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.