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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)
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
Cancer is complexCancer is complex
FDA approvals in 2014
• Ovarian cancer:1) Bevacizumab (avastin) for recurrent ovarian cancer in combination with chemotherapy2) 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.
Serous
Endometrioid
Mucinous
Clear cell
High grade low grade
High grade low grade
Ovarian cancer is separated into histological categories
• Specific molecular features define these categories and shape clinical trial design: i.e.:
Mucinous tumors: KRAS mutations1
High grade serous cancers: Homologous recombination deficiency (HRD) is common and thus displays high rate of platinum sensitivity2
Low grade serous cancers: KRAS mutations; usefulness of MEK inhibitors
Clear cell cancers: Chemotherapy insensitivity, PIK3CA mutations and sensitivity to VEGFR2 inhibitors3
Serous
Endometrioid
Mucinous
Clear cell
Ovarian cancer:
1Auner, BMC Cancer 20092Bowtell, Nature Rev Ca 20103Kuo et al, Am J Path 2009
1Auner, BMC Cancer 20092Bowtell, Nature Rev Ca 20103Kuo et al, Am J Path 2009
High grade low grade
High grade low grade
Ovarian cancer is separated into histological categories
• Specific molecular features define these categories and shape clinical trial design: i.e.:
Mucinous tumors: KRAS mutations1
High grade serous cancers: Homologous recombination deficiency (HRD) is common and thus displays high rate of platinum sensitivity2
Low grade serous cancers: KRAS mutations; usefulness of MEK inhibitors
Clear cell cancers: Chemotherapy insensitivity, PIK3CA mutations and sensitivity to VEGFR2 inhibitors3
Serous
Endometrioid
Mucinous
Clear cell
Ovarian cancer:
1Auner, BMC Cancer 20092Bowtell, Nature Rev Ca 20103Kuo et al, Am J Path 2009
1Auner, BMC Cancer 20092Bowtell, Nature Rev Ca 20103Kuo et al, Am J Path 2009
High grade
High grade low grade
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 mutations2)Somatic mutations of BRCA gene3)BRCA-independent defects in HR pathway, i.e.
alterations in other DNA repair pathway molecules
1TCGA Nature 20112Nat Rev Cancer 20093BMC Cancer 2008
1TCGA Nature 20112Nat Rev Cancer 20093BMC Cancer 2008
PARP inhibitors in clinical trials for ovarian cancer 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 ongoingFDA conditional approval in 12/2014 and European Approval Fall 2014
Veliparib (ABT-888) PO Phase I combination studiesPhase 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 Examples of Anti-angiogenic agents in clinical trials for ovarian cancer 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 completedFDA 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 anti-angiogenic agent)
• Olaparib + BKM120 (PI3kinase inhibitor)
Phase I/randomized phase II study of olaparib and cediranib
NCT01116648PI: Joyce Liu, MD
Participating sites:Dana-Farber Cancer Institute
Massachusetts General Hospital Beth Israel/Deaconess Hospital
National Cancer Institute
University of Chicago
University of MichiganCedars Sinai Medical Center
Background: cediranib and olaparibBackground: 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 combinationRationale 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 et al., Eur J Cancer 2007, 43(14): 2124-332Hegan et al., PNAS 2010, 107(5): 2201-6
Effect of ced/olap on cell invasion:
Effect of ced/olap on microvascular cell tube organization:
Data courtesy Elise Kohn, NCI/CTEP
Rationale for combinationRationale 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 et al., Eur J Cancer 2007, 43(14): 2124-332Hegan et al., PNAS 2010, 107(5): 2201-6
Effect of ced/olap on cell invasion:
Effect of ced/olap on microvascular cell tube organization:
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
Phase I 3+3dose escalation
design
Dose Level
Cediranib Olaparib
(capsule)
-1 15mg PO daily 100mg PO BID
Starting dose
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
RP2DLiu et al, Eur J of Ca, 2013
Phase I: Dose escalation in recurrent ovarian or metastatic triple-negative breast cancer
Dx:•Recurrent ovarian cancer•Recurrent metastatic triple-negative breast cancer
Phase I 3+3dose escalation
design
Dose Level
Cediranib Olaparib
(capsule)
-1 15mg PO daily 100mg PO BID
Starting dose
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
RP2DLiu et al, Eur J of Ca, 2013
-100
-80
-60
-40
-20
0
20
40
60
80
100
Dose escalation study (3+3 design) of cediranib and olaparib in
recurrent ovarian and triple negative breast cancer
20 ovarian patients (18 RECIST evaluable)
Overall response rate: 44% (8 of 18 pts)
Randomized Ph 2 trial of cediranib/olaparib vs. olaparib in
plat-sens ovarian cancer pts awaiting final analysis
Ovarian cancer pts on study
BRCAm carrierBRCA WT or unknown
Randomized Phase II Study DesignRandomized 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
Presented by: Joyce Liu, MD, MPH
Dx platinum-sensitive recurrent
ovarian cancer
Dx platinum-sensitive recurrent
ovarian cancer
Randomize 1:1Randomize 1:1Cediranib
30mg daily + Olaparib capsules
200mg BID
Cediranib 30mg daily +
Olaparib capsules
200mg BID
Olaparib capsules
400mg BID
Olaparib capsules
400mg BIDDisease
progression by RECIST v1.1
criteria
Disease progression by RECIST v1.1
criteria
NCT01116648NCT01116648Liu 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 et al, Eur J Cancer 2013 2Liu 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 CenterMemorial Sloan Kettering Cancer Center
CONFIDENTIAL SU2C PI3K DREAM TEAM
Supported by SU2Cancer PI3kinase Dream team
Pre-clinical Rationale for combination Pre-clinical Rationale for combination of BKM120 and olaparib of BKM120 and olaparib
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 SU2C PI3K DREAM TEAM
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
1Ibrahim et al, Cancer Discovery 20122Juvekar 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 FoundationPPG 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 ProfilingPI’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 Immunotherapy approaches
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
MPDL3280A
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 cancersMPDL3280A (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 inhibitorsATR and Checkpoint kinase inhibitors
Foukas et al, Ca Treatment Reviews 2014
GDC0575
VX970
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
Gyn Research TeamGyn 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
Clinical Trials Operation