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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

Primary Purpose

Melanoma, Gastrointestinal Cancer, Breast Cancer

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Peptide loaded dendritic cell vaccine

About this trial

This is an interventional treatment trial for Melanoma focused on measuring Cell Therapy, Immunotherapy, Vaccines

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA:
Metastatic melanoma or epithelial cancer with at least one lesion that is resectable or in selected cases, available peripheral blood mononuclear cells (PBMCs)
Measurable and evaluable metastatic disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
Confirmation of the diagnosis of metastatic cancer by the Laboratory of Pathology of National Cancer Institute (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 Eastern Cooperative Oncology Group (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 Human Immunodeficiency Virus (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 reverse transcriptase polymerase chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA) negative.
Hematology
- Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim
- White blood cell (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.
- Cluster of differentiation 4 (CD4) count > 200/uL
Chemistry:
- Serum alanine aminotransferase (ALT)/aspartate aminotransferase (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.

Sites / Locations

National Institutes of Health Clinical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Peptide loaded dendritic cell vaccine

Arm Description

Peptide loaded dendritic cell vaccine on days 0, 14, 28, and 42

Outcomes

Primary Outcome Measures

Percentage of Patients Who Had a Clinical Response (Complete Response (CR) + Partial Response (PR)) to Treatment

Response was assessed by the RECIST v1.1. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

Secondary Outcome Measures

Number of Participants With 2-3 Fold Increase From Baseline in Reactivity to Circulating Antigen-specific T Cells to the Mutated Peptide Compared to the Non-mutated Peptide

Enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immune absorbent spot (ELISpot) assays assessed reactivity to the mutated peptide compared to the non-mutated peptide. Differences of 2-3 fold in these assays over the baseline measurement are indicative of true biologic differences.

Number of Participants With Serious and Non-serious Adverse Events

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Full Information

NCT ID

NCT03300843

First Posted

October 3, 2017

Last Updated

November 19, 2019

Sponsor

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT03300843

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2019

Overall Recruitment Status

Terminated

Why Stopped

slow accrual

Study Start Date

April 11, 2018 (Actual)

Primary Completion Date

July 9, 2019 (Actual)

Study Completion Date

September 16, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Background: Exomes are the parts of deoxyribonucleic acid (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.

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 tumor infiltrating lymphocytes (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 Eastern Cooperative Oncology Group (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 peripheral blood mononuclear cells (PBMC). Design: Patients with metastatic melanoma or epithelial cancer will undergo surgical resection of tumor followed by exome and ribonucleic acid (RNA) sequencing to identify expressed mutations (CONDUCTED UNDER THE National Cancer Institute Surgery Branch (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.

6. Conditions and Keywords

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

Melanoma, Gastrointestinal Cancer, Breast Cancer, Ovarian Cancer, Pancreatic Cancer

Keywords

Cell Therapy, Immunotherapy, Vaccines

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

1 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Peptide loaded dendritic cell vaccine

Arm Type

Experimental

Arm Description

Peptide loaded dendritic cell vaccine on days 0, 14, 28, and 42

Intervention Type

Biological

Intervention Name(s)

Peptide loaded dendritic cell vaccine

Intervention Description

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 intravenous (IV) and SQ containing 1.0E7 to 8.0E7 cells per cycle depending upon the manufacturing yield.

Primary Outcome Measure Information:

Title

Percentage of Patients Who Had a Clinical Response (Complete Response (CR) + Partial Response (PR)) to Treatment

Description

Time Frame

up to 6 months

Secondary Outcome Measure Information:

Title

Number of Participants With 2-3 Fold Increase From Baseline in Reactivity to Circulating Antigen-specific T Cells to the Mutated Peptide Compared to the Non-mutated Peptide

Description

Time Frame

Day 0, Day 14 (± 5 d), Day 28 (± 5 d), and Day 42 (± 5 d)

Title

Number of Participants With Serious and Non-serious Adverse Events

Description

Time Frame

Date treatment consent signed to date off study, approximately 6 months and 11 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

INCLUSION CRITERIA: Metastatic melanoma or epithelial cancer with at least one lesion that is resectable or in selected cases, available peripheral blood mononuclear cells (PBMCs) Measurable and evaluable metastatic disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria Confirmation of the diagnosis of metastatic cancer by the Laboratory of Pathology of National Cancer Institute (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 Eastern Cooperative Oncology Group (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 Human Immunodeficiency Virus (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 reverse transcriptase polymerase chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA) negative. Hematology Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim White blood cell (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. Cluster of differentiation 4 (CD4) count > 200/uL Chemistry: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Steven A Rosenberg, M.D.

Organizational Affiliation

National Cancer Institute (NCI)

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

19935803

Citation

Klein L, Hinterberger M, Wirnsberger G, Kyewski B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol. 2009 Dec;9(12):833-44. doi: 10.1038/nri2669.

Results Reference

background

PubMed Identifier

20085707

Citation

Abramson J, Giraud M, Benoist C, Mathis D. Aire's partners in the molecular control of immunological tolerance. Cell. 2010 Jan 8;140(1):123-35. doi: 10.1016/j.cell.2009.12.030.

Results Reference

background

PubMed Identifier

23243587

Citation

Bos R, Marquardt KL, Cheung J, Sherman LA. Functional differences between low- and high-affinity CD8(+) T cells in the tumor environment. Oncoimmunology. 2012 Nov 1;1(8):1239-1247. doi: 10.4161/onci.21285.

Results Reference

background

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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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