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Modified Immune Cells (Autologous Dendritic Cells) and a Vaccine (Prevnar) After High-Dose External Beam Radiation Therapy in Treating Patients With Unresectable Liver Cancer

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ClinicalTrials.gov Identifier: NCT03942328
Recruitment Status : Recruiting
First Posted : May 8, 2019
Last Update Posted : June 14, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:
This early phase I trial studies the side effects of autologous dendritic cells and a vaccine called Prevnar in treating patients with liver cancer that cannot be removed by surgery 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. Giving autologous dendritic cells and Prevnar to patients with liver cancer after radiotherapy may help doctors determine if it is possible to stimulate the body's own immune system to fight against the tumor, and to see if this immune stimulation can be done safely.

Condition or disease Intervention/treatment Phase
Stage III Hepatocellular Carcinoma AJCC v8 Stage III Intrahepatic Cholangiocarcinoma AJCC v8 Stage IIIA Hepatocellular Carcinoma AJCC v8 Stage IIIA Intrahepatic Cholangiocarcinoma AJCC v8 Stage IIIB Hepatocellular Carcinoma AJCC v8 Stage IIIB Intrahepatic Cholangiocarcinoma AJCC v8 Stage IV Hepatocellular Carcinoma AJCC v8 Stage IV Intrahepatic Cholangiocarcinoma AJCC v8 Stage IVA Hepatocellular Carcinoma AJCC v8 Stage IVB Hepatocellular Carcinoma AJCC v8 Unresectable Hepatocellular Carcinoma Unresectable Intrahepatic Cholangiocarcinoma Radiation: External Beam Radiation Therapy Biological: Pneumococcal 13-valent Conjugate Vaccine Biological: Therapeutic Autologous Dendritic Cells Early Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

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).

SECONDARY OBJECTIVES:

I. To assess feasibility in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection.

II. To assess overall response rate in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection.

III. To assess progression free survival in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection.

IV. To assess clinical benefit rate in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection.

V. To assess time to response in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection.

VI. To assess duration of response in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection.

VII. To assess overall survival in patients with liver cancer treated with high-dose conformal EBRT followed by autologous DC vaccine injection.

RADIOLOGIC STUDY OBJECTIVES:

I. To assess the radiologic response over time of primary liver tumors treated with high-dose conformal EBRT followed by autologous DC vaccine injection.

CORRELATIVE RESEARCH OBJECTIVES:

I. To monitor patients? immune response after vaccine therapy. II. To assess the immune response to pneumococcal 13-valent conjugate vaccine (Prevnar).

OUTLINE:

Patients undergo 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 1-7, and pneumococcal 13-valent conjugate vaccine intramuscularly (IM) on day 1 of cycles 1-3 only. Treatment repeats every 28 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity.

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 26 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study of Intratumoral Injection of Dendritic Cells After High-Dose Conformal External Beam Radiotherapy in Patients With Unresectable Liver Cancer
Actual Study Start Date : May 17, 2019
Estimated Primary Completion Date : May 1, 2022
Estimated Study Completion Date : May 1, 2022


Arm Intervention/treatment
Experimental: Treatment (EBRT, autologous dendritic cells, Prevnar)
Patients undergo 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 1-7, and pneumococcal 13-valent conjugate vaccine IM on day 1 of cycles 1-3 only. Treatment repeats every 28 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity.
Radiation: External Beam Radiation Therapy
Undergo high-dose EBRT
Other Names:
  • Definitive Radiation Therapy
  • EBRT
  • External Beam Radiotherapy
  • External Beam RT
  • external radiation
  • External Radiation Therapy
  • external-beam radiation

Biological: Pneumococcal 13-valent Conjugate Vaccine
Given IM
Other Names:
  • PCV 13
  • PCV13 Vaccine
  • Prevnar 13

Biological: Therapeutic Autologous Dendritic Cells
Given IT




Primary Outcome Measures :
  1. Incidence of significant toxicity [ Time Frame: Up to 1 year post treatment ]
    A significant toxicity is defined as a dose limiting toxicity that is possibly, probably, or definitely related to DC treatment. Toxicities will be assessed using the Cancer Therapy Evaluation Program active version of the Common Terminology Criteria for Adverse Events.


Secondary Outcome Measures :
  1. Overall response rate [ Time Frame: Up to 1 year post treatment ]
    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.

  2. Number of patients who received at least one dose of intratumoral DC injection [ Time Frame: Up to 1 year post treatment ]
    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.

  3. Clinical benefit rate [ Time Frame: Up to 1 year post treatment ]
    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

  4. Time to response [ Time Frame: Up to 1 year post treatment ]
    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.

  5. Duration of response [ Time Frame: Up to 1 year post treatment ]
    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.

  6. Overall survival [ Time Frame: From registration to death from any cause, assessed up to 5 years after registration ]
    Kaplan-Meier methodology will be used to estimate the survival over time.

  7. Progression-free survival [ Time Frame: From registration to the first of either disease progression or death from any cause, assessed up to 5 years after registration ]
    Kaplan-Meier methodology will be used to estimate the progression-free survival over time.


Other Outcome Measures:
  1. Change in target lesion measurements [ Time Frame: Baseline up to 1 year post treatment ]
    All enhancing lesions will be evaluated over time for each patient. The percent change from baseline in target lesion measurements will be assessed over time. Differences in values over time will be summarized descriptively and graphically.

