This early phase I trial studies the side effects of autologous dendritic cells and a vaccine called Prevnar in combination with immune checkpoint inhibition (with bevacizumab and atezolizumab or atezolizumab and tiragolumab) in treating patients liver cancer that cannot be removed by surgery (unresectable) after undergoing standard high-dose external beam radiotherapy. Autologous dendritic cells are immune cells generated from patients' own white blood cells that are grown in a special lab and trained to stimulate the immune system to destroy tumor cells. A pneumonia vaccine called Prevnar may also help stimulate the immune system. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Immunotherapy with monoclonal antibodies, such as atezolizumab and tiragolumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving autologous dendritic cells and Prevnar in combination with immune checkpoint inhibition after radiotherapy may be safe, and tolerable and may stimulate the body's own immune system to fight against the tumor in patients with unresectable liver cancer.
PRIMARY OBJECTIVE: I. Evaluation of safety and tolerability of an autologous dendritic cell (DC) vaccine delivered by intra-tumoral injection in patients with primary liver cancer treated with high-dose conformal external beam radiotherapy (EBRT). (Pilot Study) II. Estimate the progression-free survival rate at 2 years post-registration to see if treatment is efficacious compared to historical data in hepatocellular carcinoma (HCC). (Phase II Group 2) II. Estimate the progression-free survival to see if treatment is efficacious compared to historical data in intrahepatic cholangiocarcinoma (iCCA) patients. (Phase II Group 3) SECONDARY OBJECTIVES: I. To assess feasibility in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection by group (Group 1 versus \[vs.\] 2 vs. 3). II. To assess overall response rate in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection by group (Group 1 vs. 2 vs. 3). III. To assess progression free survival in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection by group (Group 1 vs. 2 vs. 3). IV. To assess clinical benefit rate in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection by group (Group 1 vs. 2 vs. 3). V. To assess time to response in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection by group (Group 1 vs. 2 vs. 3). VI. To assess duration of response in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection by group (Group 1 vs. 2 vs. 3). VII. To assess overall survival in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection by group (Group 1 vs. 2 vs. 3). RADIOLOGIC STUDY OBJECTIVE: I. To assess the radiologic response over time of primary liver tumors treated with high-dose conformal EBRT followed by autologous DC vaccine injection by group (Group 1 vs. 2 vs. 3). CORRELATIVE RESEARCH OBJECTIVES: I. To monitor patients' immune response after vaccine therapy by group (Group 1 vs. 2 vs. 3). II. To assess the immune response to pneumococcal 13-valent conjugate vaccine (Prevnar) and similar pneumococcal vaccines by group (Group 1 vs. 2 vs. 3). OUTLINE: PILOT STUDY (GROUP I) (CLOSED WITH AMENDMENT 3): Patients with unresectable intrahepatic cholangiocarcinoma (CCA) undergo apheresis for dendric cell manufacturing and standard of care high-dose EBRT for 5 or 15 fractions over 1-3 weeks (cycle 1). Patients then receive autologous dendritic cells intratumorally (IT) on day 1 of cycles 2-8 and pneumococcal 13-valent conjugate vaccine intramuscularly (IM) on day 1 of cycles 2-4 only. Treatment repeats every 28 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity. PHASE II STUDY (GROUP II): Patients with unresectable HCC undergo apheresis for dendric cell manufacturing and standard of care high-dose EBRT for 5 or 15 fractions over 1-3 weeks (cycle 1). Patients then receive autologous dendritic cells IT on day 1 of cycles 2-8 and pneumococcal 13-valent conjugate vaccine or other pneumococcal vaccine IM on day 1 of cycles 2-4 only. Patients also receive standard of care atezolizumab intravenously (IV) over 30-60 minutes and bevacizumab IV over 30-90 minutes starting on day 2 of cycles 2-8. Treatment repeats every 21 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo an esophagogastroduodenoscopy (EGD) at screening and CT, PET/CT and/or MRI, biopsy and urine and blood sample collection throughout the study. PHASE II STUDY (GROUP III): Patients with iCCA undergo apheresis for dendric cell manufacturing and standard of care high-dose EBRT for 5 or 15 fractions over 1-3 weeks (cycle 1). Patients then receive autologous dendritic cells IT on day 1 of cycles 2-8 and pneumococcal 13-valent conjugate vaccine or other pneumococcal vaccine IM on day 1 of cycles 2-4 only. Patients also receive standard of care atezolizumab IV over 30-60 minutes and tiragolumab IV over 30-60 minutes starting on day 2 of cycles 2-8. Treatment repeats every 21 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo CT, PET/CT and/or MRI, biopsy and urine and blood sample collection throughout the study. After completion of study treatment, patients are followed up at 2 weeks and then every 3 months for 1 year (beginning at week 36 or 12 weeks after last autologous dendritic cell dose whichever is earlier). Patients are then followed every 3 months until disease progression, and then every 6 months until 5 years after registration.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
85
Given IV
Given IV
Undergo high-dose EBRT
Undergo apheresis
Given IM
Given IT
Given IV
Undergo EGD
Undergo CT or PET/CT
Undergo PET/CT
Undergo MRI
Undergo biopsy
Undergo urine and blood sample collection
Mayo Clinic in Rochester
Rochester, Minnesota, United States
RECRUITINGIncidence of significant toxicity (Pilot study)
A significant toxicity is defined as a dose limiting toxicity that is possibly, probably, or definitely related to dendritic cell (DC) treatment. Toxicities will be assessed using the Cancer Therapy Evaluation Program active version of the Common Terminology Criteria for Adverse Events.
Time frame: Up to completion of cycle 2 (each cycle is 28 days)
Progression-free survival rate at 2 years (Phase II)
Defined as the time from registration to disease progression or death due to all causes.
Time frame: At 2 years
PFS (Phase II Group 3)
Defined as the time from registration to disease progression or death due to all causes.
Time frame: Up to 5 years
Overall response rate
The overall response rate will be estimated by the number of patients with an objective status of complete response (CR) or partial response (PR) divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true overall response rate will be calculated.
Time frame: Up to 1 year post treatment
Number of patients who received at least one dose of intratumoral DC injection
The feasibility of the regimen will be estimated by the number of patients who received at least one dose of intratumoral DC injection divided by the total number of patients who received apheresis.
Time frame: Up to 1 year post treatment
Clinical benefit rate
The clinical benefit rate will be estimated by the number of patients with an objective status of stable disease or CR or PR at any time divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true clinical benefit rate will be calculate
Time frame: Up to 1 year post treatment
Time to response
Time to response is defined for all evaluable patients who have achieved an objective response as the date of initiation of vaccination treatment to the date at which the patient's objective status is first noted to be either a CR or PR. Time to response will be summarized descriptively using Kaplan-Meier methodology.
Time frame: Up to 1 year post treatment
Duration of response
Duration of response is defined for all evaluable patients who have achieved an objective response as the date at which the patient's objective status is first noted to be either a CR or PR to the earliest date progression is documented. Duration of response will be summarized descriptively using Kaplan-Meier methodology.
Time frame: Up to 1 year post treatment
Overall survival
Defined as the time from registration to death from any cause.
Time frame: Up to 5 years
Progression-free survival
Defined as the time from registration to disease progression or death due to all causes.
Time frame: Up to 5 years
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