umbrella and basket trials · 2019-03-25 · what is rare may not be rare any more. ... 186...
TRANSCRIPT
Umbrella and Basket Trials
Young Kwang Chae, MD, MPH, MBA
Assistant Professor of Medicine
Co-Director, Developmental Therapeutics
Lurie Cancer Center
Contents
• Background
• Concept of Basket Trial and Examples
• Concept of Umbrella Trial and Examples
• Current and Future Trial Designs
• Lung cancer treatments
(NTRK targeted therapy)
Background
• Next Generation Sequencing
• More Targeted Therapies
• Innovative Clinical Trial Design
• Precision Medicine vs. Treatment designed for average patient
• Personalized Cancer Medicine
Precision Medicine Initiative
Traditional Trial Design
• Phase 1 (dose escalation)
• Phase IB (dose expansion)
• Phase II (non-randomized, randomized)
• Phase III (randomized)
• Histology Based
• Phase 1 (3+3 design)
Drug Development Pathway
Drug Approval
Phase II/III in one
histology
Phase I trial in one histology
Phase I in multiple
histologies
6
Cancer Trials
8
• HER2
• CD30
• B-RAF
• Signature
• NCI-MATCH
Basket Trial
• BATTLE
• LUNG-MAP
• Stand Up to Cancer Melanoma
Umbrella Trial
Traditional Histology Based Trial Histology Agnostic Aberration based Trial
Erika Hurwitz’s cancer of white blood
cells is now undetectable, after she
entered a trial that uses drugs that
block mutations
• BRAF-mutant disease basket trial
with vemurafenib
• Erdheim Chester disease
(polyostotic sclerosing
histiocytosis)
Basket Trials
Across different histologies
What is rare may not be rare any more.
Great for Rare Tumors
Can be marker driven or may not be marker driven
14
Nat Genetics 2013
Rare Tumors
• Definition: annual incidence ≤6 of 100,000, prevalence of ≤200K (Orphan Disease Act)
• Molecular subtypes (Crizotinib in 5% of NSCLC)
• Two third of FDA approval trials non-randomized single arm trials
• 70% of FDA approvals relied on objective response rate as the primary efficacy endpoint.
Gadipatti, CCR, 2012
Basket Trial for Rare Tumors
Navigation Trial
FDA Approval
Trial
Hypothesis Testing
Trial
Imatinib Basket Trial
Hypereosinophilic syndrome/PDGFR (14)
Mastocytosis PDGFR/Kit (5)
MDS/MPD PDGFR (7)
Dematofibrosarcoma protuberans/PDGFR (12)
Heinrich, CCR 2008
186 patients enrolled in 40 diseases Approval in the following:
Vemurafenib basket trial
Colorectal cancer 3%
Ovarian cancer 1%
Breast cancer 1%
Lung cancer 1%
Erdheim-Chester Disease 51%
Others unknown
MEDI4736 (12-179) multiple dose-expansion cohort
Microsatellite unstable tumors
Ovarian HPV+ tumors GBM
SCLC Gastroesophageal HCC Bladder cancer
HNSCC NSCLC TNBC
Immune Checkpoint Inhibitor Basket Trial for Rare Tumors
Navigation
Adaptive Design
Phase II
Approval
No biomarker of consensus Learn as we go model All rare tumors
Biomarker-based DNA repair defect High mutation burden
Basket Trial Molecularly Defined Orphan Diseases
Biomarker-based
Genetic marker positive
Prostate Endometrial Gastroesophageal Ovarian CRC Others
Biology will dictate arm selection.
Baskets in a Basket
The Program
The SIGNATURE program rapidly matches patients to treatments that target their tumor’s molecular abnormality and brings the trial to the patient rather than the patient traveling to a trial
Genetic profiling of tissue sample
Local CLIA certified laboratory
Relapsed/refractory cancer patient
Actionable mutation?
?
1http://www.signaturetrial.com. Accessed May 16, 2014.
Protocol package
• Fixed contract • Central IRB (Quorum) • Standard budget • Standard informed consent
Study open!
• 5.7 weeks vs 34-
week* average
Call center prequalifies the patient: (1) Protocol package sent to site (2) Expedited site visit
When a patient is identified as having an actionable mutation, their oncologist contacts Novartis
1-855-744-6727
How Does the Program Work?