  2. Change in immunologic correlates before and after vaccination treatment [ Time Frame: Baseline up to 1 year post treatment ]
    Change in immunologic correlates before and after vaccination treatment will be evaluated and summarized both quantitatively and graphically. Each of the correlative endpoints will be summarized individually, but will also be evaluated in terms of their relationships to one another; i.e., will use Spearman rank correlation coefficient to assess the correlations between baseline levels as well as between changes before and after treatment in these immunologic markers.

  3. Change in immunologic correlates before and after vaccination treatment [ Time Frame: Baseline up to 1 year post treatment ]
    Change in immunologic correlates before and after vaccination treatment will be evaluated and summarized both quantitatively and graphically. Each of the correlative endpoints will be summarized individually. In addition, these immunologic markers will be correlated with cancer and treatment related outcomes (e.g. response, adverse events).

  4. Change in immunologic correlates before and after vaccination treatment [ Time Frame: Baseline up to 1 year post treatment ]
    Change in immunologic correlates before and after vaccination treatment will be evaluated and summarized both quantitatively and graphically. Each of the correlative endpoints will be summarized individually. In addition, relationships will also be explored graphically using scatter plots.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histological and/or radiologic confirmation of hepatocellular carcinoma (HCC) OR histologic confirmation of intrahepatic cholangiocarcinoma (CCA)
  • The following tumor characteristics must be met

    • Unresectable HCC or intrahepatic CCA
    • Measurable or evaluable disease
    • All lesions should be treatable by EBRT while meeting normal tissue constraints
    • Tumor lesions should be accessible using an ultrasound (US) guided approach for intratumoral DC injection
    • Patients are required to have no evidence of extrahepatic tumor (excluding tumor thrombus) by computed tomography (CT) or magnetic resonance imaging (MRI) scan

      • NOTE: Patients who are not candidates for surgical treatment or for ablation with curative intent are allowed
  • Good candidate for standard of care high-dose conformal EBRT in the view of the investigator
  • Eastern Cooperative Oncology Group( ECOG) performance status (PS) 0 or 1
  • Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior to registration)
  • Absolute lymphocyte count (ALC) >= 500/mm^3 (obtained =< 14 days prior to registration)
  • Absolute monocyte count (AMC) >= 300/mm^3 (obtained =< 14 days prior to registration)
  • Platelet count >= 50,000/mm^3 (obtained =< 14 days prior to registration)
  • Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to registration)
  • Total bilirubin < 3 mg/dL (obtained =< 14 days prior to registration)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 5 x upper limit of normal (ULN) ( obtained =< 14 days prior to registration)
  • Creatinine =< 2 mg/dL (obtained =< 14 days prior to registration)
  • Prothrombin time/International Normalized Ratio (PT/ INR) =< 1.5 x ULN (obtained =< 14 days prior to registration)
  • Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only
  • Ability to provide written consent
  • Willingness to return to enrolling institution for follow-up (during the active monitoring phase of the study)
  • Willingness to provide blood and tissue samples for correlative research purposes

Exclusion Criteria:

  • Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

    • Pregnant persons
    • Nursing persons
    • Persons of childbearing potential who are unwilling to employ adequate contraception
  • Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
  • Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy.

    • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Receiving any other investigational agent that would be considered a treatment for the primary neoplasm
  • Other active malignancy =< 3 years prior to registration. EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix

    • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer
  • Major surgery =< 4 weeks prior to enrollment (other than diagnostic surgery or surgical spacer placement in preparation for radiation treatment)
  • History of hypersensitivity or anaphylactoid reactions to pneumococcal vaccine or any component of the formulation, including diphtheria toxoid
  • Active autoimmune disease such as autoimmune hepatitis, Crohn?s disease, rheumatoid arthritis, Sjogren's disease, systemic lupus erythematosus, or similar conditions
  • Requires coagulopathy treatment (INR > 1.5) or use of anti-platelet agents that cannot be discontinued for the intratumoral injection procedure

    • NOTE: Heparin for line patency without detectable lab abnormalities in coagulation will be allowed
  • Corticosteroids =< 2 weeks prior to registration, including oral, intravenous (IV), subcutaneous, or inhaled routes of administration

    • NOTE: Patients on chronic corticosteroids for adrenal insufficiency or other reasons may enroll if they receive less than 10 mg/day of prednisone (or equivalent)
  • History of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • Child Pugh class B or C cirrhosis of the liver
  • Previously received immune modulating therapies including but not limited to immune checkpoint inhibitors targeting PD-1 PDL-1 CTLA4, etc; or prior dendritic cell therapy
  • Prior liver radiation, including radioembolization
  • Barcelona Clinic Liver Cancer (BCLC) stage D disease

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03942328


Locations
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United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Lewis R. Roberts         
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Lewis R Roberts Mayo Clinic

Additional Information:
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Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT03942328     History of Changes
Other Study ID Numbers: MC1641
NCI-2019-02452 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1641 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: May 8, 2019    Key Record Dates
Last Update Posted: June 14, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Liver Neoplasms
Cholangiocarcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Carcinoma
Carcinoma, Hepatocellular
Adenocarcinoma
Digestive System Diseases
Liver Diseases
Vaccines
Heptavalent Pneumococcal Conjugate Vaccine
Immunologic Factors
Physiological Effects of Drugs