Conditions: Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
This phase Ib/II trial studies the best dose and side effects of avelumab when given together with azacitidine and to see how well they work in treating patients with acute myeloid leukemia that is not responding to treatment or has come back. Monoclonal antibodies, such as avelumab, may interfere with the ability of cancer cells to grow and spread. Azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving avelumab and azacitidine may work better in treating patients with acute myeloid leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of avelumab in combination with azacitidine (5-azacytidine) in patients with refractory/relapsed acute myeloid leukemia (AML). (Phase IB)

II. To determine the overall response rate (ORR) defined as complete remission (CR)/complete remission with incomplete platelet recovery (CRp)/complete remission with incomplete count recovery (CRi)/partial remission (PR)/hematologic improvement (HI)/morphologic leukemia free state (MLFS) of avelumab in combination with 5-azacytidine in patients with refractory/relapsed AML. (Phase II

SECONDARY OBJECTIVES:

I. To determine the number of patients achieve \> 50% reduction in blasts on therapy with this combination.

II. To determine the duration of response, disease-free survival (DFS), and overall survival (OS) of patients with refractory/relapsed AML treated with this combination

TERTIARY OBJECTIVES:

I. To study immunological and molecular features at baseline and at predefined time-points on-therapy with avelumab and azacytidine in the peripheral blood and bone marrow to include quantify immune ligand expression by the AML blasts and AML stromal components (myeloid-derived suppressor cells \[MDSCs\] and mesenchymal stem cells \[MSCs\]) including 4-1BBL, ICOSL, PD-L1, PD-L2, OX-40L, CD137L.

II. To study immunological and molecular features at baseline and at predefined time-points on-therapy with avelumab and azacytidine in the peripheral blood and bone marrow to determine the quantitative expression of positive and negative co-stimulatory molecules on individual T-lymphocyte subsets including 4-1BB, CTLA-4, ICOS, PD-1, OX40, LAG-3 and TIM-3.

III. To study immunological and molecular features at baseline and at predefined time-points on-therapy with avelumab and azacytidine in the peripheral blood and bone marrow to identify the immunophenotype of tumor-infiltrating T-lymphocytes (TILs) pre- and post-therapy with the combination: CD8+, CD4+ effector, or CD4+ regulatory.

IV. To develop a micro-array based gene expression profile (GEP) predictor of response to anti-PDL1 and epigenetic therapy in AML.

V. To determine the correlation of responses to the combination with baseline cytogenetic and molecular abnormalities

OUTLINE: This is a phase Ib, dose-escalation study of avelumab followed by a phase II study

Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 10-40 minutes on days 1-7 or on days 1-5 and 8-9. Patients also receive avelumab IV over 60 minutes on days 1 and 14 for 4 courses (or until complete response) and on day 1 for subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity

After completion of study treatment, patients are followed up every 3-6 months for up to 5 years.

Arms:
arm 1: Patients receive azacitidine SC or IV over 10-40 minutes on days 1-7 or on days 1-5 and 8-9. Patients also receive avelumab IV over 60 minutes on days 1 and 14 for 4 courses (or until complete response) and on day 1 for subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Avelumab intervention 2: Azacitidine intervention 3: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given SC or IV intervention 3: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
Protocol Page
An Open-label Phase Ib/II Study of Avelumab in Combination with 5-azacytidine 
(Vidaza) for the Treatment of Patients with Refractory/Relapsed Acute Myeloid 
Leukemia
2016-0444
Core Protocol Information
Short Title 
Avelumab (antiPDL1) and azacytidine in AML
Study Chair: 
Naval Daver
Additional Contact:
Dana E. Brown
Vicky H. Zoeller
Leukemia Protocol Review Group
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
None
Study Staff Recipients
None
Department:
Leukemia
Phone:
713-794-4392
Unit:
428
Study Manager:
Cora M. Cheung
Full Title: 
An Open-label Phase Ib/II Study of Avelumab in Combination with 5-
azacytidine (Vidaza) for the Treatment of Patients with 
Refractory/Relapsed Acute Myeloid Leukemia
Public Description:
N/a
Protocol Type:
Standard Protocol
Protocol Phase:
Phase I/Phase II
Version Status:
Terminated 10/03/2019
Version:
15
Document Status:
Saved as "Final"
Submitted by:
Dana E. Brown--8/13/2019 10:24:00 AM
OPR Action:
Accepted by:  Elaine Kramer -- 8/22/2019 9:13:02 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol Body
 
  


 
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An Open-label Phase Ib/II Study of Avelumab in 
Combination with 5-azacytidine (Vidaza) for the Treatment 
of Patients with Refractory/ Relapsed Acute Myeloid 
Leukemia  
  
 
 
 
 
Principal Investigator: Naval Daver, M.D.  
Co-PI: Dr Jorge Cortes, M.D. 
Sponsor: University of Texas, MD Anderson Cancer Center 
IND number: 131967 
  
 
University of Texas 
  
MD Anderson Cancer Center 
Leukemia Department, Unit 
428 
 
 
 
 
 
 


 
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1.1 
OBJECTIVES 
1.2 
Primary Objectives  
Part a. Phase IB 
To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of 
avelumab in combination with 5-azacytidine in patients with refractory/ relapsed acute 
myeloid leukemia (AML). 
 
Part b. Phase II 
To determine the overall response rate (ORR) defined as complete remission (CR/complete 
remission with incomplete platelet recovery (CRp/complete remission with incomplete count 
recovery (CRi)/partial remission (PR)/hematologic improvement (HI)/morphologic leukemia 
free state (MLFS) of avelumab in combination with 5-azacytidine in patients with refractory/ 
relapsed AML. 
 
1.3 
Secondary Objectives: 
1. To determine the number of patients who achieve > 50% reduction in blasts on therapy 
with this combinaiton.  
2. To determine the duration of response, disease-free survival (DFS), and overall survival 
3. (OS) of patients with refractory/ relapsed AML treated with this combination. 
 
