Lynch Syndrome
Conditions
Keywords
Dendritic Cells, Cancer Vaccine, Hereditary Cancer, Lynch Syndrome, Prevention, Neoantigens
Brief summary
The primary objective is to assess the effect of vaccination with neopeptide-loaded dendritic cells on disease-free survival (DFS) compared to placebo in LS subjects who are known to be carrier of a germline MMR-gene mutation with no signs of disease.
Detailed description
A phase III, multicentre, randomised, double-blind, placebo-controlled trial evaluating disease-free survival after vaccination with with neopeptide-loaded dendritic cells or placebo in LS subjects aged 35-75 who are confirmed to carry a germline MMR-gene mutation in MLH1, MSH2 or MSH6 without clinical signs of disease. Participants will be treated for 6 months + 4 weeks, with an additional maximum follow-up of 51.5 months (total study duration 58.5 months).
Interventions
BIOLOGICALArm A: DC vaccination
Subjects in the DC vaccination arm will receive a maximum of 2 cycles each consisting of 3 DC injections intranodally (3-7x10\^6 DC)
BIOLOGICALArm B: Placebo vaccination
Subjects in the placeb vaccination arm will receive a maximum of 2 cycles each consisting of 3 placebo injections intranodally (3-7x10\^6 DC)
Sponsors
Radboud University Medical Center
Dutch National Health Care Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Arm A: Vaccination with neopeptide-loaded dendritic cells Arm B: Vaccination with placebo
Eligibility
Sex/Gender
ALL
Age
35 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* a confirmed gPV in MLH1 or MSH2 and without a prior history of MMR-D cancer. * a confirmed gPV in MSH6, whether or not they have a history of MMR-D cancer. MSH6 subjects with a history of MMR-D cancer have to be cancer-free for more than 1 year. * previous surgical treatment may include any resection up to and including hemicolectomy; subjects who have undergone (sub)total colectomy are excluded due to the substantially reduced risk of cancer occurrence. * aged between 35 and 75 for subjects with gPV in MLH1 and MSH2; and aged between 40 and 75 for subjects with gPV in MSH6. * Lynch syndrome subjects without clinical signs of disease. * Lynch syndrome subjects without prior treatment for LS-associated cancer, except for MSH6 subjects who are \>1 year disease-free and whose prior surgical treatment did not include subtotal colectomy. * Routine surveillance colonoscopy must be performed within 16 weeks prior to start of study, to exclude (pre)malignancy. * HLA-A02.01 genotype * Adequate hematologic, renal, and liver function as defined by laboratory values: WBC \>3.0\^109/l, lymphocytes \>0.8\^109/l, platelets \>100\^109/l, haemoglobin \>7,0 mmol/l (9.0 g/dl), estimated glomerular filtration rate \> 45 ml/min/1.73m2, AST/ALT \<3 x ULN, serum crea¬tinine \<150 µmol/l, serum bilirubin \<1.5 x ULN (exception: Gilbert's syndrome is permitted). * WHO performance status of 0 or 1 * No concomitant use of immunosuppressive drugs orally or intravenously. Topical and intranasal steroids are permitted. * No uncontrolled infectious disease, i.e., negative testing for HIV, Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) and syphilis (Treponema Pallidum Hemagglutination Assay (TPHA)). * No autoimmune disease such as, but not limited to, inflammatory bowel disease, multiple sclerosis, and lupus. Subjects with type 1 diabetes mellitus, hypothyroidism after autoimmune thyroiditis and skin disorders are not excluded. * No serious (bleeding and clotting) condition that may interfere with safe leukapheresis. * No pregnant or lactating women. hCG tests will be performed regularly during the trial to confirm absence of pregnancy. * No Women Of Child-Bearing Potential (WOCBP) or male partners of WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for up to 8 weeks after the last administration of the treatment. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal \[defined as amenorrhea \> 12 consecutive months\]. * Subjects must have absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions must be discussed with the subject before registration in the trial. * Expected adequacy of follow-up. * Written informed consent.
Exclusion criteria
* Individuals with a history of malignancy in the past. Allowed malignancies are adequately treated basal cell carcinoma and squamous cell carcinoma of the skin, carcinoma in situ (e.g., DCIS/LCIS/cervical CIS), papillary thyroid carcinoma, and low-risk prostate carcinoma; all locally resected with negative surgical margins and not treated with systemic therapy. * Organ allografts. * Known allergy to shellfish. * Inability to understand and communicate in Dutch.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free survival after DC vaccination or placebo | 58.5 months | Defined as time between 1st vaccination until development of mismatch-repair deficient colorectal adenoma, any Lynch-related carcinoma in situ or Lynch-related carcinoma, Lynch-related death, or until follow-up ends, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with Treatment-Related adverse events as assessed by CTCAE v5.0 (Safety) | 36 months | — |
| Quality of Life Questionnaires | baseline, week 3, week 28, month 12, month 24, month 36, month 48 | To evaluate whether LS subjects quality of life differs between DC vaccinated and placebo vaccinated groups. Defined as patient's self-perceived physical, psychological and social well-being in relation to their health status, assessed using questionnaires. |
| To assess whether neoantigen-specific T cells are induced by the DC vaccine (immunogenicity). | 36 months | Immunogenicity will be assessed by the percentage of participants showing a neo-antigen-specific T cell response, defined by the expansion of T cells that recognize tumor antigens and demonstrate effector functions. Non-responders are those with no T cell expansion or insufficient immune activity. |
| Health economic aspects including QALY | 58.5 months | The primary objective of the analysis is to determine the cost-effectiveness of DC vaccination compared with standard surveillance in patients with LS, expressed as cost per quality-adjusted life year (QALY) gained and incremental net monetary benefit (iNMB) from a societal perspective, over both the trial timeframe (empirical) and the long term timeframe (modelling). |
Countries
Netherlands
Outcome results
None listed