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Phase I Safety Study of Dendritic Cell Vaccine to Treat Patients With Hepatocellular Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01974661
Recruitment Status : Completed
First Posted : November 1, 2013
Last Update Posted : September 29, 2017
Sponsor:
Collaborator:
Uppsala University
Information provided by (Responsible Party):
Immunicum AB

Tracking Information
First Submitted Date  ICMJE October 21, 2013
First Posted Date  ICMJE November 1, 2013
Last Update Posted Date September 29, 2017
Study Start Date  ICMJE October 2013
Actual Primary Completion Date June 28, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 25, 2013)
Registration of adverse events as a measure of safety and tolerability [ Time Frame: Up to 6 months after last patient's last vaccination ]
  • Changes in vital signs from baseline (heart rate, blood pressure, body temperature)
  • Changes in lab parameters from baseline
  • Short term worsening in ECOG and/or Child Pugh and/or MELD score
  • Local procedural injuries, assessed by MRI or ultrasound
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 26, 2017)
  • To evaluate systemic inflammatory response [ Time Frame: Until 3 months after last vaccination ]
    Potential systemic release of relevant cytokines, chemokines and other inflammatory parameters in blood;IL-1R, IL-2,IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17A, G-CSF. GM-CSF, IFN-gamma, MCP-1, MIP-1 beta and TNF-alpha.
  • To evaluate tumor control [ Time Frame: Until 6 months after last patient's last vaccination ]
    • CT/MRI evaluation 3 and 6 months after first vaccination. Patients with stable disease or tumor response will continue tumor evaluation every 3rd month until progress or until last study patient has had his/her 6 month visit.
    • Measuring number of tumor specific T cells with flow cytometry after in vitro stimulation with different pools of HCC-associated tumor peptides (Alpha-feto protein (AFP), and hTERT)
    • Measuring AFP (alpha-feto protein) levels in blood
    • Measuring the level of circulating tumor cell, identified as tested positive for MICA, EpCAM, CD133, CD34, CK18
  • Long term changes in ECOG scores [ Time Frame: 3 and 6 months after last vaccination ]
  • Change in body weight [ Time Frame: 3 and 6 months after last vaccination ]
  • To evaluate systemic immunological response [ Time Frame: Up to 3 months after last vaccination ]
    • Vaccine cell tracking; PBMCs will be stained with antibodies specific for one HLA class I or one HLA-class II antigen that is selectively expressed on donor vaccine cells.
    • vaccine-induced alloimmunization; screening of alloantibodies against HLA-A, B, C (MHC-class I) and HLA-DR, DQ, DP (MHC-class II) antigens
    • autoimmune events; screening of autoantibodies against autoantigens, including nuclear antigens (ANA, SSA, SSB, Sm, RNP, Scl-70, Centromeres and Jo-1) and liver parenchyma-associated autoantigens (liver-kidney microsomal antigens and mitochondrial antigens)
    • complement activation; classical/alternative complement function, C3, C4, C3d, and Factor-B.
    • immune cell occurrence and activation state; CD3+ , CD3+4+ and CD3+8+ T cells, CD19+ B-cells CD3-16+56+ NK-cells, CD3-16+56+69+ NK cells, CD3+16+56+ NKT-cells, CD3+16+56+69+ NKT-cells and CD3+HLA-DR+ T cells.
  • Long term changes in Quality of Life scores [ Time Frame: 3 and 6 months after last vaccination ]
  • To evaluate immunological response [ Time Frame: Up to 3 months after last vaccination ]
    • complement activation; classical/alternative complement function, C3, C4, C3d, and Factor-B.
    • immune cell occurrence and activation state; CD3+ , CD3+4+ and CD3+8+ T cells, CD19+ B-cells CD3-16+56+ NK-cells, CD3-16+56+69+ NK cells, CD3+16+56+ NKT-cells, CD3+16+56+69+ NKT-cells and CD3+HLA-DR+ T cells.
