Phase 1/ Phase 2 Study to Assess Safety and Efficacy of Orally Administered JBI-802 in Subjects with Myeloproliferative Neoplasms (MPN) and Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) with Thrombocytosis.
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
Myeloproliferative Neoplasms (MPN)
Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)
Essential Thrombocythemia (ET)
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.
Key inclusion criteria
– Male or female subjects aged greater than 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.
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.
1. MDS/MPN (MDS/MPN-RS-T, MDS/MPN unclassifiable and CMML subjects providing the marrow blast count is less than or equal to 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 greater or equal to 9 g/dL, if subject is transfused to meet this criterion, transfusion must be completed greater or equal to 14 days prior to first dose.
• Absolute neutrophil count greater or equal to 1500 × 10^9/L
• Absolute neutrophil count greater or equal to 1000 × 10^9/L, if significant marrow infiltration
• Platelet count greater or equal to 450 × 10^9/L for dose finding
• Platelet count greater or equal to 100 × 10^9/L for expansion cohort at RP2D, if subject is transfused to meet this criterion, transfusion must be completed greater or equal to 14 days prior to first dose
• Total bilirubin less than or equal to 1.5 × ULN. Subjects with Gilbert’s syndrome may be enrolled with up to 3.0 × ULN
• Aspartate transaminase (AST) and Alanine transaminase (ALT) less than or equal to 2.5 × ULN
• Calculated creatinine clearance (CrCL) greater or equal to 30 mL/min (Cockcroft-Gault formula)
• Prothrombin Time (PT) or Activated Partial Thromboplastin Time (aPTT) less than or equal to 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).
6. Subject with Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2.
7. Subject able to swallow oral medication.
8. A subject who is 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.
Key exclusion criteria
1. Subject who is treated with systemic anticancer therapy or biological therapy or an investigational agent within 2 weeks or 5 half-lives, whichever is shorter, prior to start of study drug treatment.
• For MF subject who come off JAK2 antagonists or hydroxyurea, shorter washout is permitted as these subject progress quickly after treatment discontinuation and remain eligible (steroids must be stop at least 7 day before start of study drug treatment)
• Subject who is in need of immediate cytoreduction should be excluded
2. Subject who has undergone autologous/allogeneic Haematopoietic Stem Cell Transplantation (HSCT) therapy within 60 days of the first dose of study drug, or subject on immunosuppressive therapy post-HSCT at the time of screening, or currently with clinically significant Graft-Versus- Host Disease (GVHD) as per treating physician (subjects in relapse after allogeneic transplantation must be off treatment with systemic immunosuppressive agents for at least 4 weeks prior to screening.
3. Subject with major surgery less than or equal to 21 days prior to starting study drug or has not recovered from adverse effects of such procedure.
4. Subject who underwent surgery (e.g., stomach bypass) or medical condition that might significantly affect absorption of medicines.
5. Subject who underwent radiotherapy within 2 weeks prior to start of study drug treatment (palliative radiation or stereotactic radiosurgery within 7 days prior to start of study treatment). Subjects must have recovered from all radiotherapy-related toxicities.
6. Subject with known malignant central nervous system disease other than neurologically stable, treated brain metastases– defined as metastasis having no evidence of progression or hemorrhage for at least 4 weeks after treatment (including brain radiotherapy). Must be off any systemic corticosteroids for the treatment of symptomatic brain metastases for at least 14 days prior to enrollment.
7. Subject with severe or unstable medical condition, such as congestive heart failure ischemic heart disease, uncontrolled hypertension, uncontrolled diabetes mellitus, psychiatric condition, as well as an uncontrolled cardiac arrhythmia requiring medication ( less than or equal to Grade 2, according to NCI CTCAE Version 5), myocardial infarction within 6 months prior to starting study treatment, or any other significant or unstable concurrent cardiac illness.