1.4 
Exploratory Objectives: 
1. 
To study immunological and molecular features at baseline and at predefined time-points 
on-therapy with avelumab and azacytidine in the peripheral blood and bone marrow to 
include (a) quantify immune ligand expression by the AML blasts and AML stromal 
components (MDSCs and MSCs) including 4-1BBL, ICOSL, PD-L1, PD-L2, OX-40L, 
CD137L and (b) determine the quantitative expression of positive and negative co-
stimulatory molecules on individual T-lymphocyte subsets including 4-1BB, CTLA-4, 
ICOS, PD-1, OX40, LAG-3 and TIM-3, and (c) identify the immunophenotype of tumor-
infiltrating T-lymphocytes (TILs) pre- and post-therapy with the combination: CD8+, 
CD4+ effector, or CD4+ regulatory.  
 
2. 
To develop a micro-array based gene expression profile (GEP) predictor of response to 
anti-PDL1 and epigenetic therapy in AML.  
 
3. 
To determine the correlation of responses to the combination with baseline cytogenetic 
and molecular abnormalities. 
 
2.1 
BACKGROUND 
 
2.1.1   Acute myeloid leukemia 
Approximately, 30-40% of adults with AML fail to achieve CR with 1 or 2 cycles of induction 
chemotherapy, and are deemed primary refractory. The outcomes of patients with acute 
myeloid leukemia (AML) who are refractory to induction therapy are dismal, with low 


 
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response rates to salvage chemotherapy and poor long-term survival 1-3. We have previously 
reported a dismal median OS of 3.8 months for patients with AML who are refractory to 
HiDAC-containing induction therapy (defined as ≥ 1gm/m2 cytarabine per dose)2. Salvage 
therapy in such patient populations yielded a response rate of 18% and median response 
duration of 9 months.  
 
These results emphasize the need to explore alternate salvage regimens for patients with 
relapsed/refractory AML. The development of novel and effective anti-AML agents and/or 
combinations is crucial to improving the outcome of AML. 
 
2.1.2   Relapsed/Refractory AML: 
Therapy for AML has improved only modestly over the last 4 decades. Traditional induction 
chemotherapy produces cure rates of 30% in adults with AML4-6. Patients with relapsed AML 
have an overall survival of 1 to 4 months with current salvage therapy2,7. We have previously 
reported a dismal median OS of 3.8 months for patients with AML who are refractory to 
HiDAC-containing induction therapy (defined as ≥ 1gm/m2 cytarabine per dose). Salvage 
therapy in such patient populations yielded a response rate of 18% and median OS of 4.5 
months. The preliminary data from investigators in our group8 and from others9,10 suggest that 
immune therapies may be a crucial third modality in combination with cytotoxic and/or 
targeted molecular therapy to produce deeper and/or more durable responses in AML and 
MDS.  
These results emphasize the need to explore alternate salvage regimens for patients with 
relapsed/refractory AML. The development of novel and effective anti-AML agents and/or 
combinations is crucial to improving the outcome of AML. 
 
2.1.3   Role of PD-1/PD-L1 interactions in AML 
It is well known that negative regulatory mechanisms within the solid tumor microenvironment 
inhibit antitumor T-cell function. Proteins produced by the tumor cells often inhibit the anti-
tumor activity of the microenvironment by altering immune cells contained within the 
microenvironment and by recruitment of immune-suppressor cells to that microenvironment. 
One inhibitory mechanism is up-regulation of programmed death-ligand 1 (PD-L1) expressed 
on tumor or stromal cells, which binds to programmed death-1 (PD-1) on activated T cells11-14. 
PD-1/PD-L1 engagement results in diminished antitumor response by producing a state of 
exhaustion for tumor-infiltrating cytotoxic T-lymphocytes (CTLs).  PD-L1 expression is 
associated with poor prognosis in many cancers, including those of the lung, stomach, colon, 
breast, cervix, ovary, renal cell, and liver, as well as in adult T-cell leukemia, glioma, and 
melanoma15-17. Interaction between PD-L1 and PD-1 plays an important role in controlling 
immune responses and is involved in peripheral tolerance, autoimmunity, allergy, infection, 
and antitumor immunity15,18. 
 
The PD-1/PD-L1 pathway plays a major role in immune evasion and cytotoxic T-cell 
exhaustion in hematologic malignancies including AML and MDS9,19,20. Garcia-Manero et al 
identified ≥ 2-fold expression of PD-L1 in 34% of patients with AML or MDS20. Chen et al 
found increased expression of PD-L1 at AML progression, which was an independent negative 
prognostic factor for French-American-British type M5 AML21. Similarly, Zhou et al have 
demonstrated that AML progression in a murine model is associated with elevated PD-1 


 
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expression on CTLs and increased T-regulatory cells at the tumor site10. Both these mechanism 
decrease CTL activity at the tumor site. Elevated PD-1 expression independently dampens the 
anti-leukemic effect of CTLs. T-regulatory cells (Tregs) further suppress CTL activity and this 
suppression depends on PD-1 expression by Tregs and PD-L1 expression by antigen-presenting 
cells. Anti-PD-L1 monoclonal antibody treatment increased the proliferation and function of 
CTLs at tumor sites by reducing the interaction between PD1 and PDL1 resulting in decreased 
Treg-mediated suppression of CTLs. The enhanced CTL activity resulted in reduced AML 
tumor burden, and resulted in long-term murine survivors.  
 
