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

Constellation Pharmaceuticals

Status and phase

Completed

Phase 2

Phase 1

Conditions

Bone Marrow Disease

Myelofibrosis

Leukemia, Myelocytic, Acute

Myeloproliferative Disorders

Leukemia

Myelodysplastic/Myeloproliferative Neoplasm

Neoplasms by Histologic Type

Precancerous Conditions

Myelodysplastic Syndrome (MDS)

Neoplasms

Primary Myelofibrosis

Essential Thrombocytosis

Hematological Disease

Preleukemia

Treatments

Drug: Ruxolitinib

Drug: Pelabresib (CPI-0610)

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT02158858

0610-02

2018-000579-34 (EudraCT Number)

Details and patient eligibility

About

Phase 1 Part (Complete): Open-label, sequential dose escalation study of pelabresib 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.

Enrollment

336 patients

Sex

All

Ages

18+ years old

Volunteers

No 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 (total of greater than 6 RBC transfusions) 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
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 Myelofibrosis Symptom Assessment Form Version 4.0 ( 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 pelabresib 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.

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

336 participants in 4 patient groups

Arm 1: Prior JAKi (JAK inhibitor) Monotherapy Arm (MF patients treated with pelabresib alone)

Experimental group

Description:

* 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 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)

Treatment:

Drug: Pelabresib (CPI-0610)

Arm 2: Prior JAKi Combination Arm

Experimental group

Description:

* 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 + 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)

Treatment:

Drug: Pelabresib (CPI-0610)

Drug: Ruxolitinib

Arm 3: JAKi Naïve Combination Arm

Experimental group

Description:

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

Treatment:

Drug: Pelabresib (CPI-0610)

Drug: Ruxolitinib

Arm 4: Essential Thrombocythemia (ET) Monotherapy Arm

Experimental group