The understanding of clear cell ovarian cancer is evolving. If you’re diagnosed with clear cell ovarian cancer and eager for information specific to your subtype, we’ve got you covered! Join Dr. Jubilee Brown, Professor and Director of Gynecologic Oncology at Levine Cancer Institute, as she discusses current treatment options and any promising advances. Come with your questions and leave more informed about your subtype. 

1. What’s the latest in
clear cell ovarian cancer?
Jubilee Brown MD
Professor and Director of Gynecologic Oncology
Levine Cancer Institute, Charlotte, NC

2. Disclosures
• Speakers’ Bureau: Clovis, Eisai
• Advisory Boards: Caris, Tempus, AstraZeneca,
Verastem
• Consultant/Speaker: Clovis, Caris, Tesaro/GSK
• Principal Investigator: Tesaro/GSK, Genentech
• Steering Committee BOUQUET trial
• Co-Chair NRG Oncology Rare Tumor Committee

3. Objectives
• To discuss current trials and progress in clear cell carcinomas
of the ovary
• To specify therapy utilized to treat clear cell carcinomas of the
ovary

4. Clinical Excellence – and Education

5. Mentorship: Gained and Given

6. ”Good research tells a story”
- Anil Sood MD, PhD
…and sometimes it takes a while…and a great team
- Jubilee Brown MD

7. Overview through Time
• Prior to 2005: All rare tumors included in Phase II/III
trials without regard to histologic subtype
• 2005: Dr. Gershenson chaired the first Rare Tumor
Working Group in the GOG
• 2010: GCIG endorsed this approach
• 2011: NCI Clinical Trials Planning Meeting endorsed
• Working Group - > Full NRG Rare Tumor Committee
• Hypothesis driven research in rare tumors
• Novel agents, innovative statistical design,
translational research components
• 2022: NRG Preclinical workshop

8. PROGRESS AND SUCCESS!

10. PROGRESS AND SUCCESS!

11. PROGRESS AND SUCCESS!

12. • What are the 3 major groups of ovarian cancer?
Pathology
Epithelial Germ cell
Sex Cord
- Stromal
Kurman et al. WHO classification of tumours, 4th ed, vol 6. Lyon: International
Agency For Research On Cancer, 2014; Prat et al, Hum Pathol 2018;80:11-
27.

13. • What are the 3 major groups of ovarian cancer?
Pathology
Epithelial Germ cell
Sex Cord
- Stromal
Kurman et al. WHO classification of tumours, 4th ed, vol 6. Lyon: International
Agency For Research On Cancer, 2014; Prat et al, Hum Pathol 2018;80:11-
27.

14. • High Grade Serous
• Low Grade Serous
• Mucinous
• Endometrioid
• Clear Cell
• Brenner (Transitional)
• Mixed
• Undifferentiated
Pathology
Epithelial
90%
Kurman et al. WHO classification of tumours, 4th ed, vol 6. Lyon: International
Agency For Research On Cancer, 2014; Prat et al, Hum Pathol 2018;80:11-
27.

15. • High Grade Serous
• Low Grade Serous
• Mucinous
• Endometrioid
• Clear Cell
• Brenner (Transitional)
• Mixed
• Undifferentiated
Pathology
Epithelial
90%

16. Clear Cell Carcinoma of the Ovary
• Has distinct histology, epidemiology, molecular
biology, and clinical behavior
•1-12% in Europe
and NA
•25% in
Japan!
•Thrombosis and hypercalcemia
del Carmen MG et al.Gynecol Oncol. 2012;126:481-90.
Japanese gynecologic cancer committee.
ActaObstetGynecolJpn 2012

17. Clear Cell Carcinoma of the Ovary
Kato N, et al., Mod Pathol. 2006 Jan;19(1):83-9
Courtesy K. Fujiwara
• ER/PR, WT-1 (-)
• HNF-1Beta and
Napsin +

