Study to Assess Safety and Preliminary Efficacy of Orally Administered JBI-802 in Subjects With Myeloproliferative Neoplasms (MPN) and Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) With Thrombocytosis
This study aims to assess the safety and efficacy of orally administered JBI-802 in subjects with Myeloproliferative Neoplasms (MPN) and Myelodysplastic/ Myeloproliferative Neoplasms (MDS/MPN) with Thrombocytosis. Who is it for? You may be eligible to join this study if you are aged 18 years and over have been diagnosed with Essential Thrombocythemia and either a Morphologically confirmed diagnosis of Myeloproliferative Neoplasms (MPN) or Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN). Study details: Participants in this study will receive JBI-802 administered orally daily for a 28 day treatment cycle for up to 2-years as long as the participant experiences clinical benefit in the opinion of the Investigator and shows no signs or symptoms of unequivocal progression of disease, unacceptable toxicity, or other reasons for study discontinuation. The starting dose of the study drug is 5 mg/day, a total dose of 35 mg. Dose escalation will occur as per the 3+3 design after an internal Safety Review Committee (SRC) review of each dose stage. Dose expansion to other subtypes of MPN and MDS/MPN will occur after Recommended Phase 2 Dose is determined from the dose escalation phase. Eligibility/Screening for this study will occur within 21 days prior to starting treatment. If the study is suitable for you, you will enter the treatment period. The dose level selected for evaluation in Phase 2 will only be selected if it was safe and well tolerated during Phase 1. The treatment cycles will continue until you wish to stop, or you do not tolerate JBI-802 treatment, Some of the study procedures that include during your treatment period are :Medical, surgical, and cancer history, Height and weight, Physical examination, Vital signs, Eastern Cooperative Oncology Group (ECOG) evaluation, Electrocardiogram, Myeloproliferative neoplasm symptom assessment questionnaire,CT/MRI scan, Bone marrow biopsy, medication usage, Side effects assessment, blood and urine Sampling , liver and thyroid function tests, haematology and coagulation tests, Participants will be followed-up at the start and end of each 28-day cycle to assess safety and tolerability Blood samples will be collected to assess safety and tolerability during the study. After the end of study, subjects will be treated in accordance with local practice. Compassionate use of JBI-802 may be allowed in subjects after study completion, based on the Investigator's judgment in consultation with the Sponsor and on a case-by-case basis. Compassionate use will be controlled by a separate protocol or process as defined by the local regulatory authorities. Continuation of study therapy beyond 2 years may be approved by the Sponsor based on the safety profile and will be contingent on the continued availability of product.
⁃ \- Male or female subjects aged ≥18 years at the time of screening visit.
⁃ For Dose Escalation Phase:
⁃ Subjects diagnosed with any one of the following:
• Subject with diagnosis of Essential Thrombocythemia (ET) per World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms .
• Subject requires treatment in order to lower platelet count based on subject age over 60 or history of thrombosis.
• Subject with Morphologically confirmed diagnosis of MDS/MPN neoplasms, excluding Juvenile Myelomonocytic Leukaemia (JMML), CMML and aCML (Atypical Chronic Myeloid Leukaemia), in accordance with WHO 2016 revised criteria, that is relapsed and/or refractory or intolerant to standard of care and that, in the opinion of the Investigator, subjects who have no available therapies known to provide clinical benefits.
• Subject with Myelodysplastic/myeloproliferative neoplasm, (unclassifiable (MDS/MPN-UC) and MDS/MPN-RS-T).
⁃ For Dose Expansion Phase
⁃ Subjects diagnosed with any one of the following:
• Subject with diagnosis of Essential Thrombocythemia (ET) per WHO diagnostic criteria for myeloproliferative neoplasms which requires treatment in order to lower platelet count based on subject age over 60 or history of thrombosis.
• Subject with diagnosis of Polycythemia Vera (PV) per WHO diagnostic criteria that is relapsed and/or refractory or intolerant to standard of care and that, in the opinion of the Investigator, subjects who have no available therapies known to provide clinical benefits Subject with morphologically confirmed diagnosis of pre-fibrotic myelofibrosis (MF) subject in accordance with the WHO 2016 revised criteria, that is relapsed, intolerant, and/or refractory and that, in the opinion of the Investigator, subjects who have no available therapies known to provide clinical benefits. (Refer Appendix II)
• MDS/MPN (MDS/MPN-RS-T, MDS/MPN unclassifiable and CMML subjects providing the marrow blast count is ≤5%.). 2. Subject must have disease that failed at least one standard therapy or being intolerant to standard of care. 3. Subject must have discontinued immediate prior therapy at least 1 week (4 weeks for interferon) prior to study drug administration. 4. Subject with screening laboratory values:
• Hb ≥ 9 g/dL, if subject is transfused to meet this criterion, transfusion must be completed ≥ 14 days prior to first dose.
• Absolute neutrophil count ≥ 1500 × 109/L
• Absolute neutrophil count ≥ 1000 × 109/L, if significant marrow infiltration
• Platelet count ≥ 450 × 109/L for dose finding
• Platelet count ≥ 100 × 109/L for expansion cohort at RP2D, if subject is transfused to meet this criterion, transfusion must be completed ≥14 days prior to first dose
• Total bilirubin ≤ 1.5 × ULN. Subjects with Gilbert's syndrome may be enrolled with up to 3.0 × ULN
• Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 2.5 × ULN (unless liver metastases are present then up to 5 × ULN is allowed)
• Calculated creatinine clearance (CrCL) ≥ 30 mL/min (Cockcroft- Gault formula) (Refer Appendix IV)
• Prothrombin Time (PT) or Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN, if subject is not anticoagulated (Note: If subject is on anticoagulants, the subject must be on a stable dose for at least 2 weeks prior to screening) 5. Subject with resolution of any clinically significant toxic effects of prior therapy to Grade 0 or 1 according to the NCI CTCAE, Version 5.0 (exception of alopecia and Grade 2 peripheral neuropathy, chronic Grade 2 endocrinopathies as a result of prior immunotherapy). (Refer Appendix VII) 6. Subject with Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. (Refer Appendix III) 7. Subject able to swallow oral medication. 8. Subject who has willing and able to give informed consent and comply with protocol requirements for the duration of the study. 9. Subject who is willing to undergo bone marrow biopsy with aspiration and tissue collection for disease assessment and correlative studies during screening and periodically throughout the study. 10. Subject with willingness to use contraception by a method that is deemed effective by the Investigator by both males and female of childbearing potential (post-menopausal women must have been amenorrhoeal for at least 12 months to be considered of non-childbearing potential (i.e., surgically sterilised \[hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before the screening visit\] or postmenopausal \[where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone \[FSH\] level consistent with postmenopausal status, per local laboratory guidelines\]) and their partners throughout the treatment period and for at least 3 months following the last dose of study drug.