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

NCT03480152 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 18007418-C-0074
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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

Conditions

Melanoma; Colon Cancer; Gastrointestinal Cancer; Genitourinary Cancer; Hepatocellular Cancer

Keywords

Metastatic Cancer; Immunotherapy; Tumor Regression; Cancer Vaccine; Gene Therapy

Outcome Measures

Primary Outcomes (2)

• Number of Participants Who Had a Clinical Response (Complete Response + Partial Response) to Treatment (Objective Tumor Regression)

  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.

  up to 12 months

• Number of Non-Serious Adverse Events Probably Related to Treatment

  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).

  During treatment and up to 30 days after the first follow- up evaluation (at the second follow-up evaluation)

Secondary Outcomes (1)

• Number of Participants With an Increase in the Quantity and Quality of Circulating Antigen-specific T Cells

  Approximately 2 weeks after last vaccine

Other Outcomes (3)

• Number of Participants With Non-Serious Adverse Events Regardless of Attribution

  Date treatment consent signed to date off study, approximately 11 months and 4 days.

• Number of Dose Limiting Toxicities (DLT)

  Up to 21 days after the first vaccination

• Maximum Tolerated Dose (MTD

  Up to 21 days after the first vaccination

Study Arms (2)

1/Phase - Escalating doses of mRNA vaccine

EXPERIMENTAL

Escalating doses of messenger ribonucleic acid (mRNA) vaccine

Biological: National Cancer Institute (NCI)-4650, a messenger ribonucleic acid (mRNA)-based, Personalized Cancer Vaccine

2/Phase II -MTD of mRNA vaccine established in Phase I

EXPERIMENTAL

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

Interventions

National Cancer Institute (NCI)-4650, a messenger ribonucleic acid (mRNA)-based, Personalized Cancer Vaccine BIOLOGICAL

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.

1/Phase - Escalating doses of mRNA vaccine; 2/Phase II -MTD of mRNA vaccine established in Phase I

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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.

  PMID: 19935803 BACKGROUND

• 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.

  PMID: 23243587 BACKGROUND

• 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.

  PMID: 20085707 BACKGROUND

• Cafri G, Gartner JJ, Zaks T, Hopson K, Levin N, Paria BC, Parkhurst MR, Yossef R, Lowery FJ, Jafferji MS, Prickett TD, Goff SL, McGowan CT, Seitter S, Shindorf ML, Parikh A, Chatani PD, Robbins PF, Rosenberg SA. mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J Clin Invest. 2020 Nov 2;130(11):5976-5988. doi: 10.1172/JCI134915.

  PMID: 33016924 DERIVED

MeSH Terms

Conditions

Melanoma; Colonic Neoplasms; Gastrointestinal Neoplasms; Urogenital Neoplasms; Liver Neoplasms; Neoplasm Metastasis

Interventions

National Cancer Institute (U.S.)

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Liver Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

National Institutes of Health (U.S.); Academies and Institutes; Organizations; Health Care Economics and Organizations; United States Public Health Service; United States Dept. of Health and Human Services; United States Government Agencies; Federal Government; Government

Results Point of Contact

• Title: Dr. Steven Rosenberg
• Organization: National Cancer Institute

steven-rosenberg@nih.gov

240-858.3080

Study Officials

• Steven A Rosenberg, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 27, 2018
• First Posted: March 29, 2018
• Study Start: May 18, 2018
• Primary Completion: June 25, 2019
• Study Completion: November 5, 2019
• Last Updated: June 2, 2020
• Results First Posted: April 24, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)