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)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 336
- 试验地点
- 96
- 主要终点
- Phase 1: Frequency of Dose-limiting toxicities (DLTs)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Phase I (Dose Escalation) - Inclusion and
排除标准
- •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 ≤
- •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)
- •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:
- 另有 53 项未显示
研究组 & 干预措施
Phase 1
Patients were 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 received escalating doses of pelabresib (CPI-0610).
干预措施: Pelabresib (Drug)
Phase 2 (Arm 1): Prior JAKi Monotherapy Arm (MF patients treated with pelabresib alone)
- Cohort 1A: Was open to patients with MF who were Transfusion Dependent (TD) and who had previously been treated with a JAKi and were intolerant, resistant, refractory, or had lost response to the JAKi, or were ineligible to be treated with a JAKi (pelabresib (CPI-0610) alone).
- Cohort 1B: Was open to patients with MF who were not TD and who had previously been treated with a JAKi and were intolerant, resistant, refractory, or had lost response to the JAKi, or were ineligible to be treated with a JAKi (pelabresib (CPI-0610) alone).
干预措施: Pelabresib (Drug)
Phase 2 (Arm 3): JAKi Naïve Combination Arm
Was open to patients with MF who had not previously received a JAKi (pelabresib (CPI-0610) + Ruxolitinib).
干预措施: Ruxolitinib (Drug)
Phase 2 (Arm 2): Prior JAKi Combination Arm
- Cohort 2A: Was open to patients with MF who were Transfusion Dependent (TD) and were taking ruxolitinib but had disease that was not adequately controlled by ruxolitinib (pelabresib (CPI-0610) + Ruxolitinib).
- Cohort 2B: Was open to patients with MF who were not TD and were taking ruxolitinib but had disease that was not adequately controlled by ruxolitinib (pelabresib (CPI-0610) + Ruxolitinib).
干预措施: Pelabresib (Drug)
Phase 2 (Arm 2): Prior JAKi Combination Arm
- Cohort 2A: Was open to patients with MF who were Transfusion Dependent (TD) and were taking ruxolitinib but had disease that was not adequately controlled by ruxolitinib (pelabresib (CPI-0610) + Ruxolitinib).
- Cohort 2B: Was open to patients with MF who were not TD and were taking ruxolitinib but had disease that was not adequately controlled by ruxolitinib (pelabresib (CPI-0610) + Ruxolitinib).
干预措施: Ruxolitinib (Drug)
Phase 2 (Arm 3): JAKi Naïve Combination Arm
Was open to patients with MF who had not previously received a JAKi (pelabresib (CPI-0610) + Ruxolitinib).
干预措施: Pelabresib (Drug)
Phase 2 (Arm 4): Essential Thrombocythemia (ET) Monotherapy Arm
Was open to high-risk patients with ET who were resistant or intolerant to hydroxyurea (HU) (pelabresib (CPI-0610) alone).
干预措施: Pelabresib (Drug)
结局指标
主要结局
Phase 1: Frequency of Dose-limiting toxicities (DLTs)
时间窗: DLTs assessed during Cycle 1 (cycle = 21 days)
The maximum tolerated dose (MTD) of CPI-0610 and characterize its DLTs in patients with acute leukemia, myelodysplastic syndrome (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and myelofibrosis (MF), when given once daily by mouth for 14 consecutive days followed by a 7-day break.
Phase 2 (Cohorts 1B, 2B, and Arm 3): Splenic Response Rate by Imaging
时间窗: 24 weeks (Cycle 9, Day 1)
Splenic response rate is defined as the proportion of patients who achieve a ≥ 35% reduction from baseline spleen size by imaging (MRI or CT) after 24 weeks of treatment.
Phase 2 (Cohorts 1A and 2A): Conversion rate from Red Blood Cell (RBC) transfusion dependence (TD) to transfusion independence (TI)
时间窗: 12 consecutive weeks (rolling window, assessed after 24 weeks)
Conversion rate is defined as the proportion of patients who convert from TD to TI, where TD is defined as receiving an average of ≥ 2 units of RBC transfusions per month (total of ≥ 6 RBC transfusions during the 12 weeks) prior to enrollment and TI is defined as absence of RBC transfusions over any consecutive 12 week period
Phase 2 (Arm 4): Complete Hematological Response (CHR) Rate
时间窗: Over 2 consecutive cycles (rolling window) (1 cycle = 21 days)
Complete CHR rate is defined as the proportion of patients who meet the criteria for CHR, as assessed by modified European LeukemiaNet (ELN) criteria: platelet count ≤400 × 10⁹/L, WBC ≤10 × 10⁹/L, laboratory results confirmed after 1 cycle, and normal spleen size by palpation or imaging.
