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

NCT02158858 | Completed Phase 1 Results FDA Drug

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

Brief Summary

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.

Conditions

Leukemia, Myelocytic, Acute; Myelodysplastic/Myeloproliferative Neoplasm; Preleukemia; Primary Myelofibrosis; Myeloproliferative Disorders; Bone Marrow Disease; Hematological Disease; Precancerous Conditions; Neoplasms; Leukemia; Neoplasms by Histologic Type; Essential Thrombocytosis; Myelofibrosis; Myelodysplastic Syndrome (MDS)

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)

  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 Outcomes (38)

• Phase 1: Number of Adverse Events and Serious Adverse Events as Assessed by CTCAE Criteria

  Up to approximately 6 months

• Phase 2 (All Arms): Number of Adverse Events and Serious Adverse Events as Assessed by CTCAE Criteria

  Up to approximately 387 weeks

• Phase 2 (All Arms): Symptom Improvement From the Patient Global Impression of Change (PGIC) at 12 and 24 Weeks

  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

  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

  Week 12 (Cycle 5 Day 1), Week 24 (Cycle 9 Day 1)

Study Arms (5)

Phase 1

EXPERIMENTAL

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

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

EXPERIMENTAL

* 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

Phase 2 (Arm 2): Prior JAKi Combination Arm

EXPERIMENTAL

* 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; Drug: Ruxolitinib

Phase 2 (Arm 3): JAKi Naïve Combination Arm

EXPERIMENTAL

Was open to patients with MF who had not previously received a JAKi (pelabresib (CPI-0610) + Ruxolitinib).

Drug: Pelabresib; Drug: Ruxolitinib

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

EXPERIMENTAL

Was open to high-risk patients with ET who were resistant or intolerant to hydroxyurea (HU) (pelabresib (CPI-0610) alone).

Drug: Pelabresib

Interventions

Pelabresib DRUG

CPI-0610 was 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 was 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

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

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: June 4, 2026
• Results First Posted: June 4, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

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