A Randomized, Open-Label, Phase 3 Study Evaluating Efficacy and Safety of Navitoclax in Combination with Ruxolitinib Versus Best Available Therapy in Subjects with Relapsed/Refractory Myelofibrosis

Myelofibrosis (MF) is a rare blood cancer, notable for scarring of the bone marrow (the
spongy tissue inside bones) and the spleen becoming larger. The purpose of this study is
to assess safety and change in spleen volume when navitoclax is given in combination with
ruxolitinib, compared to best available therapy, for adult participants with MF.

Navitoclax is an investigational drug (not yet approved) being developed for the
treatment of MF. Participants in this study will be randomly selected (like picking
numbers out of a hat) to be in 1 of 2 treatment arms. Neither participants nor the study
doctor will be able to pick which treatment arm a participants enters. In Arm A,
participants will receive navitoclax in combination with ruxolitinib. In Arm B,
participants will receive the best available therapy (BAT) for MF. Adult participants
with a diagnosis of MF that came back or did not get better after earlier treatment will
be enrolled. Approximately 330 participants will be enrolled in approximately 210 sites
across the world.

In Arm A, participants will receive navitoclax tablet by mouth once daily with by mouth
ruxolitinib tablet twice daily. In Arm B, participants will receive the BAT available to
the investigator. Participants will receive the study drug until they experience no
benefit (determined by the investigator), participants cannot tolerate the study drugs,
or participants withdraw consent. The approximate treatment duration is about 3 years.

There may be higher treatment burden for participants in this trial compared to their
standard of care. Participants will attend regular visits during the study at a hospital
or clinic. The effect of treatment will be checked by medical assessments, blood and bone
marrow tests, checking for side effects, and completing questionnaires.

Inclusion Criteria:

- Must complete the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 on at least 4
out of the 7 days immediately prior to the date of randomization and must agree to
collect MFSAF data daily by ePRO device during the study collection window.

-- Has at least 2 symptoms each with an average score >= 3 or an average total score
of >= 12, as measured by the MFSAF v4.0.

- Documented diagnosis of primary myelofibrosis (MF) as defined by the World Health
Organization (WHO) classification, post polycythemia vera (PPV)-MF, or post
essential thrombocytopenia (PET)-MF, characterized by bone marrow fibrosis grades 2
or 3.

- Classified as intermediate-2 or high-risk MF, as defined by the Dynamic
International Prognostic Scoring System Plus (DIPSS+).

- Must currently be on treatment or have received prior treatment with a single Janus
Kinase 2 (JAK2) inhibitor, ruxolitinib, and meet one of the following criteria (in
addition to the minimum splenomegaly and symptom burden also required for
eligibility):

- Treatment with ruxolitinib for >= 24 weeks that was stopped due to lack of
spleen response (refractory), or loss of spleen response or symptom control
after a previous response (relapsed), or was continued despite
relapsed/refractory status.

- Treatment with ruxolitinib for < 24 weeks with documented disease progression
while on therapy as defined by any of the following:

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

- A >= 100% increase in the palpable distance below the LCM in participants
with measurable spleen distance 5 to 10 centimeters (cm) prior to the
initiation of ruxolitinib.

- A >= 50% increase in the palpable distance below the LCM in participants
with measurable spleen distance > 10 cm prior to the initiation of
ruxolitinib.

- A spleen volume increase of >= 25% (as assessed by Magnetic Resonance
Imaging [MRI] or Computed Tomography [CT] scan) in participants with a
spleen volume assessment prior to the initiation of ruxolitinib.

- Prior treatment with ruxolitinib of at least 10 mg twice daily (BID) for >= 28
days with intolerance defined as new RBC transfusion requirement (at least 2
units/month for 2 months) while receiving a total daily ruxolitinib dose of >=
30 mg but unable to reduce dose further due to lack of efficacy.

Note: Participant must not require a ruxolitinib dose less than 10 mg BID (20 mg daily)
due to prior history of ruxolitinibrelated ≥ Grade 3 toxicity.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

- Splenomegaly defined as palpable spleen measurement >= 5 cm below left costal margin
or spleen volume >= 450 cm3 as assessed centrally by MRI or CT scan.

- Baseline platelet count >= 100 × 10^9/L.

Exclusion Criteria:

- Received prior treatment with a BH3-mimetic compound, bromodomain and extra-terminal
(BET) inhibitor, or prior use of > 1 JAK2 inhibitor or stem cell transplant.

- Eligible for stem cell transplantation at the time of study entry.

- Receiving medication that interferes with coagulation or platelet function within 3
days prior to the first dose of study drug or during the study treatment period
except for low dose aspirin (up to 100 mg daily) and low molecular weight heparin
(LMWH).

- Receiving anticancer therapy for an active malignancy or MF including chemotherapy,
radiation therapy, hormonal therapy such that at least 5 half-lives of that
medication is completed at least 7 days prior to the first dose of study drug or
within 30 days prior to first dose of study drug, whichever is shorter, and during
the study treatment period (other than any overlapping therapy as part of the
selected BAT).