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Messenger RNA (mRNA)-Based, Personalized Cancer Vaccine Against Neoantigens Expressed by the Autologous Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03480152
Recruitment Status : Terminated (slow accrual)
First Posted : March 29, 2018
Results First Posted : April 24, 2020
Last Update Posted : June 2, 2020
Sponsor:
Information provided by (Responsible Party):
Steven Rosenberg, M.D., National Cancer Institute (NCI)

Brief Summary:

Background:

Exome sequencing can identify certain gene mutations in a person's tumor. This can then be used to create cancer treatments. In this study, researchers will make a treatment called a messenger ribonucleic acid (mRNA) vaccine. The vaccine might cause certain tumors to shrink.

Objective:

To see if the mRNA vaccine is safe and can cause metastatic melanoma or epithelial tumors to shrink.

Eligibility:

People 18-70 years old with metastatic melanoma or epithelial cancer

Design:

Participants will be screened under protocol 99-C-0128.

Participants will provide samples under protocol 03-C-0277:

Participants will provide a piece of their tumor from a previous surgery or biopsy.

Participants will have leukapheresis: Blood is removed through a needle in one arm and circulated through a machine that takes out the white blood cells. The blood is then returned through a needle in the other arm.

Participants will have many tests:

Scans and x-rays

Heart and lung function tests

Blood and urine tests

Participants will receive the mRNA vaccine every 2 weeks for up to 8 weeks. They will get the vaccine as an injection into the upper arm or thigh. They may receive a second course of vaccines if the study doctor determines it is needed.

Participants will have follow-up visits approximately 2 weeks after their final vaccine, then 1 month later, then every 1-2 months for the first year, and then once a year for up to 5 years. Each visit may take up to 2 days and include:

Physical exam

Blood tests

Scans

Leukapheresis at the first visit


Condition or disease Intervention/treatment Phase
Melanoma Colon Cancer Gastrointestinal Cancer Genitourinary Cancer Hepatocellular Cancer Biological: National Cancer Institute (NCI)-4650, a messenger ribonucleic acid (mRNA)-based, Personalized Cancer Vaccine Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial to Evaluate the Safety and Immunogenicity of a Messenger RNA (mRNA)-Based, Personalized Cancer Vaccine Against Neoantigens Expressed by the Autologous Cancer
Actual Study Start Date : May 18, 2018
Actual Primary Completion Date : June 25, 2019
Actual Study Completion Date : November 5, 2019

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma

Arm Intervention/treatment
Experimental: 1/Phase - Escalating doses of mRNA vaccine
Escalating doses of messenger ribonucleic acid (mRNA) vaccine
Biological: National Cancer Institute (NCI)-4650, a messenger ribonucleic acid (mRNA)-based, Personalized Cancer Vaccine
Patients will receive a messenger ribonucleic acid (mRNA)-based vaccine intramuscularly at two-week intervals for four cycles (one course of treatment). Patients may be vaccinated with a second and final course of treatment using the same vaccine dose. The second course may start approximately four weeks (plus or minus 2 weeks) from the last vaccine dose of the first course.

Experimental: 2/Phase II -MTD of mRNA vaccine established in Phase I
Maximum tolerated dose (MTD) of messenger ribonucleic acid (mRNA) vaccine established in Phase I
Biological: National Cancer Institute (NCI)-4650, a messenger ribonucleic acid (mRNA)-based, Personalized Cancer Vaccine
Patients will receive a messenger ribonucleic acid (mRNA)-based vaccine intramuscularly at two-week intervals for four cycles (one course of treatment). Patients may be vaccinated with a second and final course of treatment using the same vaccine dose. The second course may start approximately four weeks (plus or minus 2 weeks) from the last vaccine dose of the first course.




Primary Outcome Measures :
  1. Number of Participants Who Had a Clinical Response (Complete Response + Partial Response) to Treatment (Objective Tumor Regression) [ Time Frame: up to 12 months ]
    Clinical response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete Response (CR) 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 (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

  2. Number of Non-Serious Adverse Events Probably Related to Treatment [ Time Frame: During treatment and up to 30 days after the first follow- up evaluation (at the second follow-up evaluation) ]
    Here is the number of non-serious adverse events probably related to treatment assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).


Secondary Outcome Measures :
  1. Number of Participants With an Increase in the Quantity and Quality of Circulating Antigen-specific T Cells [ Time Frame: Approximately 2 weeks after last vaccine ]
    Participants blood samples were assessed by fluorescence-activated cell sorting (FACS), enzyme-linked immune absorbent (ELISA)-spot and human soluble cluster of differentiation 137 (CD137) (4-1BB) upregulation assays. Differences of 2-3 fold in these assays over the baseline measures are indicative of true biologic difference.


Other Outcome Measures:
  1. Number of Participants With Non-Serious Adverse Events Regardless of Attribution [ Time Frame: Date treatment consent signed to date off study, approximately 11 months and 4 days. ]
    Here is the count of participants with 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.