2.1.4    PD1, PDL1, OX40 and other costim receptor expression in AML (Data from MDACC)  
The expression of co-stimulatory (costim) receptors/ligands in the BM and peripheral blood PB 
in patients with AML has not been clearly defined. To define the immune landscape of AML 
we performed 17-color multi-parametric flow-cytometry (MFC) on BM aspirates from 36 
untreated AML and 39 relapsed AML between March, 2015 and January 2016 to assess the 
expression of costim ligands (4-1BBL, B7-1, B7-2, ICOSL, PDL-1, PDL-2, OX40L) on 
leukemic blasts and the costim receptors (4-1BB, CTLA-4, ICOS, PD-1, OX40, GITR, LAG-3, 
TIM-3) on T cell subsets: CD4 T effector cells [Teff]: CD3+CD4+CD127lo/+Foxp3-, CD4 T 
regulatory cells [Treg]: CD3+CD4+CD127-Foxp3+, and CD8 T cells: CD3+CD8+. Eight healthy 
human BMs were used as control. See figure 1 for T-cell population distributions. Blasts and 
T-cells were evaluated at the same time-point. OX40 and PD-1 TILs were significantly higher 
in untreated AML BM as well as relapsed AML BM as compared to healthy donor BM (Figure 
2 and 3). AML patients had significantly increased OX40+ TILs as compared to healthy 
control marrow across all three lymphocyte subsets including CD4 effector, T regs, cytotoxic 
CD8+ cells. Similarly AML patients had significantly increased PD1+ TILS as compared to 
healthy control BMs across all three lymphocyte subsets. Furthermore, PD1+ and OX40+ TILs 
were significantly higher in relapsed AML BM as compared to newly diagnosed untreated 
AML (Daver N, Sharma P et al., AACR April 2016, poster attached). There were no 
noteworthy differences in ligand expression patterns between relapsed AML and new AML. 
There was significant variability in 
BM expression of costim  
 
Figure 1. T-
cell subpopulations in 
AML pts 
(n=75) versus healthy donors (n=8) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
**
**
0
2
4
6
8
10
50
100
150
% cells expressing marker indicated
**
***
**P < 0.006
CD3+
CD4+Teff
Treg
CD8+
New
Relapse
Normal
* P < 0.05
*** P < 0.0005
**


 
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Figure 2: PD1 receptor in AML pts (n=75) vs healthy donors (n=8) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3: OX40 receptor in AML pts (n=75) vs healthy donors (n=8) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
receptors and 
ligands between 


 
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individual pts. The expression of costim receptors and ligands differed significantly between 
BM and PB from the same time-point in the same pt. A larger sample size is needed to confirm 
these data and find additional associations and this is currently underway at our institution. 
These data have been presented at AACR (Daver N, Sharma P et al. “Defining the Immune 
Landscape in AML”, AACR April 2016) and further support the evaluation of anti-PD1/PDL1 
based therapies in AML. 
 
Dr Garcia-Manero from our group analyzed 124 patients with MDS/AML and noted that 
patients with lower PD-L1 expression had a non-significant trend toward better OS (31.5 
versus 16.2 months, P=0.24)8. Patients with a greater degree of up regulation of these 
checkpoint molecules had a higher propensity of resistance to epigenetic therapy and a trend to 
inferior survival. Bone marrow samples from healthy donors were used as control for these 
studies. Another confirmation of the negative impact of PDL1 overexpression in patients with 
AML was obtained by interrogating the NEJM TCGA data by cBioportal. Patients with AML 
who had increased PDL1 mRNA had an inferior OS. 
 
2.1.5    Role of DNA methyltransferase (DNMT) inhibitor (decitabine) in immune regulation 
These findings in the baseline BM samples in AML patients (especially in relapsed AML) 
support our planned clinical trials of PD-L1 checkpoint blockade with avelumab in 
combination with decitabine in patients with AML. However, the clinical exigency of AML 
requires that chemotherapy and/or targeted therapy must be used as well, so it is necessary to 
consider how these may affect immune parameters. Dr. Garcia-Manero found that gene 
expression of PD-L1, PD-L2, and PD-1 were up regulated (≥2-fold) in >50% of 61 evaluable 
MDS/AML patients during their first course of DNMT inhibitor therapy8. There was a trend 
toward increased expression of all 3 genes in DNMT-inhibitor resistant patients compared with 
sensitive patients, suggesting up-regulation of immune makers as a mechanism of resistance to 
DNMT-inhibitor. These findings were confirmed in AML cell lines where decitabine (but not 
cytarabine at any concentration) induced dose-dependent up-regulation of PD-1 and PD-L1. 
These data suggest that concomitant inhibition of the PD-1/PD-L1 axis and potentially 
modulation of other checkpoint pathways may abrogate or overcome resistance to DNMT-
inhibitors (basis of this clinical trial). Furthermore, recent data shows that decitabine increases 
NK-cell activating receptor ligands (NKG2DL) and enhanced ADCC when administered in 
combination with CD33-targeting antibody with preserved FCγIIIa domain (Vasu et al, Blood 
May 2016 and Daver N, Ravandi F et al, Blood May 2016). In addition to azacytidine’s impact 
on T-cells costimulatory receptor and blast ligand expression we hope to further enhance the 
synergy by promoting ADCC by combining an epigenetic agent (azacytidine) with the ADCC 
inducing agent avelumab (also has a preserved FC domain to engage and activate NK cells). 
 
2.1.6    Avelumab  
Because of the known role of programmed death ligand 1 (PD-L1) in the suppression of T cell 
responses and the strong correlation between PD-L1 expression and prognosis in cancer, the 
blockade of the PD-L1/programmed death 1 (PD-1) interaction presents a highly promising 
strategy for cancer immunotherapy. 
Avelumab binds PD-L1 and blocks the interaction between PD-L1 and PD-1. This removes the 
suppressive effects of PD-L1 on anti-tumor CD8+ T cells, resulting in the restoration of 
cytotoxic T cell response. 


 
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T he acti ve p har mace utical i n gre die nt i n a vel u ma b dr u g pr o d uct i s a f ull y h u ma n a nti b o d y 
(calc ulate d m olec ular wei g ht of 1 4 3 8 3 2 Dalt o n) of t he i m m u n o gl ob uli n G (I g G) 1 is ot y pe t hat 
s pecificall y tar gets a n d bl oc ks P D- L 1, t he li ga n d f or P D- 1. 
 
