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Trial registered on ANZCTR


Registration number
ACTRN12624000478516
Ethics application status
Approved
Date submitted
13/02/2024
Date registered
18/04/2024
Date last updated
18/04/2024
Date data sharing statement initially provided
18/04/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
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.
Scientific title
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
Secondary ID [1] 311114 0
JBI-802-102
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myeloproliferative Neoplasms (MPN) 332269 0
Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) 332381 0
Essential Thrombocythemia (ET) 332427 0
Condition category
Condition code
Cancer 328986 328986 0 0
Thrombocythaemia
Cancer 329155 329155 0 0
Bone
Cancer 329156 329156 0 0
Leukaemia - Chronic leukaemia
Blood 329860 329860 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a phase 1/2, multicenter, open-label, dose-escalation, and dose-expansion study to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of orally administered JBI-802 in subjects with Myeloproliferative Neoplasms (MPN) and Myelodysplastic /Myeloproliferative Neoplasms (MDS/MPN) with thrombocytosis. Jubilant Therapeutics Inc. has developed JBI-802 as an orally active, potent, and selective dual LSD1/HDAC6 inhibitor. LSD1 (also known as KDM1A) specifically demethylates mono- and dimethyl groups of histone H3 lysine 4 (H3K4) in a FAD-dependent manner. HDACs are another class of 18 enzymes in humans that epigenetically regulate critical cellular functions. Acetylation and deacetylation of histones by histone acetyl-transferases (HATs) and HDACs play a major role in transcription regulation of cells. HDACs also have many other non-histone protein substrates that are involved in the regulation of gene expression, cell proliferation, and cell death. Specifically, HDAC6 has several specific non-histone substrates, including alpha tubulin, cortactin, heat shock protein (HSP) 90, and other chaperone proteins, peroxiredoxins, and transmembrane proteins, several of which are known to be involved in carcinogenesis. Given their role in carcinogenesis, LSD1 and HDAC6 have been the targets for the development of inhibitors. Therefore, the expectation is that simultaneous inhibition of these 2 epigenetic modifying enzymes will result in an additive or synergistic antitumor activity when compared with the single-target inhibitors. JBI-802 has shown promising results in its series of in vitro and in vivo primary pharmacology studies, biochemical and cellular assays, in vitro proliferation assays, in vivo efficacy study, safety pharmacology studies, non-clinical PK & TK studies, genotoxicity study, and toxicology studies. A first-in-human study in patients with advanced solid tumors in the US of JBI-802 was opened in 2022. Thus, JBI-802 has sufficient data to proceed with further clinical evaluations.

The primary goals of the study are first to establish Recommended Phase 2 Dose (RP2D) of JBI-802 when administered on a daily continuous basis and secondary to determine preliminary efficacy once the RP2D is determined.
The study consists of two parts as follow:
• Part 1: Dose-Escalation Phase
• Part 2: Dose-Expansion Phase
Initial dose findings will be in subjects with MPN, subjects with MPN/MDS Neoplasms, and a baseline platelet count of greater than or equal to 450×10^9/L. Dosing will start with a 5mg daily dose, a total weekly dose of 35 mg (5mg at 7 days per week) for a period of 28 days based on previous human experience that showed was safe with no substantial platelet decrease. The next cohort will be dose escalated as per the 3+3 design. This will be implemented for the remainder of the study. In the event of observing 2 DLTs at 5 mg daily dosing, the next cohort will be administered at 3 mg daily. Once a recommended phase 2 dose given orally and continuously has been determined, the safety and preliminary efficacy of this dose will be confirmed in an expanded population of subjects with MPN, (ET, PV and profibrotic MF) and MDS/MPN subjects (MDS/MPN-RS-T, MDS/MPN unclassified and CMML) with a lower threshold of platelets (value to be determined based on the safety profile and on the effect on erythroid precursors and erythrocyte parameters observed during the dose escalation). Eligible subjects will further be considered first for Part 1 and once the RP2D (tolerability) is determined, then Part 2 will be initiated.

