Phase 1, open label study of intravenous GSK3745417 to evaluate safety, tolerability, harmacokinetics, pharmacodynamics and determine RP2D and schedule in participants with relapsed or refractory myeloid malignancies including acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS)

Clinical Background: AML and MDS
MDS and AML are clonal neoplasms of myeloid progenitors that arise within the
bone marrow. They are typically manifested by peripheral cytopenias
(neutropenia, anemia, and/or thrombocytopenia), hypercellularity of the bone
marrow (because of ineffective hematopoiesis), molecular and/or karyotypic
abnormalities, and an expansion of
immature myeloid cells. It is the quantitation of these immature myeloblasts
that, in part, differentiates AML from MDS, with a 20% blast percentage marking
the transition from MDS to AML. In the US, the estimate for new cases of AML in
2020 was approximately 20,000 and the estimate for deaths from AML was
approximately 11,000. For MDS, some estimates indicate around 10,000 cases per
year. While multiple new targeted agents have been approved to treat AML in
patients that have a limited number of genetic mutations, most patients with
both MDS and AML are not eligible for these therapies. Despite modern
therapies, patients eventually relapse and may become refractory to treatment
and have a poor prognosis.
Currently, for relapsed/refractory AML patients, there is no standard of care
and clinical trial participation is recommended. The median overall survival
for relapsed/refractory AML and for high-risk MDS is short, generally less than
6 months. Therefore, new therapies to prolong survival are desperately needed.

GSK3745417 Background:
Preclinical data support the use of STING agonists for the treatment of AML.
STING is the key adaptor molecule in the cGAS-STING-TBK1 pathway that mediates
the sensing of cytosolic DNA. Activation of STING generates a distinctive set
of type I interferons (IFNα and IFNβ) and pro-inflammatory cytokines that
instigate T-cell dependent tumor immunity and tumor vascular collapse.
Preclinical studies support the hypothesis that the STING activation pathway
has the potential to boost tumor antigen presentation and tumor immunogenicity.
In animal models of AML, STING agonists have demonstrated some activity by
improving survival and inducing immune responses via induction of type I
interferons and proinflammatory cytokines, suggesting that they may play a role
in immune therapy for leukemia and possibly other hematologic malignancies.
Data demonstrated a second mechanism of action of direct induction of apoptosis
in AML cells treated with GSK3745417. Published literature also support a role
for STING activation in driving human myeloid and AML cell death. These reports
and others suggest cell death driven by a range of mechanisms including
lysosomal cell death, reactive oxygen species, and apoptosis.
GSK3745417 is a synthetic STING agonist that is being developed by
GlaxoSmithKline as an immune stimulatory agent for the treatment of cancer. It
is currently being studied in a Phase 1 first in human trial, 208850, to assess
the safety, PK, PD, and preliminary clinical activity of GSK3745417
administered alone and in combination with other immunotherapies in
participants with advanced solid tumors. Preliminary data from the 208850 study
have shown that administration of GSK3745417 results in increased
proinflammatory cytokine production after dosing in participants with solid
tumors (GSK3745417 IB). This study is ongoing and clinical activity has not yet
been evaluated.

Primary objective:
Part 1: To determine the safety, tolerability, and RP2D of a daily dosing
schedule (induction) of GSK3745417
Part 2: To evaluate clinical efficacy following the daily dosing *induction*
period of GSK3745417 in participants with relapsed/refractory AML and HR-MDS.
To determine the safety, tolerability, and recommended Phase 2 dose (RP2D) for
*maintenance*

Secondary Objectives:
Part 1: To characterize the pharmacokinetics (PK) of GSK3745417, and relevant
metabolites, as applicable, after single and repeat-dose administration.
Part 2: To further evaluate the safety, tolerability of one or more RP2D for
maintenance
To characterize the pharmacokinetics (PK) of GSK3745417, and relevant
metabolites, as applicable, after single and repeat-dose administration.