NCI-MATCH scheme
Molecular Analysis for Therapy Choice
NCI MATCH
NCI-MATCH Patient Accrual Thru 04/23/2017
Screened % of Total
Less Common Cancers 2885 61.5% Common Cancers* 1809 38.5%
Total 4694
The trial has far exceeded the goal that 25% of the 6000 patients screened have rare or less common types of cancer
Common cancers screened: Colorectal 15.5%, Breast 12.8%, NSCLC 7.6%, Prostate 2.6%
NCI-MATCH Distribution of ~1100 Participating Sites
• Trial is open and enrolling in every state, DC, and Puerto Rico
NCI-MATCH First 15 of 30 Current Treatment Arms, By Prevalence Rate of Gene Abnormality
Arm Variant Prevalence Rate % Drug Opened Accrual Goal
I PIK3CA 3.47 Taselisib Feb ‘16 70
W FGFR 2.86 AZD4547 May ’16 70
Z1I BRCA1 or BRCA2 2.79 AZD1775 Mar ‘17 35
P PTEN loss 1.93 GSK2636771 Feb ‘16 35
Z1A NRAS 1.90 Binimetinib May ’16 70
S1 NF1 1.77 Mekinist™ Feb ‘16 70
N PTEN 1.75 GSK2636771 Feb ‘16
Z1D dMMR status 1.51 Opdivo® May ‘16 70
Q HER2 amplif. 1.49 Kadcyla® Aug ‘15 70
J HER2 amplif. 1.49 Herceptin® Perjeta® Mar ‘17 35
Z1C CDK4 or CDK6 1.36 Ibrance® Mar ‘17 35
M TSC1 or TSC2 1.11 TAK-228 Mar ‘17 35
B HER2 activating 1.04 Gilotrif® Aug ‘15 70
Z1B CCND1/2/3 0.84 Ibrance® May ‘16 70
R BRAF fusions 0.80 Mekinist™ Aug ‘15 35
NCI-MATCH Remaining 15 of 30 Current Treatment Arms, By Prevalence Rate of Gene Abnormality
Arm Variant Prevalence Rate % Drug Opened Accrual Goal
Y AKT 0.77 AZD5363 May ‘16 35
H BRAF V600 E/K 0.69 Taflinar® Mekinist™ Aug ‘15 35
U NF2 loss 0.69 Defactinib (VS-6063) Aug ‘15 35
C2 MET exon 14 0.61 Xalkori® May ‘16 35
C1 MET amplif. 0.51 Xalkori® May ‘16 35
T SMO/PTCH1 0.42 Erivedge® Feb ‘16 35
L mTOR 0.31 TAK-228 Mar ‘17 35
S2 GNAQ/GNA11 0.16 Mekinist™ Feb ‘16 35
E EGFR T790M 0.11 AZD9291 Aug ‘15 35
V cKIT 0.11 Sutent® Aug ‘15 35
Z1E NTRK 0.10 Larotrectinib Mar ‘17 35
G ROS1 0.05 Xalkori® Aug ‘15 35
A EGFR activating 0.05 Gilotrif® Aug ‘15 35
F ALK 0.03 Xalkori® Aug ‘15 35
X DDR2 0.00 Sprycel® Feb ‘16 35
Levels of Evidence for Target Selection in NCI-MATCH
• Level 1: Gene variant credentialed for selection of an approved drug
• Level 2: Variant is eligibility criterion for an ongoing clinical trial for
that drug OR variant identified in an N of one response
• Level 3: Preclinical inferential data
– Models with variant respond; without variant do not
– Gain of function mutation demonstrated in preclinical model
– Loss of function (tumor suppressor genes or pathway inhibitor e.g.
NF1); stop codon or demonstrated loss of function in pre-clinical
model
Levels of Evidence for Drugs in NCI-MATCH
• Level 1: FDA-approved for any indication for that target
• Level 2: Agent met a clinical endpoint (objective response, PFS, or
OS) with evidence of target inhibition
• Level 3: Agent demonstrated evidence of clinical activity with
evidence of target inhibition at some level
FGFR pathway disruption
FGFR Implicated cancers
FGFR fusions in Lung and Other
Cancers
Capelletti 2014, CCR
Kim 2014, JCO
Anti-FGFR agents in development
Dieci et al. Cancer Discovery 2013
A Phase II Study of AZD4547 in Patients with Tumors with Aberrations in the FGFR Pathway Molecular Analysis for Therapy Choice (MATCH) Arm WYoung Kwang Chae, Christos Vaklavas, Heather H. Cheng, Fangxin Hong, Lyndsay Harris, Edith Mitchell, James Zwiebel, Larry Rubinstein, Lisa McShane, Robert Gray, Shuli Li, Percy Ivy, Sherry Ansher, Stanley Hamilton, Mickey Williams, David Patton, James Tricoli, Carlos Arteaga, Barbara Conley, Peter O'Dwyer, Alice Chen, Keith Flaherty
1Young Kwang Chae
Waterfall plot of best responses
16
No. of patients
(% among
evaluable)
PR 4 (9.5)
SD 20 (47.6)
PD 18 (42.9)
Not
evaluable
8
Total 50
Young Kwang Chae
38 cases on the plot (8, unevaluable; 5, PD due to new lesions without target lesion measurements
Molecular characteristics of PR cases
Disease site Variant Response PFS
Intrahepatic
cholangiocarcinoma
FGFR2
Y375C
69% 334
days
Transitional
cell/urothelial
carcinoma of renal
pelvis
FGFR3-
TACC3.F17T8
70% 304
days
Squamous cell
carcinoma of cervix;
p16+, HPV ISH+, HPV-associated
FGFR3-
TACC3.F17T11
33% 156
days
Transitional cell
carcinoma of bladder
FGFR3
A391
35% 166
days
17
Amp SNV Fusion Total
PR 0 2 2 4
SD 10 5 5 20
PD 7 9 2 18
Not
Eval 4 4 0 8
Total 21 20 9 50
Young Kwang Chae
Swimmer plot of duration of treatment
• Treatment duration for 24 patients who achieved PR (n=4) and SD (n=20).
• 5 cases with PFS times > 168 days (5.5 months; 168=28*6): 2 PRs and 3 SDs
• 2 PRs: Intrahepatic cholangiocarcinoma (FGFR2 Y375C), Transitional cell/urothelial carcinoma of renal pelvis (FGFR3-TACC3.F17T8)
• 3 SDs: Mucinous adenocarcinoma of colon (FGFR1 Amp), Epithelial-myoepithelial carcinoma of parotid/submandibular gland (BAG4-FGFR1.B2F6), Transitional cell carcinoma of renal pelvis (FGFR3 S249)
18Young Kwang Chae
The colored triangle marked when PR started (blue) or PD reported (yellow).
How can we do better?
How to Select Best Patients?
(Optimal Biomarker)
How to Reduce Screen Failure? (Basket Trial & Umbrella Trial)
How to Overcome Resistance?
(Rational Combiation)
NCI MATCH & SWOG DART
DART: Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors
Young Chae, MD, MPH, MBA Assistant Professor
Vice Chair, SWOG Early Therapeutics and Rare Cancers Committee
Co-Director Developmental Therapeutics Lurie Cancer Center
Northwestern University
Razelle Kurzrock, MD Professor
Chief, Division of Hematology, Medical Oncology
Chair, SWOG Early Therapeutics and Rare Cancers Committee UCSD Moores Cancer Center
Sandip Patel, MD Assistant Professor
Deputy Director, San Diego Center for Precision Immunotherapy
UCSD Moores Cancer Center
The Cancer Letter 2017
Rare Tumors Basket Study
SWOG DART Treatment/ Schema
• Basket study in rare tumors • Concurrent Combination Immunotherapy:
Ipilimumab 1 mg/kg IV every 6 weeks and nivolumab 240mg IV (fixed dose) every 2 weeks – Nivolumab monotherapy permitted for patients who experience severe immune-related toxicity on combination
ipilimumab/nivolumab
• Treatment cycle length: 6 weeks
• Imaging assessments: q8 wks until Wk 25, then q12 weeks until 3 years
Ipilimumab 1mg/kg IV q6wks
Nivolumab 240mg IV q2wks
PD, unacceptable toxicity, or withdrawal of consent
• Sample size = Minimum 50 pts. / 31 histologic cohorts + unknown primary + NOC cohort (Coordinated referral/accrual strategy from MATCH – MATCH screening/treatment failures that meet accrual criteria will be offered DART therapy at time of screen failure/discontinuation of last eligible MATCH therapy). o Accrual to cohorts will be monitored by SWOG/NCI monthly o Approximately 20% of NCI-MATCH patients met histologic criteria
• Two Stage Design: 87% power with a one-sided alpha of 13% in
each subtype o First stage: 6 eligible patients per histologic subtype • If no response is observed, accrual to that histologic subtype will be
permanently closed. • If ≥ 1 response is observed, an additional 10 patients will be accrued
in the second stage. o Second stage: 2 or more responses out of 16 will be considered
evidence that the combination regimens warrants further study in the histologic subtype • With 16 eligible patients in a histologic subtype, any toxicity with at least
a 10% chance of occurring has an 81% chance of being observed at least once.