18. Clear Cell Carcinoma of the Ovary
Takano M, et al. Int J Gynecol Cancer. 2010 Dec;20(9):1506-10.; Takano M, et al. Br J
Cancer 2006;94:1369-74; Satoh T, et al. J Clin Oncol 2010;28:1727-32; Chan JK, et al.,
Gynecol Oncol. 2008; 109(3):370-6; Goff BA, et al., Gynecol Oncol. 1996;60(3):412;
Sugiyama T, et al., Cancer 2000: 88(11):2584
• Late 40-50’s
• Early-stage: More common, good prognosis
-Fertility-sparing surgery with staging
-Consider treatment for IA since all high grade
-Platinum + taxane = standard of care
-Japanese studies: >95% OS with observation IA
• Late stage: Worse prognosis than serous or
endometriosis, platinum-resistant

19. Surgical Advances

20. Surgical Approach
• Preoperative discussion: Fertility
• Historical approach: Vertical midline incision, pelvic
washings, USO for frozen section (avoiding rupture);
comprehensive staging
• Complete versus conservative treatment?
• Childbearing complete: TAH-BSO, TRS
• Advanced disease: goal of no visible residual disease
• MIS now an option – limited study
Friedman C, et al. J Pediatr Adolesc Gynecol. 2016

21. Fertility Options
• Usually can spare one ovary/tube and uterus
– USO leads to elevated FSH, decrease in AMH, OR
4.3 early menopause, risk of infertility
• [Always] conserve uterus
• ART: Oocyte cryopreservation, Ovarian tissue
cryopreservation, Donor oocytes
– Ovarian tissue harvested, preserved, reimplanted -
restoration of function in 4m, >60 live births reported
Oelschlager J Pediatr Adolesc Gynecol 2016; Wallace
WHB Fert Steril 2016; Anderson RA Lancet 2015

22. Gershenson DM (2005) JNCI Monographs 34:43-7
• Describes USO with conservation of
normal contralateral ovary and uterus in
patients with limited disease
• Does not refer to cystectomy - No data
• Staging is STILL required (but
modified…)

23. SCST
- Does not refer to cystectomy: no data
- Lymphadenectomy is NOT routinely included
Gershenson DM (2005) JNCI Monographs 34:43-7

24. Molecular Biology Informs Clinical Trials
•PIK3CA mutations present in 40% of CCC
Wiegand KC et al N Engl J Med.2010;363:1532-43.
Kuo KT,. Am J Pathol. 2009;174:1597-601.
•Target PI3K/AKT
•mTOR inhibitors

25. Angiogenesis Inhibitors
• VEGF targeted agents: bevacizumab, aflibercept
• VEGF receptor agents: cediranib, ramucirumab
• Multiple VEGF targets: pazopanib, sunitinib, nintedanib
Zand B et al, Targeted Therapy in Gynecological Malignancy, Textbook of Uncommon
Cancers, 3rd Edition, Eds: Raghavan D, Brown J, et al, 2017

26. GOG 254 - Sunitinib
Chan J et al. Gynecol Oncol. 2018 Aug;150(2):247-252
• Phase II Trial of Sunitinib in the treatment of persistent or
recurrent clear cell ovarian cancer
• Oral receptor tyrosine kinase inhibitor: VEGFR, PDGFR,
EGFR, and kit-receptor
• N = 30 patients
• 6.7% response rate (2/30 pts)
• PFS = 2.7 months
• 6m PFS = 16.7%
• “Minimal Activity”

27. GOG 268 – Temsirolimus/P/C - Temsirolimus
• A Phase II Evaluation of Temsirolimus in Combination with
Carboplatin and Paclitaxel followed by Temsirolimus (CCI-779)
Consolidation as First-line Therapy in the Treatment of Stage
III-IV Clear Cell Carcinoma of the Ovary
• n=90 (45 US/Korea, 45 Japan)
• Primary objective: 12 m PFS; stratified by geography
• PFS>12 m in 0% of suboptimal patients; 49% optimal US pts
• 12-month PFS NOT significantly (p > 0.05) better than
historical controls
• No difference in PFS or OS between US/Korea and Japan
Farley J (PI)

