Study to Investigate the Safety and Clinical Activity of GSK3326595 and Other Agents to Treat Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukaemia (AML)

Inclusion Criteria:

- Males and females ≥18 years of age (at the time consent is obtained).

- Capable of giving signed informed consent.

- Able to swallow, retain, and absorb orally-administered medication.

- Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2.

- Diagnosis of one of the following:

Part 1:

MDS classified as intermediate, high, or very high risk by International Prognostic Scoring
System-Revised [IPSS-R] criteria, or Chronic myelomonocytic leukaemia (CMML) classified as
intermediate-2 or high risk per CMML-specific prognostic scoring system (CPSS) or
clinical/molecular CPSS (CPSS-mol) criteria, or MDS/CMML secondary to prior anti-neoplastic
therapy, of any risk score, or AML, which has evolved from an antecedent
MDS/Myeloproliferative neoplasms (MPN) of any risk score, provided that the myeloblast
percentage in the marrow is ≤ 30% or the peripheral white blood cell count is less than
20,000 cells/microliter (μL) in the absence of leukoreducing therapy (e.g., hydroxyurea,
leukapheresis) NOTE: Subjects without a documented history of antecedent MDS/MPN must have
AML with myelodysplasia-related changes or recurrent cytogenetic abnormalities per World
Health Organization (WHO) criteria

Part 2A:

MDS classified as intermediate, high, or very high risk by IPSS-R criteria, or CMML
classified as intermediate-2 or high risk per CPSS or CPSS-mol criteria, or MDS/CMML
secondary to prior anti-neoplastic therapy, of any risk score, or AML, which has evolved
from an antecedent MDS/MPN of any risk score, provided that the myeloblast percentage in
the marrow is ≤ 30% or the peripheral white blood cell count is less than 20,000 cells/μL
in the absence of leukoreducing therapy (e.g., hydroxyurea, leukapheresis).

Subjects without a documented history of antecedent MDS/MPN must have AML with
myelodysplasia-related changes or recurrent cytogenetic abnormalities per WHO criteria

Part 2B:

MDS classified as high/very high by IPSS-R criteria, or CMML classified as intermediate-2
or high risk per CPSS or CPSS-mol criteria, or MDS/CMML secondary to prior anti-neoplastic
therapy, of any risk score

Part 2C:

AML (irrespective of antecedent MDS and myeloblast percentage in the marrow, irrespective
of hydroxyurea therapy)

- Prior therapy Part 1: Subjects must have disease that failed to respond to, or
progressed despite, treatment at least one systemic therapy Part 2A: Subjects must
have disease that failed to respond to, or progressed despite, treatment with at least
one systemic therapy Part 2B: Subjects must have received no prior therapy for their
disease, or have completed no more than one cycle of a hypomethylating agent Part 2C:
Subjects must have disease that has failed to respond to, or progressed despite
treatment with, at least one but no more than four prior lines of systemic therapy

- Molecular markers Part 1: At least 12 subjects must have documented loss-of-function
mutation(s) at least one of the following genes/proteins: Splicing factor 3B subunit 1
(SF3B1), Serine and arginine rich splicing factor 2 (SRSF2), U2 Small Nuclear RNA
Auxiliary Factor 1 (U2AF1), or Zinc Finger CCCH-Type, RNA Binding Motif and
Serine/Arginine Rich 2 (ZRSR2); in addition, at least 12 subjects must have documented
wild type status of all of these genes/proteins. While enrolment will initially
proceed without consideration of mutational status, enrolment may be limited to one
group or the other as the study proceeds based on the enrolment rates in each group,
in order to ensure this minimum number of mutated and wild type subjects.

Part 2A: No specific mutational or molecular requirements Part 2B: No specific mutational
or molecular requirements Part 2C: Subjects must have a documented loss-of-function
mutation(s) at least one of the following genes/proteins: SF3B1, SRSF2, U2AF1, or ZRSR2

- Subjects with a prior history of stem cell transplant (autologous and/or allogeneic) are
allowed if: At least 3 months has elapsed from the time of transplant and the subject has
recovered from transplant-associated toxicities prior to the first dose of GSK3326595 and
For subjects with a prior history of allogeneic transplant, the subject has been off
systemic immunosuppressive medications (including but not limited to: cyclosporine,
tacrolimus, mycophenolate mofetil, or corticosteroids) for at least 1 month prior to the
first dose of GSK3326595. Topical steroids are permitted; there are no signs or symptoms of
acute graft versus host disease, other than Grade 1 skin involvement; there are no signs or
symptoms of chronic graft versus host disease requiring systemic therapy.

- All prior treatment-related toxicities must be National Cancer Institute - Common
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 ≤ Grade 1 (except
alopecia [permissible at any Grade] and peripheral neuropathy [which must be ≤ Grade
2]) at the time of treatment allocation.

