Immunological effects of local low-dose immunotherapy in early stage melanoma patients

ISRCTN ISRCTN63321797
DOI https://doi.org/10.1186/ISRCTN63321797
Secondary identifying numbers 03.199
Submission date
18/07/2016
Registration date
22/07/2016
Last edited
25/09/2017
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

Plain English summary of protocol

Background and study aims
Melanoma is a type of skin cancer that is able to spread to other organs in the body. The most common sign of the disease is a new mole appearing or a change in appearance of an existing mole. At the moment, there isn’t a widely used treatment option for early stage melanoma patients after they have had their initial therapy that will help prevent the cancer reoccurring. Indeed, the disease coming back remains the biggest challenge in the management of early stage melanoma. This study is investigating the use of stimulators of the immune system, namely unmethylated CpG type-B oligodeoxynucleotide (CpG type B) and Granulocyte/Macrophage-Colony Stimulating Factor (GM-CSF). The researchers want to know whether these substances can improve the immune response in order to fight the melanoma.

Who can participate?
Adults diagnosed with melanoma

What does the study involve?
Participants are randomly allocated to one of five groups. Those in group 1 are given an injection of CpG type B seven days at the tumour excision site (that is the site where the tumour is about to be removed) before undergoing a sentinel node biopsy (an operation that determines whether a cancer has spread beyond the original tumour into the lymphatic system). Those in group 2 are given an injection of CpG type B at the tumour excision site seven days and two days before the sentinel node biopsy. Those in group 3 are given an injection of CpG type B and GM-CSF at the tumour excision site seven days and two days before the sentinel node biopsy. Those in group 4 are given an injection of saline at the tumour excision site seven days before the sentinel node biopsy. Those in group 5 are given an injection of saline at the tumour excision site seven days and two days before the sentinel node biopsy. All participants are followed up two days after the biopsy and again after seven days to assess their immune response.

What are the possible benefits and risks of participating?
A possible benefit of participating in this trial might be that the immune system can effectively fight the melanoma cells that remain in the body after surgery. The side effects of these treatments are mild (symptoms of fever may occur) and are often easy to control.

Where is the study run from?
VU University Medical Center (Netherlands)

When is the study starting and how long is it expected to run for?
August 2003 to July 2017

Who is funding the study?
Fritz Ahlqvist Foundation

Who is the main contact?
Professor Tanja de Gruijl

Contact information

Prof Tanja de Gruijl
Scientific

VU University medical center – Cancer Center Amsterdam
Room CCA2.44
De Boelelaan 1117
Amsterdam
1081 HV
Netherlands

ORCiD logoORCID ID 0000-0003-1464-8978

Study information

Study designSingle-center single-blinded randomized and placebo (saline) controlled phase-II clinical trial
Primary study designInterventional
Secondary study design
Study setting(s)Hospital
Study typeTreatment
Participant information sheet Not available in web format, please use the contact details to request a patient information sheet (in Dutch)
Scientific titleImmune response in the sentinel node in melanoma patients after the pre-operative administration of immune modulators GM-CSF and / or CpG 7909
Study objectivesIt is expected that local administration of CpG 7909 around the primary tumor site in melanoma patients will result in an increased size of the sentinel lymph node (SLN) and we expect to see higher frequencies and activations states of DC and T cells due to the production of Th-1 type cytokines (IL-12, IL-2, IFN-γ, IFN-α).

The researchers also expect to see an increase in specific cytotoxic T-cells under the influence of both CpG 7909 and GM-CSF in the tumor positive SLN since CpG and GM-CSF can probably enhance the response against specific tumor antigens more effectively when tumor cells are present in the lymph nodes.
Ethics approval(s)Institutional Review Board of the VU University Medical Centre, 16/03/2004, ref: IRB00002991
Health condition(s) or problem(s) studiedClinical stage I-II melanoma
InterventionThere are three treatment arms and two saline (placebo) controlled arms.

Treatment arm 1: Intradermal injection at the tumor excision site with 8 mg CpG-B (PF-3512676, formerly named CPG 7909, Coley Pharmaceutical Group, Wellesley, MA) 7 days prior to the sentinel node biopsy.
Treatment arm 2: Intradermal injection at the tumor excision site with 1 mg CpG-B, 7 and 2 days prior to the sentinel node biopsy.
Treatment arm 3: Intradermal injection at the tumor excision site with 1 mg CpG-B and 100µg GM-CSF (Leukine®, Berlex Laboratories Inc. Montville, NJ) 7 and 2 days prior to the sentinel node biopsy.
Placebo arm 1: Intradermal injection at the tumor excision site with saline (0.9% NaCl) 7 days prior to the sentinel node biopsy.
Placebo arm 2: Intradermal injection at the tumor excision site with saline (0.9% NaCl) 7 and 2 days prior to the sentinel node biopsy.

All patients are followed up at day 7 and day 14 (after the sentinel node biopsy).
Intervention typeDrug
Pharmaceutical study type(s)
PhasePhase II
Drug / device / biological / vaccine name(s)1. Unmethylated CpG type-B oligodeoxynucleotide; PF-3512676 (cpg7909) 2. Granulocyte/Macrophage-Colony Stimulating Factor; Leukine
Primary outcome measureImmune status in the sentinel lymph node (SLN), specifically DC activation state and melanoma antigen specific T cells, measured using flow cytometry, interferon (IFN) gamma Elispot and tetramer analysis on immune cells that are harvested from the SLN at the day of the biopsy. .
Secondary outcome measuresSystemic anti melanoma activity measured using flow cytometry, IFN gamma Elispot and tetramer analysis on peripheral mononuclear blood cells from day -7, 0 and 14 (day 0 is the day of the SLN biopsy).
Overall study start date01/08/2003
Completion date01/07/2017

Eligibility

Participant type(s)Patient
Age groupAdult
SexBoth
Target number of participants52
Key inclusion criteriaPatients with histologically proven primary melanoma, who are eligible for a SLN biopsy.
Key exclusion criteria1. Treated with chemotherapy or immunotherapy in the last ten years
2. Autoimmune diseases
3. Congenital or acquired immunodeficiency
4. Use of immunosuppressive medications
Date of first enrolment01/06/2004
Date of final enrolment30/06/2007

Locations

Countries of recruitment

  • Netherlands

Study participating centre

VU University Medical Center
De Boelelaan 1117
Amsterdam
1081 HV
Netherlands

Sponsor information

VU University Medical Center
Hospital/treatment centre

De Boelelaan 1117
Amsterdam
1081 HV
Netherlands

Website https://www.vumc.com/
ROR logo "ROR" https://ror.org/00q6h8f30

Funders

Funder type

Charity

Fritz Ahlqvist Foundation

No information available

Results and Publications

Intention to publish date30/10/2016
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planPrimary outcome; i.e. immune stutus SLN has been published in four papers.
Clinical follow-up will be published in separate paper in conjunction with an earlier clinical study (preceding 2004) in which, in a similar set-up, the effects of single administration of GM-CSF were studied (Vuysteke et al Cancer Res 2004).
IPD sharing plan

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Results article results 15/05/2007 Yes No
Results article results 15/07/2008 Yes No
Results article results 01/05/2015 Yes No
Results article results 01/04/2016 Yes No

Editorial Notes

25/09/2017: Internal review.
04/08/2016: Added publications and changed ethics approval date from 16/03/2016 to 16/03/2004