  • Changes in HBV, HCV virus titers [ Time Frame: Day 8 after each injection and at the 3 and 6 months visit ]
    Changes in HBV, HCV virus titers vs baseline, for patients that are tested positive at screening
  • To study time to progress (TTP) [ Time Frame: Measured every 3 months until progression ]
    TTP measured as time from first dose of COMBIG-DC until radiologically proven progress according to mRECIST.
  • To study overall survival (OS) [ Time Frame: Up to 6 months after last patient's last vaccination ]
    OS measured as survival time from first dose of COMBIG-DC until end of study or death (whichever comes first)
Original Secondary Outcome Measures  ICMJE
 (submitted: October 25, 2013)
  • To evaluate systemic inflammatory response [ Time Frame: Until 3 months after last vaccination ]
    Potential systemic release of relevant cytokines, chemokines and other inflammatory parameters in blood;IL-1R, IL-2,IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17A, G-CSF. GM-CSF, IFN-gamma, MCP-1, MIP-1 beta and TNF-alpha.
  • To evaluate tumor control [ Time Frame: Until 6 months after last patient's last vaccination ]
    • CT/MRI evaluation 3 and 6 months after first vaccination. Patients with stable disease or tumor response will continue tumor evaluation every 3rd month until progress or until last study patient has had his/her 6 month visit.
    • Measuring number of tumor specific T cells with flow cytometry after in vitro stimulation with different pools of HCC-associated tumor peptides (Alpha-feto protein (AFP), and hTERT)
    • Measuring AFP (alpha-feto protein) levels in blood
    • Measuring the level of circulating tumor cell, identified as tested positive for MICA, EpCAM, CD133, CD34, CK18
  • Long term changes in ECOG scores [ Time Frame: 3 and 6 months after last vaccination ]
  • Change in body weight [ Time Frame: 3 and 6 months after last vaccination ]
  • To evaluate systemic immunological response [ Time Frame: Up to 3 months after last vaccination ]
    • Vaccine cell tracking; PBMCs will be stained with antibodies specific for one HLA class I or one HLA-class II antigen that is selectively expressed on donor vaccine cells.
    • vaccine-induced alloimmunization; screening of alloantibodies against HLA-A, B, C (MHC-class I) and HLA-DR, DQ, DP (MHC-class II) antigens
    • autoimmune events; screening of autoantibodies against autoantigens, including nuclear antigens (ANA, SSA, SSB, Sm, RNP, Scl-70, Centromeres and Jo-1) and liver parenchyma-associated autoantigens (liver-kidney microsomal antigens and mitochondrial antigens)
  • Long term changes in Quality of Life scores [ Time Frame: 3 and 6 months after last vaccination ]
  • To evaluate systemic immunological response [ Time Frame: Up to 3 months after last vaccination ]
    • complement activation; classical/alternative complement function, C3, C4, C3d, and Factor-B.
    • immune cell occurrence and activation state; CD3+ , CD3+4+ and CD3+8+ T cells, CD19+ B-cells CD3-16+56+ NK-cells, CD3-16+56+69+ NK cells, CD3+16+56+ NKT-cells, CD3+16+56+69+ NKT-cells and CD3+HLA-DR+ T cells.
Current Other Pre-specified Outcome Measures
 (submitted: October 25, 2013)
Local tissue changes in injected/non-injected tumor and surrounding tissue, assessed by MRI [ Time Frame: 1 month after each vaccination ]
An optional addition to the assessment of local procedural injuries (primary outcome).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Phase I Safety Study of Dendritic Cell Vaccine to Treat Patients With Hepatocellular Carcinoma
Official Title  ICMJE A Phase I Open-label Study to Evaluate Safety and Immunologic Response of COMBIG-DC Administered Intra-tumorally in Patients With Hepatocellular Carcinoma
Brief Summary The primary objective of this study is to answer the question "Is it possible to inject the COMBIG-DC vaccine in a hepatic tumor without getting unacceptable side effects"?
Detailed Description

