A Phase 2 Study of CPI-0610 With and Without Ruxolitinib in Patients With Myelofibrosis

Sponsor
Constellation Pharmaceuticals (Industry)
Overall Status
Recruiting
CT.gov ID
NCT02158858
Collaborator
The Leukemia and Lymphoma Society (Other)
341
Enrollment
55
Locations
4
Arms
101.1
Anticipated Duration (Months)
6.2
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Phase 1 Part (Complete): Open-label, sequential dose escalation study of CPI-0610 in patients with previously treated Acute Leukemia, Myelodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasms, and Myelofibrosis.

Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis.

CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
341 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2 Study of CPI-0610, a Small Molecule Inhibitor of BET Proteins: Phase 1 (in Patients With Hematological Malignancies) and Phase 2 (Dose Expansion of CPI-0610 With and Without Ruxolitinib in Patients With Myelofibrosis)
Actual Study Start Date :
Jul 29, 2014
Anticipated Primary Completion Date :
Dec 31, 2022
Anticipated Study Completion Date :
Dec 31, 2022

Arms and Interventions

ArmIntervention/Treatment
Experimental: Arm 1: Prior JAKi (JAK inhibitor) Monotherapy Arm

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.(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. (CPI-0610 alone)

Drug: CPI-0610

Experimental: Arm 2: Prior JAKi Combination Arm

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. (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. (CPI-0610 + Ruxolitinib)

Drug: CPI-0610

Drug: Ruxolitinib

Experimental: Arm 3: JAKi Naïve Combination Arm

Open to patients with MF who have not previously received a JAKi. (CPI-0610 + Ruxolitinib) and have DIPSS risk category Intermediate-2 or higher

Drug: CPI-0610

Drug: Ruxolitinib

Experimental: Arm 4: Essential Thrombocythemia (ET) Monotherapy Arm

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

Drug: CPI-0610

Outcome Measures

Primary Outcome Measures

  1. Phase 2 (Cohorts 1B and 2B and Arm 3): Evaluate spleen response [By imaging after 24 weeks]

  2. Phase 2 (Cohorts 1A and 2A): Evaluate the RBC (Red Blood Cell) transfusion independence rate [Absence of RBC transfusion and no hemoglobin level below 8 g/dL in the prior 12 weeks]

  3. Phase 2 (Arm 4): Evaluate the complete hematological response rate [1 cycle (21 days)]

Secondary Outcome Measures

  1. Phase 2 (Arms 1, 2, and 3): Evaluate the duration of spleen response by imaging [Through study completion or end of treatment, up to 24 weeks and beyond]

  2. Phase 2 (all arms): Evaluate the change in patient reported outcomes [Changes from baseline in the total symptom score (MFSAF v4.0) and PGIC after 24 weeks]

  3. Phase 2 (all arms): area under the curve (AUC) [Assessed during Cycle 1 (first 21 days on study)]

  4. Phase 2 (all arms): maximum observed plasma concentration (Cmax) [Assessed during Cycle 1 (first 21 days on study)]

Other Outcome Measures

  1. 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]

  2. 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]

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:

Phase 2 part: Patients with confirmed diagnosis of MF who meet all of the following criteria:

  • ANC ≥ 1 x 10^9/L without the assistance of granulocyte growth factors

  • Peripheral blood blast count <10%

  • ECOG performance status ≤ 2.

  • Adequate hematological, renal, hepatic, and coagulation laboratory assessments

  • No prior treatment with a BET inhibitor

  • Patients must give written informed consent to participate in this study before the performance of any study-related procedure.

