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

NCT02158858 | Completed Phase 1 FDA Drug

• 3 other identifiers: 0610-022018-000579-34CDAK539A12201
• Study Type: interventional
• Target: 336
• Locations: 9 countries
• Sites: 48

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.

Conditions

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

Keywords

Phase 1; Phase 2; Oncology; BET Inhibitor; Ruxolitinib; Pelabresib (CPI-0610)

Outcome Measures

Primary Outcomes (4)

• Phase 1: Frequency of Dose-limiting toxicities (DLTs)

  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.

  DLTs assessed during Cycle 1 (cycle = 21 days)

• Phase 2 (Cohorts 1B, 2B, and Arm 3): Splenic Response Rate by Imaging

  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.

  24 weeks (Cycle 9, Day 1)

• Phase 2 (Cohorts 1A and 2A): Conversion rate from Red Blood Cell (RBC) transfusion dependence (TD) to transfusion independence (TI)

  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

  12 consecutive weeks (rolling window, assessed after 24 weeks)

• Phase 2 (Arm 4): Complete Hematological Response (CHR) Rate

  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.

  Over 2 consecutive cycles (rolling window) (1 cycle = 21 days)

Secondary Outcomes (23)

• 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): Incidence rate of adverse events (AEs), serious adverse events (SAEs)

  Through Phase II completion, an average of 6 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 (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)

Study Arms (5)

Phase 1

EXPERIMENTAL

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).

Drug: Pelabresib

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

EXPERIMENTAL

* 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)

Drug: Pelabresib

Phase 2 (Arm 2): Prior JAKi Combination Arm

EXPERIMENTAL

* 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)

Drug: Pelabresib; Drug: Ruxolitinib

Phase 2 (Arm 3): JAKi Naïve Combination Arm

EXPERIMENTAL

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

Drug: Pelabresib; Drug: Ruxolitinib

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

EXPERIMENTAL

Open to high-risk patients with ET who are resistant or intolerant to hydroxyurea (HU) (pelabresib (CPI-0610) alone)

Drug: Pelabresib

Interventions

Pelabresib DRUG

CPI-0610 is administered orally once daily for 14 consecutive days, followed by a 7-day break (1 cycle = 21 days)

Also known as: CPI-0610, DAK539

Phase 1; Phase 2 (Arm 1): Prior JAKi Monotherapy Arm (MF patients treated with pelabresib alone); Phase 2 (Arm 2): Prior JAKi Combination Arm; Phase 2 (Arm 3): JAKi Naïve Combination Arm; Phase 2 (Arm 4): Essential Thrombocythemia (ET) Monotherapy Arm

Ruxolitinib DRUG

Ruxolitinib is given orally, twice daily (BID), on a continuous basis for 21 consecutive days of each 21-day cycle.

Phase 2 (Arm 2): Prior JAKi Combination Arm; Phase 2 (Arm 3): JAKi Naïve Combination Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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):

Sponsors & Collaborators

• Constellation Pharmaceuticals: lead
• The Leukemia and Lymphoma Society: collaborator

Study Sites (48)

Mayo Clinic Arizona

Phoenix, Arizona, 85054, United States

Location

UCLA Medical Center

Los Angeles, California, 90095, United States

Location

Mayo Clinic Jacksonville

Jacksonville, Florida, 32224, United States

Location

Northwestern University - Lurie Comprehensive Cancer Center

Chicago, Illinois, 60611, United States

Location

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

University of Michigan Medical Center

Ann Arbor, Michigan, 48109, United States

Location

Washington University School of Medicne Neuromuscular Division Department of Neurology Research

St Louis, Missouri, 63110, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10021, United States

Location

ICAHN School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Weill Medical College and New York Presbyterian Hospital

New York, New York, 10065, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Froedtert & Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

