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

Criteria the registry did not label

• Phase I (Dose Escalation) - Inclusion and Exclusion Criteria:
• 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
• 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:
• Inclusion Criteria (Phase II):
  • 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
  • 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
• 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