Myelofibrosis, Leukemia, Myelocytic, Acute, Myelodysplastic/Myeloproliferative Neoplasm, Myelodysplastic Syndrome (MDS), Preleukemia, Primary Myelofibrosis, Myeloproliferative Disorders, Bone Marrow Disease, Hematological Disease, Precancerous Conditions, Neoplasms, Leukemia, Neoplasms by Histologic Type, Essential Thrombocytosis
Conditions
Keywords
Phase 1, Phase 2, Oncology, BET Inhibitor, Ruxolitinib, Pelabresib (CPI-0610)
Brief summary
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.
Interventions
DRUGPelabresib
CPI-0610 is administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)
DRUGRuxolitinib
Ruxolitinib is given orally, twice daily (BID), on a continuous basis for 21 consecutive days of each 21-day cycle.
Sponsors
The Leukemia and Lymphoma Society
Constellation Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Frequency of Dose-limiting toxicities (DLTs) | 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 | 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) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | The percentage of study participants whose TSS-measured by the Myelofibrosis Symptom Assessment Form (MFSAF v4.0)-decreases by at least half compared to their baseline score, when assessed at 12 weeks and again at 24 weeks. |
| Phase 2 (Arms 1, 2 and 3): Overall splenic response rate at 12 and 24 weeks | 12 and 24 weeks | The overall splenic response rate is the proportion of patients who achieve a ≥ 35% reduction from baseline spleen size by imaging (MRI or CT). |
| Phase 2 (Arms 1, 2 and 3): Splenic response at 12 and 24 weeks | 12 and 24 weeks | The reduction in spleen size from baseline by imaging (MRI or CT) after 12 weeks (Cycle 5, Day 1) and after 24 weeks of treatment (Cycle 9, Day 1) will also be evaluated. |
| 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 | Time from first onset of TI to earliest onset of loss of TI. |
| Phase 2 (Arms 1, 2 and 3): Early anemic response rate | Through Phase II completion, an average of 6 years | Proportion of patients who achieve a hemoglobin increase of ≥1 g/dL from baseline, without RBC transfusions. |
| Phase 2 (Arms 1, 2 and 3): Anemic response rate in TI patients | Through Phase II completion, an average of 6 years | Proportion of TI patients with ≥1.5 g/dL hemoglobin increase from baseline, without RBC transfusions. |
| 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 | Time from first meeting splenic response criteria until loss of response (spleen volume \<35% reduction from baseline and increased by ≥25% from nadir). |
| 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. | Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. Cmax will be listed and summarized using descriptive statistics. |
| 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. | Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. Tmax will be listed and summarized using descriptive statistics. |
| Phase 1: Incidence rate of adverse events (AEs), serious adverse events (SAEs) | Through Phase I completion, an average of 4 years | The analysis of adverse events will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 4.03. |
| 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. | Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. AUClast will be listed and summarized using descriptive statistics. |
| 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. | Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. AUC0-8,ss will be listed and summarized using descriptive statistics. |
| 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. | Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. Cmax,ss will be listed and summarized using descriptive statistics. |
| 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. | Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. Tmax,ss will be listed and summarized using descriptive statistics. |
| 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) | The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) is a patient-reported questionnaire designed to measure symptom burden in patients with myeloproliferative neoplasms (MPNs). Patients rate the severity of several symptoms (such as fatigue, night sweats, itching, abdominal discomfort, bone pain, early satiety, and others) over the past 24 hours. Each symptom is scored on a scale from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be). The total score is the sum of all individual symptom scores, providing an overall measure of symptom burden. A 50% reduction in the MPN-SAF total score at 12 or 24 weeks means the patient's overall symptom burden has improved by half compared to their baseline (pre-treatment) score. |
| Phase 2 (Arm 4): Partial Hematological Response Rate | Over 2 consecutive cycles (rolling window) (1 cycle = 21 days) | Proportion of patients with platelets 400-600 × 10⁹/L, WBC ≤10 × 10⁹/L, confirmed after 1 cycle. |
| Phase 2 (Arm 4): Overall Hematological Response Rate | Through Phase II completion, an average of 6 years | Proportion of patients with complete or partial hematological response. |
| Phase 2 (Arm 4): Duration of Hematological Response | Through Phase II completion, an average of 6 years | Time from first onset of response to earliest onset of loss of response, including hematologic response and symptom improvement |
| Phase 2 (Arm 4): Rate of hemorrhagic and thromboembolic (TE) events | Through Phase II completion, an average of 6 years | Proportion of patients with hemorrhagic or TE events. |
| 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. | Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. Ctrough will be listed and summarized using descriptive statistics. |
| Phase 2 (All Arms): Incidence rate of adverse events (AEs), serious adverse events (SAEs) | Through Phase II completion, an average of 6 years | The analysis of adverse events will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 4.03. |
| 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) | The Patient Global Impression of Change (PGIC) is a single-question, patient-reported assessment that asks individuals to rate their overall change in myeloproliferative neoplasm (MPN) symptoms since starting study treatment. The patient select one of seven options, ranging from Very much improved to Very much worse. No Change from Baseline indicates stable symptoms (no improvement or worsening), negative change from Baseline indicates a reduction in symptom severity (improvement) and positive change from Baseline indicates an increase in symptom severity (worsening). |
| 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) | The MFSAF (Myelofibrosis Symptom Assessment Form) should be completed by patients every day for 7 days before Day 1 of each treatment cycle, including the 7 days before starting Cycle 1. It uses a 24-hour recall format, asking patients to rate the worst severity of seven symptoms (fatigue, night sweats, pruritus, abdominal discomfort, pain under the ribs on the left side, early satiety, and bone pain) during the past 24 hours. Each symptom is rated on a scale from 0 (Absent) to 10 (Worst Imaginable). The Total Symptom Score (TSS) is the sum of 7 symptoms (range: 0 - 70). No Change from Baseline indicates stable symptoms (no improvement or worsening), negative change from Baseline indicates a reduction in symptom severity (improvement) and positive change from Baseline indicates an increase in symptom severity (worsening). |
Countries
Belgium, Canada, France, Germany, Italy, Netherlands, Poland, United Kingdom, United States
Outcome results
None listed