J Gynecol Oncol.

2019 Nov;30(6):e112
https://doi.org/10.3802/jgo.2019.30.e112
pISSN 2005-0380·eISSN 2005-0399

Clinical Trial Protocol A phase II study of neoadjuvant

chemotherapy plus durvalumab and
tremelimumab in advanced-stage
ovarian cancer: a Korean Gynecologic
Oncology Group Study (KGOG 3046),
TRU-D

Jung-Yun Lee ,1 Jae-Weon Kim ,2 Myong Cheol Lim ,3 Sunghoon Kim ,1

Received: Jul 9, 2019 Hee Seung Kim ,2 Chel Hun Choi ,4 Ju Yeon Yi ,5 Sang-Yoon Park ,3
Revised: Aug 18, 2019 Byoung-Gie Kim 4, and on behalf of KGOG investigators*
Accepted: Aug 21, 2019
1
Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University
Correspondence to College of Medicine, Seoul, Korea
Byoung-Gie Kim 2
Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
Department of Obstetrics and Gynecology,
3
Division of Tumor Immunology and Center for Clinical Trial, Center for Gynecologic Cancer, Research
Samsung Medical Center, Sungkyunkwan Institute and Hospital, National Cancer Center, Goyang, Korea
University School of Medicine, 81 Irwon-ro,
4
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of
Gangnam-gu, Seoul 06351, Korea. Medicine, Seoul, Korea
5
R connect, Seoul, Korea
E-mail: bgkim@skku.edu

*Additional KGOG investigators who

participated in this study are listed in the
acknowledgments.
ABSTRACT
Copyright © 2019. Asian Society of Background: A single-arm phase II study of neoadjuvant chemotherapy plus durvalumab
Gynecologic Oncology, Korean Society of and tremelimumab in the treatment of advanced-stage ovarian cancer has begun in Korea.
Gynecologic Oncology
We hypothesized that adding durvalumab (anti-programmed death-ligand 1 antibody) and
This is an Open Access article distributed
tremelimumab (anti-cytotoxic T-lymphocyte-associated protein 4 antibody) to chemotherapy in
under the terms of the Creative Commons
Attribution Non-Commercial License (https:// treating this cancer can increase progression-free survival (PFS) with minimal effects on safety.
creativecommons.org/licenses/by-nc/4.0/) Methods: During treatment, serial biopsies will be performed on pre-treatment, at interval
which permits unrestricted non-commercial debulking surgery and progression to identify immune biomarkers and changes in the
use, distribution, and reproduction in any tumor microenvironment. Patients with histologically confirmed stage IIIC/IV epithelial
medium, provided the original work is properly
ovarian cancer are offered durvalumab, tremelimumab plus chemotherapy for neoadjuvant
cited.
chemotherapy and durvalumab plus chemotherapy for adjuvant chemotherapy. Twenty-four
ORCID iDs patients will be included from four Korean institutions within 1 year. The primary endpoint is
Jung-Yun Lee a 12-month PFS rate.
https://orcid.org/0000-0001-7948-1350
Jae-Weon Kim
https://orcid.org/0000-0003-1835-9436
Trial Registration: ClinicalTrials.gov Identifier: NCT03899610
Myong Cheol Lim
Keywords: Epithelial Ovarian Cancer; Chemotherapy; Durvalumab; Tremelimumab;
https://orcid.org/0000-0001-8964-7158
Sunghoon Kim Immunotherapy
https://orcid.org/0000-0002-1645-7473
Hee Seung Kim
https://orcid.org/0000-0001-6876-8671
Chel Hun Choi
https://orcid.org/0000-0002-0199-6669

