm B patients will be vaccinated with a personalized tumor lysate vaccine comprising autologous moDC loaded with patient-specific autologous oxidized tumor lysate (OC-DC vaccine), followed by PEP-DC2 vaccine comprised of autologous moDC loaded with up to 10 patient-specific peptides identified midway through OC-DC vaccination (8 patients).
In both arms, patients will receive a low dose cyclophosphamide the day before vaccination. Patients will be vaccinated after the end of adjuvant platinum-based chemotherapy, until vaccine exhaustion, disease recurrence, major toxicity or patient withdrawal, whichever is earlier.
Detailed Description
This will be a single center, Phase I/II randomized, two-arm, open-label study to evaluate immunogenicity, safety, and feasibility of two different vaccination regimens combined with low-dose cyclophosphamide in patients with surgically resected, advanced HGSOC. Patients with HGSOC at International Federation of Gynecology and Obstetrics (FIGO) stage III or IV who completed either primary debulking surgery (PDS) or interval debulking surgery (IDS) without residual disease (R0) and who have received at least 6 cycles of adjuvant standard of care (SOC) platinum-based chemotherapy after PDS, or 3 cycles of platinum-based perioperative chemotherapy within an IDS will be eligible for this protocol. A total of 16 patients (8 patients in each arm) will be randomized 1:1 as follows: * In arm A, patients will receive PEP-DC1 vaccine comprising autologous dendritic cells pulsed with personalized peptides detected or predicted a priori (using our current integrated antigen identification methodologies). * In arm B, patients will receive first, the OC-DC vaccine, an autologous dendritic cell vaccine loaded with autologous oxidized tumor lysate. Then, tumor antigens specifically recognized by the patients' immune response induced by OC-DC vaccination will be identified/predicted using integrated methodologies to enable production of PEP-DC2 vaccine (autologous dendritic cells pulsed with the peptides detected or predicted after vaccination with OC-DC). Finally, patients will be vaccinated with the personalized PEP-DC2 to continue maintenance vaccination. In both arms, vaccines will be administered to the patients in combination with low dose cyclophosphamide the day before vaccination. Patients will be vaccinated in the adjuvant setting, with first vaccine injected no more than 18 weeks after the end of SOC platinum-based chemotherapy. Patients will be vaccinated until vaccine exhaustion (which may happen any time after dose 6), disease recurrence, major toxicity or patient withdrawal, whichever is earlier.
Investigators
Dr. Apostolos Sarivalasis, MD
Associate Physician
Centre Hospitalier Universitaire Vaudois
Eligibility Criteria
Inclusion Criteria
- •Signed Informed Consent Form
- •Histologically confirmed diagnosis of advanced, FIGO stage III or IV, high grade serous ovarian carcinoma (HGSOC)
- •Underwent PDS or IDS without macroscopic residual disease, (R0)
- •a. Received at least 3 cycles of peri-operative platinum-based chemotherapy before IDS, with the intention to complete at least 6 cycles of peri-operative platinum-based chemotherapy.
- •OR b. Has completed 6 cycles of adjuvant platinum-based chemotherapy after PDS. In case of toxicity prohibiting 6 cycles of adjuvant platinum-based chemotherapy, a minimum of 4 cycles are required.
- •Tumor material is available and sufficient for both OC-DC preparation and identification of Top 10 personalized peptides (PEPs) required for PEP-DC vaccine preparation.
- •Age ≥18 years.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Willing and able to comply with study procedures
- •Has adequate hematologic and end organ function (kidney, liver and bone marrow), defined by the following laboratory results (complete blood count (CBC), enzyme tests) obtained within 14 days prior to randomization:
Exclusion Criteria
- •A secondary debulking surgery is foreseen.
- •Prior exposure to anti-Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) and anti-Programmed cell Death 1 (PD1) / anti-Programmed cell Death Ligand (PD-L1) antibodies or other immunotherapy.
