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

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ClinicalTrials.gov Identifier: NCT03566446
Recruitment Status : Active, not recruiting
First Posted : June 25, 2018
Last Update Posted : February 15, 2019
Sponsor:
Information provided by (Responsible Party):
Inge Marie Svane, Herlev Hospital

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.

Condition or disease Intervention/treatment Phase
Myeloproliferative Neoplasm, Unclassifiable Essential Thrombocythemia Myelofibrosis Biological: CALRLong36 peptide Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase-1-first in Man Study in Patients With CALR-mutant Myeloproliferative Neoplasms by Vaccinating With CALR Exon 9 Mutant Peptide
Actual Study Start Date : June 20, 2018
Estimated Primary Completion Date : February 20, 2020
Estimated Study Completion Date : April 30, 2021


Arm Intervention/treatment
Experimental: 36 aminoacid CALR exon 9 mutated peptide
15 vaccines, over the course of 1 year
Biological: CALRLong36 peptide
200 ug CALRLong36 peptide in water mixed with 500ul montanide




Primary Outcome Measures :
  1. Adverse events evaluated by CTCAE 4.03 [ Time Frame: 1 year ]
    Adverse events are graded 1-5 according to the criteria


Secondary Outcome Measures :
  1. Immune responses [ Time Frame: 1 year ]
    T-cell cytokine release towards target antigens


Other Outcome Measures:
  1. Mutational status [ Time Frame: 1 year ]
    CALR-mutational status

  2. Bone marrow response [ Time Frame: 1 year ]
    bone marrow description

  3. mutational landscape change [ Time Frame: 1 year ]
    Next Generation Sequencing pre- and post-treatment

  4. Overall response [ Time Frame: 1 year ]
    Revised response criteria by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

  1. Leucocytes ≥ 1,5 x 109
  2. Granulocytes ≥ 1,0 x 109
  3. Thrombocytes ≥ 20 x 109
  4. 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:

  1. 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.
  2. Significant medical condition per investigators judgement e.g. severe Asthma/chronic obstructive pulmonary disease , poorly regulated heart condition, insulin dependent diabetes mellitus.
  3. Acute or chronic viral or bacterial infection e.g. HIV, hepatitis or tuberculosis
  4. Serious known allergies or earlier anaphylactic reactions.
  5. Known sensibility to Montanide ISA-51
  6. 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.
  7. Pregnant and breastfeeding women.
  8. Fertile women not using secure contraception with a failure rate less than < 1%
  9. Patients taking immune suppressive medications incl. corticosteroids and methotrexate at the time of enrollment
  10. Psychiatric disorders that per investigator judgment could influence compliance.
  11. Treatment with other experimental drugs
  12. Treatment with other anti-cancer drugs - except interferon (IFN)-a, hydroxyurea or anagrelide.
  13. Treatment with ruxolitinib.
  14. Treatment with chemotherapy or immune therapy (excluding IFN-a, hydroxyurea or anagrelide) within the last 28 days.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03566446


Locations
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Denmark
Herlev Hospital
Herlev, Capital Region, Denmark, 2730
Sponsors and Collaborators
Inge Marie Svane
Investigators
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Principal Investigator: Jacob H Grauslund, MD Center for Cancer Immune Therapy, Denmark

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Responsible Party: Inge Marie Svane, Professor, MD, PhD, Herlev Hospital
ClinicalTrials.gov Identifier: NCT03566446     History of Changes
Other Study ID Numbers: MPN1801
2018-000132-10 ( EudraCT Number )
First Posted: June 25, 2018    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Inge Marie Svane, Herlev Hospital:
CALR mutation
Additional relevant MeSH terms:
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Primary Myelofibrosis
Myeloproliferative Disorders
Thrombocytosis
Thrombocythemia, Essential
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders