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.

Study Overview

• Status: Completed
• Conditions: Neoplasms; Neoplasms by Histologic Type; Leukemia; Preleukemia; Primary Myelofibrosis; Myeloproliferative Disorders; Myelofibrosis; Precancerous Conditions; Myelodysplastic/Myeloproliferative Neoplasm; Myelodysplastic Syndrome (MDS); Leukemia, Myelocytic, Acute; Bone Marrow Disease; Hematological Disease; Essential Thrombocytosis
• Intervention / Treatment: Drug: Pelabresib; Drug: Ruxolitinib

• Study Type: Interventional
• Enrollment (Actual): 336
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Antwerp, Belgium, 2060
    • ZNA Stuyvenberg Antwerpen
  • Viaams Braban
    • Leuven, Viaams Braban, Belgium, 3000
      • UZ Leuven - Campus Gasthuisberg
  • West-Vlaanderen
    • Bruges, West-Vlaanderen, Belgium, 8000
      • AZ Sint-Jan Burgge-Oostende AV- Campus Sint-Jan
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2G3
      • University of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 2A5
      • St. Paul's Hospital
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• France
  • Paris, France, 75010
    • CHU - Hopital Saint Louis - Centre D'Investigations Clinique
  • Gard
    • Nîmes, Gard, France, 30029
      • Institut de cancérologie du Gard - Hematologie clinique
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France, 31059
      • CHRU de Lille - Hopital Claude Huriez
  • Hauts-de-France
    • Lille, Hauts-de-France, France, 59037
      • CHRU de Lille - Hopital Claude Huriez - Maladies du Sang
  • Île-de-France Region
    • Villejuif, Île-de-France Region, France, 94805
      • Institut Gustave Roussy
• Germany
  • North Rhine-Westphalia
    • Bonn, North Rhine-Westphalia, Germany, 53127
      • Universitatsklinikum Bonn
  • Saxony
    • Leipzig, Saxony, Germany, 04103
      • Universitätsklinikum Leipzig AöR
• Italy
  • Florence, Italy, 50134
    • Azienda Ospedaliero-Universitaria Careggi
  • Novara, Italy, 28100
    • AOU Maggiore della Carità
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • Institue of Hematology "L. and A. Seràgnoli"
    • Rimini, Emilia-Romagna, Italy, 47923
      • Servizio Sanitario Regionale Emilia-Romagna - Azienda Unita Sanitaria Locale (AUSL) di Rimini - Ospedale Infermi di Rimini
  • Liguria
    • Genoa, Liguria, Italy, 16132
      • AOU S.Martino, IRCCS, IST-Istituto Nazionale Ricerca Sul Can
  • Lombardy
    • Milan, Lombardy, Italy, 20122
      • Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda
    • Pavia, Lombardy, Italy, 27100
      • IRCCS Policlinico San Matteo, Università degli studi di Pavi
    • Varese, Lombardy, Italy, 21100
      • Ospedale di Circolo, PO Varese, AO Ospedale di Circolo e Fon
• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229 HX
      • Maastricht University Medical Center
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1081 HV
      • VUmcResearch B.V.
  • South Holland
    • Rotterdam, South Holland, Netherlands, 3015 AA
      • Erasmus Universitair Medisch Centrum Rotterdam
• Poland
  • Masovian Voivodeship
    • Warsaw, Masovian Voivodeship, Poland, 02-776
      • Instytut Hematologii i Transfuzjologii w Warszawie
  • Pomeranian Voivodeship
    • Gdansk, Pomeranian Voivodeship, Poland, 80-952
      • Uniwersyteckie Centrum Kliniczne
• United Kingdom
  • Belfast, United Kingdom, BT9 7AB
    • Belfast City Hospital
  • Cambridge, United Kingdom, CB2 0QQ
    • University of Cambridge
  • Cardiff, United Kingdom, CF14 4XW
    • University Hospital of Wales
  • Glasgow, United Kingdom, G12 0YN
    • Beatson West Of Scotland Cancer Centre
  • London, United Kingdom, NW1 2PG
    • University College London Hospital's NHS foundation Trust
  • London, United Kingdom, SE1 9RT
    • Guys and St Thomas' Hospital - Haematology
  • Manchester, United Kingdom, M20 4BX
    • The Christie Hospital
  • Oxford
    • Headington, Oxford, United Kingdom, OX3 7LE
      • Oxford University Hospitals
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University - Lurie Comprehensive Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicne Neuromuscular Division Department of Neurology Research
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10065
      • Weill Medical College and New York Presbyterian Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert & Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: Pelabresib; CPI-0610 was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days); Other Names: CPI-0610; DAK539
Experimental: 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).	Drug: Pelabresib; CPI-0610 was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days); Other Names: CPI-0610; DAK539
Experimental: 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).	Drug: Pelabresib; CPI-0610 was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days); Other Names: CPI-0610; DAK539; Drug: Ruxolitinib; Ruxolitinib was given orally, twice daily (BID), on a continuous basis for 21 consecutive days of each 21-day cycle.
Experimental: 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).	Drug: Pelabresib; CPI-0610 was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days); Other Names: CPI-0610; DAK539; Drug: Ruxolitinib; Ruxolitinib was given orally, twice daily (BID), on a continuous basis for 21 consecutive days of each 21-day cycle.
Experimental: 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).	Drug: Pelabresib; CPI-0610 was administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days); Other Names: CPI-0610; DAK539

