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

Study Overview
=================
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

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 non-mutated 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 melanoma. 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 also found that TIL from 29 of 32 patients with a wide variety of metastatic gastrointestinal cancers contained lymphocytes that recognized unique mutations presented in that patient's cancer. We, therefore, aim to use this pipeline to identify immunogenic neoantigens and to predict for neoantigens binding the patient human leukocyte antigen (HLA) molecules from melanoma or epithelial cancer patients and to use these epitopes for a personalized therapeutic messenger ribonucleic acid (mRNA) vaccine. Objectives Primary objectives: Determine the clinical response rate in patients with metastatic melanoma, gastrointestinal or genitourinary cancers who receive NCI-4650 Determine the safety of NCI-4650 in patients with metastatic melanoma, gastrointestinal or genitourinary cancers Eligibility Age greater than or equal to 18 years and less than or equal to 70 years Evaluable metastatic melanoma, gastrointestinal, or genitourinary cancers refractory to standard of care treatment Metastatic cancer lesions suitable for surgical resection to perform whole exome sequencing and preparation of TIL Design: Patients with metastatic cancer will undergo surgical resection of tumor followed by exome and RNA sequencing to identify expressed mutations. This will be conducted under the NCI-SB cell harvest protocol 03-C-0277. (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols). Immunogenic neoantigens will be identified from TIL by high throughput immunologic screening using long peptides and tandem minigenes covering all mutated epitopes. Up to 15 predicted neoantigens will be selected based on exome and RNA sequencing and their binding affinity to the patient HLA molecules. The mRNA vaccine will be manufactured and supplied as Current Good Manufacturing Practice (cGMP) product by ModernaTX, Inc. The patient will be vaccinated with mRNA containing epitopes from immunogenic neoantigens, predicted neoantigens and mutations in tumor suppressor or driver genes. The mRNA vaccine will be administered intramuscularly (IM) for four cycles every two weeks. A patient may receive a second course for a total of eight cycles given. Blood samples will be taken every two weeks (during the vaccination period) and at each follow-up visit, and patients will be monitored for the quantity and quality of circulating neoantigen-specific T-cells.

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

Conditions
-----------------
Melanoma, Colon Cancer, Gastrointestinal Cancer, Genitourinary Cancer, Hepatocellular Cancer

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


Participation Criteria
=================
Eligibility 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Phase - Escalating doses of mRNA vaccine<br>Escalating doses of messenger ribonucleic acid (mRNA) vaccine | Biological: National Cancer Institute (NCI)-4650, a messenger ribonucleic acid (mRNA)-based, Personalized Cancer Vaccine<br>* 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.<br>|
| Experimental: 2/Phase II -MTD of mRNA vaccine established in Phase I<br>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<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Increase in the Quantity and Quality of Circulating Antigen-specific T Cells | 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. | Approximately 2 weeks after last vaccine | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Metastatic Cancer, Immunotherapy, Tumor Regression, Cancer Vaccine, Gene Therapy