The duration of participation for each subject will be as follows:
• Screening: 21-days
• Treatment period: Treatment cycle of 28 days each.
• End of treatment (EOT)/ Early termination (ET) visit
• Safety Follow-up: 28 days after last dose
• Survival: Every 3 months

Treatment may continue for up to 2 years from the start of treatment, 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. Continuation of study therapy beyond 2 years must be approved by the Sponsor based on the safety profile of JBI-802 and will be contingent on the continued availability of JBI-802 drug product. Efficacy and safety monitoring of these participants will continue during the course of study participation.

A 3+3 design will be employed to assess tolerability. Initially JBI-802 will be administered at a 5 mg dose, a total weekly dose of 35 mg (5mg at 7 days per week), once daily for a 28 day period. If 5 mg proves to be intolerable a 3 mg dose will be tested. If this initial dose regimen of 5mg/day is tolerable, further dosing will be escalated based on a 3+3 escalation approach, daily regimen and if 3mg/day is not tolerated, no further subjects will be recruited, and the study will be terminated. Each cohort of subjects will be evaluated over a 28 days period for tolerability using the standard 3 + 3 design and dose escalation increments in new cohorts of subjects will be determined based on the emergent tolerability profile. Intra-subject dose escalation strategy will be allowed in this study after the initial treatment cycle.

In the 3+3 design, if 3 subjects at a dose level complete the DLT evaluation period with no DLT, that dose level of JBI-802 will be deemed safe, and another 3 subjects will be treated at the next higher dose level. If 1 of the first 3 subjects experiences a DLT, 3 more subjects will be treated at the same JBI-802 dose level. If 2 or more of the 3 to 6 subjects in any dose level experience a DLT, dosing will stop at that level. Based on the previous human exposure, a dose of approximately ~40mg intermittent dosing might be intolerable (a weekly dose of 160mg showed grade 4 thrombocytopenia, 40mg at 4 days on / 3 days off) it is therefore expected that the dose escalation will be limited to that upper amount. Intermediate doses may be tested in order to better estimate the RP2D. If necessary, dose levels which have proven to be tolerable may be backfilled in order to obtain additional PK, PD, safety and efficacy data. Study participants who do not complete the DLT period for reasons other than study drug toxicity will be replaced. Participants who complete the DLT period, tolerate the doses and have been on therapy for at least one 28 day cycle without significant toxicities may proceed to a higher dose level for the following treatment cycle if the next dose cohort is deemed safe (for both acute and cumulative toxicities) at that time by the Safety Review Committee (SRC), and after consultation with the Sponsor during the current treatment with the study drug. Participants who do not proceed to a higher dose may continue to receive additional cycles at their original dose. Dose Expansion phase will not follow the 3+3 design. Every cycle in dose expansion phase is of 28 days each. Administration of JBI-802 in Dose expansion phases of this study may continue until evidence of disease progression, intolerance to study medication, or withdrawal of consent. Also, participants with MPN and participants with MPN/MDS Neoplasms will be analysed separately.

JBI-802 is provided as capsules for oral administration. The current strengths are 1, 5, and 10 mg. 5mg daily dose for a 28 days treatment cycle and the further cohorts will be dose escalated. The increase or decrease will be between 1-5mg based on the accumulated data on effects on platelets and Hb and the highest tolerable dose tested. Administration of JBI-802 in dose escalation may continue until evidence of disease progression, intolerance to study medication or withdrawal of consent. JBI-802 is to be taken orally on an empty stomach with water either approx. 2 hours after the last meal and/or approx. 1 hour before the next meal. On day 1 of each cycle, Study drug administration will be performed at the study site/clinic. Participants do not need medical/ physician supervision with dosing of JBI-802 except for on PK sampling days.

The study population will consist of approximately 30 participants. The start of the study will be the date on which the first participant provides informed consent, and the end of the study will be the last participant’s last assessment or when the decision to stop study treatment is made. The study eCRF is the primary data collection instrument for the study. Data will be collected using electronic case report forms (eCRFs) that are specifically designed for this study. All data requested will be first recorded on the source document and then on the CRF. Data will be entered at the site by the appropriately designated and trained site personnel.

