UAB Ovarian Cancer Clinical Trials. Charles A. Leath, III, MD, MSPH

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1 UAB Ovarian Cancer Clinical Trials Charles A. Leath, III, MD, MSPH

2 Disclosures I will discuss non-fda approved indications for several medications I perform contracted research for the following companies: Celsion, AstraZeneca, Novartis I have served on Advisory Boards for the following entities: Celsion, Roche/Genentech, Helomics

3 Ovarian Cancer Background Fourth most common female cancer o ~225,000K annual incidence worldwide (~22,000 in USA) Most lethal all of all gynecologic cancers in the USA o ~14,000 deaths in USA o 5- year survival 45% (all stages); <20% for stage- IV Current therapy OpMons o Surgery Primary vs. Interval o Chemotherapy Intravenous and/or Intraperitoneal o Targeted therapy Olaparib, Bevacizumab o RadiaMon (limited role) Despite recent improvements in SOC, the OS in ROC is Poor ConMnued need for new Treatment OpMons with Novel MOA Siegel RL et al. CA Cancer J Clin 2016 Morgan RJ Jr. et al. J Natl Compr Canc Netw 2013

4 Clinical Research Challenges Current state of research participation Only 3-5% of the 10M+ US adults with cancer enroll on cancer clinical trials 60% of children with cancer enter on clinical trials Under-represented in cancer trials All non-white races Hispanic ethnicity Elderly Women *Intercultural Cancer Council 2011

5 Clinical Trials Ovarian Cancer Experience GOG 22* 3 arm trial N=233 SO 1 Stage III/IV or recurrent disease Working towards the modern backbone *Omura G et al. Cancer 1983

6 Clinical Trials Ovarian Cancer Experience GOG 47* 2 arm trial N=227 (measurable disease) SO 1 Stage III/IV AddiMon of CDDP *Omura G et al. Cancer 1986

7 Clinical Trials Ovarian Cancer Experience GOG 111* 2 arm trial N=410 SO 1 Stage III/IV AddiMon of wonder drug paclitaxel *McGuire W et al. NEJM 1996

8 Clinical Trials Ovarian Cancer Experience GOG 172* 2 arm trial N=415 OpMmal 1 Stage III Different route 65.6! *Armstrong D et al. NEJM 2006

9 Clinical Trials Ovarian Cancer Experience GOG 218* 3 arm trial N= Stage III/IV Disease New wonder drug bevacizumab *Burger RA et al. NEJM 2011

10 Ovarian Cancer Clinical Research Topics Primary Therapy Neoadjuvant Only GEN-1 OVATION Study Primary Therapy Neoadjuvant or Post-Op GOG 3005 Lifestyle interventions as Maintenance Therapy GOG 225 Recurrent Ovarian Cancer SOLO3 UAB 1357 Ketogenic Diet

11 Ovarian Cancer Clinical Research Topics Primary Therapy Neoadjuvant Only GEN-1 OVATION Study Primary Therapy Neoadjuvant or Post-Op GOG 3005 Lifestyle interventions as Maintenance Therapy GOG 225 Recurrent Ovarian Cancer SOLO3 UAB 1357 Ketogenic Diet

12 Potential for IP Delivered Immunotherapy Approaches for Ovarian Cancer Local IP Therapy o Abdominal Cavity Primary Metastases Site o Local Disease Primary Cause of Death o IP Chemo more EffecMve: A sixteen month survival benefit underscores the importance of local therapy for ovarian cancer Immunotherapy o PosiMve AssociaMon b/w TILs & Survival o Inverse AssociaMon b/w Tregs and Survival o Presence of Tumor ReacMve T- cells following treatment in Mssue o Clinical Responses to cytokine, Abs, Vaccines & T- cell Transfer

13 Phase I Trial of GEN-1 + Neoadjuvant Chemo in Newly Diagnosed Ovarian Cancer Patients (OVATION Trial) Primary ObjecMve: Safety, tolerability, MTD Secondary ObjecMve: ObjecMve Tumor Response Rate, pcr, PFS, OS Cohort TranslaMonal Research Newly Diagnosed Ovarian Cancer Number of Subjects GEN- 1 (mg/m 2 ) CarboplaMn (AUC) Paclitaxel (mg/m 2 ) NCT

14 Translational Research Objectives of the OVATION Trial Immune response analysis T- lymphocyte infiltramon in tumor and peritoneum Immune smmulatory/suppressive cytokines Immune related gene expression analysis Results from the TR studies to assist in: Designing mechanism- directed combinamon approaches with other therapies Defining an enhanced pament populamon by pament/tumor characterismcs

15 Ovarian Cancer Clinical Research Topics Primary Therapy Neoadjuvant Only GEN-1 OVATION Study Primary Therapy Neoadjuvant or Post-Op GOG 3005 Lifestyle interventions as Maintenance Therapy GOG 225 Recurrent Ovarian Cancer SOLO3 UAB 1357 Ketogenic Diet