For Arm 1 and 2 the following criteria should be considered:
  • Patients with confirmed diagnosis of MF who meet all of the following criteria

  • Dynamic International Prognostic Scoring System (DIPSS) risk category of intermediate-2 or higher

  • Spleen volume ≥ 450 cm^3 by MRI or CT for Cohorts 1B and 2B OR RBC transfusion dependent (defined as an average of ≥2 units of RBC transfusions per month over the 12 weeks prior to enrollment for Cohorts 1A and 2A)

  • At least 2 symptoms measurable (Score ≥ 1) using the Myelofibrosis Symptom Assessment Form Version 4.0 (MFSAF v4.0)

  • Platelet count ≥ 75 x 10^9/L without the assistance of thrombopoietic factors or transfusions for at least 14 days

Monotherapy Arm (Arm 1): Previously treated with a JAK inhibitor and be intolerant, resistant, refractory, or lost response to the JAK inhibitor; have not received the JAK inhibitor within 2 weeks prior to the start of study drug, or are ineligible to be treated with a JAK inhibitor

Combination Arm (Arm 2): Must have received single agent ruxolitinib and be on a stable dose for a minimum 8 weeks but have disease that is not being adequately controlled by ruxolitinib

For Arm 3 (JAK inhibitors naïve) the following criteria should be considered:
  • Patients with confirmed diagnosis of MF who meet all of the following criteria

  • Dynamic International Prognostic Scoring System (DIPSS) risk category of intermediate-2 or higher

  • Platelet count ≥ 100 x 10^9/L without the assistance of thrombopoietic factors or transfusions

  • Spleen volume ≥ 450 cm^3 by MRI/CT

  • At least 2 symptoms measurable (Score ≥ 3) or a total score of ≥ 10 using the MFSAF v4.0

  • No prior treatment with JAKi allowed

For Arm 4 (ET Expansion) the following criteria should be considered:
  • Patients with a confirmed diagnosis of ET

  • High-risk disease, defined as meeting at least one of the following criteria:

  • Age > 60 years

  • Platelet count > 1500 × 10^9/L (at any point during the patient's disease)

  • Previously documented thrombosis, erythromelalgia, or migraine

  • Previous hemorrhage related to ET

  • Diabetes or hypertension requiring pharmacological therapy for > 6 months

  • Have ≥2 symptoms with an average score ≥ 3 over the 7-day period prior to Cycle 1 Day 1 or an average total score of ≥15 over the 7-day period prior to Cycle 1 Day 1 using the using the MPN SAF

  • Platelets > 600 × 10^9/L

  • Resistant or intolerant to HU

Exclusion Criteria:
  • Current known active or chronic infection with human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C.

  • Impaired cardiac function or clinically significant cardiac diseases

  • Patients with Child-Pugh Class B or C

  • Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of CPI-0610 and/or ruxolitinib, including any unresolved nausea, vomiting, or diarrhea that is CTCAE Grade >1

  • Prior treatment with a BET inhibitor.

  • Pregnant or lactating women

  • Any other concurrent severe and/or uncontrolled concomitant medical condition that could compromise participation in the study

  • Patients unwilling or unable to comply with this study protocol.

