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

Primary Purpose

Hepatocellular Carcinoma

Status

Completed

Phase

Phase 1

Locations

Sweden

Study Type

Interventional

Intervention

COMBIG-DC (ilixadencel)

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Dept. of Transplantation and Liver Surgery, Sahlgrenska University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

COMBIG-DC

Arm Description

COMBIG-DC (allogeneic dendritic cells) Cancer Vaccine 3 vaccinations: 5, 10 or 20 million cells per injection

Outcomes

Primary Outcome Measures

Registration of adverse events as a measure of safety and tolerability

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

Secondary Outcome Measures

To evaluate systemic inflammatory response

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

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

Change in body weight

To evaluate systemic immunological response

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

To evaluate immunological response

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

Changes in HBV, HCV virus titers vs baseline, for patients that are tested positive at screening

To study time to progress (TTP)

TTP measured as time from first dose of COMBIG-DC until radiologically proven progress according to mRECIST.

To study overall survival (OS)

OS measured as survival time from first dose of COMBIG-DC until end of study or death (whichever comes first)

Full Information

NCT ID

NCT01974661

First Posted

October 21, 2013

Last Updated

September 27, 2017

Sponsor

Mendus

Collaborators

Uppsala University

1. Study Identification

Unique Protocol Identification Number

NCT01974661

Brief Title

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

Official Title

A Phase I Open-label Study to Evaluate Safety and Immunologic Response of COMBIG-DC Administered Intra-tumorally in Patients With Hepatocellular Carcinoma

Study Type

Interventional

2. Study Status

Record Verification Date

September 2017

Overall Recruitment Status

Completed

Study Start Date

October 2013 (undefined)

Primary Completion Date

June 28, 2017 (Actual)

Study Completion Date

June 28, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Mendus

Collaborators

Uppsala University

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hepatocellular Carcinoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

COMBIG-DC

Arm Type

Experimental

Arm Description

COMBIG-DC (allogeneic dendritic cells) Cancer Vaccine 3 vaccinations: 5, 10 or 20 million cells per injection

Intervention Type

Biological

Intervention Name(s)

COMBIG-DC (ilixadencel)

Other Intervention Name(s)

ilixadencel

Intervention Description

Allogenic dendrite-cell based therapeutic vaccine

Primary Outcome Measure Information:

Title

Registration of adverse events as a measure of safety and tolerability

Description

Time Frame

Up to 6 months after last patient's last vaccination

Secondary Outcome Measure Information:

Title

To evaluate systemic inflammatory response

Description

Time Frame

Until 3 months after last vaccination

Title

To evaluate tumor control

Description

Time Frame

Until 6 months after last patient's last vaccination

Title

Long term changes in ECOG scores

Time Frame

3 and 6 months after last vaccination

Title

Change in body weight

Time Frame

3 and 6 months after last vaccination

Title

To evaluate systemic immunological response

Description

Time Frame

Up to 3 months after last vaccination

Title

Long term changes in Quality of Life scores

Time Frame

3 and 6 months after last vaccination

Title

To evaluate immunological response

Description

Time Frame

Up to 3 months after last vaccination

Title

Changes in HBV, HCV virus titers

Description

Changes in HBV, HCV virus titers vs baseline, for patients that are tested positive at screening

Time Frame

Day 8 after each injection and at the 3 and 6 months visit

Title

To study time to progress (TTP)

Description

TTP measured as time from first dose of COMBIG-DC until radiologically proven progress according to mRECIST.

Time Frame

Measured every 3 months until progression

Title

To study overall survival (OS)

Description

OS measured as survival time from first dose of COMBIG-DC until end of study or death (whichever comes first)

Time Frame

Up to 6 months after last patient's last vaccination

Other Pre-specified Outcome Measures:

Title

Local tissue changes in injected/non-injected tumor and surrounding tissue, assessed by MRI

Description

An optional addition to the assessment of local procedural injuries (primary outcome).

Time Frame

1 month after each vaccination

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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 eligible for sorafenib treatment or having ongoing sorafenib treatment for not more than 4 weeks ant the time for inclusion or 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.: P-Prothrombincomplex (PK) >1.4, Platelet count <50 75 x109/L Leukocyte count <3.0 x 109/L 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Magnus Rizell, MD, PhD

Organizational Affiliation

Sahlgrenska University Hospital, Sweden

Official's Role

Principal Investigator

Facility Information:

Facility Name

Dept. of Transplantation and Liver Surgery, Sahlgrenska University Hospital

City

Gothenburg

ZIP/Postal Code

SE-413 45

Country

Sweden

12. IPD Sharing Statement

Citations:

PubMed Identifier

30719425

Citation

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.

Results Reference

derived

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

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