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

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