Patients diagnosed with hepatocellular carcinoma will get COMBIG-DC vaccinations at three occasions with 2-3 weeks and 3-5 weeks between vaccination 2 and 3 respectively. Adverse events will be registered until 6 months after last vaccination, as well as changes in vital signs (heart rate, blood pressure and body temperature) and lab parameters. Immunologic response will be evaluated by measuring immunologic markers in blood. The size of the tumor/tumors will be evaluated after 3 and 6 months and thereafter every three months until tumor progression.

For patients included after approval of Amendment 3 (2015-12-10), COMBIG-DC will be given as add on to standard treatment; sorafenib or Transarterial Chemoembolization (TACE).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hepatocellular Carcinoma
Intervention  ICMJE Biological: COMBIG-DC (ilixadencel)
Allogenic dendrite-cell based therapeutic vaccine
Other Name: ilixadencel
Study Arms  ICMJE Experimental: COMBIG-DC
COMBIG-DC (allogeneic dendritic cells) Cancer Vaccine 3 vaccinations: 5, 10 or 20 million cells per injection
Intervention: Biological: COMBIG-DC (ilixadencel)
Publications * Rizell M, Sternby Eilard M, Andersson M, Andersson B, Karlsson-Parra A, Suenaert P. Phase 1 Trial With the Cell-Based Immune Primer Ilixadencel, Alone, and Combined With Sorafenib, in Advanced Hepatocellular Carcinoma. Front Oncol. 2019 Jan 21;9:19. doi: 10.3389/fonc.2019.00019. eCollection 2019.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 19, 2016)
18
Original Estimated Enrollment  ICMJE
 (submitted: October 25, 2013)
12
Actual Study Completion Date  ICMJE June 28, 2017
Actual Primary Completion Date June 28, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Be informed of the nature of the study and have provided written informed consent
  • At least 18 years of age.
  • Diagnosis of hepatocellular carcinoma according to EASL criteria or pathology.
  • Radiologically measurable liver tumor(s), i.e. at least 20 mm in longest uni-dimensional diameter as measured by CT/MRI
  • Not eligible for curatively aiming treatment or TACE. Tumor stage B or C according to BCLC.
  • For patients included according to Amendment 3: tumour stage A, B or C according to BCLC and

    1. eligible for sorafenib treatment or having ongoing sorafenib treatment for not more than 4 weeks ant the time for inclusion or
    2. eligible for TACE or having received not more than 1 previous TACE treatment.

Exclusion Criteria:

  • Performance status > ECOG 2
  • Liver function according to Child-Pugh >7 points.
  • Known major reaction/adverse event in connection with previously made vaccination (e.g. asthma, anaphylaxia or other serious reaction).
  • Known major reaction/adverse event in connection with previous transfusions of blood products
  • Active autoimmune disease requiring treatment with systemic immunosuppressive agents, e.g. inflammatory bowel disease, multiple sclerosis, sarcoidosis, psoriasis, autoimmune hemolytic anemia, rheumatoid arthritis, SLE, vasculitis, Sjögren's syndrome, scleroderma, autoimmune hepatitis, and other rheumatological diseases.
  • Tested positive for HIV
  • Active disease (HBV and HCV) requiring antiviral treatment
  • Ongoing infection that requires treatment with antibiotics or antiviral medication
  • Treatment with immunosuppressive treatments like corticosteroids (Immunosuppression (within 28 days) prior to the first injection of COMBIG-DC. Inhaled, intranasal and local steroids accepted), or mTor inhibitors within 28 days before first vaccination.
  • Patients with prior history of malignancy other than HCC, within the preceding 3 years OR with relaps after complete response, except for 5 years follow-up of adequately treated in situ carcinoma without recurrences or non-melanoma skin cancer.
  • Inadequate laboratory parameters, i.e.:

    1. P-Prothrombincomplex (PK) >1.4,
    2. Platelet count <50 75 x109/L
    3. Leukocyte count <3.0 x 109/L
    4. P-APT time outside normal limit
  • Previous organ transplantation
  • Women of Childbearing Potential (WOCBP) refusing to use adequate contraception (oral or injectable contraceptives, hormone releasing intrauterine device) throughout the study period.
  • Pregnant or lactating women
  • Life expectancy less than 3 months.
  • Concomitant anti-tumor treatment (within 28 days) prior to the first injection of COMBIG-DC, except for sorafenib or TACE for patients included according to Amendment 3.
  • For patients included according to Amendment 3: Previous systemic anti-cancer treatment.
  • Investigational treatment (within 28 days) prior to the first injection of COMBIG-DC.
  • Known blood dyscrasia (bleeding complication).
  • Known malignancy in CNS
  • Any reason that, in the opinion of the investigator, contraindicates that the patient participates in the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01974661
Other Study ID Numbers  ICMJE IM-102
2013-001787-31 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Immunicum AB
Study Sponsor  ICMJE Immunicum AB
Collaborators  ICMJE Uppsala University
Investigators  ICMJE
Principal Investigator: Magnus Rizell, MD, PhD Sahlgrenska University Hospital, Sweden
PRS Account Immunicum AB
Verification Date September 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP