1. Beat AML Umbrella Study
A new effort to rapidly transition effective new patient friendly therapeutics for AML therapy that greatly impact patient’s lives

2. AML: The Disease
Most common adult leukemia (20,830 cases in 2015, median age 67 years)
Diagnosis
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
Relatively small number per case (average 7 with approximately 100 common variants)
Significant differences between cases with co-mutational patterns
Groups of mutations converge on common mechanisms of transformation (TET/IDH/WT1)
Relapse represents more complex mixture of disease
Presence of pre-existence and/or evolution of resistant subsets within single AML patient making ability to target “one disease” unlikely 2

3. 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Byrd JC and Bloomfield CD: unpublished Alliance data

4. Two Pt Groups with Extended Overall Survival With Chemotherapy
Shorter Follow Up
CBF AML
NPM1 Mutated/FLT3 WT
Sherif S. Farag et al. Blood 2006;108:63-73
Heiko Becker et al. JCO 2010;28:

5. Little Change in AML Treatment: How Can We Accelerate This?
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
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)
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
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
Drug development in AML has often focused on AML as a common disease and also in the setting of relapse
History tells us that even active drugs (azacitidine, decitabine, clofarabine) have minimal or no activity in relapse
Lets do something different

6. RATIONAL FOR MASTER TRIAL CONCEPT IN AML
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)
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
Designed to facilitate FDA approval of new drugs where big effects are observed

7. Schematic Study Design
Phase 2, newly diagnosed AML patients, > 60 yrs
Targeted Agent→ Add HM (decitabine or azacitidine) if no response or
Targeted agent + HM
Assign Treatment by Marker
All others
Patient Registration Consent
Bone Marrow Sample
Primary Endpoint: CR, CRp, PR with establishment of normal cts
Durability important
Genomic Screening
< 1 Week (7 days)
Chemotherapy Benefit Marker
7 + 3 chemotherapy and
Targeted agent
Chemo Responsive Less Responsive
Definitely: CBF AML Other groups
Maybe: NPM1+/FLT3-
Co-primary Endpoint: CR; 2-yr DFS
Extensive correlative studies

8. 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
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.

9. Along the Way to a Trial (Jan 2015-current)
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

10. 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

11. Acknowledgement Principals Amy Burd PhD Clinical Investigators
Ross Levine MD
Brian Druker MD
John C. Byrd MD
Clinical Investigators
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
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