N o ncli nic al p h ar m ac ol o g y 
T he n o ncli nical p har mac ol o g y st u di es ha ve s h o w n t hat a vel u ma b f u ncti o nall y e n ha nces T cell 
acti vati o n i n vitr o a n d si g nifica ntl y i n hi bits t he gr o wt h of P D - L 1 e x pressi n g t u m ors i n vi v o. 
 
A vel u ma b bi n ds t o h u ma n P D- L 1 wit h a hi g h affi nit y of 0. 7 n M a n d n ot t o a n y ot her B 7 fa mil y 
pr otei ns, a n d c o m petiti vel y bl oc ks  t he i nteracti o n of P D- L 1 with P D- 1. T he i n vitr o st u d y 
res ults ha ve s h o w n t hat b y bi n din g t o P D- L 1, a vel u ma b effecti vel y e n ha nces T cell acti vati o n 
as meas ure d b y i nterle u ki n (I L)- 2 or i nterfer o n- ga m ma (I F N-
 pr o d ucti o n. I n a d diti o n, as a 
f ull y h u ma n I g G 1 a nti b o d y, a vel u ma b has t he p ote ntial t o tri g ger t he a nti b o d y- depe n de nt cell-
me diate d c yt ot o xicit y( A D C C) a ga i nst tar get cells e x pressi n g P D- L 1. 
 
As a m o n ot hera p y, a vel u ma b has de m o nstrate d a nti-t u m or acti vit y  a gai nst m uri ne M C 3 8 c ol o n 
carci n o ma t u m ors t hat are c har acterize d b y a hi g h le vel of P D- L 1 e x pressi o n. A d ose-
de pe n de nt tre n d was o bser ve d, a n d 4 0 0 μ g per d ose ( 2 0 m g/ k g, a p pr o xi matel y) was i de ntifie d 
as t he o pti mall y effecti ve d ose w h e n gi ve n e ver y t hir d da y f or 3 t otal d oses. 
 
T he i n vi v o a nti-t u m or effects were f o u n d t o be pri maril y me dia te d b y C D 8 + T cells as 
e vi de nce d b y t he o bser vati o n t hat  i n vi v o de pleti o n of t his cell t y pe c o m pletel y a br o gate d t he 
a nti-t u m or efficac y of a vel u ma b. T he c o ntri b uti o n of A D C C as a p ote ntial mec ha nis m of a nti-
t u m or acti vit y was f urt her de m o nstrate d i n vi v o usi n g a de gl yc os ylate d versi o n of a vel u ma b t o 
a br o gate fra g me nt cr ystalli ne ( Fc) rece pt or bi n di n g or via t he s yste mic de pleti o n of nat ural 
killer ( N K) cells. I n b ot h setti n gs, l oss of i n vi v o A D C C p ote n tial si g nifica ntl y re d uce d t he 
a nti-t u m or acti vit y. 
 
T he c o m bi nati o n of a vel u ma b wit h c o m m o nl y use d ca ncer treat me nt s, s uc h as c yt ot o xic a ge nts 
a n d ra diati o n t hera p y, res ulte d i n a n i m pr o ve d a nti-t u m or acti v it y. C he m ot hera p y wit h 
c o m bi nati o n t hera p y ( wit h f o li nic aci d, 5-fl u or o uracil, a n d o xali plati n [ F O L F O X], a n d 
ra diati o n t hera p y s h o we d t he better t u m or gr o wt h i n hi biti o n. I n partic ular, ra diati o n t hera p y 
was f o u n d t o be a hi g hl y s y ner gisti c c o m bi nati o n wit h a vel u ma b ca pa ble of ca usi n g c o m plete 
re gressi o n ofesta blis he d t u m ors pr o ba bl y t hr o u g h ge nerati n g a nti-t u m or i m m u ne me m or y. 
 
Vari o us i m m u n o m o nit ori n g assa ys we re i nc or p orate d i nt o t he i n vi v o st u dies. Treat me nt wit h 
a vel u ma b res ulte d i n a c o nsiste nt  i ncrease i n t he perce nta ge of C D 8 + P D- 1 + T cells a n d a n 
i ncrease d fre q ue nc y of C D 8 + T cells wit h a n effect or me m or y ( T EM) p he n ot y pe as deter mi ne d 
b y fl o w c yt o metr y. F urt her m ore, t hese c ha n ges c orrelate d wit h t he a nti-t u m or effect. I ncreases 
i n t u m or a nti ge n-s pecific T cell res p o nses, as meas ure d b y e nz yme-li n ke d i m m u n os or be nt s p ot 
a n d pe nta mer i m m u n oassa ys, were e vi de nt f oll o wi n g treat me nt wit h a vel u ma b a n d t hese 
res p o nses were e n ha nce d w he n c o mbi ne d wit h F O L F O X or ra diati o n.  He nce, i ncreases i n 
C D 8 + P D- 1 + T cells, C D 8 + T E M cells , a n d a nti ge n-s pecific T cell res p o nses, ma y be le vera ge d 
as p har mac o d y na mics ( P D) bi o mar kers wit h tra nslati o nal rele va nce t o t he cli nical setti n g. 
 


 
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Nonclinical pharmacokinetics and metabolism 
As expected for a monoclonal antibody (MoAb) binding to a cellular target, avelumab 
demonstrated pronounced non-linear pharmacokinetic (PK) characteristics in mice and 
monkeys in single dose studies at doses below 20 mg/kg, suggesting a combination of first 
order catabolic clearance and saturable target-mediated clearance. Toxicokinetic data from 
repeated dose toxicity studies in mice, rats, and monkeys indicated that the PK of avelumab 
was linear within the dose range of 20 to 140 mg/kg, suggesting that the target mediated 
clearance could be saturated when higher doses than 20 mg/kg are administered. Similar 
terminal half-lives (t1/2) of approximately 60 to 70 hours were observed in toxicity studies in 
mice and monkeys. 
 