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Frequency of Dose-limiting Toxicities (DLTs)	A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed by the Investigator as unrelated to disease progression, intercurrent illness, or concomitant medications that occurred within the first cycle of treatment (21-day cycle) with pelabresib (CPI-0610), and that met any of the criteria specified in the protocol.	Up to 21 days
Phase 2 (Cohorts 1B, 2B, and Arm 3): Number of Participants With Splenic Response Rate (SVR35) at Week 24	Splenic Response Rate (SVR35) at Week 24 was defined as the proportion of participants who demonstrated a reduction of at least 35% in spleen size from baseline, as measured by imaging techniques (MRI or CT), following 24 weeks of treatment.	Week 24 (Cycle 9 Day 1)
Phase 2 (Cohorts 1A and 2A): Number of Participants Enrolled as Transfusion Dependent (TD) With Conversion Rate From Red Blood Cell (RBC) Transfusion Dependence (TD) to Transfusion Independence (TI)	Conversion rate was defined as the proportion of participants who converted from transfusion dependence (TD) to transfusion independence (TI). TD was characterized by receiving an average of at least 2 units of red blood cell (RBC) transfusions per month-amounting to a minimum of 6 units over the 12 weeks prior to enrollment-while TI was defined as the absence of RBC transfusions during any consecutive 12-week period.	Any 12 consecutive weeks (rolling window) during active treatment with pelabresib (CPI-0610), from first dose through treatment discontinuation (up to approximately 8 years for Phase II)
Phase 2 (Arm 4): Number of Participants With Complete Hematological Response (CHR) Rate	Complete Hematological Response (CHR) Rate was defined as the proportion of participants who fulfilled the criteria for CHR, based on the modified European LeukemiaNet (ELN) guidelines (Barosi et al 2009): platelet count ≤400 × 10⁹/L, white blood cell (WBC) count ≤10 × 10⁹/L, confirmation of laboratory values after one treatment cycle, and normal spleen size determined by palpation or imaging.	Over 2 consecutive cycles (rolling window) (1 cycle = 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Number of Adverse Events and Serious Adverse Events as Assessed by CTCAE Criteria	The distribution of adverse events was performed through the analysis of frequencies for treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs), based on the monitoring of relevant clinical and laboratory safety parameters. Treatment-emergent adverse events (TEAEs) in this study were defined as events that began after the first dose of study treatment and continued until 30 days after the last dose, or events that were present prior to the first dose and increased in severity based on preferred term within 30 days following the last dose of pelabresib (CPI-0610).	Up to approximately 6 months
Phase 2 (All Arms): Number of Adverse Events and Serious Adverse Events as Assessed by CTCAE Criteria	The distribution of adverse events was performed through the analysis of frequencies for treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs), based on the monitoring of relevant clinical and laboratory safety parameters. Treatment-emergent adverse events (TEAEs) in this study were defined as events that began after the first dose of study treatment and continued until 30 days after the last dose, or events that were present prior to the first dose and increased in severity based on preferred term within 30 days following the last dose of pelabresib (CPI-0610).	Up to approximately 387 weeks
Phase 2 (All Arms): Symptom Improvement From the Patient Global Impression of Change (PGIC) at 12 and 24 Weeks	The Patient Global Impression of Change (PGIC) was a single-question, patient-reported assessment that asked individuals to rate their overall change in myeloproliferative neoplasm (MPN) symptoms since starting study treatment. The participants selected one of seven options, ranging from 'Very much improved' to 'Very much worse'. 'No Change from Baseline' indicated stable symptoms (no improvement or worsening), negative change from Baseline indicated a reduction in symptom severity (improvement), and positive change from Baseline indicated an increase in symptom severity (worsening).	Week 12 (Cycle 5 Day 1), Week 24 weeks (Cycle 9 Day 1)