28. GOG 283 – Dasatanib
• A Phase II Trial of DCTD-Sponsored Dasatinib In
Recurrent/Persistent Ovary, Fallopian Tube, Primary Peritoneal,
Endometrial, or Endometriosis-Associated Clear Cell Carcinoma
Characterized for the Retention or Loss of BAF250a Expression
(40-60% of CCC are ARID1A+, coding for BAF250a)
• Orally bioavailable multi targeted tyrosine kinase inhibitor (MET)
• Primary endpoint: 6 m PFS and CR/PR
• n = 13 patients
• No responses

29. GY-016: A Phase II Study of MK-3475 (Pembrolizumab) +
Epacadostat in Recurrent Clear Cell Carcinoma of the Ovary
• PD-1 inhibitor and oral IDO-1 inhibitor
• Primary endpoint: ORR within 7m of entry
• 14 patients accrued rapidly (9/18-4/19)
• ORR 21% (95%CI: 5-51%); 3 PRs
• Median PFS 4.8 m (95% CI: 1.9-9.6 m)
• OS 18.9 m (95% CI: 1.9-NR)
• MET CRITERIA FOR 2 STAGE
• Study closed due to insufficient drug supply
• Gien L et al, IGCS 2022

30. GY-016: A Phase II Study of MK-3475 (Pembrolizumab) +
Epacadostat in Recurrent Clear Cell Carcinoma of the Ovary
• PD-1 inhibitor and oral IDO-1 inhibitor
• Primary endpoint: ORR within 7m of entry
• 14 patients accrued rapidly (9/18-4/19)
• ORR 21% (95%CI: 5-51%); 3 PRs
• Median PFS 4.8 m (95% CI: 1.9-9.6 m)
• OS 18.9 m (95% CI: 1.9-NR)
• MET CRITERIA FOR 2 STAGE
• Study closed due to insufficient drug supply
• Gien L et al, IGCS 2022

31. GY-001 – Phase II Study of Single-Agent Cabozantinib in
Patients with Recurrent Clear Cell Ovarian, Primary
Peritoneal or Fallopian Tube Cancer (NRG-GY001)
• Small molecule inhibitor of c-Met and VEGFR2
• Cabozantinib 60 mg po daily until progression or toxicity (n=13)
• Primary endpoint: 6m PFS and CR or PR
• No responses
• 23% (3/13/ patients) had PFS > 6m
• Median PFS 3.6 m; Medial OS 8.1 m
• 5 thromboembolic events
Konstaintinopoulos P, et al. Gynecol Oncol 2018 Jul; 150(1): 9-13

32. Ongoing Trials
• GY-014: Phase II Study of Tazemetostat in Recurrent/Persistent
Endometrioid/Clear Cell Carcinoma of the Ovary, and Recurrent
or Persistent Endometrioid Endometrial Adenocarcinoma
• Anlotinib Combined With Niraparib Dual Therapy in Platinum-
resistant Recurrent Ovarian Clear Cell Carcinoma. (CC-ANNIE)
• Pembrolizumab and Lenvatinib in Clear Cell Ovarian Cancer
• Study Of Nintedanib Compared To Chemotherapy in Patients
With Recurrent Clear Cell Carcinoma Of The Ovary Or
Endometrium (NiCCC)
• Etigilimab and Nivolumab for the Treatment of Platinum-
Resistant Recurrent Clear Cell Ovarian, Primary Peritoneal, or
Fallopian Tube Cancer

33. The Case for Immunotherapy in CCC Ovary
•I/O in Ovarian Cancer
• 20 evaluable patients received either 1 or 3 mg/kg nivolumab
• Best clinical response rate = 15%
• Clinical benefit rate = 45%
• 10% durable response rate
• PD-L1 did not correlate
• 2 CR’s: 1 serous, 1 clear cell
Hamanishi J et al, J Clin Oncol 2015;33(34):4015

34. Biomarkers of Immunotherapy Response in
Solid Tumors
• 487 of 877 TMB high tumors did not express high levels of PD-L1
• Assessing multiple markers of immunotherapy sensitivity
maximizes identification of patients who may benefit
Vanderwalde et al. Cancer Med. (2018)

