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

Constellation Pharmaceuticals

Status and phase

Completed

Phase 2

Phase 1

Conditions

Bone Marrow Disease

Myelofibrosis

Leukemia, Myelocytic, Acute

Myeloproliferative Disorders

Leukemia

Myelodysplastic/Myeloproliferative Neoplasm

Neoplasms by Histologic Type

Precancerous Conditions

Myelodysplastic Syndrome (MDS)

Neoplasms

Primary Myelofibrosis

Essential Thrombocytosis

Hematological Disease

Preleukemia

Treatments

Drug: Pelabresib

Drug: Ruxolitinib

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT02158858

0610-02

2018-000579-34 (EudraCT Number)

CDAK539A12201 (Other Identifier)

Details and patient eligibility

About

Phase 1 Part: Open-label, sequential dose escalation study of pelabresib (CPI-0610) in patients with previously treated Acute Leukemia, Myelodysplastic/Myeloproliferative Neoplasms, and Phase 2 Part: Open-label study of pelabresib (CPI-0610) with and without Ruxolitinib in patients with Myeloproliferative Neoplasms (Myelofibrosis and Essential Thrombocythemia).

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

Enrollment

336 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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):
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
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

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

336 participants in 5 patient groups

Phase 1

Experimental group

Description:

Patients are enrolled in sequential cohorts (acute leukemia, including acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and acute undifferentiated or biphenotypic leukemia; chronic myelogenous leukemia (CML) in blast crisis; myelodysplastic syndrome (MDS); myelodysplastic/myeloproliferative neoplasms (MDS/MPN); or myelofibrosis (MF)) and receive escalating doses of pelabresib (CPI-0610).

Treatment:

Drug: Pelabresib

Phase 2 (Arm 1): Prior JAKi Monotherapy Arm (MF patients treated with pelabresib alone)

Experimental group

Description:

* Cohort 1A: Open to patients with MF who are Transfusion Dependent (TD) and who have previously been treated with a JAKi and are intolerant, resistant, refractory or lost response to the JAKi, or are ineligible to be treated with a JAKi (pelabresib (CPI-0610) alone) * Cohort 1B: Open to patients with MF who are not TD and who have previously been treated with a JAKi and are intolerant, resistant, refractory or lost response to the JAKi, or are ineligible to be treated with a JAKi. (pelabresib (CPI-0610) alone)

Treatment:

Drug: Pelabresib

Phase 2 (Arm 2): Prior JAKi Combination Arm

Experimental group

Description:

* Cohort 2A: Open to patients with MF who are Transfusion Dependent (TD) and are currently taking ruxolitinib but have disease that is not being adequately controlled by ruxolitinib (pelabresib (CPI-0610) + Ruxolitinib) * Cohort 2B: Open to patients with MF who are not TD and are currently taking ruxolitinib but have disease that is not being adequately controlled by ruxolitinib. (pelabresib (CPI-0610) + Ruxolitinib)

Treatment:

Drug: Ruxolitinib

Drug: Pelabresib

Phase 2 (Arm 3): JAKi Naïve Combination Arm

Experimental group

Description:

Open to patients with MF who have not previously received a JAKi (pelabresib (CPI-0610) + Ruxolitinib)

Treatment:

Drug: Ruxolitinib

Drug: Pelabresib

Phase 2 (Arm 4): Essential Thrombocythemia (ET) Monotherapy Arm

Experimental group