A PK/ PD study in C57BL/6 mice was used to correlate receptor occupancy data of avelumab 
in blood with drug concentrations. A plasma concentration of 58.5 μg/mL was calculated as 
required for 95% target occupancy (TO) in this model. 
 
Avelumab is immunogenic in mice, rats, and monkeys with a lower incidence of anti-drug 
antibodies (ADAs) at higher doses. The latter is probably due to interference of free avelumab 
with the immunogenicity assay (drug interference). In animals, the generated ADAs seem to 
have the potential to increase the clearance of the avelumab. As the fully human avelumab 
represents a foreign protein to the immune system of animals, the observed immunogenicity of 
avelumab in rodents and non-human primates is not deemed predictive for an immune response 
to avelumab in humans. 
 
Nonclinical toxicology 
The toxicological profile of avelumab was evaluated in repeat-dose toxicity studies of 4-week 
duration with once weekly Iv bolus injection/infusion of avelumab in mice, rats, and 
cynomolgus monkeys. A repeat-dose toxicity study with intermittent once weekly Iv infusion 
of avelumab over 13 weeks followed by an 8-week recovery period in cynomolgus monkeys 
was also conducted. In addition, in vitro cytokine release assays (CRA) in human and 
cynomolgus monkey whole blood and peripheral blood mononuclear cells (PBMCs) followed 
by an optimized CRA in phytohemagglutinin (PHA) pre-stimulated PBMCs from 16 human 
volunteers was completed. Tissue cross reactivity (TCR) studies in normal human and 
cynomolgus monkey tissues have also been was performed. 
 
On the basis of the binding affinity data, the cynomolgus monkey and the mouse were selected 
as relevant species for the nonclinical safety testing of avelumab. Due to severe 
hypersensitivity reactions after repeated administration of avelumab in mice and the low 
binding affinity in rats, rodent species are not considered appropriate for nonclinical safety 
testing of avelumab and therefore, a single species approach (cynomolgus monkey only) is 
applied. 
 
In cynomolgus monkeys neither in the pilot 4-week Iv repeat-dose toxicity study nor in the 
pivotal 13-week study, clinical signs of hypersensitivity have been seen after repeated 
treatment with avelumab at dose levels of 20, 60, and 140 mg/kg, respectively. For the pilot 4-
week study as well as for the pivotal 13-week Iv repeat-dose toxicity study, a no observed 
adverse effect level (NOAEL) of 140 mg/kg for systemic toxicity was established. 


 
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I nitial C R A i n h u ma n a n d c y n o m ol g us m o n ke y w h ole bl o o d a n d P B M Cs re veale d n o clear-c ut 
e vi de nce f or release of pr o-i nfla m mat or y c yt o ki nes. H o we ver, a s u bse q ue nt, o pti mize d C R A 
de m o nstrate d e vi de nce of p ote ntia l c yt o ki ne release i n P H A pre-sti m ulate d P B M Cs. 
 
Cli nic al s afet y 
A vel u ma b is c urre ntl y i n cli nical de vel o p me nt acr oss P hases I, II, a n d III. T his I n vesti gat or’s 
Br oc h ure i ncl u des safet y data f r o m t he f oll o wi n g 4 cli nical trials: 
 E M R 1 0 0 0 7 0- 0 0 1: A P hase I, o pe n-la bel, m ulti ple asce n di n g d ose trial t o i n vesti gate t he 
safet y, t olera bilit y, p har mac o kinetics, bi ol o gical a n d cli nical  acti vit y of a vel u ma b i n s u bjects 
wit h metastatic or l o call y a d va nce d s oli d t u m ors a n d e x pa nsi o n t o selecte d i n dicati o ns 
 
 E M R 1 0 0 0 7 0- 0 0 2: A P hase I trial to i n vesti gate t he t olera bili t y, safet y, p har mac o ki netics, 
bi ol o gical a n d cli nical  acti vit y of a vel u ma b i n Ja pa nese s u bjects wit h metastatic or l ocall y 
a d va nce d s oli d t u m ors, wit h e x pa nsi o n part i n Asia n s u bjects wi t h gastric ca ncer 
 
 E M R 1 0 0 0 7 0- 0 0 3: A P hase II, si n gle ar m, o pe n-la bel, m ultice nter trial t o i n vesti gate t he 
cli nical acti vit y a n d safet y of a vel u ma b i n s u bjects wit h Mer ke l cell carci n o ma ( M C C) 
 
 E M R 1 0 0 0 7 0- 0 0 4: A P hase III o pe n-la bel, m ultice nter trial of a vel u ma b vers us d oceta xel i n 
s u bjects wit h n o n-s mall cell l u n g ca ncer t hat has pr o gresse d af ter a plati n u m-c o ntai ni n g 
d o u blet  
 
