A First-in-Human Study of the Safety, Pharmacokinetics, and Pharmacodynamics of JNJ-88549968, a T-cell Redirecting Bispecific Antibody for CALR-mutated Myeloproliferative Neoplasms (88549968MPN1001).

Studio Clinico

Patologia: Neoplasie ematologiche

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: No

Fase di studio: 1,

Linee di trattamento: Seconda linea, Terza/N linea

Criteri di inclusione: 

1. Be ≥18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever the greater) at the time of informed consent.

Type of Participant and Disease Characteristics
2. Have a diagnosis of either ET or MF as defined by the 2022 WHO criteria (WHO Classification of Tumours Editorial Board 2022) that meets the stated risk criteria:
- Essential Thrombocythemia
- High-risk of thrombosis or hemorrhage, defined as any 1 of the following:
    - Age >60 years
    - Platelet count >1500 x 109/L at any point during the participant’s disease
    - Previous documented thrombosis (including TIA), erythromelalgia, or migraine (severe, recurrent, requiring medications, and felt to be secondary to the MPN) either after diagnosis or within 10 years before diagnosis and considered to be disease-related.
    - Previous hemorrhage or coagulopathy related to ET
    - Diabetes mellitus or hypertension requiring pharmacological therapy >6 months
AND
Intolerant or resistant or refractory to HU, defined as any 1 of the following according to NCCN Guidelines Version 1.2023:
    - Platelet count >600 x 109/L after 3 months of at least 2 g/day or MTD of HU (2.5 g/day in participants with a body weight >80 kg)
    - Platelet count >400 x 109/L and WBC <2.5 x 109/L at any dose of HU (for a period of at least 3 months)
    - Platelet count >400 x 109/L and hemoglobulin <10 g/dL at any dose of HU (for a period of at least 3 months)
    - Presence of leg ulcers or other unacceptable mucocutaneous manifestations at any dose of HU
    - HU-related fever/Myelofibrosis (primary or post-ET)

Primary Myelofibrosis Post-ET MF
DIPSS (Table 27; Passamonti 2010)
Intermediate 1-2 or High-Risk with a blast percentage not consistently exceeding 20% in blood or bone marrow
MYSEC-PM (Table 28; Passamonti 2017) Intermediate 1-2 or High-Risk with a blast percentage not consistently
exceeding 20% in blood or bone marrow
AND
Ineligible for Hematopoietic Stem Cell Transplantation (HSCT)
AND
Ineligible or intolerant or resistant / refractory to JAKi therapy

Ineligible
JAKi contraindicated due to prior history of severe infections such as tuberculosis, progressive multifocal leukoencephalopathy, and skin malignancies that are known to be associated or exacerbated by JAKi, or other significant considerations as documented by the treating physician.

Intolerant
a) Hematologic toxicity - platelet count <50 × 109/L and/or neutrophils ≤0.5 × 109/L despite recommended dose adjustments and interruptions;
or
b) ≥Grade 3 nonhematologic toxicity as per the CTCAE Version 5.0, 2017

Resistant / Refractory
Evidence would include:
a) persistent splenomegaly or
b) lack of symptom improvement or
c) persistent leukoerythroblastosis or
d) anemia <10g/dL or
e) leukocytosis >11 x 109/L
3. Positive for a CALR driver mutation of ET or MF.
4. Criterion modified per Amendment EEA-4:
4.1. Have received prior therapy(ies):

Essential Thrombocythemia Myelofibrosis
At least 2 lines (unless unavailable or contraindicated) of prior cytoreductive therapy, at least 1 of which must have been HU.
At least 1 prior JAKi therapy unless ineligible as described in Criterion 2
5. Have discontinued concurrent use of the following therapies:
   Essential Thrombocythemia Myelofibrosis
   Interferon-⍺ (pegylated or standard preparation), anagrelide, busulfan.
   Exception: HU is permitted.
   JAKi, immunomodulatory drug therapy (such as thalidomide), danazol, or other therapy intended to lead to disease modification
6. Criterion modified per Amendment EEA-1:
6.1 Have an ECOG performance status grade of 0 or 1 (Oken 1982)7. Have the following clinical hematology laboratory values predose:
   a. Hemoglobin ≥8.0 g/dL
   b. Neutrophils ≥0.75 x 109/L without the assistance of granulocyte growth factors within 4 weeks of the first dose of study drug
   c. Platelets ≥50 x 109/L without the assistance of thrombopoietic factors or transfusions
8. Criterion modified per Amendment EEA-3:
8.1 Participants should have the following clinical chemistry laboratory values predose:
   a. ALT: ≤3 x ULN
   b. AST: ≤3 x ULN
   c. Direct bilirubin: ≤1.5 x ULN
   d. Renal function: Estimated or measured glomerular filtration rate ≥40 mL/min per CKD-EPI (Creatinine) or BIS1 formula (See Appendix 9)
9. Known HIV-positive participants are eligible if they meet all of the following:
   a. No detectable viral load (ie, <50 copies/mL) at screening
   b. CD4+ count >300 cells/mm3 at screening
   c. No AIDS-defining opportunistic infection within 6 months of screening
   d. Receiving HAART. Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening.
Note: HAART that could interfere with study treatment is excluded (consult the sponsor for a review of medications prior to enrollment).