Subjects will be asked about their compliance at each visit. The subject dosing diary will be prepared and given to subjects for recording the drug administration. The site personnel will train the subject on diary completion. This information will be appropriately recorded at scheduled visits in the CRF. Compliance will be assessed by drug intake history and the data noted in the participant dosing diary. JBI-802 capsules will be dispensed from a bulk supply, returned drug will be counted and compliance calculated. JBI-802 will be self-administered by the subject and documented in a subject dosing diary. The diary will be brought to each visit for review and reconciliation against the capsule counts to confirm that the diary is being completed accurately. If compliance drops below 70%, subjects will be re-educated on the need for remaining compliant with daily dosing. Participants who are judged to be non-compliant will be counselled on the importance of daily intake of study drug, as prescribed. Participants who are repeatedly or severely non-compliant may be discontinued, at investigator’s discretion after discussion with the medical monitor.
Intervention code [1] 327700 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 336986 0
PART 1
To determine the Recommended Phase 2 Dose (RP2D) of JBI-802 in subjects with MPN (ET) and MDS/MPN neoplasms (MDS/MPN-RS-T and MDS/MPN unclassifiable). All subjects must have thrombocytosis.
Timepoint [1] 336986 0
Incidence of dose-limiting toxicity (DLT) events during the DLT monitoring period.
[Timeframe: Baseline through Day 28 of Cycle 1]
ECOG Performance status - will be assessed by the status from baseline upto last safety follow up visit, every 28day Cycle, for up to approximately 2 years post-treatment commencement.
Adverse Events - AEs assessment will be performed throughout the study period.
Vital Signs and ECG Time points
Cycle 1 Day 1 - Pre dose, 0.25, 0.5, 1 , 2, 4, 8 hours
Cycle 1 Day 2 - Pre dose
Cycle 1 Day 8- Pre dose, 0.25, 0.5, 1 , 2, 4, 8 hours
Cycle 1 Day 15 - Pre dose
Cycle 1 Day 22 - Pre dose
Laboratory Tests - Hematology, Serum chemistry, Urinalysis will be collected from Baseline through to Safety follow-up visit, every 28day Cycle, for up to approximately 2 years post-treatment commencement.
Primary outcome [2] 336987 0
PART 2 - Dose Expansion Phase
To obtain preliminary evidence of efficacy at the RP2D in subjects with:
- MPN (ET, PV and prefibrotic MF).
Timepoint [2] 336987 0
• Assessment of spleen size and volume by physical examination - Physical exam will be performed throughout the study from Baseline to end of treatment, every 28day Cycle, for up to approximately 2 years post-treatment commencement.
• Evaluation of haematology (Anaemia response, duration of anaemia response rate of red blood cell (RBC) and transfusion dependency) - Haematology blood tests exam will be performed throughout the study from Baseline to end of treatment, every 28day Cycle, for up to approximately 2 years post-treatment commencement.
• Bone marrow aspiration and/or biopsy - will be collected at every 12 months for Essential Thrombocythemia (ET) patients, at every 6 months for other patients, for up to approximately 2 years post-treatment commencement.
Primary outcome [3] 337639 0
To obtain preliminary evidence of efficacy at the RP2D in subjects with:
- MDS/MPN (MDS/MPN-RS-T, MDS/MPN unclassifiable and CMML subjects).
Timepoint [3] 337639 0
• Assessment of spleen size and volume by physical examination - Physical exam will be performed throughout the study from Baseline to end of treatment, every 28day Cycle, for up to approximately 2 years post-treatment commencement.
• Evaluation of haematology (Anaemia response, duration of anaemia response rate of red blood cell (RBC) and transfusion dependency) - Haematology blood tests exam will be performed throughout the study from Baseline to end of treatment, every 28day Cycle, for up to approximately 2 years post-treatment commencement.
• Bone marrow aspiration and/or biopsy - will be collected at every 12 months for Essential Thrombocythemia (ET) patients, at every 6 months for other patients, for up to approximately 2 years post-treatment commencement.
Secondary outcome [1] 430314 0
Part 1 - To evaluate the overall safety and tolerability of JBI-802 as a single agent.
Timepoint [1] 430314 0
- Incidence of AEs characterized overall and by type, seriousness, relationship to study treatment, timing, and severity graded according to the NCI CTCAE Version 5.0.[Timeframe: every 28day Cycle, for up to approximately 2 years post-treatment commencement. ]
- Changes in clinical laboratory parameters, vital signs, ECG parameters, and physical examination findings. [Timeframe: every 28day Cycle, for up to approximately 2 years post-treatment commencement.]
Secondary outcome [2] 430315 0
Part 1 - To characterize the pharmacokinetic (PK) profile of JBI-802 as a single agent and their relationship to safety and efficacy.
Timepoint [2] 430315 0
Pharmacokinetic Timepoints - Cycle 1 Day 1 - Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose
Cycle 1 Day 2- Pre-dose (24 hours post dose)
Cycle 1 Day 8 - Pre-dose, 0.5, 2, 4 and 8 hours post-dose
Cycle 1 Day 15 - Pre-dose, 0.5, 2, 4 and 8 hours post-dose
Cycle 1 Day 22- Pre-dose, 0.5, 2, 4 and 8 hours post-dose
Cycle 2 Day 1 - Pre-dose, 0.5, 2, 4 and 8 hours post-dose
Cycle 2 Day 15 - Pre-dose, 0.5, 2, 4 and 8 hours post-dose
Cycle 3 Day 1 - Pre-dose, 0.5, 2, 4 and 8 hours post-dose
Cycle 5 Day 1 and every other cycle - Pre-dose, 0.5, 2, 4 and 8 hours post-dose
End of Treatment (EOT)/Early Termination (ET)- Predose

