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Ability of a Dendritic Cell Vaccine to Immunize Melanoma or Epithelial Cancer Patients Against Defined Mutated Neoantigens Expressed by the Autologous Cancer

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ClinicalTrials.gov Identifier: NCT03300843
Recruitment Status : Recruiting
First Posted : October 4, 2017
Last Update Posted : August 3, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Exomes are the parts of DNA that make proteins. Researchers are finding a way to read the letters in the exome. Incorrect letters are called mutations. Tumors contain specific mutations. Researchers can find these mutations in tumors to make treatments. Researchers want to use pieces of participants tumors to find the tumor-specific mutations. They also will take participants white blood cells to make a vaccine that they hope will shrink the tumors.

Objectives:

To see if dendritic vaccine tumor-fighting cells are safe and can cause certain cancer tumors to shrink.

Eligibility:

Adults ages 18-70 who have metastatic melanoma or metastatic epithelial cancer

Design:

The first part of this study was done under protocol 03-C-0277. In that study, white blood cells and pieces of participants' tumors were taken to make a vaccine.

In this study, participants will get a vaccine every 2 weeks for 8 weeks. It will be given both in a vein and under the skin. At each visit, participants will have a physical exam and have blood taken. They will talk about any side effects they have.

After treatment ends, participants will have many follow-up visits for the first year, then once each year after that. Visits will last up to 2 days each. They will include lab tests, imaging studies, and a physical exam. Blood will be taken at each visit. At the first follow-up visit, participants may have leukapheresis, which they also had as part of protocol 03-C-0277. Participants may not have to return to the Clinical Center for these visits.


Condition or disease Intervention/treatment Phase
Melanoma Gastrointestinal Cancer Breast Cancer Ovarian Cancer Pancreatic Cancer Biological: Peptide loaded dendritic cell vaccine Phase 2

Detailed Description:

Background:

  • Therapeutic vaccination against cancer has proven very challenging with little clinical benefit.
  • Vaccines against non-viral tumors have mainly targeted differentiation antigens, cancer testis antigens, and overexpressed antigens. However negative selection in the thymus against these normal nonmutated antigens severely limits the ability to generate high avidity anti-cancer T cells. Such depletion can impair their antitumor activity and limit tumor elimination.
  • The National Cancer Institute Surgery Branch (NCI SB ) has developed a pipeline for the identification of immunogenic T cell epitopes derived from neoantigens.
  • In recent studies, we identified the neoantigens recognized by TIL that mediated regression in patients with metastatic cancer. Using whole exome sequencing of a resected metastatic nodule followed by high throughput immunologic screening, we were able to demonstrate that tumor regressions were associated with the recognition by the administered TIL of unique somatic mutations that occurred in the cancer.
  • We, therefore, aim to use this pipeline to identify immunogenic neoantigens from epithelial cancer patients and to use these defined epitopes for a personalized therapeutic dendritic cell (DC) vaccine.

Objectives:

-Primary objectives:

--To determine the clinical response rate in patients with metastatic melanoma or epithelial cancer who receive this DC vaccine

Eligibility:

  • Age greater than or equal to 18 and less than or equal to 70 years
  • ECOG 0 - 2
  • Evaluable metastatic melanoma or epithelial cancer refractory to standard treatment
  • Metastatic melanoma or epithelial cancer lesion(s) that is resectable for TIL or in selected cases, available PBMC.

Design:

