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

A Phase 1/2 Study of CPI-0610, a Small Molecule Inhibitor of BET Proteins: Phase 1 (Dose Escalation of CPI-0610 in Patients With Hematological Malignancies) and Phase 2 (Dose Expansion of CPI-0610 With and Without Ruxolitinib in Patients With Myeloproliferative Neoplasms)

Phase 1 Part: This was an open-label, sequential dose escalation study of pelabresib (CPI-0610) in patients who had previously been treated for Acute Leukemia, Myelodysplastic/Myeloproliferative Neoplasms.

Phase 2 Part: This was an open-label study of pelabresib (CPI-0610), administered with and without Ruxolitinib, in patients diagnosed with Myeloproliferative Neoplasms (Myelofibrosis and Essential Thrombocythemia).

Pelabresib (CPI-0610) was a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins.

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