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CALR Exon 9 Mutant Peptide Vaccine to Patients With CALR-mutant Myeloproliferative Neoplasms

Primary Purpose

Myeloproliferative Neoplasm, Unclassifiable, Essential Thrombocythemia, Myelofibrosis

Status

Completed

Phase

Phase 1

Locations

Denmark

Study Type

Interventional

Intervention

CALRLong36 peptide

About this trial

This is an interventional treatment trial for Myeloproliferative Neoplasm, Unclassifiable focused on measuring CALR mutation

Eligibility Criteria

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

Inclusion Criteria:

1. Diagnosis of essential thrombocythemia, post essential thrombocythemia myelofibrosis, prefibrotic myelofibrosis or primary myelofibrosis according to the World Health Organization criteria33 2. Verified mutation in CALR exon 9. 4. Performance status ≤ 2 (ECOG-scale) 5. Expected survival > 3 months 6. Sufficient bone marrow function, i.e.

Leucocytes ≥ 1,5 x 109
Granulocytes ≥ 1,0 x 109
Thrombocytes ≥ 20 x 109
Hemoglobin ≥ 7 mmol/L 7. Creatinine < 2.5 upper normal limit, i.e. < 300 µmol/l 8. Sufficient liver function, i.e.

a. Alanine aminotransferase < 2.5 upper normal limit, i.e. ALAT <112 U/l b. Bilirubin < 30 U/l 9. For women: Agreement to use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 120 days after the last treatment.

10. For men: Agreement to use contraceptive measures and agreement to refrain from donating sperm.

Exclusion Criteria:

Other malignancies in the medical history excluding squamous cell carcinoma. Patients cured for another malignant disease with no sign of relapse three years after ended treatment is allowed to enter the protocol.
Significant medical condition per investigators judgement e.g. severe Asthma/chronic obstructive pulmonary disease , poorly regulated heart condition, insulin dependent diabetes mellitus.
Acute or chronic viral or bacterial infection e.g. HIV, hepatitis or tuberculosis
Serious known allergies or earlier anaphylactic reactions.
Known sensibility to Montanide ISA-51
Any active autoimmune diseases e.g. autoimmune neutropenia, thrombocytopenia or hemolytic anemia, systemic lupus erythematosus, scleroderma, myasthenia gravis, autoimmune glomerulonephritis, autoimmune adrenal deficiency, autoimmune thyroiditis etc.
Pregnant and breastfeeding women.
Fertile women not using secure contraception with a failure rate less than < 1%
Patients taking immune suppressive medications incl. corticosteroids and methotrexate at the time of enrollment
Psychiatric disorders that per investigator judgment could influence compliance.
Treatment with other experimental drugs
Treatment with other anti-cancer drugs - except interferon (IFN)-a, hydroxyurea or anagrelide.
Treatment with ruxolitinib.
Treatment with chemotherapy or immune therapy (excluding IFN-a, hydroxyurea or anagrelide) within the last 28 days.

Sites / Locations

Herlev Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

36 aminoacid CALR exon 9 mutated peptide

Arm Description

15 vaccines, over the course of 1 year

Outcomes

Primary Outcome Measures

Adverse events evaluated by CTCAE 4.03

Adverse events are graded 1-5 according to the criteria

Secondary Outcome Measures

Immune responses

T-cell cytokine release towards target antigens

Full Information

NCT ID

NCT03566446

First Posted

June 11, 2018

Last Updated

July 12, 2023

Sponsor

Inge Marie Svane

1. Study Identification

Unique Protocol Identification Number

NCT03566446

Brief Title

CALR Exon 9 Mutant Peptide Vaccine to Patients With CALR-mutant Myeloproliferative Neoplasms

Official Title

A Phase-1-first in Man Study in Patients With CALR-mutant Myeloproliferative Neoplasms by Vaccinating With CALR Exon 9 Mutant Peptide

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Completed

Study Start Date

June 20, 2018 (Actual)

Primary Completion Date

February 20, 2020 (Actual)

Study Completion Date

April 30, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Inge Marie Svane

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

A phase-I-first in man study in patients with calreticulin(CALR)-mutant MPN by vaccinating with exon 9 mutated peptide with the adjuvant Montanide ISA-51 to monitor safety and toxicity and the immunological response to vaccination.

Detailed Description

The Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPN) are acquired cancer diseases, that arise due to mutations in the hematopoietic stem cells in the bone marrow. Median age at diagnosis is approximately 65 years of age and approximately 400 Danes are diagnosed with MPN annually. The MPN comprise essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). In December 2013 two independent research groups reported on the occurrence of somatic mutations in exon 9 of the calreticulin gene in patients with ET and PMF. The overall rationale for a vaccine with CALR-mutant epitopes is that it will initiate a CALR-mutant specific immune response, which will "release the brakes" on the CALR-mutant specific immune response. 10 patients treated with standard therapy are needed for the trial and each patient will receive 15 vaccinations over the course of one year.