Eligibility
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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
A 3+3 design will be employed to assess tolerability in this study. Each cohort of subjects will be evaluated over a 28 days period for tolerability using the standard 3 + 3 design and dose escalation increments in new cohorts of subjects will be determined based on the emergent tolerability profile. Intra-subject dose escalation strategy will be allowed in this study after the initial treatment cycle. In the 3+3 design, if 3 subjects at a dose level complete the DLT evaluation period with no DLT, that dose level of JBI-802 will be deemed safe, and another 3 subjects will be treated at the next higher dose level. If 1 of the first 3 subjects experiences a DLT, 3 more subjects will be treated at the same JBI-802 dose level. If 2 or more of the 3 to 6 subjects in any dose level experience a DLT, dosing will stop at that level. Subjects who complete the DLT period, tolerate the doses and have been on therapy for at least one 28 day cycle without significant toxicities may proceed to a higher dose level for the following treatment cycle if the next dose cohort is deemed safe (for both acute and cumulative toxicities) at that time by the Safety Review Committee (SRC), and after consultation with the Sponsor during the current treatment with the study drug. Subjects who do not proceed to a higher dose may continue to receive additional cycles at their original dose.
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The initial cohort will initially enroll 3 subjects based on the 3+3 schema. The initial sample size will be to enroll approximately up to 30 subjects. Since it is not possible to determine the exact sample size now and further additional subjects may be enrolled Depending on the number of subjects needed for dose escalation and the required total number of subjects with ET.

Missing data
Efficacy
No imputation will be done on missing efficacy data.

Safety
No imputation will be done on missing safety data, unless for partially incomplete dates for remote events such as AE, Prior, Concomitant medication etc. The detailed information on imputing partial dates will be detailed in SAP.

Study Population Data
Demographic characteristics (including age, sex at birth, ethnicity, and race) and baseline characteristics (including height, weight, and disease characteristics) will be presented
descriptively. PK and PD endpoints will be analyzed using respective PK and PD population.Statistical analyses will be performed using Statistical Analysis System (SAS) software Version 9.4 or higher.