Phase 2 (Arms 1, 2 and 3): Percent Change From Baseline in Total Symptom Score (TSS) From the Myelofibrosis Symptom Assessment Form (MFSAF v4.0) at 12 and 24 Weeks	The MFSAF (Myelofibrosis Symptom Assessment Form) was completed by participants every day for 7 days before Day 1 of each treatment cycle, including the 7 days before starting Cycle 1. It used a 24-hour recall format, asking participants 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 was rated on a scale from 0 (Absent) to 10 (Worst Imaginable). The Total Symptom Score (TSS) was the sum of 7 symptoms (range: 0-70). 'No Change from Baseline' indicated stable symptoms (no improvement or worsening), negative change from Baseline indicated a reduction in symptom severity (improvement), and positive change from Baseline indicated an increase in symptom severity (worsening).	Baseline, Week 12 (Cycle 5 Day 1), Week 24 (Cycle 9 Day 1)
Phase 2 (Arms 1, 2 and 3): Number of Participants Who Achieved a ≥ 50% Reduction in Total Symptom Score (TSS) at 12 and 24 Weeks	The proportion of study participants who experienced a reduction of at least 50% in their Total Symptom Score (TSS), as assessed using the Myelofibrosis Symptom Assessment Form (MFSAF v4.0), was evaluated at both 12 and 24 weeks relative to their baseline score.	Week 12 (Cycle 5 Day 1), Week 24 (Cycle 9 Day 1)
Phase 2 (Arms 1, 2 and 3): Number of Participants With Overall Splenic Response Rate (Overall SVR35)	Overall Splenic Response Rate (SVR35) was defined as the proportion of participants who achieved a reduction of at least 35% in spleen size from baseline, as measured by imaging (MRI or CT), at any point between Cycle 1 Day 1 and the End of Study Visit, whichever occurred first.	Through Phase II completion, an average of 6 years
Phase 2 (Arms 1, 2 and 3): Duration of Overall Splenic Response (Overall SVR35)	Duration of Overall Splenic Response (overall SVR35) was defined as the time from the first occurrence of a at least 35% reduction in spleen volume from baseline until the earliest of the following: a reduction of less than 35% from baseline combined with an increase of more than 25% from the nadir in spleen volume (as measured by MRI or CT), or death. The nadir was defined as the lowest spleen volume recorded after baseline and up to the evaluation point at which the initial splenic response was achieved.	From first onset of splenic response until loss of response, assessed up to approximately 6 years
Phase 2 (Cohorts 1A and 2A): Number of Participants With Splenic Response Rate (SVR35) at 12 and 24 Weeks	Splenic Response Rate (SVR35) at 12 and 24 weeks was defined as the proportion of participants who achieved a reduction of at least 35% in spleen size from baseline, as determined by imaging (MRI or CT), following 12 and 24 weeks of treatment, respectively.	Week 12 (Cycle 5 Day 1), Week 24 weeks (Cycle 9 Day 1)
Phase 2 (Cohorts 1A and 2A): Duration of Red Blood Cell (RBC) Transfusion Independence (TI) in Participants Who Enroll as Transfusion Dependent (TD)	Duration of Red Blood Cell (RBC) Transfusion Independence (TI) was defined as the longest continuous period during which participants, having achieved at least 12 weeks of transfusion independence, remained free from RBC transfusions.	From first onset of TI to earliest onset of loss of TI, assessed up to approximately 6 years
Phase 2 (Cohorts 1A and 2A): Early Anemic Response Rate in Participants Who Enroll as Transfusion Dependent (TD)	Early anemic response rate was defined as the proportion of participants who achieved an average increase of at least 1 g/dL in hemoglobin concentration over any rolling 8-week (56-day) period following baseline. This calculation was performed after applying the 14/3 day rule, which stipulates that hemoglobin measurements must be spaced at least 14 days apart, and that at least 3 such measurements are required within the 8-week window to ensure a reliable average. Importantly, this increase had to occur without any red blood cell (RBC) transfusions during the treatment period and up to the time of the latest hemoglobin assessment for each patient.	Through Phase II completion, an average of 6 years
Phase 2 (Cohorts 1B, 2B, and Arm 3): Number of Participants With Splenic Response Rate (SVR35) at 12 Weeks	Splenic Response Rate (SVR35) at Week 12 was defined as the proportion of participants who achieved a reduction of at least 35% in spleen size from baseline, as measured by imaging (MRI or CT), following 12 weeks of treatment.	Week 12 (Cycle 5 Day 1)