次要结局
- Phase 1: Incidence rate of adverse events (AEs), serious adverse events (SAEs)(Through Phase I completion, an average of 4 years)
- Phase 2 (All Arms): Change from Baseline in Patient Global Impression of Change (PGIC) at 12 and 24 weeks(Baseline, 12 weeks (Cycle 5, Day 1), 24 weeks (Cycle 9, Day 1))
- Phase 2 (All Arms): Incidence rate of adverse events (AEs), serious adverse events (SAEs)(Through Phase II completion, an average of 6 years)
- Phase 2 (Arms 1, 2 and 3): Change from Baseline in Myelofibrosis Symptom Assessment Form (MFSAF v4.0) at 12 and 24 weeks(Baseline, 12 weeks (Cycle 5, Day 1), 24 weeks (Cycle 9, Day 1))
- Phase 2 (Arms 1, 2 and 3): Percentage of patients who achieve a ≥ 50% reduction in Total Symptom Score (TSS) at 12 and 24 weeks(12 weeks (Cycle 5, Day 1), 24 weeks (Cycle 9, Day 1))
- Phase 2 (Arms 1, 2 and 3): Overall splenic response rate at 12 and 24 weeks(12 and 24 weeks)
- Phase 2 (Arms 1, 2 and 3): Duration of Transfusion Independence (TI)(From first onset of TI to earliest onset of loss of TI, assessed up to approximately 6 years)
- Phase 2 (Arms 1, 2 and 3): Splenic response at 12 and 24 weeks(12 and 24 weeks)
- Phase 2 (Arms 1, 2 and 3): Early anemic response rate(Through Phase II completion, an average of 6 years)
- Phase 2 (Arms 1, 2 and 3): Anemic response rate in TI patients(Through Phase II completion, an average of 6 years)
- Phase 2 (Arms 1, 2 and 3): Duration of splenic response(From first onset of splenic response until loss of response, assessed up to approximately 6 years)
- Phase 2 (Arms 2 and 4): Maximum observed plasma concentration (Cmax) of pelabresib and ruxolitinib(Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.)
- Phase 2 (Arms 2 and 4): Time to reach maximum concentration (tmax) of pelabresib and ruxolitinib(Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.)
- Phase 2 (Arms 2 and 4): Predose (trough) concentration at the end of a dosing interval (Ctrough) of pelabresib and ruxolitinib(Cycle 1 Day 1, Cycle 1 Day 14, Cycle 3 Day 1: predose. 1 cycle = 21 days.)
- Phase 2 (Arms 2 and 4): Area under the concentration-time curve from time zero to the last observed concentration (AUClast) of pelabresib and ruxolitinib(Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.)
- Phase 2 (Arms 2 and 4): Area under the concentration-time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of pelabresib and ruxolitinib(Cycle 1 Day 14, Cycle 3 Day 1. 1 cycle = 21 days.)
- Phase 2 (Arms 2 and 4): Maximum concentration at steady state (Cmax,ss) of pelabresib and ruxolitinib(Cycle 1 Day 14, Cycle 3 Day 1. 1 cycle = 21 days.)
- Phase 2 (Arms 2 and 4): Time to reach maximum concentration at steady state (tmax,ss) of pelabresib and ruxolitinib(Cycle 1 Day 14, Cycle 3 Day 1. 1 cycle = 21 days.)
- Phase 2 (Arm 4): Percentage of patients who achieve a ≥50% reduction from baseline in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total score(Baseline, 12 weeks (Cycle 5, Day 1), 24 weeks (Cycle 9, Day 1))
- Phase 2 (Arm 4): Partial Hematological Response Rate(Over 2 consecutive cycles (rolling window) (1 cycle = 21 days))
- Phase 2 (Arm 4): Overall Hematological Response Rate(Through Phase II completion, an average of 6 years)
- Phase 2 (Arm 4): Duration of Hematological Response(Through Phase II completion, an average of 6 years)
- Phase 2 (Arm 4): Rate of hemorrhagic and thromboembolic (TE) events(Through Phase II completion, an average of 6 years)