Exploratory:
Part 1:
To evaluate:
- clinical efficacy following GSK3745417 administration in participants with
relapsed/refractory AML or high risk MDS.
- the relationship between GSK3745417 exposure and other safety parameters.
- the relationship between GSK3745417 dose and pharmacodynamic response.
- the relationship between GSK3745417 dose with clinical activity of GSK3745417.
- evidence of proof of mechanism(s) of GSK3745417 in AML/MDS, including direct
cell killing and/or immune activation.
To investigate biomarkers of sensitivity and resistance to GSK3745417.

Part 2:
To evaluate:
- duration of response (DoR) and event-free survival (EFS) in participants with
relapsed/refractory AML and HR-MDS
- other efficacy measures in participants with relapsed/refractory AML and
HR-MDS
- the relationship between GSK3745417 exposure and other safety parameters.
- the relationship between GSK3745417 dose and pharmacodynamic response.
- the relationship between GSK3745417 dose with clinical activity of GSK3745417.
- evidence of proof of mechanism(s) of GSK3745417 in AML/MDS, including direct
cell killing and/or immune activation.
To investigate biomarkers of sensitivity and resistance to GSK3745417.

This is a Phase 1, open label, dose escalation study to evaluate safety,
pharmacokinetics, and pharmacodynamics of intravenous GSK3745417 in
participants with relapsed or refractory AML or high risk MDS.
The study will be conducted in a staged approach consisting of 2 parts.

Part 1 will evaluate a dosing schedule of a 5 days on/2 days off schedule for 2
weeks, and then have an additional 2 weeks off dose for observation for a total
of 28 days in each cycle (5 / 2/ 5 q28d). Once a maximum tolerated dose (MTD)
has been established, additional cohorts may be opened to refine dosing
frequency optimization. Each cohort will include at least 3 participants and
dosing of participants entering the study will be staggered by at least 5 days
from D1 of previous patient for the first cohort only. Part 1 will include
intra-patient dose escalation for 3 cycles, according to safety and
tolerability parameters. The starting dose for Cycle 1 will be escalated in the
next dose-escalation cohort until a cohort level starting dose-based MTD is
reached. Individual patients may titrate above the starting dose-based MTD
based on tolerability. Dose escalation cohorts will start with Cycle 1 at 12.5
µg GSK3745417. Within a cohort for an individual subject the dose may double
for Cycle 2, and double again for Cycle 3 based on individual tolerability. The
starting dose of subsequent cohorts will increase by 2-fold from Cycle 1 of the
previous cohort. Patients may be dose reduced for subsequent cycles if there is
lack of tolerability in the previous cycle. The DLT period will be 28 days
starting at Day 1 of Cycle 1 of each cohort. After 3 induction cycles, if a
complete response (CR) or partial response (PR) (IWG) is observed each patient
will continue with maintenance weekly dosing at the Cycle 3 dose level until
disease progression or unacceptable toxicity. Participants with progressive
disease after 3 induction cycles will be withdrawn from study. Participants
with stable disease or PR after 3 cycles might receive additional cycles if the
assessment by the investigator determined a benefit and GSK Medical Monitor
agrees.

Intervention
For Part 1, approximately 22 participants will receive dosing in the hospital
on a 5 days on/2 days off schedule for 2 weeks, and then have an additional 2
weeks off dose for observation. The participant will be observed for at least
24 hours after the final dose in each cycle. All participants will be
hospitalized the day before a new dosing cycle starts to receive tumor lysis
syndrome (TLS) prophylaxis in line with institutional guidelines (all
participants should receive IV fluids ± allopurinol as well as alkalinization
of urine with renal consult if this is in line with institutional guidance).
TLS prophylaxis will continue alongside daily dosing as clinically indicated.

