ENSAYO CLÍNICO

Reclutando

Fase I

Neoplasias mieloproliferativas crónicas Philadelphia(-), Terapia celular y T-CARs

Febrero, 2024

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18 years of age
2.1. Criterion modified per EEA-4: 2.2 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 10^9 /L at any point during the participants disease - Previous documented thrombosis (including transient ischemic attack [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 (unless contraindicated), defined as any 1 of the following according to NCCN Guidelines Version 1.2023: - Platelet count >600 x 10^9 /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 10^9 /L and WBC 400 x 10^9 /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: DIPSS -Intermediate 1-2 or High-Risk with a blast percentage not consistently exceeding 20% in blood or bone marrow. Post-ET MYSEC-PM 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 EITHER Ineligible or intolerant or resistant / refractory to JAKi therapy
Positive for CALR mutation
Criterion modified per Amendment EEA-4: 4.1. Have received prior therapy(ies): ET: have received at least 2 (unless unavailable or contraindicated) lines of prior cytoreductive therapy
Have discontinued concurrent use of the following therapies: ET: Interferon- (pegylated or standard preparation), anagrelide, busulfan. Exception: HU is permitted. MF: JAKi, immunomodulatory drug therapy (such as thalidomide), danazol, or other therapy intended to lead to disease modification
Have an ECOG performance status grade of 0 or 1
Required clinical hematology laboratory values predose: o Hemoglobin 8.0 g/dL o Neutrophils 0.75 x 10^9/L without the assistance of granulocyte growth factors within 4 weeks of the first dose of study drug o Platelets 50 x 10^9/L without the assistance of thrombopoietic factors or transfusions
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.)
Known HIV-positive participants are eligible if they meet all of the following at screening: o No detectable viral load o CD4+ count >300 cells/mm^3 o No AIDS-defining opportunistic infection within 6 months o Receiving HAART.

Chemo, targeted therapy, immunotherapy or cytoreductive therapy at 5 half-lives prior planned first study treatment
Any prior treatment with CALRmut-targeted therapy.
Concurrent or recently diagnosed or treated malignancies present at the time of screening
Prior solid organ transplant
HSCT restriction: HSCT6mo, GVHD that requires chronic immunosuppressant therapy
Active autoimmune disease that requires systemic immunosuppressive medication
Uncontrolled CV disease within 6 months of first dose
Clinically significant pulmonary compromise
Reported temperature > 38ºC within 48 hours of first dose
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.
History of pneumonitis or interstitial lung disease.
Active or uncontrolled infection within 14 days of first dose
Those without evidence of stable anticoagulant therapy, defined as 4 weeks of unmodified anticoagulant therapy prior to the first administration of study treatment.
History of HLH/MAS
Trauma or major surgery within 28 days of first dose
Administration of live attenuated vaccine within 4 weeks of first dose
Active or chronic HBV or HCV infection
Body weight is <40 kg at screening and/or at the time of their first dose
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
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
A prohibited medication that cannot be discontinued or substituted, or temporally interrupted during the study. Prohibited therapies are described in Section 6.8.4

Part 1 (Dose Escalation) To characterize safety and to determine the putative RP2D(s) and optimal dosing schedule(s) of JNJ-88549968 in monotherapy (ET and MF) and in combination with ruxolitinib or momelotinib (MF only) Part 2 (Cohort Expansion) To further characterize the safety of JNJ-88549968 at the putative RP2D(s) in monotherapy (ET and MF) and in combination with ruxolitinib or momelotinib (MF only)

bispecific antibody, myeloproliferative neoplasm