https://ejgo.org 1/8
Front-line immunotherapy in ovarian cancer

Ju Yeon Yi INTRODUCTION
https://orcid.org/0000-0002-4423-1076
Sang-Yoon Park Ovarian cancer is the deadliest gynecological cancer in Korea [1]. The standard therapy is
https://orcid.org/0000-0001-8325-6009
surgical cytoreduction followed by taxane-platinum combination chemotherapy. Several
Byoung-Gie Kim
https://orcid.org/0000-0002-0572-8450 phase 3 clinical trials have demonstrated that survival, postoperative morbidity, and mortality
rates after neoadjuvant chemotherapy followed by interval debulking surgery are no worse
Trial Registration than those after primary debulking surgery in patients with stages III–IV ovarian cancer [2-4].
ClinicalTrials.gov Identifier: NCT03899610
Therefore, neoadjuvant chemotherapy followed by interval debulking surgery is an alternative
Funding option for patients with unresectable high tumor burden. Most patients with advanced-stage
This work is supported by AstraZeneca ovarian cancer will achieve complete or partial remission after standard-of-care treatment
and by a faculty research grant of Yonsei but eventually will have a relapse. Recent randomized phase 3 studies showed median
University College of Medicine for 6-2018-
progression-free survival (PFS) was only 12 months with current chemotherapy in stages III/
0169. Research grants are administered by
the Ministry of Science, ICT & Future Planning
IV disease [2,4]. Therefore, there is an urgent need to improve the outcomes of patients with
(2017M3A9E8029714). this aggressive cancer.

Conflict of Interest Some recent clinical trials have studied the addition of immune-oncology drugs to
Jung-Yun Lee received honoraria for speaker's
current chemotherapy as a front-line treatment. Researchers have especially studied to
bureaus from AstraZeneca, Janssen, Roche
and research fund from AstraZeneca, Clovis determine the optimal approach to using immune checkpoint inhibitors. Most strategies
Oncology, Janssen, MSD, Roche for clinical considered in front-line settings have been combinations of anti-programmed cell death
trials or contracted research. Jae-Weon protein 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) inhibitors and chemotherapy.
Kim has served on local advisory boards IMagyn050 (NCT00262847) is a phase III randomized study designed to compare
for AstraZeneca, Takeda, Pfizer, Janssen.
the efficacy and safety of atezolizumab+paclitaxel+carboplatin+bevacizumab versus
Received honoraria for speaker's bureaus from
AstraZeneca, Takeda, Pfizer, Janssen, Roche.
placebo+paclitaxel+carboplatin+bevacizumab in 1,300 ovarian cancer patients [5]. JAVELIN
Myoung Chel Lim disclose COI with following OVARIAN 100 (NCT02718417) is a phase III randomized study investigating avelumab in
companies on the one of the advisory board combination with and/or as a maintenance treatment after a regime of carboplatin/paclitaxel
member, honoraria, research funding or travel chemotherapy in treating 998 ovarian cancer patients. However, when used as part of a planned
for the meeting (AstraZeneca, Cellid, Clovis, interim analysis, JAVELIN OVARIAN 100 does not permit having a primary endpoint for PFS.
MSD, Pfizer, Roche, Takeda & Tessa).

