Description:
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.
Title
- Brief Title: Mutant CALR-peptide Based Vaccine in Patients With Mutated CALR Myeloproliferative Neoplasm
- Official Title: A Phase I Open Label Peptide Based Vaccine in Patients With Myeloproliferative Neoplasm Harboring CALR Mutations
Clinical Trial IDs
- ORG STUDY ID:
GCO 17-2449
- NCT ID:
NCT05025488
Conditions
- Myelofibrosis
- Essential Thrombocythemia
- MPN
Interventions
| Drug | Synonyms | Arms |
|---|
| Peptide-based vaccine | | CALR mutated |
| Poly ICLC | | CALR mutated |
Purpose
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.
Detailed Description
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| CALR mutated | Experimental | peptide-based vaccine in patients with myeloproliferative neoplasm (myelofibrosis and essential thrombocythemia) with CALR mutations | - Peptide-based vaccine
- Poly ICLC
|
Eligibility Criteria
Inclusion Criteria
- Subjects must be ≥18 years of age at the time of signing the informed consent form.
- Confirmed diagnosis of chronic phase MPN: high risk ET (HU failure/intolerance),
low-intermediate 1 (DIPSS 0-1) PMF
- Verified mutation in CALR exon 9
- PS ≤ 2
- 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.
- INR<2 if off of anticoagulation. Patients on anticoagulation therapy with an
INR>2 may be enrolled at the discretion of the investigator if they have not had
any episodes of severe hemorrhage.
- 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 before
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 child bearing
potential even if they have had a successful vasectomy.
- Ability to understand and the willingness to sign a written informed consent.
- Ability to adhere to the study visit schedule and all protocol requirements
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 Ruxolitinib or Fedratinib use
- Current use of hydroxyurea
- Current use of INF (use of anagrelide is permitted)
- Treatment with other experimental drugs
- Any significant psychiatric/medical condition per investigators judgment
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Number of Participants with Dose Limiting Toxicity (DLT) |
| Time Frame: | 32 weeks |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | Number of Adverse Events |
| Time Frame: | Week 32 |
| Safety Issue: | |
| Description: | The type, incidence, severity, seriousness, and relatedness of adverse events (AEs) per NCI CTCAE v5.0. |
| Measure: | Number of laboratory abnormalities |
| Time Frame: | Baseline through Week 32 |
| Safety Issue: | |
| Description: | Number of observations, severity, and relatedness of clinical laboratory tests (hematology, biochemistry) |
| Measure: | Change in Immune Milieu Composite |
| Time Frame: | Baseline through Weeks 55 or 80 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Change in CALR VAF |
| Time Frame: | Baseline through Weeks 55 or 80 |
| Safety Issue: | |
| Description: | The % change in driver mutation burden (CALR VAF) as compared to baseline |
| Measure: | Proportion of participants who normalize their platelet number |
| Time Frame: | Week 32 and weeks 55 or 80 |
| Safety Issue: | |
| Description: | The proportion of patients who normalize their platelet number and/or achieve platelets less than 600 if started with platelet above 600. |
| Measure: | Proportion of participants achieving response |
| Time Frame: | Baseline and Week 32 |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Myelofibrosis Symptom Assessment Form (MF-SAFv4.0) |
| Time Frame: | Week 32 and weeks 55 or 80 |
| Safety Issue: | |
| Description: | 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. |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Not yet recruiting |
| Lead Sponsor: | Michal Bar-Natan |
Trial Keywords
Last Updated
August 27, 2021