8. Subject with congenital long QT syndrome or corrected QT interval by Fridericia (QTcF interval) greater than 450 msec for males and greater than 470 msec for females at screening.
9. Subject with history of other previous or concurrent cancer that would interfere with the determination of safety or efficacy assessments with respect to the qualifying solid tumor malignancy.
10. Subject with live vaccines within 30 days prior to the first dose of JBI-802.
11. Subjects who receive Glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest or for use as a premedication in participants with a known history of an IV contrast allergy administered as part of CT radiography.
12. Bisphosphonates and/or receptor activator of nuclear factor kappa-B ligand inhibitor therapies cannot be initiated after the Informed Consent Document(s) has been signed. These therapies may be continued if treatment with an agent from 1 of these 2 classes was initiated prior to signing the Informed Consent Document(s).
13. Subject with prophylactic antidiarrheals and antiemetics before the first dose of on Day 1.
14. Subject with prophylactic anti-inflammatory or antipyretic drugs (e.g., nonsteroidal anti-inflammatory drugs, acetaminophen, corticosteroids)before the first dose of on Day 1.
15. Subject with Prophylactic use of colony-stimulating factors (including G-CSF, pegylated G-CSF, or granulocyte-macrophage colony-stimulating factor) before the first dose of on Day 1.
16. Subject with use of strong inhibitors of cytochrome P450 3A (CYP3A) within 14 days or 5 half-lives (whichever is longer) or grapefruit juice or grapefruit containing products within 7 days prior to Cycle 1 Day 1.
17. Subject with use of strong inducers of CYP3A within 14 days or 5 halflives prior to Cycle 1 Day 1.
18. Subject with use of strong inhibitors of CYP2D6 within 14 days or 5 halflives prior to Cycle 1 Day 1
19. Subject with use of strong inducers of CYP2D6 within 14 days or 5 halflives prior to Cycle 1 Day 1.
20. Subject with known active Human Immunodeficiency Viruses (HIV)infection or active infection with hepatitis B or C.
21. Subject with active gastrointestinal disease (e.g., Crohn’s disease,ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption
22. Subject with acute illness within 14 days prior to first dose of study treatment unless mild in severity and approved by the Investigator and Sponsor’s medical representative.
23. Subject with presence of active infection requiring systemic antibiotics.
24. Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 90 days after the last dose of trial treatment.
25. Subject with current participation in another clinical study of an investigational agent. Simultaneous participation in observational studies is acceptable after Sponsor approval.
26. Subject with COVID vaccine within 7 days prior to Cycle 1 Day 1.
27. Subject with previously received JBI-802.
28. Subject with any other condition that in the opinion of the Investigator would place the participant at an unacceptable risk or cause the participant to be unlikely to fully participate or comply with study procedures.
• For MF subject who come off JAK2 antagonists or hydroxyurea, shorter washout is permitted as these subject progress quickly after treatment discontinuation and remain eligible (steroids must be stop at least 7 day before start of study drug treatment)
• Subject who is in need of immediate cytoreduction should be excluded
2. Subject who has undergone autologous/allogeneic Haematopoietic Stem Cell Transplantation (HSCT) therapy within 60 days of the first dose of study drug, or subject on immunosuppressive therapy post-HSCT at the time of screening, or currently with clinically significant Graft-Versus- Host Disease (GVHD) as per treating physician (subjects in relapse after allogeneic transplantation must be off treatment with systemic immunosuppressive agents for at least 4 weeks prior to screening.
3. Subject with major surgery less than or equal to 21 days prior to starting study drug or has not recovered from adverse effects of such procedure.
4. Subject who underwent surgery (e.g., stomach bypass) or medical condition that might significantly affect absorption of medicines.
5. Subject who underwent radiotherapy within 2 weeks prior to start of study drug treatment (palliative radiation or stereotactic radiosurgery within 7 days prior to start of study treatment). Subjects must have recovered from all radiotherapy-related toxicities.
