Back to results

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

Primary Purpose

Myelofibrosis, Essential Thrombocythemia, MPN

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Peptide-based vaccine

Poly ICLC

About this trial

This is an interventional treatment trial for Myelofibrosis focused on measuring CALR, Vaccine, MF, ET, peptide

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Icahn School of Medicine at Mount SinaiRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

CALR mutated

Arm Description

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Number of Adverse Events

The type, incidence, severity, seriousness, and relatedness of adverse events (AEs) per NCI CTCAE v5.0.

Number of laboratory abnormalities

Number of observations, severity, and relatedness of clinical laboratory tests (hematology, biochemistry)

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.

Change in CALR VAF

The % change in driver mutation burden (CALR VAF) as compared to baseline

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.

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

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.

Full Information

NCT ID

NCT05025488

First Posted

August 24, 2021

Last Updated

April 4, 2023

Sponsor

Marina Kremyanskaya

1. Study Identification

Unique Protocol Identification Number

NCT05025488

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Recruiting

Study Start Date

April 4, 2023 (Actual)

Primary Completion Date

January 2024 (Anticipated)

Study Completion Date

January 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Marina Kremyanskaya

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myelofibrosis, Essential Thrombocythemia, MPN

Keywords

CALR, Vaccine, MF, ET, peptide

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

CALR mutated

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Peptide-based vaccine

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Poly ICLC

Intervention Description

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.

Primary Outcome Measure Information:

Title

Number of Participants with Dose Limiting Toxicity (DLT)

Description

Time Frame

32 weeks

Secondary Outcome Measure Information:

Title

Number of Adverse Events

Description

The type, incidence, severity, seriousness, and relatedness of adverse events (AEs) per NCI CTCAE v5.0.

Time Frame

Week 32

Title

Number of laboratory abnormalities

Description

Number of observations, severity, and relatedness of clinical laboratory tests (hematology, biochemistry)

Time Frame

Baseline through Week 32

Title

Change in Immune Milieu Composite

Description

Time Frame

Baseline through Weeks 55 or 80

Title

Change in CALR VAF

Description

The % change in driver mutation burden (CALR VAF) as compared to baseline

Time Frame

Baseline through Weeks 55 or 80

Title

Proportion of participants who normalize their platelet number

Description

The proportion of patients who normalize their platelet number and/or achieve platelets less than 600 if started with platelet above 600.

Time Frame

Week 32 and weeks 55 or 80

Title

Proportion of participants achieving response

Description

Time Frame

Baseline and Week 32

Title

Myelofibrosis Symptom Assessment Form (MF-SAFv4.0)

Description

Time Frame

Week 32 and weeks 55 or 80

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Marina Kremyanskaya, MD, PhD

Phone

(212) 241-4106

marina.kremyanskaya@mssm.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Mikaela Dougherty

Phone

212-241-8839

mikaela.dougherty@mssm.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Marina Kremyanskaya, MD, PhD

Organizational Affiliation

Icahn School of Medicine at Mount Sinai

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Nina Bhardwaj, MD, PhD

Organizational Affiliation

Icahn School of Medicine at Mount Sinai

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Camelia Iancu-Rubin, PhD

Organizational Affiliation

Icahn School of Medicine at Mount Sinai

Official's Role

Study Chair

Facility Information:

Facility Name

Icahn School of Medicine at Mount Sinai

City

New York

State/Province

New York

ZIP/Postal Code

10029

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Mikaela Dougherty, BS

Phone

212-241-8839

mikaela.dougherty@mssm.edu

First Name & Middle Initial & Last Name & Degree

Marina Kremyanskaya, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

Not determined at this time

Learn more about this trial

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

We'll reach out to this number within 24 hrs