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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Essential Thrombocythemia; Myelofibrosis; MPN
• Intervention / Treatment: Drug: Peptide-based vaccine; Drug: Poly ICLC

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.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Marina Kremyanskaya, MD, PhD; Phone Number: (212) 241-4106; Email: marina.kremyanskaya@mssm.edu
• Study Contact Backup: Name: Mikaela Dougherty; Phone Number: 212-241-8839; Email: mikaela.dougherty@mssm.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • Icahn School of Medicine at Mount Sinai
      • Principal Investigator: Marina Kremyanskaya, MD, PhD
      • Contact: Mikaela Dougherty, BS; Phone Number: 212-241-8839; Email: mikaela.dougherty@mssm.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CALR mutated; peptide-based vaccine in patients with myeloproliferative neoplasm (myelofibrosis and essential thrombocythemia) with CALR mutations

Drug: Peptide-based vaccine; 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.; Drug: Poly ICLC; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Marina Kremyanskaya
• Investigators: Principal Investigator: Marina Kremyanskaya, MD, PhD, Icahn School of Medicine at Mount Sinai; Study Chair: Nina Bhardwaj, MD, PhD, Icahn School of Medicine at Mount Sinai; Study Chair: Camelia Iancu-Rubin, PhD, Icahn School of Medicine at Mount Sinai

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2023
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: August 24, 2021
• First Submitted That Met QC Criteria: August 24, 2021
• First Posted (Actual): August 27, 2021

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 14, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Vaccine; MF; peptide; CALR; ET
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Blood Coagulation Disorders; Blood Platelet Disorders; Neoplasms; Thrombocytosis; Thrombocythemia, Essential; Myeloproliferative Disorders; Physiological Effects of Drugs; Immunologic Factors; Interferon Inducers; Poly ICLC
• Other Study ID Numbers: GCO 17-2449

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Not determined at this time

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No