Subjects with treatment-related toxicities that are unlikely to resolve per the
investigator may be enrolled on a case-by-case basis after discussion with the medical
monitor

- Adequate organ system functions (at both screening and where applicable pre first

Dose are defined as follows:

For hematologic:

Platelets laboratory values were >=10 X 10^9/Liter (subjects may receive transfusion to
ensure adequate platelet counts); Prothromin time (PT)/ International normalized ratio
(INR) and Partial Thromboplastin Time (PTT) laboratory values were <=1.5 X upper limit of
normal (ULN), unless subject is receiving systemic anticoagulation;

For hepatic:

Albumin laboratory values were >=2 grams per deciliter (g/dL); Total bilirubin laboratory
values were <=1.5 x ULN. NOTE: Isolated bilirubin >1.5 X ULN is acceptable if: bilirubin is
fractionated and direct bilirubin <35% OR subject has a diagnosis of Gilbert's syndrome
Alanine aminotransferase (ALT) laboratory values were <=2.5 x ULN;

For Renal:

Estimated glomerular filtration rate (eGFR)a laboratory value was >=60 mL/min/1.73m2 (a=
EGFR should be calculated using the Chronic Kidney Disease Epidemiology Collaborative
(CKD-Epi) method:- Females, serum creatinine >62 μmol/L: 144 x (serum creatinine x
0.0113/0.7)−1.209 x 0.993age; Females, serum creatinine <=62 μmol/L: 144 x (serum
creatinine x 0.0113/0.7)−0.329 x 0.993age; Males, serum creatinine >80 μmol/L: 141 x (serum
creatinine x 0.0113/0.9)−1.209 x 0.993age; Males, serum creatinine ≤80 μmol/L: 141 x (serum
creatinine x 0.0113/0.9)−0.411 x 0.993age);

For Cardiac:

Ejection fraction >=Lower limit of normal (LLN) by echocardiogram (minimum of 50%) Troponin
(I or T) <= ULN. In situations where laboratory results are outside the permitted range,
the investigator may opt to retest the subject and the subsequent within range screening
result may be used to confirm eligibility.

- Agree to abide by the gender-specific contraceptive requirements

Exclusion Criteria:

- History of prior solid organ transplant

- History of a second malignancy, excluding non-melanoma skin cell cancer, within the
last three years Subjects with second malignancies that were indolent, in situ or
definitively treated may be enrolled even if less than three years have elapsed since
treatment. Subjects with a recent history of ductal carcinoma in situ (DCIS) that has
been definitively treated may be enrolled irrespective of the time since diagnosis.
Consult the GSK Medical Monitor if second malignancies meet the requirements specified
above.

- Active severe or uncontrolled infection. Controlled infections are permitted.

- Symptomatic or untreated Central Nervous System (CNS) disease Note that lumbar
puncture (LP) is not required for study enrollment unless there is clinical suspicion
for CNS disease Subjects with a history of CNS disease are permitted to enroll if they
have previously received appropriate therapy and CNS remission has been documented.
Subjects on maintenance intrathecal chemotherapy may be enrolled and continue to
receive therapy.

- Recent prior therapy, defined as follows:

Any non-monoclonal anti-cancer therapy within 14 days or 5 half-lives, whichever is longer,
prior to the first dose of Investigational product (IP).

Subjects in cohort 2B may enroll during the first cycle of 5-azacitidine and continue cycle
1 in combination with IP, after discussion between the investigator and the medical
monitor.

Prior therapy with biologic agents (including monoclonal antibodies) within 28 days prior
to the first dose of IP.

Any radiotherapy within 14 days or major surgery within 28 days prior to the first dose of
IP.

Note: subjects receiving hormonal therapy for a definitively-treated malignancy (e.g.,
adjuvant therapy of localized breast or prostate cancer) may continue to receive adjuvant
therapy during study, after discussion with the medical monitor

- Prior therapy with any Protein arginine methyltransferase 5 (PRMT5) inhibitor

- Current use of a prohibited medication or planned use of any forbidden medications
during treatment with study drug(s)

- History of known human immunodeficiency virus (HIV) infection, or positive HIV test
result at screening.

- Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test
result at screening.

NOTE: Subjects with positive Hepatitis C antibody due to prior resolved disease can be
enrolled only if a confirmatory negative Hepatitis C RNA polymerase chain reaction (PCR)
(or comparable test) is obtained.

- Any of the following cardiac abnormalities:

History, within the past 6 months prior to first dose of study drug(s), of acute coronary
syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or
stenting Baseline Corrected QT (Fridericia's formula) interval (QTcF) ≥480 msec.
Uncontrolled arrhythmias. Subjects with rate-controlled atrial fibrillation prior to first
dose of study drug(s) may be eligible.

Class II, III or IV heart failure as defined by the New York Heart Association (NYHA)
functional classification system.

- History of sensitivity to any of the study medications, or components thereof, or a
history of drug or other allergy that, in the opinion of the investigator or Medical
Monitor, contraindicates their participation.