Safety and Tolerability Study of Mivebresib Tablet Alone or in Combination With Ruxolitinib Tablet or Navitoclax Tablet in Adult Participants With Myelofibrosis

Inclusion Criteria:

Laboratory values indicative of adequate bone marrow, renal, and hepatic function meeting protocol criteria
Completion of the Myelofibrosis System Assessment Form (MFSAF) on at least 4 out of the 7 days prior to Day 1 with at least 2 symptoms with a score >=3 or a total score of >=10.
Documented diagnosis of intermediate or high-risk primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocytopenia myelofibrosis (PET-MF) as defined by World Health Organization (WHO).
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
Intermediate - 2, or High-Risk disease as defined by the Dynamic International Prognostic Scoring System (For Segment A only, Intermediate - 1 with palpable splenomegaly >=5 centimeters [cm] below costal margin are also eligible).
Splenomegaly defined as spleen palpation measurement >= 5 centimeters (cm) below costal margin or spleen volume >= 450 cubic cms as assessed by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) scan (for Segments A and c, baseline spleen assessment must be obtained > 7 days after discontinuation of most recent Myelofibrosis (MF) therapy. If possible, this assessment should occur within 10 days of Cycle 1 Day 1).

Segment-Specific Prior Therapy Criteria:

Segment A:

--Prior exposure to one or more Janus Kinase Inhibitors (JAKi), the most recent of which was discontinued > 28 days prior to Cycle 1 Day 1.

Segment B:

Currently receiving ruxolitinib; AND
Willingness to reduce dose (if on a higher dose); and on a stable dose for 14 days or longer prior to Cycle 1 Day 1; AND

At least one of the following criteria (a, b, or c):

>= 24 weeks duration of current ruxolitinib course, with evidence of disease that is resistant, refractory, or has lost response to ruxolitinib monotherapy;

< 24 weeks duration of current ruxolitinib course with documented disease progression as defined by any of the following:

Appearance of new splenomegaly that is palpable to at least 5 centimeters (cm) below the left costal margin (LCM), in participants with no evidence of splenomegaly prior to the initiation of ruxolitinib.

100% increase in the palpable distance below the LCM, in participants with measurable spleen distance 5 - 10 cm prior to the initiation of ruxolitinib.
50% increase in the palpable distance below the LCM, in participants with measurable spleen > 10 cm prior to the initiation of ruxolitinib.
A spleen volume increase >= 25% (as assessed by MRI or CT) in participants with a spleen volume assessment available prior to the initiation of ruxolitinib.

Prior treatment with ruxolitinib for >= 28 days complicated by any of the following:

Development of red blood cell transfusion requirement (at least 2 units/month for 2 months).
Grade >= 3 adverse events of neutropenia and/or anemia while on ruxolitinib treatment, with improvement or resolution upon dose reduction.

Segment C:

Prior exposure to one or more JAKi (the most recent of which was discontinued > 28 days prior to Cycle 1 Day 1), and are intolerant, resistant, refractory or lost response to teh JAKi.

Exclusion Criteria:

Segment-Specific Prior Therapy Criteria:

Segment A:

--Prior exposure to one or more Bromodomain and Extra Terminal (BET) inhibitors.

Segment B:

--Prior exposure to one or more BET inhibitors.

Segment C:

--Prior exposure to one or more BET inhibitors and/or any B-Cell Lymphoma 2 (BCL2) and/or B-Cell Lymphoma XL (BCLXL) inhibitor, including navitoclax.

Segment D:

Prior exposure to JAKi and/or any BET inhibitor.