Author Contributions So far, emerging clinical data shows a limited clinical efficacy of immune checkpoint
Conceptualization: L.J.Y., K.J.W., L.M.C., P.S.Y., inhibitors in ovarian cancer; the results have been objective response rates (ORRs) of
K.B.G.; Data curation: L.J.Y., L.M.C., K.S., 10%–15%, with some durable responses. Because ovarian cancer is an immunologically
K.H.S., Y.J.Y., P.S.Y., K.B.G.; Formal analysis:
cold tumor [6], the use of PD-1 or PD-L1 inhibitors alone likely will have limited benefit. We
L.J.Y., K.J.W., K.S., K.H.S., C.C.H.; Funding
acquisition: L.J.Y., C.C.H., P.S.Y.; Investigation: suggest combination therapy to turn cold tumor into hot tumor. To improve the efficacy of
L.J.Y., K.J.W., L.M.C., K.S., K.H.S., C.C.H., P.S.Y., a PD-L1 inhibitor, a combination of a cytotoxic T-lymphocyte-associated protein 4 (CTLA-
K.B.G.; Methodology: L.J.Y., K.J.W., L.M.C., 4) inhibitor and chemotherapy has been suggested with promising prospects. NRG GY003
K.S., Y.J.Y., K.B.G.; Project administration: showed that combining nivolumab and ipilmumab was more effective than nivolumab alone
L.J.Y., K.J.W., K.H.S., Y.J.Y., K.B.G.; Resources:
(ORR: 31.4% vs. 12.2%) in recurrent ovarian cancer. Korean Gynecologic Oncology Group
L.J.Y., L.M.C., K.S., K.H.S., K.B.G.; Software:
L.J.Y., K.J.W., L.M.C., C.C.H., P.S.Y., K.B.G.;
(KGOG) 3045 is an umbrella study of biomarker-driven targeted therapy in patients with
Supervision: L.J.Y., K.J.W., C.C.H., K.B.G.; platinum-resistant recurrent ovarian cancer. In this study, one of treatment arms includes
Validation: L.J.Y., K.S., Y.J.Y.; Visualization: durvalumab and tremelimumab plus nonplatinum-based standard of chemotherapy (SOC)
L.J.Y., K.J.W., L.M.C., K.H.S., Y.J.Y., P.S.Y.; (weekly palictaxel, topotecan, or liposomal doxorubicin). In other solid cancers, several
Writing - original draft: L.J.Y.; Writing - review ongoing studies such as POSEIDON continue to evaluate the efficacy and safety of the anti-
& editing: L.J.Y., K.J.W., L.M.C., K.S., K.H.S.,
PD-L1 and anti-CTLA-4 antibodies plus chemotherapy. In addition, some chemotherapeutic
C.C.H., Y.J.Y., P.S.Y., K.B.G.
agents induce immunogenic cells and potentially improve the efficacy of immune
checkpoint inhibitors [7]. Therefore, we proposed a combination therapy of durvalumab,
tremelimumab, and chemotherapy to improve outcomes in advanced-stage ovarian cancer.
KGOG 3046 will be uniquely positioned to elucidate whether dual checkpoint inhibition
(durvalumab+tremelimumab) with chemotherapy can improve survival without excess
toxicity for patients.

https://ejgo.org https://doi.org/10.3802/jgo.2019.30.e112 2/8

Front-line immunotherapy in ovarian cancer

This study protocol was approved by AstraZeneca in June 2018 and the Scientific Review Board
of the KGOG in October 2018. Patient enrollment began in June 2019. We obtained approval
from the Institutional Review Board before initiating patient accrual at each institution (4-2019-
0083). This trial has been registered with ClinicalTrials.gov NCT03699449.

PROTOCOL OF THE KGOG 3046 STUDY

1. Objective
This single-arm phase II study aims to explore the synergistic effects of durvalumab and
tremelimumab plus chemotherapy in advanced-stage ovarian cancer.

The secondary objective is to explore the safety of durvalumab and tremelimumab plus
chemotherapy in advanced-stage ovarian cancer.

An exploratory objective is to identify changes in immune biomarkers by comparing tissue

and blood samples before and after treatment.

2. Endpoints
The primary endpoint of the study is a 12-months PFS rate.

The secondary endpoints include response rates by Response Evaluation Criteria in Solid
Tumors version 1.1 after neoadjuvant chemotherapy, immune-related response criteria after
neoadjuvant chemotherapy, response rates by PET Response Criteria in Solid Tumors after
neoadjuvant chemotherapy, R0 rate at interval debulking surgery, the rate of chemotherapy
response scores (CRS) of 3 at interval debulking surgery, overall survival (OS), safety, and
duration of response.

PFS is defined as the time from the start of treatment until the first documented sign of
disease progression or death from any cause; OS is defined as the time from first treatment
until death from any cause. We will estimate PFS and OS using Kaplan-Meier techniques and
calculate 95% confidence intervals.

The following are the details of how (CRS) will be analyzed. An experienced gynecologic
pathologist (Prof. Hyun Soo Kim and Sang Yong Song) will score each slide independently
according to the 3-tiered CRS system proposed by Bohm et al. Resected specimens from
interval debulking surgery will be formalin-fixed and paraffin-embedded according to
standard procedures and stained with hematoxylin and eosin stain. The slide with the most
viable tumor and/or the least chemotherapy response will be selected from the omentum.

