Mutant CALR-peptide Based Vaccine in Patients With Mutated CALR Myeloproliferative Neoplasm

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase I Open Label Peptide Based Vaccine in Patients With Myeloproliferative Neoplasm Harboring CALR Mutations

Conditions
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Myelofibrosis, Essential Thrombocythemia, MPN

Intervention / Treatment
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* Drug: Peptide-based vaccine
* Drug: Poly ICLC


Participation Criteria
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Eligibility Criteria
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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 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CALR mutated<br>peptide-based vaccine in patients with myeloproliferative neoplasm (myelofibrosis and essential thrombocythemia) with CALR mutations | Drug: Peptide-based vaccine<br>* 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.<br>Drug: Poly ICLC<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Dose Limiting Toxicity (DLT) | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events | The type, incidence, severity, seriousness, and relatedness of adverse events (AEs) per NCI CTCAE v5.0. | Week 32 | 
| Number of laboratory abnormalities | Number of observations, severity, and relatedness of clinical laboratory tests (hematology, biochemistry) | Baseline through Week 32 | 
| Change in Immune Milieu Composite | 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 | 
| Change in CALR VAF | The % change in driver mutation burden (CALR VAF) as compared to baseline | Baseline through Weeks 55 or 80 | 
| Proportion of participants who normalize their platelet number | 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 | 
| Proportion of participants achieving response | 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 | 
| Myelofibrosis Symptom Assessment Form (MF-SAFv4.0) | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CALR, Vaccine, MF, ET, peptide