Phase 2 (Cohorts 1B, 2B, and Arm 3): Anemic Response Rate in Participants Who Enroll as Non-transfusion-dependent (Non-TD)	Anemic response was defined as a sustained average increase in hemoglobin concentration of at least 1.5 g/dL over any rolling 12-week (84-day) period following baseline. This calculation excluded periods involving red blood cell (RBC) transfusions and was performed after applying the 14/3-day rule for valid hemoglobin assessments. The response had to be maintained through to the most recent available hemoglobin measurement for each patient.	Through Phase II completion, an average of 6 years
Phase 2 (Arm 4): Percentage of Participants Who Achieve a ≥50% Reduction From Baseline in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) Total Score	The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) is a patient-reported questionnaire designed to measure symptom burden in participants with myeloproliferative neoplasms (MPNs). Participants 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.	Baseline, 12 weeks (Cycle 5, Day 1), 24 weeks (Cycle 9, Day 1)
Phase 2 (Arm 4): Partial Hematological Response Rate (PHR)	Partial Hematological Response Rate (PHR) was defined as the proportion of participants who met the following criteria over two consecutive cycles up to the last administration of study treatment: Platelet count > 400-600 x 10^9/L; WBC count within normal range (i.e., ≤ 10 x 10^9/L); Laboratory results confirmed after 1 cycle (after 3weeks)	Over 2 consecutive cycles (rolling window) (1 cycle = 21 days)
Phase 2 (Arm 4): Overall Hematological Response Rate (OHR)	Confirmed Overall Hematological Response (OHR) Rate was defined as the proportion of participants with either a confirmed complete or a partial hematological response at any time.	Through Phase II completion, an average of 6 years
Phase 2 (Arm 4): Duration of Overall Hematological Response Rate (OHR)	Duration of Overall Hematological Response (OHR) Rate was defined as the time from when the overall hematological response was first met until the time at which the overall hematological response was lost, i.e., the criteria for an overall hematological response (CHR or PHR) were not observed or death occurred, whichever came first.	Through Phase II completion, an average of 6 years
Phase 2 (Arm 4): Rate of Hemorrhagic and Thromboembolic (TE) Events	Rate of hemorrhagic and thromboembolic (TE) events was defined as the proportion of participants with hemorrhagic or thromboembolic events throughout the study.	Through Phase II completion, an average of 6 years
Phase 2 (All Arms): Maximum Observed Plasma Concentration (Cmax) of Pelabresib	Pharmacokinetic (PK) parameters were calculated based on Pelabresib plasma concentrations and actual sampling time points. Cmax was listed and summarized using descriptive statistics.	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 (All Arms): Time to Reach Maximum Concentration (Tmax) of Pelabresib	Pharmacokinetic (PK) parameters were calculated based on Pelabresib plasma concentrations and actual sampling time points. Tmax was listed and summarized using descriptive statistics.	Cycle 1 Day 14 (predose, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.
Phase 2 (All Arms): Predose (Trough) Concentration at the End of a Dosing Interval (Ctrough) of Pelabresib	Pharmacokinetic (PK) parameters were calculated based on Pelabresib plasma concentrations and actual sampling time points. Ctrough was listed and summarized using descriptive statistics.	Cycle 1 Day 14 (predose, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.