Statistical Considerations
DART Activated: 1/13/17; First Patient Treated: 1/30/17
As of 3/16/2019:
• 875 sites approved to enroll through CTSU
• Total enrollment: 560 patients
• 37 Cohorts originally
• 53 cohorts in upcoming amendment 5 including PD-L1 amplified cohort
DART To Date
Potential outcomes
• New treatment options
• New FDA approval
• New NCCN guideline treatment options
• Neuroendocrine carcinoma of any histology origin
• Adrenal Cortical Carcinoma, etc.
Precision Immuno-oncology PD-L1 IHC Immune biomarkers Germline DNA
sequencing
Proteomic immune
signature
cDNA sequencing Tumor DNA/RNA
Performing Lab CIMACs CIMACs Counsyl Biodesix Circulogene MatchBox and CIMACs
WES/RNASeq
Sample source Tumor tissue (FFPE) or
unstained slide
Blood in collected in Tempus
tubes
(one 2cc vial for RNA, another
2cc vial for DNA)
Blood collected in the
EDTA tube
Blood collected in
the EDTA tube
Blood collected in the
EDTA tube
Tumor tissue (FFPE)
collected as part of NCI-
MATCH
Biomarker Target PD-L1 protein expression
by 28-8 IHC analysis
DNA, RNA sequencing 0of
tumor tissue and blood
Leukocyte DNA
sequencing (Illumina)
Serum proteins Cell free DNA sequencing
(Illumina)
Tumor next-generation
sequencing
(Ion Torrent)
Specimen Estimate 150 (baseline tissue) 240 (baseline blood) 240 (baseline blood) 240 (baseline
blood)
240 (baseline blood) 300 (baseline tissue)
Biomarker output PD-L1 strata will be
grouped <1%, 1-5%, 6-
25%, 26-49%, >50%
Immune and Cancer pathway
Nanostring (gene expression of
770 genes assaying 24 immune
cell types and 500 immune
response genes)
Genetic alteration Predictive
signature (good,
intermediate, poor
group)
Genetic alteration and
mutational load
Genetic alteration and
mutational load
Statistical Considerations Binary endpoint by strata Log-expression Categorical variable Categorical variable Percentile rank of
mutational load
Percentile rank of
mutational load
Sample time points Tissue: Baseline Tissue: baseline
Blood: DNA and RNA at three
time points
Blood at baseline Blood: at three
time points
Blood: at three time
points
Tissue: baseline
Other Innovative Trial Designs
• Continuous Reassessment Method (CRM)
• Efficacy-Toxicity Method (EffTox)
• Seamless Phase 1/2/3 Design with interim analyses
• Octopus Design (multiple histology/dose/regimen arms in phase ½ trial)
• Platform Based (BATTLE, I-SPY, MATCH, Lung-MAP)
NTRK as a target
NTRK fusion across tumor types
NRTK fusion assays
NRTK and lung cancer
NTRK 1 & 3 0.23% of all lung cancers
Current NTRK inhibitors
• Larotrectinib (US FDA approval for all tumors including lung cancer with NTRK 1/2/3 fusions. Nov. 2018): ORR = 75% (22% CR and 53% PR), DOR >12 months = 39%
• Entrectinib
• LOXO-195
• TPX-0005
Take Home Message
• Histology agnostic basket trials or histology & pathway based umbrella trials are new innovative ways to develop treatments for many “molecular orphan diseases”.
• Upfront or timely NGS testing is recommended to explore actionable genomic alterations.
• NRTK fusions are found to be a new target in many cancers including lung cancer.