6. Subject with known malignant central nervous system disease other than neurologically stable, treated brain metastases– defined as metastasis having no evidence of progression or hemorrhage for at least 4 weeks after treatment (including brain radiotherapy). Must be off any systemic corticosteroids for the treatment of symptomatic brain metastases for at least 14 days prior to enrollment.
7. Subject with severe or unstable medical condition, such as congestive heart failure ischemic heart disease, uncontrolled hypertension, uncontrolled diabetes mellitus, psychiatric condition, as well as an uncontrolled cardiac arrhythmia requiring medication ( less than or equal to Grade 2, according to NCI CTCAE Version 5), myocardial infarction within 6 months prior to starting study treatment, or any other significant or unstable concurrent cardiac illness.
8. Subject with congenital long QT syndrome or corrected QT interval by Fridericia (QTcF interval) greater than 450 msec for males and greater than 470 msec for females at screening.
9. Subject with history of other previous or concurrent cancer that would interfere with the determination of safety or efficacy assessments with respect to the qualifying solid tumor malignancy.
10. Subject with live vaccines within 30 days prior to the first dose of JBI-802.
11. Subjects who receive Glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest or for use as a premedication in participants with a known history of an IV contrast allergy administered as part of CT radiography.
12. Bisphosphonates and/or receptor activator of nuclear factor kappa-B ligand inhibitor therapies cannot be initiated after the Informed Consent Document(s) has been signed. These therapies may be continued if treatment with an agent from 1 of these 2 classes was initiated prior to signing the Informed Consent Document(s).
13. Subject with prophylactic antidiarrheals and antiemetics before the first dose of on Day 1.
14. Subject with prophylactic anti-inflammatory or antipyretic drugs (e.g., nonsteroidal anti-inflammatory drugs, acetaminophen, corticosteroids)before the first dose of on Day 1.
15. Subject with Prophylactic use of colony-stimulating factors (including G-CSF, pegylated G-CSF, or granulocyte-macrophage colony-stimulating factor) before the first dose of on Day 1.
16. Subject with use of strong inhibitors of cytochrome P450 3A (CYP3A) within 14 days or 5 half-lives (whichever is longer) or grapefruit juice or grapefruit containing products within 7 days prior to Cycle 1 Day 1.
17. Subject with use of strong inducers of CYP3A within 14 days or 5 halflives prior to Cycle 1 Day 1.
18. Subject with use of strong inhibitors of CYP2D6 within 14 days or 5 halflives prior to Cycle 1 Day 1
19. Subject with use of strong inducers of CYP2D6 within 14 days or 5 halflives prior to Cycle 1 Day 1.
20. Subject with known active Human Immunodeficiency Viruses (HIV)infection or active infection with hepatitis B or C.
21. Subject with active gastrointestinal disease (e.g., Crohn’s disease,ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption
22. Subject with acute illness within 14 days prior to first dose of study treatment unless mild in severity and approved by the Investigator and Sponsor’s medical representative.
23. Subject with presence of active infection requiring systemic antibiotics.
24. Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 90 days after the last dose of trial treatment.
25. Subject with current participation in another clinical study of an investigational agent. Simultaneous participation in observational studies is acceptable after Sponsor approval.
26. Subject with COVID vaccine within 7 days prior to Cycle 1 Day 1.
27. Subject with previously received JBI-802.
28. Subject with any other condition that in the opinion of the Investigator would place the participant at an unacceptable risk or cause the participant to be unlikely to fully participate or comply with study procedures.
HaematologyCTU.HPH@ramsayhealth.com.au
08 9346 6637
Name: Dr Andrew McQuillan
Address: Hollywood Private Hospital, 101 Monash Avenue, Nedlands WA 6009
Country: Australia
Phone: +61 893861811
Email: andrew@qmedical.com.au
Jubilant Therapeutics
Phase 1
Phase 2
JBI-802-102
ACTRN12624000478516