Download UAB Ovarian Cancer Clinical Trials

UAB Ovarian Cancer Clinical Trials
Charles A. Leath, III, MD, MSPH
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
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 
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Surgery – Primary vs. Interval Chemotherapy – Intravenous and/or Intraperitoneal Targeted therapy – Olaparib, Bevacizumab 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 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 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 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 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 Clinical Trials – Ovarian Cancer Experience
•  GOG 172* –  2 arm trial –  N=415 –  OpMmal 1° Stage III –  Different route *Armstrong D et al. NEJM 2006 65.6! Clinical Trials – Ovarian Cancer Experience
•  GOG 218* –  3 arm trial –  N=1873 –  1° Stage III/IV Disease –  New “wonder drug” bevacizumab *Burger RA et al. NEJM 2011 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
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
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 
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PosiMve AssociaMon b/w TILs & Survival Inverse AssociaMon b/w Tregs and Survival Presence of Tumor ReacMve T-­‐cells following treatment in Mssue Clinical Responses to cytokine, Abs, Vaccines & T-­‐cell Transfer 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 TranslaMonal Research Newly Diagnosed Ovarian Cancer Cohort Number of Subjects GEN-­‐1 (mg/m2) CarboplaMn (AUC) Paclitaxel (mg/m2) 1 3-­‐6 36 6 80 2 3-­‐6 47 6 80 3 3-­‐6 61 6 80 4 3-­‐6 79 6 80 5 3-­‐6 103 6 80 NCT 02480374 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 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
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 Can PARPi therapy Improve Outcomes in
Primary Disease?
NCT 02470585 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
The role of maintenance therapy following
adjuvant chemotherapy (GOG 178)?
PFS
22 vs. 14 months
P= 0.006
OS
53 vs. 48 months
P= 0.34
Markman M et al. Gynecol Oncol 2009 So if maintenance chemotherapy does not
improve OS (GOG 225)…..
NCT00719303 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
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 Is PAPRi better than chemotherapy?
NCT 02282020 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
What can we do to reverse chemotherapy
resistance?
Steg AD et al. Mol Cancer Ther 2012 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 Recurrent PlaMnum Resistant Ovarian Cancer Cohort Number of Subjects LDE225 (mg) Paclitaxel (mg/m2) 1 3-­‐6 200 80 2 3-­‐6 400 80 3 3-­‐6 600 80 4 3-­‐6 800 80 NCT 02195973 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
“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
Diet choice affects mitochondrial function.
Signaling molecules from the mitochondria lead
to genetic changes characteristic of cancer
“Engines” of the cells; Burn fuel, produce energy (ATP) Insulin Glucose Mitochondria Gene expression GeneMc ↑FermentaMon genes Changes ↑Oncogenes •  Myc •  TOR CH3 •  NFKB •  CHOP •  Ras ↓DNA repair genes OxidaMve Stress Muta<ons Genomic instability 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
–  [email protected]
•  Call 934-7639 if interested in participating
Funded by the American InsMtute for Cancer Research 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
Thank you!