  2. Number of Dose Limiting Toxicities (DLT) [ Time Frame: Up to 21 days after the first vaccination ]
    A DLT is all Grade 3 or greater toxicities related to the messenger ribonucleic acid vaccine with exception of Grade 3 fever, Grade 3 pruritic/itching, Grade 3 fatigue, Grade 3 metabolic laboratory abnormalities without significant clinical sequela that resolves to Grade 2 or less within 7 days, Grade 3 autoimmune toxicity that resolves to Grade 2 or less in 7 days and events that are clearly related to the patient's disease.

  3. Maximum Tolerated Dose (MTD [ Time Frame: Up to 21 days after the first vaccination ]
    A MTD is the highest dose at which ≤1 of 6 patient's experienced a dose limiting toxicity (i.e., All Grade 3 or greater toxicities related to the messenger ribonucleic acid vaccine with exception of Grade 3 fever, Grade 3 pruritic/itching, Grade 3 fatigue, Grade 3 metabolic laboratory abnormalities without significant clinical sequela that resolves to Grade 2 or less within 7 days, Grade 3 autoimmune toxicity that resolves to Grade 2 or less in 7 days and events that are clearly related to the patient's disease.) or the highest dose level studied if DLT's are not observed at any of the dose levels.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:
  • Measurable (per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria), metastatic melanoma, gastrointestinal, or genitourinary cancer with at least one lesion that is resectable. Only patients with metastatic gastrointestinal cancer will be eligible for enrollment on the Phase I portion of the study. Patients with metastatic melanoma, gastrointestinal, or genitourinary cancer will be eligible for enrollment on the Phase II portion of the study.
  • Confirmation of diagnosis of metastatic cancer by the National Cancer Institute (NCI) Laboratory of Pathology.
  • 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.
  • Prior therapy with at least one first-line standard of care treatment or second-line treatment of proven effectiveness. Patients must have progressive disease after prior treatment. Prior first-or second-line treatments would include the following:

    • Patients with metastatic melanoma: Receipt of a checkpoint inhibitor as first-line therapy
    • Patients with metastatic melanoma with an activating mutation of KIT: Receipt of Imatinib
    • Patients with a BRAF V600 activating mutation: Receipt of appropriate targeted therapy
    • Patients with metastatic gastrointestinal cancer: Receipt of up to two forms of approved first- and/or second-line chemotherapy regimens
    • Patients with metastatic genitourinary cancers: Receipt of a first- or second-line therapy appropriate for their histologic subtype
  • Age greater than or equal to 18 years and less than or equal to 70 years.
  • Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
  • 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 may have decreased immune-competence and thus may be 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 transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) ribonucleic acid (RNA) negative.
  • Hematology

    • Absolute neutrophil count (ANC) > 1000/mm(3) without the support of growth factors.
    • 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.
  • Chemistry

    • Serum Alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) less than or equal to 5.0 times upper limit of normal (ULN)
    • Serum creatinine <1.5 times ULN or measured creatinine clearance (calculated using Cockcroft-Gault formula) > 40 ml/min
    • Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert's Syndrome, who must have a total bilirubin < 3.0 mg/dl.
  • More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the immunization regimen, and patients' toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
  • 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:

  • Pregnant or breastfeeding women who do not consent to stop breast-feeding while on study treatment and for 30 days after the use of the investigational vaccine where pregnancy is confirmed by a positive, rising human chorionic gonadotropin (hCG) laboratory test.

    • Women of child-bearing potential, defined as all women capable of becoming pregnant, unless they agree to use an appropriate method of contraception during dosing and for 120 days after the last dose (i.e., final vaccine). Effective contraception methods include a combination of any two of the following (unless method is abstinence or sterilization, in which only one method is required):

      • Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%). In case of use of oral contraception, women should have been stable on the same pill for a minimum of 6 months before taking study treatment.
      • Placement of an intrauterine device or intrauterine system.
      • Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
      • Total abstinence
      • Female sterilization at least eight weeks before taking study treatment.
      • Male sterilization (at least six months prior to screening).
  • Sexually active males must use a condom during intercourse during dosing and for 120 days after the last dose (i.e., final vaccine), and should not father a child in this period.
  • Any systemic steroid therapy or other form of immunosuppressive therapy within 7 days of the first dose of the vaccine. A physiologic dose of systemic corticosteroids may be approved. Inhaled or topical steroids, and less than or equal to 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
  • Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses of the cardiovascular, respiratory, or immune system.
  • 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).
  • Any vaccinations four weeks prior to the first vaccination cycle or live vaccines at any time during the study.

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): NCT03480152


Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
  Study Documents (Full-Text)

Documents provided by Steven Rosenberg, M.D., National Cancer Institute (NCI):
Informed Consent Form  [PDF] January 28, 2019

Publications:
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Responsible Party: Steven Rosenberg, M.D., Principal Investigator, National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03480152    
Other Study ID Numbers: 180074
18-C-0074
First Posted: March 29, 2018    Key Record Dates
Results First Posted: April 24, 2020
Last Update Posted: June 2, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Steven Rosenberg, M.D., National Cancer Institute (NCI):
Metastatic Cancer
Immunotherapy
Tumor Regression
Cancer Vaccine
Gene Therapy
Additional relevant MeSH terms:
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Gastrointestinal Neoplasms
Liver Neoplasms
Carcinoma, Hepatocellular
Urogenital Neoplasms
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Liver Diseases
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial