Transcript No Slide Title

What is on the horizon for new
therapeutics for gynecologic cancers?
Ursula Matulonis, M.D.
May 9, 2015
Agenda
• Discuss our program’s goals at DFCI for
2015
• Review what’s new in drug development
for gynecologic cancers
Scientific Vision and Goals for 2015
1. Develop practice-changing clinical
trials and trial concepts for gynecologic
cancers
2. Continue junior faculty development
3. Continued translational and basic
science collaborations
Scientific Vision and Goals for 2015
1. Develop practice-changing clinical
trials and trial concepts for gynecologic
cancers
 PARP-inhibitor studies
 Focus on introducing immunotherapy
studies into trial portfolio
 Biologic combination studies driven by
pre-clinical data
 Novel Phase 1 agents (strong ADC focus)
Cancer is complex
Figure 6 Therapeutic Targeting of the Hallmarks of Cancer Drugs that interfere with each of
the acquired capabilities necessary for tumor growth and progression have been developed
and are in clinical trials or in some cases approved for clinical use.
Cell, Volume 144, Issue 5, 2011, 646 - 674
FDA approvals in 2014
• Ovarian cancer:
1) Bevacizumab (avastin) for recurrent
ovarian cancer in combination with
chemotherapy
2) Olaparib (PARP inhibitor) for recurrent
germline BRCA+ ovarian cancer
• Cervical cancer:
1) Bevacizumab (avastin) for recurrent
cancer in combination with chemotherapy
Ovarian cancer is separated into
histological categories
Ovarian cancer clinical trials have enrolled all
histologic subtypes together.
High grade
low grade
Serous
Mucinous
Endometrioid
High grade
low grade
Clear cell
Ovarian cancer is separated into
histological categories
• Specific molecular features define
these categories and shape
clinical trial design: i.e.:
Ovarian cancer:
High grade
low grade
Serous
Mucinous
Endometrioid
Mucinous tumors:
KRAS mutations1
High grade serous cancers:
Homologous recombination
deficiency (HRD) is common and
thus displays high rate of platinum
sensitivity2
Clear cell
Low grade serous cancers:
KRAS mutations; usefulness of
MEK inhibitors
High grade
low grade
Clear cell cancers:
Chemotherapy insensitivity,
PIK3CA mutations and sensitivity
to VEGFR2 inhibitors3
1Auner,
BMC Cancer 2009
Nature Rev Ca 2010
3Kuo et al, Am J Path 2009
2Bowtell,
Ovarian cancer is separated into
histological categories
• Specific molecular features define
these categories and shape
clinical trial design: i.e.:
Ovarian cancer:
High grade
Serous
Endometrioid
Mucinous
Mucinous tumors:
KRAS mutations1
High grade serous cancers:
Homologous recombination
deficiency (HRD) is common
and thus displays high rate of
platinum sensitivity2
Clear cell
Low grade serous cancers:
KRAS mutations; usefulness of
MEK inhibitors
High grade
low grade
Clear cell cancers:
Chemotherapy insensitivity,
PIK3CA mutations and sensitivity
to VEGFR2 inhibitors3
1Auner,
BMC Cancer 2009
Nature Rev Ca 2010
3Kuo et al, Am J Path 2009
2Bowtell,
BRCA-related Ovarian Cancer
• Mostly high grade serous ovarian cancer but other
cancers as well (clear cell, endometrioid, etc)
• BRCA = BReast CAncer gene (cause of
hereditary breast/ovarian/pancreas/melanoma,
etc
• Abnormal BRCA accounts for up to ~50% of
ovarian cancer1-3
1) Germline BRCA1 and BRCA2 mutations
2) Somatic mutations of BRCA gene
3) BRCA-independent defects in HR pathway, i.e.
alterations in other DNA repair pathway
molecules
TCGA Nature 2011
1
2Nat
Rev Cancer 2009
Cancer 2008
3BMC
PARP inhibitors in clinical trials for ovarian cancer
PARP inhibitor
Route
Type of studies for ovarian cancer ongoing
or completed
Olaparib (AZD2281)
PO
Phase I combinations, II and III ongoing
FDA conditional approval in 12/2014 and European
Approval Fall 2014
Veliparib (ABT-888)
PO
Phase I combination studies
Phase II: BRCA deficient ovarian cancer (GOG
280)
Ph IIII in upfront ov cancer
Rucaparib (CO338,
AGO14699 and
PF01367338)
PO
Phase I, II; Phase III ongoing in ovary cancer
Niraparib (MK4827)
PO
Phase I, II; Phase III ongoing in ovary cancer
BMN 673
PO
Phase I and dose expansions in BRCAm ovarian
cancer
Adapted from Liu et al, Gyn Onc 2014
Examples of Anti-angiogenic agents in clinical trials
for ovarian cancer
Anti-angiogenic agent
Route
Type of studies for ovarian cancer ongoing
or completed
Bevacizumab
IV
Phase I combinations ongoing; phase II and III
completed
FDA reviewing application for use in recurrent
cancer
Aflibercept
IV
Phase I and randomized phase II studies
Cediranib
PO
Phase I, II; Phase III ongoing and planned in
ovary cancer
Sunitinib (sutent)
PO
Phase I, II
Pazopanib
PO
Phase I, II and III completed and ongoing
Cabozantinib (XL184)
PO
Phase I and randomized phase II study
AMG386
IV
Multiple phase III studies completed.
Combinations of PARP inhibitor and another
biologic agent
• Olaparib + cediranib (oral antiangiogenic agent)
• Olaparib + BKM120 (PI3kinase
inhibitor)
Phase I/randomized phase II study of
olaparib and cediranib
NCT01116648
PI: Joyce Liu, MD
Participating sites:
Dana-Farber Cancer Institute
Massachusetts General Hospital
Beth Israel/Deaconess Hospital
National Cancer Institute
University of Chicago
University of Michigan
Cedars Sinai Medical Center
Background: cediranib and olaparib
• Cediranib
 Oral tyrosine kinase inhibitor of VEGFR-1, -2, -3; also
has effects on c-kit and PDGFR-beta
 Major toxicities: fatigue, diarrhea, hypertension
 Has single agent activity in ovarian cancer
• Olaparib
 Oral PARP-inhibitor
 Major toxicities: fatigue, myelosuppression, nausea
 Has single agent activity in ovarian cancer
Rationale for combination
• PARP-inhibitors and
anti-angiogenics with
known activity in ovarian
cancer
• Pre-clinical data
suggesting potential
synergy between PARPi
and anti-angiogenics
• Pre-clinical data
demonstrating in vitro
synergy between
cediranib and olaparib
1Tentori
Effect of ced/olap on cell invasion:
Effect of ced/olap on microvascular
cell tube organization:
et al., Eur J Cancer 2007, 43(14): 2124-
33
2Hegan et al., PNAS 2010, 107(5): 2201-6
Data courtesy Elise Kohn, NCI/CTEP
Rationale for combination
• PARP-inhibitors and
anti-angiogenics with
known activity in ovarian
cancer
• Pre-clinical data
suggesting potential
synergy between PARPi
and anti-angiogenics
• Pre-clinical data
demonstrating in vitro
synergy between
cediranib and olaparib
1Tentori
Effect of ced/olap on cell invasion:
Effect of ced/olap on microvascular
cell tube organization:
et al., Eur J Cancer 2007, 43(14): 2124-
33
2Hegan et al., PNAS 2010, 107(5): 2201-6
Data courtesy Elise Kohn, NCI/CTEP
Phase I: Dose escalation in recurrent ovarian or
metastatic triple-negative breast cancer
Dx:
•Recurrent ovarian
cancer
•Recurrent metastatic
triple-negative breast
cancer
Liu et al, Eur J of Ca, 2013
Dose
Level
Phase I 3+3
dose escalation
design
RP2D
Starting
dose
Cediranib
Olaparib
(capsule)
-1
15mg PO daily
100mg PO BID
0
20mg PO daily
100mg PO BID
1
20mg PO daily
200mg PO BID
2
30mg PO daily
200mg PO BID
3
30mg PO daily
400mg PO BID
Phase I: Dose escalation in recurrent ovarian or
metastatic triple-negative breast cancer
Dx:
•Recurrent ovarian
cancer
•Recurrent metastatic
triple-negative breast
cancer
Liu et al, Eur J of Ca, 2013
Dose
Level
Phase I 3+3
dose escalation
design
Starting
dose
RP2D
Dose escalation study (3+3 design)
of cediranib and olaparib in
recurrent ovarian and triple negative
breast cancer
Cediranib
Olaparib
(capsule)
-1
15mg PO daily
100mg PO BID
0
20mg PO daily
100mg PO BID
1
20mg PO daily
200mg PO BID
2
30mg PO daily
200mg PO BID
3
30mg PO daily
400mg PO BID
Ovarian cancer pts on study
100
80
60
20 ovarian patients (18 RECIST
evaluable)
Overall response rate: 44% (8 of 18
pts)
40
20
0
-20
-40
Randomized Ph 2 trial of
cediranib/olaparib vs. olaparib in
plat-sens ovarian cancer pts
awaiting final analysis
-60
-80
-100
BRCAm carrier
BRCA WT or unknown
Randomized Phase II Study Design
• Phase 2 open-label randomized study
• 1:1 randomization to cediranib/olaparib combination or single agent
olaparib
• Platinum-sensitive recurrent ovarian, fallopian tube, or primary
peritoneal cancer
• Continuation on treatment with CT or MRI imaging every 8 weeks until
disease progression by RECIST v1.1 criteria
• Patients randomized to cediranib/olaparib arm required to take twice
daily blood pressures
Dx platinumsensitive
recurrent
ovarian cancer
Presented by: Joyce
Liu, MD, MPH
NCT01116648
Olaparib
capsules
400mg BID
Randomize 1:1
Cediranib
30mg daily +
Olaparib
capsules
200mg BID
Disease
progression by
RECIST v1.1
criteria
Liu et al, ASCO 2014,
Lancet Oncology
Additional development of Cediranib/olaparib
• 09-293:
 Phase 1/2 study1,2
 Ongoing Phase 1-T study (09-293)
• CTEP 9825:
 Phase 2 biomarker study (CTEP 9825)
 DFCI-led, multicenter across the ET-CTN
 Translational and PK endpoints: PK (Jeff Supko);
BROCA-HR (Elizabeth Swisher); WES/RNASeq (Levi
Garraway); plasma angiome (Andrew Nixon)
• Phase 3 studies (NRG)
 GY-004 (OVM1403): Phase III, platinum-sensitive
 GY-005 (OVM1405): Phase II/III, platinum-resistant
1Liu
2Liu
et al, Eur J Cancer 2013
et al, Lancet Oncol 2014
Phase I BKM120 + Olaparib
NCT01623349
PI: Ursula Matulonis, MD
Participating sites:
Dana-Farber Cancer Institute
Massachusetts General Hospital
Beth Israel/Deaconess Hospital
MD Anderson Cancer Center
Memorial Sloan Kettering Cancer Center
CONFIDENTIAL SU2C
PI3K DREAM TEAM
Supported by SU2Cancer PI3kinase
Dream team
Pre-clinical Rationale for combination
of BKM120 and olaparib
1) In TNBC cells without BRCA mutations,
PI3K inhibition led to:
DNA damage, downregulation of BRCA1/2, and
sensitization to PARP inhibition1
2) In vivo synergy of the PI3Kinase inhibitor
BKM120 with the PARP-Inhibitor olaparib
is observed2
Response of breast-tumor-bearing BRCA1-/-p53+/mice to Olaparib alone (upper panel) versus the
combination of Olaparib and PI3Kinse inhibitor
BKM120 (lower panel). Model used : MMTV-Cre
Brca1(f/f)Trp53(+/-) mouse model of breast cancer
CONFIDENTIAL
1Ibrahim
2Juvekar
SU2C PI3K DREAM TEAM
et al, Cancer Discovery 2012
et al, Cancer Discovery 2012
Ovarian cancer PDX models
• Ongoing collaboration
with Belfer and Gyn Onc
Program
• Tumor cells isolated
from malignant ascites
and injected
intraperitoneally in mice
• 15 models now
luciferized as platform
for target discovery and
validation
 Clinical annotation
 Molecular
characterization
Vehicle
Carboplatin
Paclitaxel
Carbo/paclitaxel
Palakurthi, Liu et al, AACR 2015
• Ovarian Cancer Research Foundation
PPG Awarded January 2014 (PI: Matulonis)
Rational combinations of novel biologic agents for ovarian
cancer therapy
Project 1: Optimization of combined PI3kinase and PARP
inhibition and determinants of mechanisms of resistance.
