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

Phase 2RecruitingNCT07612280

Jubilant Therapeutics Inc.30 enrolled

Overview

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.

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: \- 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. 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 the exception: * Patient with previous cancers can be included to the study provided they are in remission at the time of screening and enrolment. * Patient with localized skin cancer can also be included for screening and enrollment. 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. If a patient is taking low dose steroids for therapeutic purposes (less than or equal to 10 mg prednisone or its equivalent), they are eligible to participate in the study provided they meet all other pertinent criteria. 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.

Outcomes

Primary Outcomes

Dose Escalation - Incidence of Dose-Limiting Toxicities (DLTs)

Number of participants with dose-limiting toxicity (DLT) events during the DLT monitoring period. DLTs are defined per protocol criteria and graded using NCI CTCAE Version 5.0. Units: Number of participants

Time frame: At the end of Cycle 1 (each cycle is 28 days)

Dose Expansion - Overall Response Rate (ORR)

Percentage of participants with best overall response of complete response or partial response according to MPN IWG-MRT or MDS/MPN IWG criteria. Units: Percentage of participants

Time frame: Up to 2 years

Dose Expansion - Complete Remission (CR) Rate

Percentage of participants achieving complete remission per IWG criteria. Units: Percentage of participants

Time frame: Up to 2 years

Dose Expansion - Progression-Free Survival (PFS)

Time from first dose to disease progression or death from any cause. Units: Months

Time frame: At 6 months and up to approximately 2 years

Dose Expansion - Overall Survival (OS)

Time from first dose to death from any cause. Units: Months

Time frame: Up to 2 years

Dose Expansion - Platelet Count ≤400 ×10⁹/L Without Thromboembolic Events

Number of participants achieving platelet count ≤400 ×10⁹/L in absence of thromboembolic events. Units: Number of participants

Time frame: Up to 2 years

Secondary Outcomes

Dose Escalation - Incidence of Treatment-Emergent Adverse Events (TEAEs)

Number of participants with treatment-emergent adverse events, classified by system organ class and severity according to NCI CTCAE v5.0. Units: Number of participants

Time frame: From first dose up to 2 years

Maximum Plasma Concentration (Cmax) of JBI-802

Maximum observed plasma concentration of JBI-802 following dosing. Units: ng/mL

Time frame: From Cycle 1 Day 1 up to Cycle 3 Day 1 (each cycle is 28 days)

Area Under the Plasma Concentration-Time Curve (AUC0-t) of JBI-802

Area under the plasma concentration-time curve from time 0 to last measurable concentration.

Time frame: From Cycle 1 Day 1 up to Cycle 3 Day 1 (each cycle is 28 days)

Time to Maximum Plasma Concentration (Tmax) of JBI-802

Time to reach maximum plasma concentration.

Time frame: From Cycle 1 Day 1 up to Cycle 3 Day 1 (each cycle is 28 days)

Overall Response Rate (ORR)

Percentage of participants with best overall response of complete response or partial response according to MPN IWG-MRT or MDS/MPN IWG criteria. Units: Percentage of participants

Time frame: Up to 2 years

Duration of Response (DOR)

Time from first documented response to disease progression or death.

Time frame: Up to 2 years

Platelet Count ≤400 ×10⁹/L Without Thromboembolic Events

Number of participants achieving platelet count ≤400 ×10⁹/L in absence of thromboembolic events. Units: Number of participants

Time frame: Up to 2 years

Dose Expansion - Change From Baseline in MPN-SAF Total Symptom Score (TSS)

Change from baseline in MPN-SAF TSS (0-10 scale per symptom). Units: Score change

Time frame: Up to 2 years

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

Overview

Conditions

Interventions

Eligibility

Locations (7)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts