A Randomized, Double-blind, Adaptive, Phase II/III Study of GSK3359609 or Placebo in Combination with Pembrolizumab for First-Line Treatment of PD-L1 Positive Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (study 209229)

Pembrolizumab alone and in combination with 5FU/platinum chemotherapy improved
the survival of patients with recurrent or metastatic (R/M) Head and Neck
Squamous Cell Carcinoma (HNSCC) as first-line treatment compared with cetuximab
and 5FU/platinum chemotherapy. The degree of overall survival (OS) improvement
for both monotherapy and combination depended on the programmed cell death
receptor 1-ligand 1 (PD-L1) status (CPS), with OS improvement in the total
PD-L1 population requiring pembrolizumab in combination with 5FU-platinum
regimen. The frequency of all treatment related toxicities and *Grade 3 events
were much less with pembrolizumab alone as compared with the cetuximab and
5FU/platinum regimen.
There remains an unmet need due to the limited population of benefit. The aim
should be to further improve disease control, and to improve survival across
all HNSCC populations.
Combining immunomodulatory agents that target different components of the
cancer immunity cycle may be able to overcome the mechanisms of immune
suppression which prohibit an effective antitumor immune response.
Thus, targeting both the ICOS and PD-1 axes may translate into enhanced
clinical activity and expand the population that benefits with the combination
of GSK3359609 (ICOS agonist antibody) and pembrolizumab (PD-1 blocking
antibody). This is supported by non-clinical and clinical evidence, e.g. in the
INDUCE-1 study the 28% overall response rate (ORR) observed with the
combination of GSK3359609 and pembrolizumab was higher than that observed with
GSK3359609 monotherapy and higher than that reported for pembrolizumab alone as
first-line therapy or subsequent-line therapy in R/M HNSCC.
The purpose of the present study is to evaluate if the addition of GSK3359609
to pembrolizumab improves the efficacy of pembrolizumab in patients with PD-L1
expression positive R/M HNSCC.

protocol amendment 3 (August 2021):
During the interim analysis after 140 subjects in April 2021 it became clear
that the addition of GSK3359609 to Pembrolizumab did not result in additional
efficacy.
In line with the advice of the IDMC the inclusion of new subjects as well as
the treatment with GSK3359609 has been discontinued at once. All subjects were
given the opportunity to continue with Pembrolizumab monotherapy up to 35
infusions (=about 2 years) in total.
It has been decided to reduce the burden for the subject as much as possible by
drastically reduce the number of study tests:
Visits every 3 weeks (because of Pembrolizumab infusions).
Blood tests on average 7,5 mL per visit in stead of 40 mL
Scans according to the standard of care in the centre
No more questionnaires
No more biopsies.
The ABR form has not been changed with regard to the above. So this form
reflects the original study design.
The Dutch centres that did not include any subjects yet at the time of the
enrollment stop, have been closed (NKI-AVL, VUmc, UMC Utrecht, UMC Groningen).

Primary:
• Compare the efficacy of GSK3359609 in combination with pembrolizumab to
pembrolizumab plus placebo in the PD-L1 expression positive (CPS >=1) population
and in the PD-L1 expression high (CPS>=20) population
Secondary:
• Further efficacy.
• Safety and tolerability.
• Disease related symptoms and impact on function and health-related quality of
life.

Phase II/III, prospective, randomized, double blind, multi-center trial.
Screening max. 4 weeks. Randomization 1:1 to either pembrolizumab (200 mg IV in
30 min.) plus GSK3359609 (24 mg IV in 30 min.) or pembrolizumab (200 mg IV in
30 min.) plus placebo. Up to 35 cycles of 3 weeks (approx... 2 years). Both
infusions on day 1 of each cycle.
A 2-in-1 adaptive phase II/III design is considered, with the option to expand
the phase II study seamlessly into phase III study, without changing the
eligibility criteria, endpoints or randomization scheme.
374 randomized patients. Should the decision be made to expand the phase II
study into phase III study an additional 226 participants will be randomized.

Treatment with pembrolizumab plus GSK3359609 or pembrolizumab plus placebo.

Risk: Adverse effects of study treatment.
Burden:
Treatment:
Pembrolizumab 200 mg IV Q3W (100 mL in 30 min.). Max. 35 infusions.
GSK3359609 24 mg IV Q3W (100 mL in 30 min.). Max. 35 infusions.
Physical examination: every visit (=37 times).
Blood tests: every visit, 40 mL per occasion.
Pregnancy test (if relevant) monthly.
ECG and echocardiogram or MUGA-scan: once.
CT/MRI scan: HN, chest, abdomen every 6 weeks for the first year and every 12
weeks thereafter.
Tumor biopsy: 0-1 (screening).
Questionnaires: EORTC IL50; EORTC IL51; BPI-I3 PROMIS PF 8c; EQ-5D-3L; PGIS;
FACT GP5: PGIC: first year every 6 weeks, thereafter every 12 weeks.
Optional tumor biopsy: 0-2 during and at the end of treatment.