Metastatic Melanoma Clinical Trial
Official title:
Phase 1 Study of Local Modulation of Immune Receptor Function to Enhance Immune Responses to Dendritic Cell Vaccination in Subjects With Metastatic Melanoma
Verified date | April 2014 |
Source | Duke University |
Contact | n/a |
Is FDA regulated | No |
Health authority | United States: Food and Drug Administration |
Study type | Interventional |
Our proposed study is designed to test the safety of a new vaccine against melanoma. The
induction of immune activity against cancers such as melanoma is a promising approach to
cancer treatment, but to date, only a few clinically significant immune responses have been
seen following vaccine therapy. This is an important problem, since there are very limited
treatment options for patients with metastatic melanoma (melanoma that has spread to lymph
nodes and organs).
Studies suggest that monoclonal antibodies (mAbs) that block inhibitory receptors on immune
cells can enhance the immune responses against cancer, but the intravenous injection of such
mAbs has caused severe side effects in animals and humans. In our laboratory, we have
developed a method to deliver mAbs and other proteins that block such inhibitory receptors
locally at the site where immune responses against melanoma proteins are stimulated by
vaccination, enhancing anti-melanoma immunity while avoiding the side-effects associated
with intravenous injection of these immune modulators. This is achieved by loading dendritic
cells, a type of immune cell, with RNA that encodes the immune modulator. The RNA-loaded
dendritic cells then make the immune modulatory proteins and release them locally. By mixing
these dendritic cells with additional dendritic cells loaded with melanoma proteins, the
immune modulators are released at the site where anti-melanoma immune cells are stimulated.
In this phase I trial, subjects with metastatic melanoma will undergo the process of
leukapheresis, in which white blood cells are removed from the body. Monocytes, a type of
immune cell, will then be purified from the white blood cells and cultured under conditions
that will change them into dendritic cells. Half of these dendritic cells are then loaded
with melanoma antigen RNA, which will lead to the production of melanoma antigen proteins
within the dendritic cells. The remaining half of the dendritic cells will be either
untreated or loaded with RNA encoding immune modulators so that these dendritic cells will
release immune modulators at the site of vaccination. These dendritic cells will be mixed
with the melanoma antigen-loaded dendritic cells and injected as a vaccine into lymph nodes.
Each subject will receive six weekly injections of their own dendritic cells. Safety and
toxicity will be closely monitored. In addition, immune responses against melanoma, as well
as clinical responses, will be assessed.
Status | Terminated |
Enrollment | 2 |
Est. completion date | October 2013 |
Est. primary completion date | October 2013 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 18 Years and older |
Eligibility |
Inclusion Criteria: - Patients with confirmed metastatic melanoma - Karnofsky performance status greater than or equal to 70%. - Estimated life expectancy > 6 months. - Age > 17 years. - Adequate hematologic function with: - WBC >= 3000 mm3 - hemoglobin >= 9 mg/dl - platelets >= 100,000/mm3 - Adequate renal and hepatic function with: - serum creatinine < 2.5 mg/dl - bilirubin < 2.0 mg/dl - AST/SGOT < 70 U/L - ALT/SGPT < 70 U/L - Alkaline Phosphatase = 135 U/L - Ability to understand and provide signed informed consent that fulfills Institutional Review Board guidelines. - Ability to return to Duke University Medical Center for adequate follow-up as required by this protocol. Exclusion Criteria: - Subjects undergoing concurrent chemotherapy, radiation therapy, or immunotherapy will be excluded. - The subject has previously irradiated, surgically treated, or newly diagnosed central nervous system (CNS) metastases will be excluded (Pre-enrollment head CT is not required if not indicated by clinical signs or symptoms). - Subjects with a history of autoimmune disease such as, but not restricted to, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, or multiple sclerosis will be excluded. - Subjects with serious concurrent chronic or acute illness such as pulmonary (asthma or COPD), cardiac (NYHA class III or IV) or hepatic disease, or other illness considered by the principal investigator to constitute an unwarranted high risk for investigational drug administration will be excluded. - Subjects with medical or psychological impediment to probable compliance with the protocol will be excluded. - Subjects with concurrent second malignancy other than melanoma or non-melanoma skin cancer will be excluded. In the event of prior non-melanoma malignancies treated surgically, the subject must be considered NED (no evidence of disease) for a minimum of 3 years prior to enrollment. - Presence of an active acute or chronic infection, including symptomatic urinary tract infection, HIV (as determined by ELISA and confirmed by Western Blot) or viral hepatitis (as determined by HBsAg and Hepatitis C serology) will lead to subject exclusion. - Subjects receiving steroid therapy (or other immunosuppressive agents such as azathioprine or cyclosporine A) are excluded on the basis of potential immune suppression. - Subjects with inadequate peripheral vein access to undergo leukapheresis will be excluded. - Female subjects with a positive pregnancy test, as well as those who have not previously undergone hysterectomy and/or bilateral oophorectomy and are unwilling to utilize a medically approved form of contraception, from the time of enrollment until 6 weeks after the final immunization, will be excluded. - Male subjects, not previously surgically sterilized, who are unwilling to use a condom with spermicide during any sexual activity occurring over the entire immunization period and for the 6 weeks that immediately follow the final immunization will be excluded. - Subjects with a documented history of severe allergic reaction to beta-lactams, eggs or soy products. |
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Factorial Assignment, Masking: Open Label
Country | Name | City | State |
---|---|---|---|
United States | Duke University Medical Center | Durham | North Carolina |
Lead Sponsor | Collaborator |
---|---|
Duke University |
United States,
Boczkowski D, Lee J, Pruitt S, Nair S. Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy. Cancer Gene Ther. 2009 Dec;16(12):900-11. doi: 10.1038/cgt.2009.39. Epub 2009 Jun 5. — View Citation
Pruitt SK, Boczkowski D, de Rosa N, Haley NR, Morse MA, Tyler DS, Dannull J, Nair S. Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. Eur J Immunol. 2011 Dec;41(12):3553-63. doi: 10.1002/eji.201141383. Epub 2011 Oct 26. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Number of Participants with Adverse Events as a Measure of Safety and Tolerability | Safety and Tolerability will be assessed for all subjects during the vaccination period and then regularly during the post-vaccination period. All subjects will then be followed clinically as would be done any subject with melanoma for a total of 5 years. | A minimum of 6 months | Yes |
Secondary | Cellular anti-melanoma immune responses will be assessed | T cells from blood collected after each vaccination and following the full course of vaccination will be assessed for melanoma antigen-specificity using Interferon-gamma Elispot and cytotoxicity assays. Immune responses will be assessed following each vaccination and then will continue to be assessed until anti-melanoma immune responses return to baseline levels. | A minimum of 4 months | No |
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