6. Conditions and Keywords

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

Myeloproliferative Neoplasm, Unclassifiable, Essential Thrombocythemia, Myelofibrosis

Keywords

CALR mutation

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 (Actual)

8. Arms, Groups, and Interventions

Arm Title

36 aminoacid CALR exon 9 mutated peptide

Arm Type

Experimental

Arm Description

15 vaccines, over the course of 1 year

Intervention Type

Biological

Intervention Name(s)

CALRLong36 peptide

Intervention Description

200 ug CALRLong36 peptide in water mixed with 500ul montanide

Primary Outcome Measure Information:

Title

Adverse events evaluated by CTCAE 4.03

Description

Adverse events are graded 1-5 according to the criteria

Time Frame

1 year

Secondary Outcome Measure Information:

Title

Immune responses

Description

T-cell cytokine release towards target antigens

Time Frame

1 year

Other Pre-specified Outcome Measures:

Title

Mutational status

Description

CALR-mutational status

Time Frame

1 year

Title

Bone marrow response

Description

bone marrow description

Time Frame

1 year

Title

mutational landscape change

Description

Next Generation Sequencing pre- and post-treatment

Time Frame

1 year

Title

Overall response

Description

Revised response criteria by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report

Time Frame

1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 1. Diagnosis of essential thrombocythemia, post essential thrombocythemia myelofibrosis, prefibrotic myelofibrosis or primary myelofibrosis according to the World Health Organization criteria33 2. Verified mutation in CALR exon 9. 4. Performance status ≤ 2 (ECOG-scale) 5. Expected survival > 3 months 6. Sufficient bone marrow function, i.e. Leucocytes ≥ 1,5 x 109 Granulocytes ≥ 1,0 x 109 Thrombocytes ≥ 20 x 109 Hemoglobin ≥ 7 mmol/L 7. Creatinine < 2.5 upper normal limit, i.e. < 300 µmol/l 8. Sufficient liver function, i.e. a. Alanine aminotransferase < 2.5 upper normal limit, i.e. ALAT <112 U/l b. Bilirubin < 30 U/l 9. For women: Agreement to use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 120 days after the last treatment. 10. For men: Agreement to use contraceptive measures and agreement to refrain from donating sperm. Exclusion Criteria: Other malignancies in the medical history excluding squamous cell carcinoma. Patients cured for another malignant disease with no sign of relapse three years after ended treatment is allowed to enter the protocol. Significant medical condition per investigators judgement e.g. severe Asthma/chronic obstructive pulmonary disease , poorly regulated heart condition, insulin dependent diabetes mellitus. Acute or chronic viral or bacterial infection e.g. HIV, hepatitis or tuberculosis Serious known allergies or earlier anaphylactic reactions. Known sensibility to Montanide ISA-51 Any active autoimmune diseases e.g. autoimmune neutropenia, thrombocytopenia or hemolytic anemia, systemic lupus erythematosus, scleroderma, myasthenia gravis, autoimmune glomerulonephritis, autoimmune adrenal deficiency, autoimmune thyroiditis etc. Pregnant and breastfeeding women. Fertile women not using secure contraception with a failure rate less than < 1% Patients taking immune suppressive medications incl. corticosteroids and methotrexate at the time of enrollment Psychiatric disorders that per investigator judgment could influence compliance. Treatment with other experimental drugs Treatment with other anti-cancer drugs - except interferon (IFN)-a, hydroxyurea or anagrelide. Treatment with ruxolitinib. Treatment with chemotherapy or immune therapy (excluding IFN-a, hydroxyurea or anagrelide) within the last 28 days.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jacob H Grauslund, MD

Organizational Affiliation

Center for Cancer Immune Therapy, Denmark

Official's Role

Principal Investigator

Facility Information:

Facility Name

Herlev Hospital

City

Herlev

State/Province

Capital Region

ZIP/Postal Code

2730

Country

Denmark

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

33718228

Citation

Handlos Grauslund J, Holmstrom MO, Jorgensen NG, Klausen U, Weis-Banke SE, El Fassi D, Schollkopf C, Clausen MB, Gjerdrum LMR, Breinholt MF, Kjeldsen JW, Hansen M, Koschmieder S, Chatain N, Novotny GW, Petersen J, Kjaer L, Skov V, Met O, Svane IM, Hasselbalch HC, Andersen MH. Therapeutic Cancer Vaccination With a Peptide Derived From the Calreticulin Exon 9 Mutations Induces Strong Cellular Immune Responses in Patients With CALR-Mutant Chronic Myeloproliferative Neoplasms. Front Oncol. 2021 Feb 26;11:637420. doi: 10.3389/fonc.2021.637420. eCollection 2021.

Results Reference

derived

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CALR Exon 9 Mutant Peptide Vaccine to Patients With CALR-mutant Myeloproliferative Neoplasms

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