16 PARPi The Next Generation of Ovarian Cancer Therapeutics? N=193, All BRCA +, 4.3±2.2 prior therapies, 86.5% measurable dz, 31% RR (3% CR, 28%PR) Kaufman et al. JCO 2015

17 Can PARPi therapy Improve Outcomes in Primary Disease? NCT

18 Ovarian Cancer Clinical Research Topics Primary Therapy Neoadjuvant Only GEN-1 OVATION Study Primary Therapy Neoadjuvant or Post-Op GOG 3005 Lifestyle interventions as Maintenance Therapy GOG 225 Recurrent Ovarian Cancer SOLO3 UAB 1357 Ketogenic Diet

19 The role of maintenance therapy following adjuvant chemotherapy (GOG 178)? PFS 22 vs. 14 months P= OS 53 vs. 48 months P= 0.34 Markman M et al. Gynecol Oncol 2009

20 So if maintenance chemotherapy does not improve OS (GOG 225).. NCT

21 Ovarian Cancer Clinical Research Topics Primary Therapy Neoadjuvant Only GEN-1 OVATION Study Primary Therapy Neoadjuvant or Post-Op GOG 3005 Lifestyle interventions as Maintenance Therapy GOG 225 Recurrent Ovarian Cancer SOLO3 UAB 1357 Ketogenic Diet

22 Is PARPi better than chemotherapy? PLD vs. Olaparib* 3 arm trial, all BRCA+ N=97 Recurrence with 12mo of plamnum 61/97 (62.9%) pts with 3+ prior therapies *Kaye SB et al. JCO 2012

23 Is PAPRi better than chemotherapy? NCT

24 Ovarian Cancer Clinical Research Topics Primary Therapy Neoadjuvant Only GEN-1 OVATION Study Primary Therapy Neoadjuvant or Post-Op GOG 3005 Lifestyle interventions as Maintenance Therapy GOG 225 Recurrent Ovarian Cancer SOLO3 UAB 1357 Ketogenic Diet

25 What can we do to reverse chemotherapy resistance? Steg AD et al. Mol Cancer Ther 2012

26 Phase IB/II Trial of LDE225 and Paclitaxel in Recurrent Ovarian Cancer Primary ObjecMve: Safety, tolerability, MTD, Phase 2 Dose Secondary ObjecMve: ObjecMve Tumor Response Rate, PFS, OS Cohort Recurrent PlaMnum Resistant Ovarian Cancer Number of Subjects LDE225 (mg) Paclitaxel (mg/m 2 ) NCT

27 Ovarian Cancer Clinical Research Topics Primary Therapy Neoadjuvant Only GEN-1 OVATION Study Primary Therapy Neoadjuvant or Post-Op GOG 3005 Lifestyle interventions as Maintenance Therapy GOG 225 Recurrent Ovarian Cancer SOLO3 UAB 1357 Ketogenic Diet

28 Targeted disruption of cancer cell metabolism and growth through modification of diet quality. The metabolic environment predisposes to cancer Cancer calls are glycolytic and use glucose exclusively for fuel High circulating concentrations of glucose, insulin, growth factors, and markers of inflammation are permissive to cancer cell growth and replication Commonly observed in obesity and diabetes A diet that restricts glucose ( ketogenic ) will: Decrease insulin, growth factors, and inflammation Increase ketone bodies, which impair cancer cell growth and replication

29 Diet choice affects mitochondrial function. Signaling molecules from the mitochondria lead to genetic changes characteristic of cancer Insulin Glucose Engines of the cells; Burn fuel, produce energy (ATP) Mitochondria Gene expression FermentaMon genes Oncogenes Myc TOR NFKB CHOP Ras DNA repair genes CH3 GeneMc Changes OxidaMve Stress Genomic instability Muta<ons

30 RCT: Effect of ketogenic diet on metabolism and cancer status Currently recruiting 66 women with recurrent ovarian or endometrial cancer 12 weeks of diet therapy: standard diet vs. ketogenic (carbohydrate restricted) diet Outcomes: CA-125, tumor size, growth factors, body composition, inflammation, fatigue/energy, depression, quality of life Investigators: Alvarez, Gower, Fontaine Call if interested in participating Funded by the American InsMtute for Cancer Research

31 UAB Ketogenic diet prescription Transition to fat oxidation and ketone production <20 g/d CHO 2 cup/day salad greens 1 cup/day non-starchy vegetables <100 g/d protein (poultry, fish, red meat, pork, eggs) Unlimited fat Olive oil, coconut oil, coconut milk, butter, meat fat Limited fat Cheese (4 oz/d) Olives (6/d); ½ avocado Mayonnaise and cream (2 Tb/d) This diet will starve cancer cells

32 Thank you!