A Phase III, Randomized, Double-Blind, Placebo Controlled, Multi-Center, International Study of Durvalumab Given Concurrently With Definitive Chemoradiation Therapy in Patients With Locally Advanced, Unresectable Esophageal Squamous Cell Carcinoma (KUNLUN)
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In the past 20 years, curative intent definitive radiotherapy concurrent with
cisplatin plus fluorouracil has evolved as a standard modality for patients
with inoperable, locally advanced esophageal cancer. However, the survival
outcomes of definitive chemoradiation therapy (dCRT) with cisplatin plus
fluorouracil regimen are sub optimal with a 40% 5-year overall survival (OS)
rate, and >50% patients progressing within 2 years after dCRT, highlighting
high unmet medical need. As such, a new treatment modality to improve patient
outcome is warranted.

PD-1/PD-L1 inhibition in combination with chemoradiotherapy has demonstrated
synergistic antitumor activity in both preclinical models and in clinical
trials. As such, triggering or augmenting an antigenic antitumor response with
CRT and combining this treatment with an PD-L1 therapy, may result in enhanced
antitumor activity by improving local control and decreasing systemic spread.

Durvalumab is a human mAb of the IgG 1 kappa subclass that blocks the
interaction of PD-L1 with PD-1 on T cells and CD80 (B7.1) on immune cells.
Given this, it is hypothesized that the administration of durvalumab in
combination with dCRT may have added clinical benefit, and demonstrate
improved outcome for ESCC patients versus dCRT alone.

Primary Objectives:
- To assess the efficacy of durvalumab + dCRT compared with placebo + dCRT in
all randomized patients based on PFS (per RECIST 1.1 as assessed by BICR)
- To assess the efficacy of durvalumab + dCRT compared with placebo + dCRT in
patients with PD-L1 High tumors based on PFS (per RECIST 1.1 as assessed by
BICR)

Secondary Objectives:
- To assess the efficacy of durvalumab + dCRT compared to placebo + dCRT in
terms of OS in all randomized patients
- To assess the efficacy of durvalumab + dCRT compared to placebo + dCRT in
terms of OS in patients with PD-L1 High tumors

This is a Phase III, randomized, double-blind, placebo-controlled, multi-center
international study to assess the efficacy and safety of durvalumab
administered concurrently with dCRT in patients with locally advanced,
unresectable esophageal squamous cell carcinoma.

Approximately 600 patients with locally advanced, unresectable ESCC (AJCC 8th
cStage IIIVA) will be randomized in a 2:1 ratio to receive either durvalumab +
dCRT or placebo + dCRT. Patients will be stratified by geographical region
[Asia versus Non-Asia], cStage: [II versus III
+IVA] and level of PD-L1 expression [PD-L1 High versus PD-L1 Low].

Randomization of patients with cervical ESCC will be capped at approximately
10% of the planned total number of randomized patients.

Patients will be randomized in a 2:1 ratio to receive either durvalumab + dCRT
or placebo + dCRT:
- Durvalumab + dCRT: Durvalumab 1500 mg Q4W will be administered concurrently
with dCRT. Patients without PD after completion of CRT will continue to receive
durvalumab 1500 mg Q4W up to 24 months from the date of randomization.
- Placebo + dCRT: Placebo Q4W will be administered concurrently with dCRT.
Patients without PD after completion of dCRT will continue to receive placebo
Q4W up to 24 months from the date of randomization.

Chemotherapy regimen as part of dCRT choice of 2 options:
- Cisplatin + Capecitabine: Cisplatin 30 mg/m2 IV on Day 1 weekly for 5 weeks
and Capecitabine 800 mg/m2 PO BID on Days 1-5 weekly for 5 weeks
- Cisplatin + Fluorouracil: Cisplatin 75-100 mg/m2 on Day 1 of each cycle and
Fluorouracil 750-1000 mg/m2 IV continuous infusion over 24 hours daily on Days
1*4 q28 days × 2 cycles. Optional: 2 consolidation cycles after radiotherapy is
completed

Radiation regimen as part of dCRT:
- Total 50-64Gy (1.8-2.0 Gy/d) 25Fr-36Fr, 5 fractions/week for 5-8 weeks

Patients are subject to the following assessments throughout the study:
- Anamnesis (at screening, including medical history)
- Physical examination
- ECOG performance status
- Vital functions (blood pressure, heart rate, body temperature, respiratory
rhythm)
- Measurement of body weight
- FDG-PET/CT scan
- CT/MRI-scan
- ECG
- Blood and urine examination
- Questionnaires (EORTC QLQ-C30, QLQ-OES18, EQ-5D-5L, PGIS en PGI-TT)
- Pregnancy test when applicable
- AE/SAE assessment
- IP administration
- Biopsy (new biopsy or archival (<3 months old))

The side effects of durvalumab can range from mild to severe or in some cases
even life-threatening. Conditions have been built into the study to identify
serious side effects as early as possible.

Very common (seen in more than 1 in 10 people):
Fatigue/tiredness, diarrhea, rash/dry itchy skin, liver problems, nausea,
vomiting and abdominal pain, oedema, upper respiratory tract infections,
decreased appetite, shortness of breath, cough, pain in muscles and joints,
fever

Common (seen in more than 1 in 100 people):
Pneumonitis, colitis, low or high thyroid (hypothyroidism or hyperthyroidism),
kidney injury, nervous system problems, infusion related reactions and allergic
reactions, pneumonia, influenza, hoarse voice, painful urination, night sweats,
oral thrush, dental infections, soft tissue infections.

Moreover, the study procedures could also have risks:
- Pain or bruises through collection of blood/tumor biopy
- Rash through ECG stickers
- Health risks through radiation of CT/MRI scan