Phase 2 (All Arms): Area Under the Concentration-Time Curve From Time Zero to the Last Observed Concentration (AUClast) of Pelabresib	Pharmacokinetic (PK) parameters were calculated based on Pelabresib plasma concentrations and actual sampling time points. AUClast was listed and summarized using descriptive statistics.	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 (All Arms): Area Under the Concentration-Time Curve From Time Zero to 8 Hours Post-dose at Steady State (AUC0-8,ss) of Pelabresib	Pharmacokinetic (PK) parameters were calculated based on Pelabresib plasma concentrations and actual sampling time points. AUC0-8,ss was listed and summarized using descriptive statistics.	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 (All Arms): Time of Last Measurable Concentration (Tlast) of Pelabresib	Pharmacokinetic (PK) parameters were calculated based on Pelabresib plasma concentrations and actual sampling time points. Tlast was listed and summarized using descriptive statistics.	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 (Arm 2 - Cohort 2A): Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Cmax was listed and summarized using descriptive statistics.	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 (Arm 2 - Cohort 2A): Time to Reach Maximum Concentration (Tmax) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Tmax was listed and summarized using descriptive statistics.	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 (Arm 2 - Cohort 2A): Predose (Trough) Concentration at the End of a Dosing Interval (Ctrough) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Ctrough was listed and summarized using descriptive statistics.	Cycle 1 Day 14 (predose, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.
Phase 2 (Arm 2 - Cohort 2A): Area Under the Concentration-Time Curve From Time Zero to the Last Observed Concentration (AUClast) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. AUClast was listed and summarized using descriptive statistics.	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 (Arm 2 - Cohort 2A): Area Under the Concentration-Time Curve From Time Zero to 8 Hours Post-dose at Steady State (AUC0-8,ss) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. AUC0-8,ss was listed and summarized using descriptive statistics.	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 (Arm 2 - Cohort 2B): Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Cmax was listed and summarized using descriptive statistics.	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 (Arm 2 - Cohort 2B): Time to Reach Maximum Concentration (Tmax) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Tmax was listed and summarized using descriptive statistics.	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 (Arm 2 - Cohort 2B): Predose (Trough) Concentration at the End of a Dosing Interval (Ctrough) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Ctrough was listed and summarized using descriptive statistics.	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 (Arm 2 - Cohort 2B): Area Under the Concentration-Time Curve From Time Zero to the Last Observed Concentration (AUClast) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. AUClast was listed and summarized using descriptive statistics.	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 (Arm 2 - Cohort 2B): Area Under the Concentration-Time Curve From Time Zero to 8 Hours Post-dose at Steady State (AUC0-8,ss) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. AUC0-8,ss was listed and summarized using descriptive statistics.	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 (Arm 3): Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Cmax was listed and summarized using descriptive statistics.	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 (Arm 3): Time to Reach Maximum Concentration (Tmax) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Tmax was listed and summarized using descriptive statistics.	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 (Arm 3): Predose (Trough) Concentration at the End of a Dosing Interval (Ctrough) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. Ctrough was listed and summarized using descriptive statistics.	Cycle 1 Day 14 (predose, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.
Phase 2 (Arm 3): Area Under the Concentration-Time Curve From Time Zero to the Last Observed Concentration (AUClast) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. AUClast was listed and summarized using descriptive statistics.	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 (Arm 3): Area Under the Concentration-Time Curve From Time Zero to 8 Hours Post-dose at Steady State (AUC0-8,ss) of Ruxolitinib	Pharmacokinetic (PK) parameters were calculated based on ruxolitinib plasma concentrations and actual sampling time points. AUC0-8,ss was listed and summarized using descriptive statistics.	Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Other Outcome Measures