E M R 1 0 0 0 7 0- 0 0 1 is a P hase I, o pe n-la bel, m ulti ple asce n di n g d os e trial t o i n vesti gate t he 
safet y, t olera bilit y, P K, bi olo gical a n d cli nical  acti vit y of avel u ma b i n s u bjects wit h metastatic 
or l ocall y a d va nce d s oli d t u m ors a n d e x pa nsi o n t o selecte d i n di cati o ns. T his trial c o nsists of 2 
parts. I n t he d ose escalati o n part , se q ue ntial c o h orts of s u bjects were e nr olle d at pr o gressi vel y 
hi g her d ose le vels (ra n gi n g fr o m 1. 0, 3. 0, 1 0. 0, a n d 2 0. 0 m g/ k g  o nce e ver y 2 wee ks) wit h a 3 + 
3 al g orit h m desi g n f or deter mi nati o n of t he ma xi m u m t olerate d d ose ( M T D) of a vel u ma b; i n 
t he treat me nt e x pa nsi o n p hase, s u bjects i n differe nt t u m or c o h orts are bei n g treate d wit h 1 0 
m g/ k g of a vel u ma b o nce e ver y 2 wee ks u ntil, c o nfir me d pr o gressi o n, u nacce pta ble t o xicit y, or 
a n y reas o n f or wit h dra wal occ urs . M ore t ha n 1 5 0 0 s u bjects ha ve bee n e nr olle d i n t he E M R 
1 0 0 0 7 0- 0 0 1 trial. T he 3 + 3 d ose escalati o n al g orit h m t o deter m i ne t he M T D is c o m plete a n d a 
d ose of 1 0 m g/ k g o nce e ver y 2 wee ks was deter mi ne d f or t he t u m o r e x pa nsi o n c o h orts o n t he 
basis of safet y, P K, a n d P D o bser vati o ns. T he treat me nt e x pa nsi o n part of t he trial c o nsists of 
1 6 t u m or treat me nt c o h orts. As  of 0 5 N o ve m ber 2 0 1 5 ( data c ut off f or a pre- pla n ne d safet y data 
re vie w b y t he st u d y Safet y M o nit ori n g C o m mittee [ S M C]), 5 3 s u bjects i n t he d ose escalati o n 
part ha d recei ve d a vel u ma b ( 4, 1 3, 1 5, a n d 2 1 s u bjects ha d rece i ve d 1. 0, 3. 0, 1 0. 0, a n d 2 0. 0 
m g/ k g of a vel u ma b, res pecti vel y)  a n d 1 3 0 0 s u bjects i n t he p o oled e x pa nsi o n part ha d recei ve d 
1 0 m g/ k g a vel u ma b a n d were f oll o we d u p f or at least 4 wee ks. 
 
T he safet y s u m mar y fr o m t he c urre nt I n vesti gat or’s Br oc h ure (I B  F E B 2 0 1 6 versi o n 5; 
A p pe n di x C ) s u m marizes data fr o m 1 3 0 0 s u bjects treate d i n t he p o ole d treat me nt e x pa nsi o n 
c o h ort fr o m t he o n g oi n g P hase I Trial E M R 1 0 0 0 7 0- 0 0 1 (as of 0 5 N o ve m ber 2 0 1 5). T he 
p o ole d data i ncl u de d s u bjects tr eate d i n all t u m or e x pa nsi o n c o h orts, i ncl u di n g n o n-s mall cell 
l u n g ca ncer ( N S C L C), metastatic gastric ca ncer, breast ca ncer, c ol orectal ca ncer, castrate-
resista nt pr ostate ca ncer, a dren oc ortical carci n o ma, mela n o m a, mes ot heli o ma, ur ot helial 


 
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carcinoma, ovarian cancer, renal cell carcinoma, and squamous cell cancer of the head and 
neck. Safety data are also summarized for 52 subjects in the ongoing Phase I Trial EMR 
100070-002 and for 88 subjects in the ongoing Phase II Trial EMR 100070-003 (as of 17 
December 2015). For Trial EMR 100070-004, an overview of the serious adverse events 
(SAEs) is provided. 
 
Most of the observed adverse events (AEs) were either in line with those expected in subjects 
with advanced solid tumors or with class effects of MoAb blocking the PD-1/PD-L1 axis. 
Infusion-related reactions including drug hypersensitivity reactions and immune-mediated 
adverse reactions have been identified as important risks for avelumab. Respective risk 
mitigation measures have been implemented in all ongoing clinical studies with avelumab 
 
Clinical efficacy 
The clinical efficacy information summarized in this Investigator’s Brochure includes data 
from the NSCLC and ovarian cancer expansion cohorts of the ongoing Phase I Trial EMR 
100070-001, and for 20 subjects in the gastric cancer expansion cohort of the ongoing 
Phase I Trial EMR 100070-002. 
 
The NSCLC expansion cohort in the ongoing Phase I Trial EMR 100070-001 had a cutoff date 
of 15 January 2015, 6 months after start of avelumab treatment of the last subject in this 
expansion cohort (a total of 184 treated subjects). The objective response rate (ORR) based on 
confirmed and unconfirmed responses for subjects treated in the NSCLC expansion cohort was 
14.1% (26 of 184 NSCLC subjects). Progression free survival (PFS) and overall survival (OS) 
were all evaluated for all NSCLC subjects treated in the expansion phase. As of 15 January 
2015, the median PFS and OS for the NSCLC treatment expansion cohort were 11.6 weeks and 
8.4 months, respectively. 
 
The clinical activity of avelumab was also evaluated by subjects’ tumor PD-L1 expression 
status in the NSCLC expansion cohort. An objective response was observed in 20 of 122 
subjects (16.4%) who were PD-L1 positive (defined as having at least 1% PD-L1 positive 
tumor cells) compared with 2 of 20 subjects (10.0%) who were considered PD-L1 negative 
(defined as having less than 1% PD-L1 positive tumor cells). A longer median PFS (12.0 vs 5.9 
weeks) and OS (8.9 vs 4.6 months) were both observed in PD-L1 positive compared with PD-
L1 negative subjects. 
 
The ovarian cancer expansion cohort had a data cutoff of 13 February 2015, approximately 
13 weeks after the start of avelumab treatment on the last subject who was included in this 
pre-planned interim analysis on this expansion cohort. The ORR based on confirmed and 
unconfirmed responses for subjects treated in the ovarian cancer expansion cohort was 10.7% 
(8 of 75 subjects). The median PFS for the ovarian cancer expansion cohort was 11.4 weeks 
(95% confidence interval (CI): 6.3 to 12.0 weeks). 
 
