Mutáns CALR-peptid alapú vakcina mutált CALR mieloproliferatív daganatos betegekben
Fázis I. nyitott peptid alapú vakcina mieloproliferatív neoplazmában szenvedő betegeknél, amelyek CALR mutációkat hordoznak
The primary objective of this study is to assess the safety and tolerability of administrating mutated-CALR peptide Vaccine to patients with MPN. The researchers plan to enroll 10 patients over a 12 month period. Maximum length of participation in 80 weeks. Patients will be asked to complete questionnaires, bone marrow biopsies, research lab collection, and standard of care lab draw. This research will be taking place only at The Mount Sinai Hospital, specifically at the Ruttenberg Treatment Center.
A tanulmány áttekintése
Állapot
Körülmények
Beavatkozás / kezelés
Részletes leírás
Current MPN treatments are geared towards symptom palliation and not on changing the natural course of the disease. Mutations in calreticulin gene (CALR) is the second most common driver mutation in ET and MF patients (30%). All CALR mutations identified to date in MPN patients result in the formation of an altered protein with an identical 36-amino acid sequence in the C-terminus. This altered protein results in a MPN-specific shared neo-antigen. The mutated CALR neoantigen present in patient with MPN represents an ideal antigen for targeted immunotherapy as it is stably and specifically expressed by the malignant cells and is absent in the normal tissues. CALR neoantigen is immunogenic, effector T cells are capable of recognizing this neo-antigen, and hematopoietic cells carrying the mutation can be potently killed by these specific effector T-cells in vitro.
The researchers believe that a mutated-CALR vaccine will enhance mutated-CALR-specific T cell immunity in MPN patients carrying CALR mutations, which in turn would target and eliminate CALR+ malignant cells, thereby leading to improved clinical outcomes in this patient population.
Tanulmány típusa
Beiratkozás (Tényleges)
Fázis
- 1. fázis
Kapcsolatok és helyek
Tanulmányi helyek
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New York
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New York, New York, Egyesült Államok, 10029
- Icahn School of Medicine at Mount Sinai
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Részvételi kritériumok
Jogosultsági kritériumok
Tanulmányozható életkorok
Egészséges önkénteseket fogad
Tanulmányozható nemek
Leírás
Inclusion Criteria:
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Subjects must be ≥18 years of age at the time of signing the informed consent form.
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Confirmed diagnosis of chronic phase MPN:
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Previously treated or relapsed/refectory high risk ET
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Low to intermediate 1 risk (DIPSS 0-1) PMF or ET-MF
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Verified mutation in CALR exon 9
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PS ≤ 2
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Adequate organ function:
- Absolute neutrophil count ≥ 1000/mm3,
- Platelet count ≥ 50,000/mm3,
- Creatinine ≤ 2.5 mg/dL,
- Total bilirubin ≤ 2 mg/dL, (except in patients with Gilbert Syndrome who can have total bilirubin < 3.0 mg/dL)
- Transaminases < 3 times above the upper limits of the institutional normal.
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Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to starting study medication and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks prior to first dose of vaccine. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy.
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Ability to understand and the willingness to sign a written informed consent.
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Ability to adhere to the study visit schedule and all protocol requirements.
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Subjects receiving cytoreductive therapy with hydroxyurea must be on a stable dose for at least 8 weeks prior to week 1.
Exclusion Criteria:
- Other invasive malignancy in the past 3 years except non-melanoma skin cancer, localized cured prostate cancer and early stage breast cancer on HRT.
- Active autoimmune disease.
- Uncontrolled serious infection.
- Known immunodeficiency.
- Pregnant and breastfeeding women.
- Not willing to use contraception.
- Current use of immunosuppressive medications including steroids.
- Current JAK inhibitor use.
- Current use of IFN (use of anagrelide is permitted).
- Treatment with other experimental drugs within 30 days of week 1.
- Treatment with any MPN directed therapy unless otherwise noted within 5 half-lives of week 1.
- Any significant psychiatric/medical condition per investigators judgment.
Tanulási terv
Hogyan készül a tanulmány?
