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.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 3/20/2024. Questions regarding updates should be directed to the study team contact.