A Phase 1/2 Study of CPI-0610 With and Without Ruxolitinib in Patients With Hematologic and Myeloproliferative Malignancies

Inclusion Criteria

• 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