For Part 2, efficacy will be evaluated after an induction phase in
approximately 50 participants, 25 AML participants and 25 HR-MDS participants.
The induction phase consists of a treatment regimen cycles at the dose/doses
determined to be safe in Part 1 (RP2D). The number of cycles, number of doses
investigated in the induction phase, and/or dosing schedule of 5 / 2 / 5 q28d
treatment will be determined and may be modified based on a review of safety
and PK data generated from Part 1. After the induction phase, patients will
continue to either a weekly (Q1W), every three weeks (Q3W), or less frequent
dosing schedule for maintenance treatment, if a CR or PR is observed
(Participants with stable disease or PR after 3 induction cycles might receive
additional cycles Up to three dose levels for maintenance treatment will be
evaluated in the maintenance dose escalation. The DLT period for the
maintenance dose escalation portion of Part 2 will be 28 days starting at Day 1
of each cycle. Dose escalation for the maintenance schedule will start at the
highest dose cleared for safety in Part 1. Part 2 will evaluate the efficacy of
the induction regimen separately for AML and HR-MDS as well as the tolerability
and duration of response of the Q1W or Q3W maintenance schedules to determine
the best dose and schedule for further studies.

The study includes a screening period, a treatment period (consisting of -
3-cycle induction phase and a maintenance phase), and a follow-up period.
Participants will be screened for eligibility beginning up to 4 weeks before
the start of treatment. GSK3745417 will be centrally administered IV according
to the dosing schedule in the corresponding cohort the participant is enrolled.
Participants will be assessed for response according to the IWG response
criteria for AML or MDS at end of each induction cycle including (at 28 days
[after Cycle 1], at 56 days [after Cycle 2], and at 84 days [after Cycle 3]).
Within the maintenance phase, assessment will be at 3 weeks and then every 6
weeks thereafter. Participants will be treated until disease progression,
unacceptable toxicity, withdrawal of consent, or termination of the study by
GSK.

Other immune activating drugs have reported side effects related to cytokine
release syndrome (CRS). CRS symptoms are similar to those of moderate to severe
flu.

The side effects observed as very common (may affect more than 1 in 10 people):
• Chills / shaking episodes
• Fever
• Headache
• Low number of red cells in the blood (anemia)
• Fast heart rate
• Cytokine release syndrome These were mild to moderate in
severity.
• Changes in blood pressure, including both raising blood pressure and lowering
blood pressure

Side effects observed as uncommon (may affect up to 1 in 100 people):
• Inflammation of the heart muscle (myocarditis)
Different anti-cancer drugs that are similar to the STING study drug in how
they might work in causing fast break down of cancer cells have been evaluated
in people and animals and side effects were seen. These side effects may
include:
• Fast breakdown of cancer cells with release of cancer cell contents into blood
including potassium, phosphate and uric acid. Excess levels of these cell
contents
in blood may cause problems including life-threatening kidney damage or heart
and
nerve function problems (tumor lysis syndrome)

Risks from blood draws: people may feel faint (lightheadedness), or experience
mild pain, bruising, irritation or redness at the site. A cannula stays in the
arm, the vein in the arm can also be blocked after having the cannula placed in
the vein. In rare cases, people may get an infection or damage to nerves at the
site.

Risks from Holter monitor, echocardiogram or MUGA, and Electrocardiogram (ECG):
Skin irritation is rare but could occur from the patches or the gel that is
used. A MUGA (Multi-Gated Acquisition) heart scan involves an injection of a
small amount of radioactive liquid and imaging with a special camera.

Risks from bone marrow biopsy and aspirate:
These might include feeling faint (light-headedness), local mild pain, pressure
or pain from the needle, soreness or tenderness at the biopsy site, swelling or
redness, and scarring at the biopsy site. In rare cases, people might get an
infection. Additional unforeseeable risks could occur.

Risks from brain CT/MRI: The amount of radiation from one CT scan of the brain
is about 2 mSv. This is generally equal to 8 months of the average natural
radiation that people may be exposed from sources in everyday life. An MRI scan
does not result in radiation exposure. CT and MRI scans involve contrast agent
being injected into one of the veins. There is a risk of allergic reaction to
the contrast agent.