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

Locations

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: CPI-0610 Drug: Ruxolitinib	Phase 1/Phase 2

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

Arm	Intervention/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

Phase 2 (Cohorts 1B and 2B and Arm 3): Evaluate spleen response [By imaging after 24 weeks]
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]
Phase 2 (Arm 4): Evaluate the complete hematological response rate [1 cycle (21 days)]

Secondary Outcome Measures

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]
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]
Phase 2 (all arms): area under the curve (AUC) [Assessed during Cycle 1 (first 21 days on study)]
Phase 2 (all arms): maximum observed plasma concentration (Cmax) [Assessed during Cycle 1 (first 21 days on study)]

Other Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

	Site	City	State	Country	Postal Code
1	Mayo Clinic - Research Center	Phoenix	Arizona	United States	85054
2	UCLA Medical Center	Los Angeles	California	United States	90095
3	Mayo Clinic - Cancer Clinical Research Office	Jacksonville	Florida	United States	32224
4	Northwestern University - Lurie Comprehensive Cancer Center	Chicago	Illinois	United States	60611
5	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
6	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
7	Washington University School of Medicne Neuromuscular Division Department of neurology	Saint Louis	Missouri	United States	63110
8	Memorial Sloan Kettering Monmounth	Middletown	New Jersey	United States	07748
9	Memorial Sloan Kettering Bergen	Montvale	New Jersey	United States	07645
10	Memorial Sloan Kettering Cancer Center Commack	Commack	New York	United States	11725
11	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
12	Columbia University Medical Centre	New York	New York	United States	10032
13	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
14	Weill Cornell Medical College-New York Presbyterian Hospital	New York	New York	United States	10065
15	MD Anderson Cancer Center	Houston	Texas	United States	77030
16	Froedtert & Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
17	ZNA Stuyvenberg Antwerpen	Antwerpen		Belgium	2060
18	AZ Sint-Jan Burgge-Oostende - Campus Sint-Jan	Brugge		Belgium	8000
19	UZ Leuven - Campus Gasthuisberg	Leuven		Belgium	3000
20	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2G3
21	St. Paul's Hospital	Vancouver	British Columbia	Canada	V6Z 2A5
22	Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 5C2
23	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
24	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
25	CHRU de Lille - Hopital Claude Huriez - Maladies du Sang	Lille		France	59000
26	Institut de cancérologie du Gard - Hematologie clinique	Nîmes		France	30029
27	CHU - Hopital Saint Louis - Centre D'Investigations Clinique	Paris		France	75010
28	CHRU de Lille - Hopital Claude Huriez	Toulouse		France	31100
29	Institut Gustave Roussy	Villejuif		France	94800
30	Universitätsklinikum Jena, Innere Medizin II	Jena		Germany	07747
31	Universität zu Köln	Köln		Germany	50937
32	Universitätsklinikum Leipzig AöR	Leipzig		Germany	04103
33	Institue of Hematology "L. and A. Seràgnoli"	Bologna		Italy	40138
34	Azienda Ospedaliero-Universitaria Careggi	Firenze		Italy	50134
35	AOU S.Martino, IRCCS, IST-Istituto Nazionale Ricerca Sul Can	Genova		Italy	16132
36	IRCCS Policlinico San Matteo, Università degli studi di Pavi	Genova		Italy	16132
37	Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda	Milano		Italy	20122
38	AOU Maggiore della Carità	Novara		Italy	28100
39	Servizio Sanitario Regionale Emilia-Romagna - Azienda Unita Sanitaria Locale (AUSL) di Rimini - Ospedale Infermi di Rimini	Rimini		Italy	47923
40	Ospedale di Circolo, PO Varese, AO Ospedale di Circolo e Fon	Varese		Italy	21100
41	Academisch Ziekenhuis Vrije Universiteit	Amsterdam		Netherlands	1081 BT
42	Maastricht University Medical Center	Maastricht		Netherlands	6229 HX
43	Erasmus Universitair Medisch Centrum Rotterdam	Rotterdam		Netherlands	3015 AA
44	Uniwersyteckie Centrum Kliniczne	Gdańsk		Poland	80-214
45	SPZOZ Szpital Uniwersytecki w Krakowie	Kraków		Poland	31-501
46	Instytut Hematologii i Transfuzjologii w Warszawie	Warszawa		Poland	02-776
47	Belfast City Hospital	Belfast		United Kingdom	BT9 7AB
48	University of Cambridge	Cambridge		United Kingdom	CB2 0QQ
49	University Hospital of Wales	Cardiff		United Kingdom	CF14 4XW
50	Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom	G12 0YN
51	Oxford University Hospitals	Headington		United Kingdom	OX3 7LE
52	Clatterbridge Cancer Centre	Liverpool		United Kingdom	L7 8XP
53	University College London Hospital's NHS foundation Trust	London		United Kingdom	NW1 2BU
54	Guys and St Thomas' Hospital - Haematology	London		United Kingdom	SE1 9RT
55	The Christie Hospital	Manchester		United Kingdom	M20 4BX