Clinical Research Directory

Phase I (Dose Escalation) - Inclusion and Exclusion Criteria: 1. Inclusion Criteria (Phase I): * Age: Adults ≥18 years. * Diagnosis: Histologically or cytologically confirmed diagnosis of one of the following hematologic malignancies: * Acute myelogenous leukemia (AML) * Acute lymphocytic leukemia (ALL) * Acute undifferentiated or biphenotypic leukemia * Chronic myeloid leukemia (CML) in blast crisis * Myelodysplastic syndrome (MDS) * Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) * Myelofibrosis (MF) * Performance Status: ECOG ≤2. * Organ Function: * Serum total bilirubin ≤1.5 × ULN * AST/ALT ≤2.5 × ULN (up to 5 × ULN if due to leukemic infiltration) * Serum creatinine ≤2.0 × ULN or CrCl ≥30 mL/min * Hematology (MF only): * Platelet count ≥50 × 10⁹/L and ANC ≥1 × 10⁹/L (MF not on ruxolitinib) * Platelet count ≥75 × 10⁹/L and ANC ≥1 × 10⁹/L (MF on ruxolitinib) * Other: * DIPSS-plus risk category of intermediate-2 or high (MF only) * Serum glucose ≤160 mg/dL (or HbA1C ≤7%) * Fully recovered from major surgery and acute toxic effects of prior therapy * Negative pregnancy test for women of childbearing potential * Agreement to use appropriate contraception * Written informed consent 2. Exclusion Criteria (Phase I): * Untreated newly diagnosed acute leukemia (unless AML with myelodysplasia-related changes and 20-30% blasts) * Relapsed/refractory acute leukemia where further induction chemotherapy is beneficial * Acute leukemia relapse \<6 months after allogeneic SCT * CML in blast crisis treated with only one TKI * Very low/low risk MDS without prior treatment * CNS involvement by leukemia (unless resolved) * Active HIV, Hepatitis B or C infection * GI impairment affecting absorption (unresolved nausea, vomiting, diarrhea \>CTCAE grade 1) * Significant cardiac disease (recent MI/angina, high cTn, QTcF \>470 ms, LVEF \<50%, uncontrolled arrhythmia, etc.) * Severe/uncontrolled comorbidities * Recent systemic anti-cancer therapy (other than hydroxyurea/radiotherapy) \<2 weeks prior * Ongoing or recent JAK inhibitor use (\<2 weeks prior, MF only) * Recent therapeutic antibody (\<4 weeks) or investigational agent (\<2 weeks or \<5 half-lives) * Use of strong CYP450 inhibitors/inducers or drugs with Torsades de Pointes risk * Immunosuppressive treatment that cannot be discontinued * Pregnant/lactating women * Inadequate contraception * Inability/unwillingness to comply with protocol Phase II (Expansion) - Inclusion \& Exclusion Criteria: 1. Inclusion Criteria (Phase II): 1. MF Arms (Prior JAKi, Add-on JAKi, JAKi Naïve) * Age: Adults ≥18 years * Diagnosis: Confirmed primary MF or MF evolved from ET or PV * Risk: DIPSS intermediate-2 or higher * Platelets: * ≥75 × 10⁹/L (Arms 1 \& 2) * ≥100 × 10⁹/L (Arm 3, JAKi naïve) * ANC: ≥1 × 10⁹/L * Spleen Volume: ≥450 cm³ by MRI/CT (non-TD cohorts) OR * Transfusion Dependence: Average ≥2 RBC transfusions/month (total ≥6 in prior 12 weeks) for TD cohorts * Peripheral Blood Blasts: \<10% * Symptoms: At least 2 symptoms measurable (score ≥1 for Arms 1 \& 2; score ≥3 or total ≥10 for Arm 3) using MFSAF v4.0 * Treatment History: * Arm 1 (Prior JAKi): Previously treated with JAKi and intolerant, resistant, refractory, or lost response, or ineligible for JAKi * Arm 2 (Add-on JAKi): On ruxolitinib ≥6 months, stable dose ≥8 weeks, not adequately controlled * Arm 3 (JAKi Naïve): No prior JAKi, eligible for ruxolitinib * Performance Status: ECOG ≤2 * Organ Function: Serum direct bilirubin \<2 × ULN, AST/ALT ≤2.5 × ULN (up to 5 × ULN if due to liver involvement), CrCl ≥45 mL/min * Other: Fully recovered from major surgery/acute toxic effects, effective contraception, written informed consent 2. ET Arm (High-Risk ET) * Age: Adults ≥18 years * Diagnosis: Confirmed ET (WHO 2016 criteria) * High-Risk: At least one of: * Age \>60 years * Platelets \>1500 × 10⁹/L * Prior thrombosis, erythromelalgia, or migraine (disease-related) * Prior hemorrhage related to ET * Diabetes/hypertension requiring therapy \>6 months * Symptoms: ≥2 symptoms with average score ≥3 or total score ≥15 (MPN-SAF) * Platelets: \>600 × 10⁹/L * Resistant/Intolerant to HU: As defined by ELN * Performance Status: ECOG ≤2 * Life Expectancy: \>24 weeks * ANC: ≥1 × 10⁹/L * Organ Function: Serum direct bilirubin \<2 × ULN, AST/ALT ≤2.5 × ULN, CrCl ≥45 mL/min * Other: Fully recovered from major surgery/acute toxic effects, effective contraception, written informed consent 2. Exclusion Criteria (Phase II) * Prior splenectomy (MF non-TD cohorts) * Splenic irradiation within 3 months * Active or chronic HIV, Hepatitis B/C infection * Active clinically significant infection (until recovery ≥2 weeks) * Anemia deemed clinically significant (iron/B12/folate deficiency, hemolytic anemia) * Major bleeding event (≥2 g/dL Hgb drop or ≥2 units transfused in last 6 months) * Liver cirrhosis Child-Pugh B or C * GI impairment affecting absorption (unresolved nausea, vomiting, diarrhea \>CTCAE grade 1) * Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption (Arm 3) * Hypersensitivity to ruxolitinib formulation (Arm 3) * History of PML (Arm 3) * Significant cardiac disease (recent MI/angina, QTcF \>500 ms \[\>450 ms in France/Germany\], uncontrolled arrhythmia, etc.) * Ongoing uncontrolled hypertension * Severe/uncontrolled comorbidities * Systemic anticancer treatment (other than ruxolitinib for Arm 2, HU/ANA up to 24h prior) \<2 weeks or \<5 half-lives prior * Prior treatment with any BET inhibitor * Hematopoietic growth factor or androgenic steroids \<4 weeks prior * Systemic corticosteroids ≥10 mg prednisone equivalent within 4 weeks (exceptions for short courses) * Concurrent/second malignancy (except certain adequately treated cancers) * Pregnant/lactating women, or planning pregnancy within protocol-defined window * Inability/unwillingness to comply with protocol