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.

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.