3. Study design
Single arm, phase II study.

ELIGIBILITY CRITERIA
1. Inclusion criteria
1) Histologically confirmed adenocarcinoma of ovary, fallopian tube, primary peritoneum
(non-mucinous).

https://ejgo.org https://doi.org/10.3802/jgo.2019.30.e112 3/8

Front-line immunotherapy in ovarian cancer

2) Clinical stages IIIC/IV.

3) Eastern Cooperative Oncology Group performance status of 0–1.
4) Females aged 20 years or older at the time of acquisition of informed consent.
5) Adequate organ function.
6) Body weight >30 kg.

2. Exclusion criteria
1) A serious concomitant systemic disorder that, in the opinion of the investigator, would
compromise the patient's ability to complete the study.
2) Patients with active or uncontrolled infections or with serious illnesses or medical
conditions.
3) Active pulmonary tuberculosis.
4) Known acute or chronic hepatitis B or C by serological evaluation.
5) Known human immunodeficiency virus infection.
6) History of another primary malignancy that is currently clinically significant or currently
requires active intervention.
7) Inability to comply with protocol or study procedures.

RANDOMIZATION
Not applicable.

TREATMENT
Patients with histologically confirmed ovarian cancer are offered durvalumab, tremelimumab
plus chemotherapy. KGOG 3046 regimen consists of 21-day cycles with durvalumab,
tremelimumab plus chemotherapy for neoadjuvant chemotherapy and durvalumab plus
chemotherapy for adjuvant chemotherapy (Fig. 1).

Neoadjuvant chemotherapy Adjuvant chemotherapy

Paclitaxel-carboplatin Q3W Paclitaxel-carboplatin Q3W
Tremelimumab 75 mg Q3W
Interval
Biopsy Durvalumab 1,500 mg Q3W debulking Durvalumab 1,120 mg Q3W (to C15 or PD) Biopsy
surgery

C1 C2 C3 C4 C5 C6

Pre-treatment: Biopsy #1 Surgical specimen: Biopsy #2 Post-treatment: Biopsy #3

Fresh frozen Fresh frozen Fresh frozen (optional)

Immune marker analysis using FACS Immune marker analysis using FACS Immune marker analysis using FACS
PD-L1 expression (SP263) PD-L1 expression (SP263) PD-L1 expression (SP263)
Exome sequencing Exome sequencing Exome sequencing
RNA sequencing RNA sequencing RNA sequencing

Fig. 1. Study schema.

FACS, fluorescence-activated cell sorting; PD-L1, programmed death-ligand 1; Q3W, every 3 weeks.

https://ejgo.org https://doi.org/10.3802/jgo.2019.30.e112 4/8

Front-line immunotherapy in ovarian cancer

1. Treatment arm
Neoadjuvant treatment: standard chemotherapy+durvalumab +tremelimumab.

Durvalumab: 1,500 mg every 3 weeks (Q3W; 3 total doses).

Tremelimumab: 75 mg Q3W (3 total doses).

Chemotherapy regimen: paclitaxel 175 mg/m2, carboplatin area under the curve (AUC) 5–6
Q3W (3 total doses).

Adjuvant treatment: standard chemotherapy+durvalumab.

Durvalumab: 1,120 mg Q3W (12 total doses).

Chemotherapy regimen: paclitaxel 175 mg/m2, carboplatin AUC 5–6 Q3W (3 total doses).

Safety run-in phase

There will be a safety run-in phase with up to 7 patients. After that, a phase II expansion
phase will be conducted with dosage levels considered safe.

Based on historical data, the proportion of patients who experience G3 or more treatment-
related adverse events (TRAEs) in the neoadjuvant chemotherapy will be approximately
30%–50%, even without durvalumab and tremelimumab [8-10].

