Clinical trial NCT03566446: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Myeloproliferative Neoplasm, Unclassifiable
Essential Thrombocythemia
Myelofibrosis
Keywords: CALR mutation
Lead sponsor: Herlev Hospital
Sponsor class: OTHER
First posted: 2018-06-25
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

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.

Primary outcomes:
measure: Adverse events evaluated by CTCAE 4.03
timeFrame: 1 year
Secondary outcomes:
measure: Immune responses
timeFrame: 1 year
Other outcomes:
measure: Mutational status
timeFrame: 1 year
measure: Bone marrow response
timeFrame: 1 year
measure: mutational landscape change
timeFrame: 1 year
measure: Overall response
timeFrame: 1 year
Locations:
city: Herlev
country: Denmark
facility: Herlev Hospital
state: Capital Region
Study officials:
affiliation: Center for Cancer Immune Therapy, Denmark
name: Jacob H Grauslund, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.