The preliminary efficacy data for the ongoing Phase I Trial EMR 100070-002 are based on a 
data cutoff of 11 March 2015. As of the data cutoff, 3 of 20 subjects responded to trial 
treatment (all responses were partial responses [PRs] and all responses were confirmed 
responses), and the best overall response (BOR) was 15.0% (95% CI: 3.2% to 37.9%). The 


 
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median PFS of this group was 11.9 weeks (95% CI: 6.0 to 12.3 weeks). 
 
Further details can be found in the avelumab Investigators Brochure (Appendix C), which 
contains comprehensive pharmacology, toxicology, pharmacokinetics, pharmacodynamics, 
metabolism, preclinical, and clinical efficacy and safety data information 
 
2.1.7    5-azacytidine (Vidaza):  
5-azacytidine, an analog of the pyrimidine nucleoside cytidine, has effects on cell 
differentiation, gene expression, and deoxyribonucleic acid (DNA) synthesis and metabolism. 
Since the early 1970s, 5-azacytidine has been investigated primarily in the US for the treatment 
of acute leukemia. Clinical studies have focused mainly on patients with disease refractory to 
conventional chemotherapy. Results of these investigations demonstrated activity of 5-
azacytidine in the treatment of AML. Clinical studies subsequently evaluated the effects of 5-
azacytidine in a variety of other malignant and hematologic disorders, including solid tumors, 
hemoglobinopathies (e.g., thalassemia and sickle cell anemia), and MDS. In 1984, the Cancer 
and Leukemia Group B (CALGB) began a series of clinical studies with 5-azacytidine in 
patients with MDS. These studies, in addition to other supportive data, led to the approval of 
Vidaza® (5-azacytidine) in May 2004 for the treatment of MDS.  
 
5-azacytidine inhibits the methylation of newly synthesized DNA by inhibiting DNA 
methyltransferase (DNMT).22-24 Increased methylation of DNA (hypermethylation) may result 
in the silencing of critical genes responsible for cell growth control and differentiation. 
Hypermethylation of CpG islands spanning the promoter regions of tumor suppressor genes is 
commonly associated with cancers.25 It is now widely recognized that hypermethylation of 
DNA is frequently associated with myelodysplastic syndromes and other cancers,26-28 such as 
renal,29 melanoma,30 breast,31 colorectal,32 non-small cell lung33 and hematologic 
malignancies.34 5-azacytidine is believed to exert its antineoplastic effects through 
hypomethylation and cytotoxicity on abnormal hematopoietic cells in the bone marrow.35-39 
Hypomethylation may restore normal function to genes that are critical for differentiation and 
proliferation.25,40,41 The cytotoxic effects of 5-azacytidine cause the death of rapidly dividing 
cells, including cancer cells that are no longer responsive to normal growth control 
mechanisms.35,42-44  
 
The cytotoxicity of 5-azacytidine is proportional to dose and exposure time.35,36 Although the 
mechanisms of cytotoxicity are complex and multifaceted, there is general agreement that 
incorporation of 5-azacytidine into DNA and ribonucleic acid (RNA), and inhibition of protein 
synthesis, are critically important.45 Cytotoxicity is greatest in cells that are proliferating 
(S phase) and metabolically active.35 Cytotoxic effects may also be mediated through induction 
of the DNA damage response pathways.44 Nonproliferating cells are relatively insensitive to 5-
azacytidine.35  
 
Toxicology studies have been conducted in mice, rats, dogs, and Rhesus monkeys.46 Most of 
the studies were performed during the 1970s and early 1980s according to existing guidelines 
and standards in place during that period. The preclinical studies identified the bone marrow, 
liver, kidneys, and lymphoid tissues (spleen, lymph nodes, and thymus) as the main target 
organs of toxicity for 5-azacytidine.46 In single-dose studies, the lethal dose of 5-azacytidine 


 
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after intravenous (IV) administration in mice, rats, and dogs was approximately 250 mg/m2. 
Repeated daily dosing appears to increase the toxicity of 5-azacytidine.46 The genotoxicity of 
5-azacytidine is consistent with that of other nucleoside analogs that interact with nucleic 
acids.46 Likewise, similar to other agents with cytostatic properties, 5-azacytidine was 
embryotoxic and reduced the reproductive performance in mice and rats.46 
 
Limited 5-azacytidine pharmacokinetic data are currently available. Based on human plasma 
concentrations of total radioactivity (which represents parent drug plus circulating metabolites), 
5-azacytidine is rapidly absorbed when given subcutaneously (SC), with maximum plasma 
concentrations found 0.5 to 2 hours after dosing.46 5-azacytidine and/or its by-products are then 
rapidly cleared by the kidneys. The half-lives and percent radioactivity recovered in urine are 
similar following IV and SC routes of administration. The effects of renal or hepatic 
impairment, gender, age, or race on the pharmacokinetics of 5-azacytidine have not been 
studied.46 A single dose (75 mg/m2) SC versus IV crossover study in 6 MDS subjects47 
revealed an approximate bioavailability of 89% for the SC dose (range 52% to 128%) with 
mean half-lives of 0.69 hour and 0.36 hour after SC and IV administration, respectively. These 
results demonstrated that 5-azacytidine is rapidly and nearly completely absorbed after SC 
administration and that elimination is also rapid. The apparent SC clearance (167 L/h or 
2791 mL/min) and systemic IV clearance (147 L/h) of 5-azacytidine exceeded the glomerular 
filtration rate (approximately 125 mL/min) and total renal blood flow (1200 mL/min) in 
healthy subjects. This indicates that non-renal elimination (e.g., metabolism, hydrolysis, and/or 
degradation) plays a role in the elimination of parent 5-azacytidine. In addition, 5-azacytidine 
75 mg/m2 was generally well-tolerated after single SC injection or IV infusion over 
10 minutes.47  
 
A number of studies have looked at different parenteral doses and schedules of 5-azacytidine, 
finding maximum tolerated doses of up to 500 mg/m2 when administered weekly.48 
 