  • Patients with metastatic melanoma or epithelial cancer will undergo surgical resection of tumor followed by exome and RNA sequencing to identify expressed mutations (CONDUCTED UNDER THE nci sb COMPANION PROTOCOL 03-c-0277).
  • Patients will undergo apheresis and DC will be cryopreserved for vaccine preparation.
  • Immunogenic neoantigens will be identified from TIL and PBMC by high throughput immunologic screening using long peptides and tandem minigenes covering all mutated epitopes.
  • Patient will be vaccinated with autologous mature dendritic cells loaded with long peptides and minimal epitopes from defined neoantigens or highly expressed mutations in tumor suppressor or driver genes.
  • DC will be administered intravenously and subcutaneously for four cycles at biweekly intervals.
  • Blood samples will be taken every two weeks, and patients will be monitored for the quantity and quality of circulating neoantigen-specific T cells.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 participants
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial to Evaluate the Ability of a Dendritic Cell Vaccine to Immunize Melanoma or Epithelial Cancer Patients Against Defined Mutated Neoantigens Expressed by the Autologous Cancer
Actual Study Start Date : April 11, 2018
Estimated Primary Completion Date : February 2, 2027
Estimated Study Completion Date : February 2, 2028


Arm Intervention/treatment
Experimental: Experimental Therapy
Peptide loaded dendritic cell vaccine on days 0, 14, 28, and 42
Biological: Peptide loaded dendritic cell vaccine
On days 0, 14 (+/- 5 days), 28 (+/- 5 days), and 42 (+/- 5 days). The vaccine will be administered as both an intravenous (IV) infusion and a subcutaneous (SQ) injection. The total dose will be divided equally between IV and SQ containing 1.0E7 to 8.0E7 cells per cycle depending upon the manufacturing yield.




Primary Outcome Measures :
  1. Response rate [ Time Frame: 2 weeks after 4th vaccine, then 1 month x1, then every 2 months for the 1st year, then as annually. ]
    Percentage of patients who have a clinical response to treatment


Secondary Outcome Measures :
  1. Quantity and quality of circulating antigen-specific T cells [ Time Frame: approximately 6 years after cell infusion ]
    Eliza and Elispot assays assessing reactivity to the mutated peptidecompared to the non-mutated peptide

  2. Frequency of treatment related adverse [ Time Frame: 30 days after the first follow-up evaluation on Day 56 ]
    Aggregate of all adverse events and their frequency



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Metastatic melanoma or epithelial cancer with at least one lesion that is resectable or in selected cases, available PBMCs
  • Measurable and evaluable metastatic disease per RECIST 1.1 criteria
  • Confirmation of the diagnosis of metastatic cancer by the Laboratory of Pathology of NCI.
  • All patients must be refractory to approved standard systemic therapy.
  • Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
  • Greater than or equal to 18 years of age and less than or equal to 70 years of age.
  • Clinical performance status of ECOG 0, 1, 2
  • Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after treatment.
  • Serology:

    • Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus are less responsive to the experimental treatment and more susceptible to its toxicities.)
    • Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then the patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
  • Hematology

    • Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim
    • WBC greater than or equal to 3000/mm^3
    • Platelet count greater than or equal to 100,000/mm^3
    • Hemoglobin > 8.0 g/dl. Subjects may be transfused to reach this cut-off.
    • CD4 count > 200/uL
  • Chemistry:

    • Serum ALT/AST less than 5.0 x ULN
    • Serum Creatinine less than or equal to 1.6 mg/dl
    • Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert's Syndrome, who must have a total bilirubin less than or equal to 3.0 mg/dl.
  • More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the vaccine, and patients toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).

Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.

  • Ability of subject to understand and the willingness to sign a written informed consent document.
  • Subjects must be co-enrolled On protocol 03-C-0277.

EXCLUSION CRITERIA:

  • Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  • Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
  • Active systemic infections (requiring anti-infective treatment), coagulation disorders or any other active or uncompensated major medical illnesses.
  • Patients who are receiving any other investigational agents.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03300843


Contacts
Contact: Margaret Shovlin, R.N. (866) 820-4505 IRC@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center    866-820-4505    irc@nih.gov   
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03300843     History of Changes
Other Study ID Numbers: 170177
17-C-0177
First Posted: October 4, 2017    Key Record Dates
Last Update Posted: August 3, 2018
Last Verified: August 1, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Cell Therapy
Immunotherapy
Vaccines

Additional relevant MeSH terms:
Melanoma
Pancreatic Neoplasms
Gastrointestinal Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gastrointestinal Diseases
Vaccines
Immunologic Factors
Physiological Effects of Drugs