Sex and Contraceptive/Barrier Requirements
10. A participant of childbearing potential must have a negative highly sensitive serum (eg, β-hCG) pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study.
11. A participant of childbearing potential must practice at least 1 highly effective method of contraception (details in Appendix 5) throughout the study and at least 90 days after the last dose of study treatment.
Note: If the participant becomes of childbearing potential after the start of the study, the participant must comply with this criterion.
12. A participant using oral contraceptives must use an additional barrier contraceptive method (details in Appendix 5).
13. A participant must agree not to be pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 90 days after the last dose of study treatment.
14. A participant must agree not to donate gametes (ie, eggs or sperm) or freeze for future use for the purposes of assisted reproduction during the study and for a period of 6 months after receiving the last dose of study treatment. Participants should consider preservation of gametes prior to study treatment as anticancer treatments may impair fertility.

Criteri di esclusione: 

Medical Conditions
1. Known allergies, hypersensitivity, or intolerance to the excipients of the study treatment.
2. Chemotherapy, cytoreductive therapy, targeted therapy, or immunotherapy at 5 half-lives or 2 weeks, whichever is shorter, prior to the planned first dose of study treatment.
EXCEPTIONS:
   a. HU is permitted on study
   b. JAK inhibitor withdrawal to be tapered with 1 week washout as per Section 6.8.4.1
3. Criterion modified per EEA-1:
3.1 Any prior treatment with CALRmut-targeted therapy.
4. Concurrent or recently diagnosed or treated malignancies present at the time of participant screening. Exceptions are squamous and basal cell carcinoma of the skin, carcinoma in situ of the cervix, and any malignancy that is considered cured or has minimal risk of recurrence within 1 year of first dose of study treatment in the opinion of both the investigator and
sponsor’s medical monitor. Participants cured of another malignant disease with no sign of relapse ≥3 years after treatment ended are allowed to enter the study. (See Appendix 7.)
5. Prior solid organ transplantation.
6. Either of the following regarding hematopoietic stem cell transplantation:
   a. Prior treatment with allogenic stem cell transplant ≤6 months before the first dose of JNJ- 88549968 or
   b. Evidence of GVHD that requires immunosuppressant therapy
7. Active autoimmune disease that requires systemic immunosuppressive medications (eg, chronic corticosteroid, methotrexate, or tacrolimus).
8. Toxicities from previous anticancer therapies that have not resolved to baseline levels, or to Grade 1 or less, or to Grade ≤2 for alopecia, peripheral neuropathy, and vitiligo.9. History of clinically significant cardiovascular disease within 6 months prior to the first dose of study treatment including, but not limited to:
   a. Myocardial infarction
   b. Severe or unstable angina
   c. Clinically significant ventricular arrhythmias or unexplained syncope, not believed to be vasovagal in nature or due to dehydration
   d. History of severe non-ischemic cardiomyopathy
   e. Congestive heart failure (New York Heart Association class III-IV)
   f. Uncontrolled (persistent) hypertension: systolic blood pressure >159 mm Hg OR diastolic blood pressure >99 mm Hg
   g. Stroke or TIA
   h. Pericarditis or clinically significant pericardial effusion
   i. Myocarditis
   j. Endocarditis
   k. Acute ischemic limb
10. Clinically significant pulmonary compromise, particularly the need for supplemental oxygen use to maintain adequate oxygenation.
11. Criterion modified per EEA-1:
11.1 Evidence of active viral (including chronic EBV), bacterial, or uncontrolled systemic fungal infection requiring systemic treatment within 14 days before the first dose of study treatment.
12. Fever (body temperature ≥38.0°C/100.4°F) in the 48 hrs prior to first dose of study treatment
13. Trauma or major surgery (eg, requiring general anesthesia) within 28 days prior to the first dose of study treatment. Note: Participants with planned surgical procedures to be conducted under local anesthesia may participate.
14. Any serious underlying medical or psychiatric condition (eg, alcohol or drug abuse), dementia or altered mental status; or any issue that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site, to
understand informed consent, or that in the opinion of the investigator would contraindicate the participation in the study or confound the protocol-specified assessments or results of the study.
15. A prohibited medication that cannot be discontinued or substituted, or temporally interrupted during the study. Prohibited therapies are described in Section 6.8.4.
16. Vaccination with a live, attenuated vaccine within 4 weeks before the first administration of study treatment.
17. Body weight is <40 kg at screening and/or at the time of their first administration of study treatment.

Trattamento sperimentale: 

JNJ-88549968 in dose escalation/sottocute

Trattamento di controllo: 

NO

Note generali: 

Linea di trattamento:
- Essential Thrombocythemia
At least 2 lines (unless unavailable or contraindicated)of prior cytoreductive therapy.

- Myelofibrosis
At least 1 prior JAKi therapy unless ineligible

Centri partecipanti

Nord Italia

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2023-505584-36

Data di inserimento: 27.04.2026

Promotore

Janssen Research & Development, LLC

Principal Investigator ITALIA

Riferimento: Dr. - -

Telefono: 00000

Email: na@na.it

Localita: na