Phase I First Time in Human Open Label Study of GSK3745417 administered with and without Anticancer Agents in Participants with Advanced Solid Tumors (study 208850)

The immune system plays a critical role in protecting the body from neoplastic
disease. Immune checkpoint inhibitors anti-PD(L)-1 and anti-CTLA-4 have
demonstrated therapeutic benefit across multiple tumor types, yielding durable
responses in some patients. However, a majority of patients do not respond to
monotherapy with checkpoint inhibitors, at least in part due to the
non-inflamed nature of the tumor. Therefore, strategies to increase the tumor
immunogenicity are being actively explored.
Pre-clinical data strongly suggest that the STimulator of INterferon Genes
(STING) pathway is the tumor sensing pathway of the immune system. Therefore,
activation of the STING pathway has the potential to boost tumor antigen
presentation and the tumor immunogenicity. Potent and durable anti-tumor
response has been demonstrated in tumor models with STING agonist treatment.
In addition, the effect of STING activation in boosting tumor antigen
presentation suggests potential combination benefit with immune check point
modulators. Given their non-overlapping mechanisms of action, the combination
of the two could simultaneously accelerate separate steps in the
cancer-immunity cycle, i.e., the tumor antigen presentation process and the T
cell activation process, therefore generating synergistic anti-tumor effect.
GSK3745417 is a synthetic STING agonist that is being developed as an immune
stimulatory agent for the treatment of cancer. This study will be the first
time in human study of GSK3745417 administered alone and in combination with
other immunotherapies to participants with advanced solid tumors. The initial
combination partner is pembrolizumab, but subsequent combination partners
and/or additional routes of administration may be evaluated (following protocol
amendment/s) based on biologic rationale, nonclinical data, and/or emerging
clinical data.
This FTIH, open label, dose escalation study will assess the safety, PK,
pharmacodynamics, and preliminary clinical activity of GSK3745417 in
participants with selected advanced or recurrent solid tumors as monotherapy
(Part 1), in combination with pembrolizumab (Part 2), and potentially in
combination with additional therapies. The monotherapy cohort expansion (Part
1B) and the combination with pembrolizumab (Part 2) of the study will only be
opened by protocol amendment.

The current application is focussed to the dose escalation part of GSK3745417
alone (part 1A).

Amendment 03 (December 2020):
The study originally consisted of part 1A, 1B, 2A and 2B. Part 1B and 2B, the
desired and undesirable effects of the doses in a larger group of participants,
has been removed. In part 2A, the study medication pembrolizumab has been
replaced by dostarlimab. The Netherlands did not participate in part 2A and 2B
of the study and will now also only participate in part 1A. Furthermore, the
optional PK / PD cohorts have been removed.

Amendment 04 (May 2021):
This protocol amendment was generated in response to the Dear Investigator
Letter (dated 11-02-21) and mainly contains risk mitigating changes:
requirements for improved cardiac monitoring, reduced dosage and the side
effects section is updated. After approval of this protocol, enrollment of
patients will be resumed in all cohorts.

Amendment October 2021:
In May 2021 the addition of Dostarlimab has been realized per protocol
amendment. The Netherlands could not be included in this amendment due to
patent issues for Dostarlimab. At present NL is able to participate in the
Dostarlimab arm. Hence this protocol amendment.

Amendment March 2022
Introduction of an Imaging Sub-study to be conducted in the Netherlands. The
aim of the Imaging Sub-study consisting of 2 parts is a) to investigate if
GSK3745417 monotherapy followed by combination with dostarlimab results in
T-cell activation as assessed by the T-cell uptake of an investigational marker
of T-cell activation, 18F-labeled analog of arabinofuranosyl guanine
([18F]F-AraG) visualized by positron emission tomography (PET) imaging, and b)
to investigate the biodistribution of radiolabelled GSK3745417
([11C]GSK3745417). Hence this protocol amendment.

Amendment 9 (October 2023):
The sponsor has decided to halt further inclusion in the study, after the
decision to stop further development of GSK3745417 in solid tumours. This
decision is based on recent data that show a lack of expectted activity
tresholds. As a consequence planned monotherapy (1B) and combination therapy
(2B) cohort expansioins will not be opened for inclusion. In addition: the sub
study will be stopped and part B of the sub study has not started.

Primary (PART 1A ONLY):
Dose escalation: To determine the safety, tolerability, and the recommended
phase 2 dose (RP2D) of GSK3745417 alone administered intravenously to
participants with selected advanced/recurrent solid tumors.
Secondary: (PART 1A ONLY):
Dose expansion: Antitumor activity and PK properties of GSK3745417 alone.

Phase I, first time in humans (FTIH), open-label, repeat-dose, non-randomized
study to evaluate the safety, tolerability, and preliminary clinical activity
and establish a recommended dose of GSK3745417 administered intravenously (IV)
alone (Part 1) or co-administered (Part 2) with pembrolizumab in participants
with refractory/relapsed solid tumors. Each part consists of a dose escalation
phase and a cohort expansion phase.
It is estimated that a total of approximately 300 participants will be enrolled
in this study, approximately 120 for dose escalation cohorts, and approximately
180 in the expansion cohorts, including PK/PD, and 6 tumor specific expansion
cohorts. Additional tumor specific cohort(s) and combinations may be added
based upon emerging pre-clinical data, or clinical data from the dose
escalation portion of the study.
Participants will initially receive GSK3745417 as monotherapy during dose
escalation in Part 1A. Part 2A will be conducted following protocol amendment.
GSK3745417 will be administered every week or every three weeks. The
investigator determines the frequency of administration.
In Part 2A, escalating doses of GSK3745417 in combination with 200 mg
pembrolizumab will be evaluated. In Part 1B and 2B, participants will receive a
single dose level of GSK3745417 as identified based on data from Part 1, either
alone or in combination with pembrolizumab. Part 1b and 2B will not be opened
anymore.

PART 1A: Treatment with GSK3745417 alone.

Risk: Adverse events of the study medication. First in human study.
Burden:
• Weekly visits during 2 years.
• Approx. 104 infusions met GSK3745417, 5 min. per infusion of 10 ml.
• Possibility for 24 hour observation period after the first 6 infusions.
• Physical examination: every visit.
• Neurological examination: once
• Blood draws: every visit. 15-90 mL blood per occasion.
• ECG en echocardiography (alternative: MUGA scan): once.
• Holter monitoring: once.
• telemetry: once, only by patients who receive GSK3745417 every week.
• CT/MRI scan every 9 weeks.
• Tumor biopsy: 0-1 times.
• Photos to measure the size of the tumor if you have tumors on your skin
Optional:
• Request images of 3 scans (CT/MRI) during last year: once

Burden Imaging substudy:
• Deel A: 3 AraG scans, 1 FDG PET scan