- •Woman of child-bearing potential (WOCBP). By definition, all patients with HGSOC of FIGO stage III to IV who have undergone PDS or IDS, will have undergone total hysterectomy with bilateral salpingo-oophorectomy, and will therefore be women without child-bearing potential. Therefore, no pregnancy tests have to be performed because no WOCBP will be enrolled in this trial.
- •Breastfeeding women
- •Other malignancy within 2 years prior to randomization, except for those (for example ductal carcinoma in situ of breast and cervical intraepithelial neoplasia) treated with curative intent. Patients with a predicted 5-year recurrence-free survival rate ≥95% can be included at the investigator's discretion.
- •Patients with diagnosis of paraneoplastic syndrome.
- •Current, recent (within 4 weeks prior to randomization), or planned participation in an experimental drug study.
- •Patient has a serious, non-healing wound, ulcer, or bone fracture.
- •Patients with Glucose-6-phosphate dehydrogenase (G6PD) deficiency are excluded. Patients with high bleeding risk or any other hereditary coagulation disorder can be enrolled after careful evaluation, at principal investigator (PI)'s discretion.
- •Past history with cardiac or vascular problems:
Arms & Interventions
Arm A - PEP-DC1 + low dose cyclophosphamide
In arm A, patients will receive PEP-DC1 vaccine in combination with low dose cyclophosphamide.
Intervention: PEP-DC1
Arm A - PEP-DC1 + low dose cyclophosphamide
In arm A, patients will receive PEP-DC1 vaccine in combination with low dose cyclophosphamide.
Intervention: Low dose cyclophosphamide
Arm B - OC-DC + low dose cyclophosphamide followed by PEP-DC2 + low dose cyclophosphamide
In arm B, patients will receive first, the OC-DC vaccine in combination with low dose cyclophosphamide, then PEP-DC2 vaccine in combination with low dose cyclophosphamide. Finally, patients will be vaccinated with the personalized PEP-DC2 to continue maintenance vaccination.
Intervention: OC-DC
Arm B - OC-DC + low dose cyclophosphamide followed by PEP-DC2 + low dose cyclophosphamide
In arm B, patients will receive first, the OC-DC vaccine in combination with low dose cyclophosphamide, then PEP-DC2 vaccine in combination with low dose cyclophosphamide. Finally, patients will be vaccinated with the personalized PEP-DC2 to continue maintenance vaccination.
Intervention: PEP-DC2
Arm B - OC-DC + low dose cyclophosphamide followed by PEP-DC2 + low dose cyclophosphamide
In arm B, patients will receive first, the OC-DC vaccine in combination with low dose cyclophosphamide, then PEP-DC2 vaccine in combination with low dose cyclophosphamide. Finally, patients will be vaccinated with the personalized PEP-DC2 to continue maintenance vaccination.
Intervention: Low dose cyclophosphamide
Outcomes
Primary Outcomes
Immunogenicity of OC-DC + PEP-DC vaccine vs. PEP-DC vaccine
Time Frame: through study completion, an average of 7 years
The number of personalized tumor antigen (PTAs) ranked as Top 100 will be identified for each patient before and after treatment and the difference will be compared between the two arms at least at two time-points, first at the end of the 3rd cycle (C3W3), and second, at end of treatment (EOT) visit (if possible at C6W4-W6 also). Specifically, an immunogenicity scoring will be determined as follows: for each of the 100 pre-determined top PTAs, a score will indicate how many peptides either become newly detected (shift from undetectable to detectable) or have a magnitude (frequency of T-cell directed against the epitope) increased by ≥ 2 fold.
Secondary Outcomes
- Feasibility of vaccines production and administration in each arm(3 years after study activation)
- Assessment of adverse events in each treatment arm(From signature of informed consent form (ICF) until 30 days after the last treatment (vaccine/cyclophosphamide))
- Time to progression (TTP)(5 years)
- Disease free survival (DFS) rate(Evaluated at 12, 24, and 36 months)
- Overall survival (OS)(Evaluated at 5 years)