Enrollment will be suspended until after seven subjects have undergone surgery. Data and
Safety Monitoring Board will review the safety of this trial and suggest recommendations,
taking into consideration such examples as the following:

If patients who experience grade 3 or more TRAEs (except hematologic toxicity) are ≥4,
then the trial will be stopped; If patients who experience grade 3 or more TRAEs (except
hematologic toxicity) are ≤3, then the trial will proceed to phase II.

Any recommendations issued as a result of the above situations will be used to decide
whether to stop the trial or proceed to phase II.

A single-arm phase II study

Durvalumab 1,500 mg IV, tremelimumab 75 mg IV, paclitaxel 175 mg/m2, and carboplatin
AUC 5 or 6 will be administered every 3 weeks. Three cycles of neoadjuvant chemotherapy
will be performed before interval debulking surgery. After surgery, durvalumab 1,120 mg IV,
paclitaxel 175 mg/m2, and carboplatin AUC 5 or 6 will be administered every 3 weeks. Three
cycles of adjuvant chemotherapy and 12 cycles of durvalumab will be performed after interval
debulking surgery.

Treatment response assessments will be implemented every 3 cycles during the treatment
period. For patients who achieve disease control after 12 months of treatment, tumor
assessments should be performed relative to the date of first infusion as follows: every 12
weeks for the first 2 years, then every 24 weeks thereafter until confirmed PD. All patients will
be followed for at least 5 years after treatment is completed. Enhanced abdominal computed
tomography and/or magnetic resonance imaging, chest computed tomography, and tumor

https://ejgo.org https://doi.org/10.3802/jgo.2019.30.e112 5/8

Front-line immunotherapy in ovarian cancer

markers will be evaluated at least every 12 weeks until disease progression or death. Efficacy
analyses are based on a modified intent-to-treat approach (patients should receive at least
one treatment dose).

SAMPLE SIZE JUSTIFICATION

The sample size was calculated based on the 1-sample log-rank test.

Median PFS is 12 months in advanced-stage ovarian cancer from European Organisation

for Research and Treatment of Cancer 55971 and Chemotherapy or Upfront Surgery.
The rate of patients with disease-free status at 12 months is expected to be 50% with
conventional chemotherapy (SOC). The rate of patients with disease-free status at 12
months is expected to be 70% with the addition of immunotherapy (combination of
durvalumab+tremelimumab+SOC followed by durvalumab+SOC) (hazard ratio=0.515). With
80% statistical power and 5% of 1-sided type I errors, 21 patients are needed when patients
are accrued for 12 months and followed for 30 months after the last patients is enrolled. The
number of expected events would be 14. In anticipation of a 10% drop-out rate, 24 patients
will be enrolled in this study.

MONITORING
The investigator or a designated representative must enter in the electronic case report form
all information required by the protocol. The Data and Safety Monitoring Committee will
review the results independently from the investigators and the study group statistician. The
KGOG Data Center and study coordinator will conduct central monitoring and will issue a
monitoring report every 6 months to evaluate study progress and improve data integrity and
patient safety. For quality assurance, the KGOG Audit Committee will perform site audits. No
interim analysis is planned for this study.

PARTICIPATING INSTITUTIONS
Yonsei University Severance Hospital, Seoul National University Hospital, Samsung Seoul
Medical Center, National Cancer Center.

ACKNOWLEDGMENTS
This investigator-initiated trial was supported by a faculty research grant of Yonsei University
College of Medicine for 6-2018-0169. Research grants are administered by the Ministry
of Science, ICT & Future Planning (2017M3A9E8029714). This trial was also supported by
AstraZeneca. We thank AstraZeneca for providing funding and durvalumab/tremelimumab. We
appreciate the contribution of investigators and study teams at the participating sites and KGOG.