Tervezési részletek
- Elsődleges cél: Kezelés
- Kiosztás: N/A
- Beavatkozó modell: Egyetlen csoportos hozzárendelés
- Maszkolás: Nincs (Open Label)
Fegyverek és beavatkozások
Résztvevő csoport / kar |
Beavatkozás / kezelés |
|---|---|
|
Kísérleti: CALR mutated
peptide-based vaccine in patients with myeloproliferative neoplasm (myelofibrosis and essential thrombocythemia) with CALR mutations |
ten (10) doses of Mutant-CALR peptides with KLH as helper peptide (in the first vaccine only). Mutant-CALR vaccine will administered every 2 weeks for the first 4 doses and then every 4 weeks for additional 6 doses. Maintenance Treatment The protocol allows for a continued administration of up to four (4) additional Mutant-CALR vaccine and four (4) Poly-ICLC administrations, 12 weeks apart. ten (10) doses of Poly-ICLC. Poly-ICLC will be given on weeks 1, 3, 5, 7, 11, 15, 19, 23, 27 and 31. each Poly-ICLC dose must be given the day after the corresponding Mut-CALR vaccination. |
Mit mér a tanulmány?
Elsődleges eredményintézkedések
Eredménymérő |
Intézkedés leírása |
Időkeret |
|---|---|---|
|
Number of Participants with Dose Limiting Toxicity (DLT)
Időkeret: 32 weeks
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The Dose Limiting Toxicity (DLT) rate, defined as the proportion of patients with at least 1 grade 3 or higher AE considered to be at least possibly related to the treatment with Poly ICLC and CALR vaccines. |
32 weeks
|
Másodlagos eredményintézkedések
Eredménymérő |
Intézkedés leírása |
Időkeret |
|---|---|---|
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Number of Adverse Events
Időkeret: Week 32
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The type, incidence, severity, seriousness, and relatedness of adverse events (AEs) per NCI CTCAE v5.0. |
Week 32
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Number of laboratory abnormalities
Időkeret: Baseline through Week 32
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Number of observations, severity, and relatedness of clinical laboratory tests (hematology, biochemistry) |
Baseline through Week 32
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Change in Immune Milieu Composite
Időkeret: Baseline through Weeks 55 or 80
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Changes in the immune milieu (which is a composite of expression of cytokines, presence of antibodies, alterations in number and phenotype of immune cells and induction of vaccine-specific T cell response) due to the vaccines as compared to baseline values. |
Baseline through Weeks 55 or 80
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Change in CALR VAF
Időkeret: Baseline through Weeks 55 or 80
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The % change in driver mutation burden (CALR VAF) as compared to baseline |
Baseline through Weeks 55 or 80
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Proportion of participants who normalize their platelet number
Időkeret: Week 32 and weeks 55 or 80
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The proportion of patients who normalize their platelet number and/or achieve platelets less than 600 if started with platelet above 600. |
Week 32 and weeks 55 or 80
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Proportion of participants achieving response
Időkeret: Baseline and Week 32
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The proportion of patients achieving response or improvement in their disease status by ELN/IWG criteria for the categories: Complete Response; Partial Response; Clinical Improvement and Stable Disease |
Baseline and Week 32
|
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Myelofibrosis Symptom Assessment Form (MF-SAFv4.0)
Időkeret: Week 32 and weeks 55 or 80
|
The proportion of patients who achieve improvement in quality of life as assessed by the by the Myelofibrosis Symptom Assessment Form. Each of the items are scored 0 to 10, with total score from 0 to 100, with higher score indicating more symptoms. |
Week 32 and weeks 55 or 80
|
Együttműködők és nyomozók
Szponzor
Nyomozók
- Kutatásvezető: Marina Kremyanskaya, MD, PhD, Icahn School of Medicine at Mount Sinai
- Tanulmányi szék: Nina Bhardwaj, MD, PhD, Icahn School of Medicine at Mount Sinai
- Tanulmányi szék: Camelia Iancu-Rubin, PhD, Icahn School of Medicine at Mount Sinai
Tanulmányi rekorddátumok
Tanulmány főbb dátumok
Tanulmány kezdete (Tényleges)
Elsődleges befejezés (Becsült)
A tanulmány befejezése (Becsült)
Tanulmányi regisztráció dátumai
Először benyújtva
Először nyújtották be, amely megfelel a minőségbiztosítási kritériumoknak
Első közzététel (Tényleges)
Tanulmányi rekordok frissítései
Utolsó frissítés közzétéve (Tényleges)
Az utolsó frissítés elküldve, amely megfelel a minőségbiztosítási kritériumoknak
Utolsó ellenőrzés
Több információ
A tanulmányhoz kapcsolódó kifejezések
További vonatkozó MeSH feltételek
Egyéb vizsgálati azonosító számok
- GCO 22-1330
Terv az egyéni résztvevői adatokhoz (IPD)
Tervezi megosztani az egyéni résztvevői adatokat (IPD)?
IPD terv leírása
Not determined at this time
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