Outcome Measure	Time Frame
Phase 2 (Arms 1, 2, and 3): Evaluate response category rate	Rate of response by the International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria after 24 weeks
Phase 2 (Arms 1, 2, and 3): Evaluate the rate of RBC transfusion and the RBC transfusion dependence rate	Average number of RBC units per subject-month, up to 24 weeks and beyond

Collaborators and Investigators

• Sponsor: Constellation Pharmaceuticals
• Collaborators: The Leukemia and Lymphoma Society
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Stein EM, Fathi AT, Harb WA, Colak G, Fusco A, Mangan JK. Results from phase 1 of the MANIFEST clinical trial to evaluate the safety and tolerability of pelabresib in patients with myeloid malignancies. Leuk Lymphoma. 2024 Apr;65(4):503-510. doi: 10.1080/10428194.2023.2300710. Epub 2024 Jan 23.
• Gupta V, Mascarenhas J, Kremyanskaya M, Rampal RK, Talpaz M, Kiladjian JJ, Vannucchi AM, Verstovsek S, Colak G, Dey D, Harrison C. Matching-adjusted indirect comparison of the pelabresib-ruxolitinib combination vs JAKi monotherapy in myelofibrosis. Blood Adv. 2023 Sep 26;7(18):5421-5432. doi: 10.1182/bloodadvances.2023010628.
• Mascarenhas J, Kremyanskaya M, Patriarca A, Palandri F, Devos T, Passamonti F, Rampal RK, Mead AJ, Hobbs G, Scandura JM, Talpaz M, Granacher N, Somervaille TCP, Hoffman R, Wondergem MJ, Salama ME, Colak G, Cui J, Kiladjian JJ, Vannucchi AM, Verstovsek S, Curto-Garcia N, Harrison C, Gupta V. MANIFEST: Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naive Myelofibrosis. J Clin Oncol. 2023 Nov 10;41(32):4993-5004. doi: 10.1200/JCO.22.01972. Epub 2023 Mar 7.

Study record dates

Study Major Dates

• Study Start (Actual): July 16, 2014
• Primary Completion (Actual): January 9, 2025
• Study Completion (Actual): January 9, 2025

Study Registration Dates

• First Submitted: June 5, 2014
• First Submitted That Met QC Criteria: June 5, 2014
• First Posted (Estimated): June 9, 2014

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: May 8, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Ruxolitinib; Phase 1; Oncology; Phase 2; BET Inhibitor; Pelabresib (CPI-0610)
• Additional Relevant MeSH Terms: Blood Coagulation Disorders; Leukemia, Myeloid; Hemorrhagic Disorders; Blood Platelet Disorders; Hemic and Lymphatic Diseases; Thrombocytosis; Neoplasms; Leukemia; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Thrombocythemia, Essential; Primary Myelofibrosis; Precancerous Conditions; Bone Marrow Diseases; ruxolitinib; CPI-0610
• Other Study ID Numbers: 0610-02; 2018-000579-34 (EudraCT Number); CDAK539A12201 (Other Identifier: Novartis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No