Download New Trisomy 8

Beat AML Umbrella Study
A new effort to rapidly transition
effective new patient friendly
therapeutics for AML therapy that
greatly impact patient’s lives
AML: The Disease
Most common adult leukemia (20,830 cases in 2015, median age 67 years)
Diagnosis
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Average age of patient with AML is 67 years old
Symptoms include bruising, fatigue, infections, and/or headache with sub-acute presentation
Standard therapy (7/3 cytarabine/daunorubicin followed by consolidation or allogeneic
stem cell transplant) resulting in hospitalization 1-6 months; has not changed
Until recently, classified predominately by metaphase cytogenetics and select mutations
with some potentially targetable [MLL rearrangements and CBF leukemia]
Growing number of gene mutations identified that offer potential for targeted therapy
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Relatively small number per case (average 7 with approximately 100 common variants)
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Significant differences between cases with co-mutational patterns
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Groups of mutations converge on common mechanisms of transformation (TET/IDH/WT1)
Relapse represents more complex mixture of disease
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Presence of pre-existence and/or evolution of resistant subsets within single AML patient
making ability to target “one disease” unlikely
Outcome for ALL AML Patients with Standard Therapy Not Good
Age 60 and
> worse
10 yr DFS
Byrd JC and Bloomfield CD: unpublished Alliance data
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Two Pt Groups with Extended Overall Survival With Chemotherapy
Shorter Follow Up
CBF AML
Sherif S. Farag et al. Blood 2006;108:63-73
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NPM1 Mutated/FLT3 WT
Heiko Becker et al. JCO 2010;28:596-604
Little Change in AML Treatment: How Can We Accelerate This?
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Lack of change in treatment options is not due to a lack of resources or interest although
NO agents approved by FDA for AML since 2nd generation athracyclines
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Heterogeneous disease with a growing number of mutations makes it difficult to develop
treatments which work for all AML patients regardless of genotype (i.e. herceptin story)
with rare exception (we are not giving up on the gleevac or ibrutinib for AML)
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AML until recently has lead sequencing efforts, although clinical translation of this is still
needed. Low frequency of mutations does allow more sophisticated assessment of driver
clone and subclones for choice of therapy
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Majority of patients with AML relapse and at this time have impaired immune system and
also sequencing studies show much more diversity in driver and subclones
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Drug development in AML has often focused on AML as a common disease and also in the
setting of relapse
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History tells us that even active drugs (azacitidine, decitabine, clofarabine) have minimal
or no activity in relapse
Lets do something different
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RATIONAL FOR MASTER TRIAL CONCEPT IN AML
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Overall intent to yield measurable efficiencies in terms of
• Improving genomic screening of AML patients at the time of clinical trial entry
• Feasibility of 7 day waiting period while genomic studies completed
• Assign therapy on basis of molecular marker targetable with a novel agent
• Different from other studies, also incorporate a marker negative arm so all patients are
offered a opportunity to gain benefit
• Improved timelines for drug biomarker testing of targeted agent and adaptation
• Use chemotherapy only when benefit demonstrated (NPM1 mut/FLT3 wt; CBF AML)
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Multi-arm master protocol
• Each arm independent from one another with consistent eligibility
• Provide network for junior and senior AML clinical investigators to lead trials
• Window design allows for testing of “large effects”
• Focus initially on age >60 years as this group does poorly with 7/3 chemotherapy
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Designed to facilitate FDA approval of new drugs where big effects are observed
Schematic Study Design
Phase 2, newly diagnosed AML patients, > 60 yrs
Assign
Treatment
by Marker
Targeted Agent→ Add HM
(decitabine or azacitidine) if no
response
or
Targeted agent + HM
Patient
Registration
Consent
Bone
Marrow
Sample
Chemo Responsive
Definitely: CBF AML
Maybe: NPM1+/FLT3-
Genomic Screening
< 1 Week (7 days)
Less Responsive
Other groups
Primary Endpoint: CR, CRp, PR
with establishment of normal cts
Durability important
7 + 3 chemotherapy and
Targeted agent
Co-primary Endpoint: CR; 2-yr DFS
Extensive correlative studies
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Potential Treatment Groups and How To Get Involved
Genetic Group*
CBF
NPM1 only mut
MLL re-arrangement or MLL-PTD
IDH1 mut
IDH2 mut
TP53 mut/Complex karyotype
FLT3 ITD/TKD ut
TET2, WT1 and IDH1/2 mutant
(hypermethylation group)
RAS/PTPN11/PTEN mut
Marker Neg
Other Groups may be added
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The Leukemia & Lymphoma Society (LLS) is seeking
clinical sites to participate in a Master Clinical Trial for
acute myeloid leukemia (AML) patients based on a
personalized medicine approach.
If your institution is interested, contact Amy Burd.
[email protected]
Along the Way to a Trial (Jan 2015-current)
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Establish purpose of WHY we are doing this study
Partnership with FDA on how best to proceed (multiple interactions)
Identifying AML patients that are appropriate for (NCTN Group data)
Listening to what patients want (FDA and LLS patient meeting)
Identifying molecular vendor for testing
Attracting and collaborating with industry partners in novel trial
design and cost model relative to industry standards
Identifying a CRO to coordinate novel study
Compiling both master protocol and also sub-protocols
Identifying an ideal biorepository
Identifying second generation of clinical sites
Fundraising to fulfill LLS commitment to this effort
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What We Have Learned
• Attitude in disease field to this type of study is mixed but NCI, ASH,
FDA, and industry have been highly cooperative and collaborative
• Biomarker assessment and group stratification is not straight forward
– Variant allele frequency prioritization versus targetable lesion?
– When variant allele frequency not easy (FLT3-ITD)?
– Desire to be inclusive to most patients by marker negative group versus having a
true distinct molecular group
– Incorporation of different technologies often difficult (NGS, mRNA, cytogenetics)
• Obtaining single central IRB oversight outside of an NCI study not
always easy but essential to assure appropriate transition of study
• Model of de-emphasizing credit to any individual as part of bylaw has
helped this move forward at quick pace (Jan 2015-current)
• As study develops, more targets for specific arms become apparent
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Acknowledgement
• Principals
– Amy Burd PhD
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Ross Levine MD
Brian Druker MD
John C. Byrd MD
• Clinical Investigators
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William Blum MD
Alice Mims MD, MS
Martin Tallman
Eytan Stein MD
Richard Stone MD
Jacqueline Garcia MD
Amir Fathi MD, PhD
Uma Borate MD
Elie Traer MD, PhD
• Statisticians
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Abigail Shoben, Abigail PhD
Amy Stark MS
Investors in A New Vision for Acute
Myeloid Leukemia Treatment
Food and Drug
Administration
American Society of Hematology
Industry Collaborators and vendors