Population Pharmacokinetics
Population PK-based modeling approach may also be applied for PK characterization and PK covariate analyses. The steady-state PK profile may be projected based on the population PK model. Population PK data may be analyzed using modeling approaches and may also be pooled with data from other studies to investigate any association between investigational drug exposure and efficacy or significant safety endpoints. The results of these analyses, if performed, may be reported separately.

Efficacy Analyses
Efficacy Analyses (Part-1 & Part-2)
Proportion of subjects with Progression free survival will be summarized by the number and percentages of subjects using safety analysis set. Response rate, Overall response rate, proportion of subjects with overall survival will be summarized by frequencies and percentages using the Safety analysis set. The Binomial proportion confidence interval will be presented along with the estimate. More analysis details for all efficacy endpoints will be described in the SAP. All efficacy analysis will be based on Safety analysis set for Part-1 dose-escalation phase and for Part-2 dose-expansion phase. For Part-2 dose-expansion phase in addition to safety analysis set, Per Protocol analysis set will also be used to evaluate the efficacy in absence of major protocol deviation that would affect the efficacy.

Pharmacokinetic Analyses
All pharmacokinetic endpoint analysis will be done using Pharmacokinetic Analysis set. All the PK parameters will be summarized for single dose and steady state separately using the following descriptive statistics: number of non-missing values (n), minimum, arithmetic mean, median,maximum, standard deviation (SD) and coefficient of variation (CV%).

Pharmacodynamics Analyses
The Pharmacodynamic (PD) parameters will be analyzed using Pharmacodynamic set; The PD parameters will be summarized using descriptive statistics

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
29/04/2024
Actual
Date of last participant enrolment
Anticipated
15/04/2026
Actual
Date of last data collection
Anticipated
15/06/2028
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,WA
Recruitment hospital [1] 25963 0
Hollywood Private Hospital - Nedlands
Recruitment hospital [2] 25964 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 26179 0
Perth Blood Institute - West Perth
Recruitment postcode(s) [1] 41805 0
6009 - Nedlands
Recruitment postcode(s) [2] 41806 0
5000 - Adelaide
Recruitment postcode(s) [3] 42050 0
6005 - West Perth

Funding & Sponsors
Funding source category [1] 315372 0
Commercial sector/Industry
Name [1] 315372 0
Jubilant Therapeutics, Inc.
Country [1] 315372 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Jubilant Therapeutics, Inc.
Address
Jubilant Therapeutics, Inc.
Country
United States of America
Secondary sponsor category [1] 317433 0
Commercial sector/Industry
Name [1] 317433 0
Avance Clinical Pty Ltd
Address [1] 317433 0
213 Glynburn Road, Firle, South Australia 5070
Country [1] 317433 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314289 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 314289 0
Ethics committee country [1] 314289 0
Australia
Date submitted for ethics approval [1] 314289 0
06/12/2023
Approval date [1] 314289 0
06/03/2024
Ethics approval number [1] 314289 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 131074 0
Dr Andrew McQuillan
Address 131074 0
Hollywood Private Hospital, 101 Monash Avenue, Nedlands WA 6009
Country 131074 0
Australia
Phone 131074 0
+61 893861811
Fax 131074 0
Email 131074 0
andrew@qmedical.com.au
Contact person for public queries
Name 131075 0
Andrew McQuillan
Address 131075 0
Hollywood Private Hospital, 101 Monash Avenue, Nedlands WA 6009
Country 131075 0
Australia
Phone 131075 0
+61 893861811
Fax 131075 0
Email 131075 0
andrew@qmedical.com.au
Contact person for scientific queries
Name 131076 0
Melda Dolan
Address 131076 0
Jubilant Therapeutics Inc. 1430 US Highway 206, Suite 110 Bedminster, NJ 07921, United States
Country 131076 0
United States of America
Phone 131076 0
+1 267 888 4319
Fax 131076 0
Email 131076 0
melda.dolan@jubl.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Privacy and Intellectual property considerations


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.