Yonsei University Health System, Severance Hospital

Eun Ji Nam
Sang Wun Kim

https://ejgo.org https://doi.org/10.3802/jgo.2019.30.e112 6/8

Front-line immunotherapy in ovarian cancer

Kyung Jin Eoh

Yong Jae Lee
Jeongeun Roh
Hye Min Kim

Sungkyunkwan University Samsung Medical Center

Duk-Soo Bae
Jeong Won Lee
Tae-Joong Kim
Yoo Young Lee
Eun Hwa Choi
SangYong Song
Hyun-Soo Kim

Seoul National University Hospital

Maria Lee
Se Ik Kim
Eun-Ji Lee
Sook-In Kwon

National Cancer Center

Wonkyo Shin
Sang-Soo Seo
Sokbom Kang

KGOG
Min Seo Kim
Jong Soon Kim

Samsung Genome Institute

Jegun Joung
Jongsuk Chung

REFERENCES
1. Lee JY, Kim S, Kim YT, Lim MC, Lee B, Jung KW, et al. Changes in ovarian cancer survival during the 20
years before the era of targeted therapy. BMC Cancer 2018;18:601.
PUBMED | CROSSREF
2. Kehoe S, Hook J, Nankivell M, Jayson GC, Kitchener H, Lopes T, et al. Primary chemotherapy versus
primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised,
controlled, non-inferiority trial. Lancet 2015;386:249-57.
PUBMED | CROSSREF
3. Onda T, Satoh T, Saito T, Kasamatsu T, Nakanishi T, Nakamura K, et al. Comparison of treatment
invasiveness between upfront debulking surgery versus interval debulking surgery following neoadjuvant
chemotherapy for stage III/IV ovarian, tubal, and peritoneal cancers in a phase III randomised trial: Japan
Clinical Oncology Group Study JCOG0602. Eur J Cancer 2016;64:22-31.
PUBMED | CROSSREF
4. Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. Neoadjuvant chemotherapy or
primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010;363:943-53.
PUBMED | CROSSREF

https://ejgo.org https://doi.org/10.3802/jgo.2019.30.e112 7/8

Front-line immunotherapy in ovarian cancer

5. Moore KN, Pignata S. Trials in progress: IMagyn050/GOG 3015/ENGOT-OV39. A Phase III, multicenter,
randomized study of atezolizumab versus placebo administered in combination with paclitaxel,
carboplatin, and bevacizumab to patients with newly-diagnosed stage III or stage IV ovarian, fallopian
tube, or primary peritoneal cancer. Int J Gynecol Cancer. Forthcoming 2019.
PUBMED
6. Kim HS, Kim JY, Lee YJ, Kim SH, Lee JY, Nam EJ, et al. Expression of programmed cell death ligand 1 and
immune checkpoint markers in residual tumors after neoadjuvant chemotherapy for advanced high-grade
serous ovarian cancer. Gynecol Oncol 2018;151:414-21.
PUBMED | CROSSREF
7. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunological effects of conventional
chemotherapy and targeted anticancer agents. Cancer Cell 2015;28:690-714.
PUBMED | CROSSREF
8. Becker DA, Thomas ED, Gilbert AL, Boone JD, Straughn JM Jr, Huh WK, et al. Improved outcomes with
dose-dense paclitaxel-based neoadjuvant chemotherapy in advanced epithelial ovarian carcinoma.
Gynecol Oncol 2016;142:25-9.
PUBMED | CROSSREF
9. Garcia YG, Juan AD, Mendiola C, Barretina-Ginesta MP, Prat A, Santaballa A, et al. Phase II randomized
trial of neoadjuvant (NA) chemotherapy (CT) with or without bevacizumab (Bev) in advanced epithelial
ovarian cancer (EOC) (GEICO 1205/NOVA TRIAL). 2017 ASCO Annual Meeting; 2017 Jun 2; Chicago, IL:
American Society of Clinical Oncology; 2017. Abstract 5508.
10. Yoshihama T, Nomura H, Iwasa N, Kataoka F, Hashimoto S, Nanki Y, et al. Efficacy and safety of dose-
dense paclitaxel plus carboplatin as neoadjuvant chemotherapy for advanced ovarian, fallopian tube or
peritoneal cancer. Jpn J Clin Oncol 2017;47:1019-23.
PUBMED | CROSSREF

https://ejgo.org https://doi.org/10.3802/jgo.2019.30.e112 8/8