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

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

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.

Study Overview

• Status: Completed
• Conditions: Essential Thrombocythemia; Myelofibrosis; Myeloproliferative Neoplasm, Unclassifiable
• Intervention / Treatment: Biological: CALRLong36 peptide

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.

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

Contacts and Locations

Study Locations

• Denmark
  • Capital Region
    • Herlev, Capital Region, Denmark, 2730
      • Herlev Hospital

Participation Criteria

Eligibility Criteria

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

Description

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.

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: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events evaluated by CTCAE 4.03	Adverse events are graded 1-5 according to the criteria	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune responses	T-cell cytokine release towards target antigens	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mutational status	CALR-mutational status	1 year
Bone marrow response	bone marrow description	1 year
mutational landscape change	Next Generation Sequencing pre- and post-treatment	1 year
Overall response	Revised response criteria by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report	1 year

Collaborators and Investigators

• Sponsor: Inge Marie Svane
• Investigators: Principal Investigator: Jacob H Grauslund, MD, Center for Cancer Immune Therapy, Denmark

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2018
• Primary Completion (Actual): February 20, 2020
• Study Completion (Actual): April 30, 2021

Study Registration Dates

• First Submitted: June 11, 2018
• First Submitted That Met QC Criteria: June 21, 2018
• First Posted (Actual): June 25, 2018

Study Record Updates

• Last Update Posted (Actual): July 13, 2023
• Last Update Submitted That Met QC Criteria: July 12, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: CALR mutation
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Blood Coagulation Disorders; Blood Platelet Disorders; Neoplasms; Thrombocytosis; Thrombocythemia, Essential; Myeloproliferative Disorders
• Other Study ID Numbers: MPN1801; 2018-000132-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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