PI’s: Gerburg Wulf, MD, PhD and Ursula Matulonis, MD
Project 2: Combination of inhibitors of PARP and Heat shock
protein 90 (HSP90) for the treatment of recurrent ovarian
cancer.
PI: Panos Konstantinopoulos, MD, PhD
Project 3: Prioritizing pathway inhibitors in ovarian cancer via
Dynamic BH3 Profiling
PI’s: Anthony Letai, MD, PhD and Joyce Liu MD
New agents and ways to treat
• Antibody Drug Conjugates (ADC’s)
• Drugs that interact with the immune
system
• Checkpoint kinase inhibitors
• Single agents that are more precisely
targeted
Antibody-drug conjugates
MAbs. 2014 Jan 1; 6(1): 34–45.
Antibody-drug conjugates
MAbs. 2014 Jan 1; 6(1): 34–45.
Antibody Drug Conjugates
• IMGN853 (anti-folate receptor): being
tested in ovarian cancer and endometrial
cancer
• DMUC4064A (anti-MUC16): ovarian cancer
• DNIB0600A (anti-NaPi2b): ovarian cancer
• PF-06647263 (anti-EFNA4): ovarian cancer
Immunotherapy approaches
MPDL3280A
Figure 2 Two General Mechanisms for Expression of Checkpoint Ligands in the TME The examples in this figure use the PD-1
ligand PD-L1 for illustrative purposes, although the concept likely applies to multiple checkpoint ligands. Top: innate immune
resista...
Cancer Cell, Volume 27, Issue 4, 2015, 450 - 461
Immunotherapy efforts
• Clinical trials: upcoming and completed:
 Single agent and combination MK-3475 + PLD
 Collaborative effort with George Coukos/Ludwig Institute of
PLD + MEDI4736 (anti-PDL1 antibody) + motolimod (TLR8
agonist)
 Completed:
Pembrolizumab (PD1 inhibitor): for ovarian, endometrial,and
cervical cancers. Currently open for vulvar cancer and small
cell cancers
MPDL3280A (PDL1 inhibitor): for endometrial cancer
• Translational




Panos Konstantinopoulos
Michael Goldberg
Jung-Min Lee/Elise Kohn (NCI)
Kwok-Kin Wong/Liu/Konstantinopoulos/Belfer
ATR and Checkpoint kinase inhibitors
VX970
GDC0575
Foukas et al, Ca Treatment Reviews 2014
Agents based on molecular alterations:
Eligibility depends on specific genetic
alterations
• AKT inhibitor (for PI3kinase pathway
alteration) (Ovary and endometrial
cancer)
• Wee 1 inhibitors (p53 mutations) (Ovarian
cancer)
• AKT inhibitor plus MEK inhibitor for
recurrent cervical cancer
Clinical Trials Operation
Gyn Research Team
• Research Group Management
 1 Clinical Research Manager
 1 Assistant Clinical Research Manager
• Therapeutic Trials




1 Clinical Research Nurse (40 hrs)
3 Clinical Research Nurses (30 hrs)
2 Senior CRCs
5 CRCs
• Multicenter Trial Staff (shared with BOC)
 1 Project Manager
 1 Clinical Research Specialist/Monitor
• Tumor Banking/Minimal Risk Protocols
 2 Research Data Specialists
• Quality of Life
 1 Research Data Specialist
34