UZ Leuven - Campus Gasthuisberg

Leuven, Viaams Braban, 3000, Belgium

Location

AZ Sint-Jan Burgge-Oostende AV- Campus Sint-Jan

Bruges, West-Vlaanderen, 8000, Belgium

Location

ZNA Stuyvenberg Antwerpen

Antwerp, 2060, Belgium

Location

University of Alberta Hospital

Edmonton, Alberta, T6G 2G3, Canada

Location

St. Paul's Hospital

Vancouver, British Columbia, V6Z 2A5, Canada

Location

Juravinski Cancer Centre

Hamilton, Ontario, L8V 5C2, Canada

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

Institut de cancérologie du Gard - Hematologie clinique

Nîmes, Gard, 30029, France

Location

CHRU de Lille - Hopital Claude Huriez

Toulouse, Haute-Garonne, 31059, France

Location

CHRU de Lille - Hopital Claude Huriez - Maladies du Sang

Lille, Hauts-de-France, 59037, France

Location

CHU - Hopital Saint Louis - Centre D'Investigations Clinique

Paris, 75010, France

Location

Institut Gustave Roussy

Villejuif, Île-de-France Region, 94805, France

Location

Universitätsklinikum Bonn

Bonn, North Rhine-Westphalia, 53127, Germany

Location

Universitätsklinikum Leipzig AöR

Leipzig, Saxony, 04103, Germany

Location

Institue of Hematology "L. and A. Seràgnoli"

Bologna, Emilia-Romagna, 40138, Italy

Location

Servizio Sanitario Regionale Emilia-Romagna - Azienda Unita Sanitaria Locale (AUSL) di Rimini - Ospedale Infermi di Rimini

Rimini, Emilia-Romagna, 47923, Italy

Location

AOU S.Martino, IRCCS, IST-Istituto Nazionale Ricerca Sul Can

Genoa, Liguria, 16132, Italy

Location

Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda

Milan, Lombardy, 20122, Italy

Location

IRCCS Policlinico San Matteo, Università degli studi di Pavi

Pavia, Lombardy, 27100, Italy

Location

Ospedale di Circolo, PO Varese, AO Ospedale di Circolo e Fon

Varese, Lombardy, 21100, Italy

Location

Azienda Ospedaliero-Universitaria Careggi

Florence, 50134, Italy

Location

AOU Maggiore della Carità

Novara, 28100, Italy

Location

Maastricht University Medical Center

Maastricht, Limburg, 6229 HX, Netherlands

Location

VUmcResearch B.V.

Amsterdam, North Holland, 1081 HV, Netherlands

Location

Erasmus Universitair Medisch Centrum Rotterdam

Rotterdam, South Holland, 3015 AA, Netherlands

Location

Instytut Hematologii i Transfuzjologii w Warszawie

Warsaw, Masovian Voivodeship, 02-776, Poland

Location

Uniwersyteckie Centrum Kliniczne

Gdansk, Pomeranian Voivodeship, 80-952, Poland

Location

Oxford University Hospitals

Headington, Oxford, OX3 7LE, United Kingdom

Location

Belfast City Hospital

Belfast, BT9 7AB, United Kingdom

Location

University of Cambridge

Cambridge, CB2 0QQ, United Kingdom

Location

University Hospital of Wales

Cardiff, CF14 4XW, United Kingdom

Location

Beatson West of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

Location

University College London Hospital's NHS foundation Trust

London, NW1 2PG, United Kingdom

Location

Guys and St Thomas' Hospital - Haematology

London, SE1 9RT, United Kingdom

Location

The Christie Hospital

Manchester, M20 4BX, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 38259250 DERIVED

• 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.

  PMID: 37530627 DERIVED

• 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.

  PMID: 36881782 DERIVED

MeSH Terms

Conditions

Primary Myelofibrosis; Leukemia, Myeloid, Acute; Myelodysplastic-Myeloproliferative Diseases; Myelodysplastic Syndromes; Preleukemia; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Neoplasms; Leukemia; Neoplasms by Histologic Type; Thrombocythemia, Essential

Interventions

CPI-0610; ruxolitinib

Condition Hierarchy (Ancestors)

Hemic and Lymphatic Diseases; Leukemia, Myeloid; Blood Coagulation Disorders; Thrombocytosis; Blood Platelet Disorders; Hemorrhagic Disorders

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 5, 2014
• First Posted: June 9, 2014
• Study Start: July 16, 2014
• Primary Completion: January 9, 2025
• Study Completion: January 9, 2025
• Last Updated: October 8, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

BE (3); FR (5); DE (2); IT (8); US (12); CA (5); GB (8); NL (3); PL (2)