35. Importance of Comprehensive Molecular
Profiling
• Allows treatment based on genomic drivers of tumorigenesis
• Dramatic responses in treatment-refractory disease
• Broad panel testing measures levels of genes or gene products
• Biomarkers of response prediction and prognosis
El Deiry WS et al. CA Cancer J Clinicians 2019

36. 57 yo Recurrent Stage IA CCC Ovary
EGFR+ (failed cetuximab on TAPUR); PD-L1+
Pre-nivolumab

37. 57 yo Recurrent Stage IA CCC Ovary
EGFR+ (failed cetuximab on TAPUR); PD-L1+
Pre-nivolumab
6 months post-nivolumab

38. Data on CCC Ovary - Caris
Mutation % Positive Actionable Drug
ARID1A 53.4% Y EZH2 Inh
PIK3CA 47.5% Y PI3Kinase Inh
TP53 13.4% N -
KRAS 11.6% Y MEK Inh
PTEN 6.8% Y AKT / mTOR Inh
TMB 5.4% Y Immunotherapy
ATM 4.8% Y PARP Inh
MSI 4.1% Y Immunotherapy
PIK3R1 3.1% Y PI3K,AKT,mTOR Inh
PIK3CA 2.5% Y mTOR Inh
ERBB2 2.5% Y HER2 Inh, mAb
MSH6 2.5% Y Insufficient info
ERBB3 2.3% Y HER 3 Inh, mAb
NF1 2.2% Y PI3K Inh
BRCA2, MUTYH 2% each Y PARP Inh
MSH2 2% each Y Insufficient info
BRAF 2% Y BRAF Inh
AKT1 2% each Y AKT/mTOR Inh
Up to 1% each: ATRX, CDKN2A, FGFR2, NF2, NRAS, PMS2, TSC2, BAP1, BRIP1, ERCC2, MLH1, PALB2, PTCH1,
BRCA1, CCND1/3, EGFR, FGFR3, HRAS, MAP2K1, NOTCH1, PMS1
[Brown et al, SGO 2020]

39. Data on Rare Tumors - Caris
Histology Minimum %+ N
Ovary - SCST 9.8% 228
Ovary - Germ Cell 20% 52
Ovary - Mucinous 62% 132
Ovary - LG Serous/Endometrioid 28.9% 91
Ovary - Clear Cell 53.4% 367
Ovary - MMMT 7.2% 112
Uterine Sarcoma 40.1% 4670
Vulvar CA 28.7% 166
Neuroendocrine GYN CA 20.6% 103
• There ARE targetable mutations in rare tumors
• You cannot generalize – they are all different!
Brown et al, SGO 2020

40. Rare Tumor Profiling
Brown et al, SGO 2020

41. Submitted Concept
• DT2337: A Single-Arm, Phase II Evaluation of Durvalumab and
Tremelimumab for Recurrent or Metastatic Ovarian Clear Cell
Carcinoma and Endometrial Carcinoma with PPP2R1A Loss-of-
function Mutations. (Lin)

42. GOG 3051 - the BOUQUET trial
A Phase II, Open-Label, Multicenter, Platform Study Evaluating the Efficacy and Safety of
Biomarker-Driven Therapies in Patients With Persistent or Recurrent Rare Epithelial Ovarian Tumors
Ipatasertib +
Paclitaxel Cobimetinib Trastuzumab Emtansine
Atezolizumab +
Bevacizumab
BRAF, KRAS,
NRAS, nF1
PTEN, PIK3CA, AKT ERBB2 NOS

43. TAKE HOME POINTS - EPITHELIAL
• Low Grade Serous: KRAS, MEK, Trametinib, GY-019
• Mucinous:
• Accurate diagnosis is difficult
• Lymphadenectomy not necessary
• Consider capecitabine and oxaliplatin +/- bevacizumab
• KRAS - ?Targetable
• Clinical trials needed – central pathology review
• Clear Cell:
• Keep working on it… accrue to GY-014 – tazemetostat
• AND BOUQUET GOG-3051 FOR ALL!

44. “I don’t care what you do in life, just leave a
positive footprint in the world” - Mom (me)
jubilee.brown@atriumhealth.org
832-289-6133 cell

45. Thank you!
jubilee.brown@atriumhealth.org
832-289-6133 cell