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1Mayo Clinic - Research CenterPhoenixArizonaUnited States85054
2UCLA Medical CenterLos AngelesCaliforniaUnited States90095
3Mayo Clinic - Cancer Clinical Research OfficeJacksonvilleFloridaUnited States32224
4Northwestern University - Lurie Comprehensive Cancer CenterChicagoIllinoisUnited States60611
5Massachusetts General HospitalBostonMassachusettsUnited States02114
6University of Michigan Medical CenterAnn ArborMichiganUnited States48109
7Washington University School of Medicne Neuromuscular Division Department of neurologySaint LouisMissouriUnited States63110
8Memorial Sloan Kettering MonmounthMiddletownNew JerseyUnited States07748
9Memorial Sloan Kettering BergenMontvaleNew JerseyUnited States07645
10Memorial Sloan Kettering Cancer Center CommackCommackNew YorkUnited States11725
11Icahn School of Medicine at Mount SinaiNew YorkNew YorkUnited States10029
12Columbia University Medical CentreNew YorkNew YorkUnited States10032
13Memorial Sloan-Kettering Cancer CenterNew YorkNew YorkUnited States10065
14Weill Cornell Medical College-New York Presbyterian HospitalNew YorkNew YorkUnited States10065
15MD Anderson Cancer CenterHoustonTexasUnited States77030
16Froedtert & Medical College of WisconsinMilwaukeeWisconsinUnited States53226
17ZNA Stuyvenberg AntwerpenAntwerpenBelgium2060
18AZ Sint-Jan Burgge-Oostende - Campus Sint-JanBruggeBelgium8000
19UZ Leuven - Campus GasthuisbergLeuvenBelgium3000
20University of Alberta HospitalEdmontonAlbertaCanadaT6G 2G3
21St. Paul's HospitalVancouverBritish ColumbiaCanadaV6Z 2A5
22Juravinski Cancer CentreHamiltonOntarioCanadaL8V 5C2
23Princess Margaret Cancer CentreTorontoOntarioCanadaM5G 2M9
24Jewish General HospitalMontrealQuebecCanadaH3T 1E2
25CHRU de Lille - Hopital Claude Huriez - Maladies du SangLilleFrance59000
26Institut de cancérologie du Gard - Hematologie cliniqueNîmesFrance30029
27CHU - Hopital Saint Louis - Centre D'Investigations CliniqueParisFrance75010
28CHRU de Lille - Hopital Claude HuriezToulouseFrance31100
29Institut Gustave RoussyVillejuifFrance94800
30Universitätsklinikum Jena, Innere Medizin IIJenaGermany07747
31Universität zu KölnKölnGermany50937
32Universitätsklinikum Leipzig AöRLeipzigGermany04103
33Institue of Hematology "L. and A. Seràgnoli"BolognaItaly40138
34Azienda Ospedaliero-Universitaria CareggiFirenzeItaly50134
35AOU S.Martino, IRCCS, IST-Istituto Nazionale Ricerca Sul CanGenovaItaly16132
36IRCCS Policlinico San Matteo, Università degli studi di PaviGenovaItaly16132
37Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' GrandaMilanoItaly20122
38AOU Maggiore della CaritàNovaraItaly28100
39Servizio Sanitario Regionale Emilia-Romagna - Azienda Unita Sanitaria Locale (AUSL) di Rimini - Ospedale Infermi di RiminiRiminiItaly47923
40Ospedale di Circolo, PO Varese, AO Ospedale di Circolo e FonVareseItaly21100
41Academisch Ziekenhuis Vrije UniversiteitAmsterdamNetherlands1081 BT
42Maastricht University Medical CenterMaastrichtNetherlands6229 HX
43Erasmus Universitair Medisch Centrum RotterdamRotterdamNetherlands3015 AA
44Uniwersyteckie Centrum KliniczneGdańskPoland80-214
45SPZOZ Szpital Uniwersytecki w KrakowieKrakówPoland31-501
46Instytut Hematologii i Transfuzjologii w WarszawieWarszawaPoland02-776
47Belfast City HospitalBelfastUnited KingdomBT9 7AB
48University of CambridgeCambridgeUnited KingdomCB2 0QQ
49University Hospital of WalesCardiffUnited KingdomCF14 4XW
50Beatson West of Scotland Cancer CentreGlasgowUnited KingdomG12 0YN
51Oxford University HospitalsHeadingtonUnited KingdomOX3 7LE
52Clatterbridge Cancer CentreLiverpoolUnited KingdomL7 8XP
53University College London Hospital's NHS foundation TrustLondonUnited KingdomNW1 2BU
54Guys and St Thomas' Hospital - HaematologyLondonUnited KingdomSE1 9RT
55The Christie HospitalManchesterUnited KingdomM20 4BX

Sponsors and Collaborators

  • Constellation Pharmaceuticals
  • The Leukemia and Lymphoma Society

Investigators

  • Study Director: Debbie Johnson, Constellation Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Constellation Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT02158858
Other Study ID Numbers:
  • 0610-02
First Posted:
Jun 9, 2014
Last Update Posted:
Mar 18, 2022
Last Verified:
Mar 1, 2022

Study Results

No Results Posted as of Mar 18, 2022