During the two decades between the start of the CALGB studies and the approval of 5-
azacytidine, a new understanding of MDS has developed, such as the World Health 
Organization (WHO) diagnostic criteria, the International Prognostic Scoring System (IPSS), 
and the International Working Group (IWG) response criteria. Silverman et al. reevaluated the 
combined data (N = 309) from 3 of the CALGB studies using the WHO classification system 
for MDS and AML and the IWG response criteria.49 Using the IWG response criteria in MDS 
patients, response rates were between 40% and 70% in 5-azacytidine treated patients. Ten to 
17% of patients achieved a complete remission; partial remission was rare; and 23% to 36% of 
patients had a hematologic improvement. In patients with AML (N = 103), 35% to 48% had 
hematologic improvement or better responses. The median survival time for 27 patients 
assigned to 5-azacytidine was 19.3 months compared with 12.9 months for the 25 patients 
assigned to observation.49 
 
A randomized international Phase III trial (Study 5-azacytidine PH GL 2003 CL 001) for 
higher-risk MDS patients, classified by FAB as RAEB, RAEB-T, or CMML with 0-29% 
marrow blasts, with an IPSS of Intermediate -2 or High by central pathology/cytogenetic 
review was recently reported.50 Patients were randomized to 5-azacytidine (75 mg/m2/day x 
7days in 28 day cycles) or conventional care regimens (CCR), where CCR was pre-selected by 


 
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the Investigator as best supportive care (transfusions, antibiotics, and G-CSF for neutropenic 
infection), low-dose cytarabine (20 mg/m2/day x 14 days in 28 day cycles); or standard 
chemotherapy (conventional induction/consolidation). Patients were stratified by FAB/IPSS 
and randomized 1:1 to 5-azacytidine or CCR. This trial did not allow erythropoietin. Three 
hundred fifty eight patients (70% male) were randomized at 79 centers to 5-azacytidine 
(N=179) or CCR (N=179): best supportive care only (N=105, 59%), low-dose cytarabine 
(N=49, 27%), or standard chemotherapy (N=25, 14%). Median age was 69 years (range 38-88 
years). The 5-azacytidine and CCR groups were comparable for baseline patient characteristics. 
At baseline, 95% of patients were higher risk: RAEB (58%), RAEB-T/WHO AML (34%), 
CMML (3%), and other (5%). By IPSS, 87% were higher risk: Intermediate -2 (40%), High 
(47%), and 13% Indeterminate/other. 5-azacytidine was administered for a median of 9 cycles; 
low-dose cytarabine for 4 cycles. Median follow-up for the survival analysis was 21.1 months. 
5-azacytidine demonstrated statistically superior overall survival compared to CCR, with a 
median overall survival of 24.4 months vs. 15 months for CCR (stratified log-rank p=0.0001, 
hazard ration 0.58). Two-year survival approximately doubled in the 5-azacytidine arms 
compared to CCR: 51% vs. 26% (p<0.0001). 5-azacytidine was well tolerated with safety data 
consistent with previous reports.  
 
Further details can be found in the 5-azacytidine drug information (Appendix D), which 
contains comprehensive pharmacology, toxicology, pharmacokinetics, pharmacodynamics, 
metabolism, preclinical, and clinical efficacy and safety data information.46  
 
2.1.8    Rationale for study 
            The PD-1/PD-L1 pathway plays a major role in immune evasion and cytotoxic T-cell 
exhaustion in AML9,10,21. PD-L1 expression in AML samples is increased at the time of disease 
progression or after exposure to IFN-gamma21,51. Overexpression of PD-L1 is an independent 
negative prognostic factor in AML21. Hypomethylating agents may alter immune regulation52. 
Yang et al have recently demonstrated that hypomethylating therapy leads to up regulation of 
PD-L1, PD-1, and PD-L2 gene expression20. Patients resistant to hypomethylating therapy had 
higher increments in gene expression suggesting that PD-1 up regulation may promote 
resistance to hypomethylating agents. Demethylation of the PD-L1 gene by chronic viral 
infection results in PD-L1 up-regulation and CTL exhaustion53. Similarly, exposure to 
azacytidine up regulates PD-L1, PD-1 and PD-L2 by demethylation of the PD-L1 locus20. 
These data suggest that blockage of PD-L1 by avelumab may improve response and abrogate 
resistance to hypomethylating agents. Furthermore, recent data shows that azacytidine 
increases NK-cell activating receptor ligands (NKG2DL) and enhanced ADCC when 
administered in combination with CD33-targeting antibody with preserved FCγIIIa domain 
(Vasu et al, Blood May 2016 and Daver N, Ravandi F et al, Blood May 2016). In addition to 
azacytidine’s impact on T-cells costimulatory receptor and blast ligand expression we hope to 
promote ADCC by combining an epigenetic agent (azacytidine) with an agent that has 
preserved Fc receptor to engage NK cells (avelumab). Enhanced ADCC may be a second 
mechanism of antileukemic synergy when azacytidine and avelumab are administered in 
combination. 
 
In this initial trial, we propose to explore these concept in patients with refractory/ relapsed 
AML with both clinical and focused correlative analysis. We propose to introduce PD-1 


 
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blockade early, when there are still leukemia cells that can prime the immune competent cells 
for eventual eradication.  If the combination proves to be well tolerated and results in responses 
as expected, we would expand the use of this approach in the frontline setting for elderly AML 
and high-risk MDS (10-20% blast) patients who are not candidates for or refuse standard 
cytotoxic therapy either as an extension of this study or as a separate study. 
 
3.0 
STUDY DESIGN 
 
 This will be a phase II, single-arm, open-label, non-randomized study with a safety lead-in 
phase IB. 
 
 Patients will receive 5-azacytidine subcutaneously or intravenously daily for 7 days of each 
treatment cycle. For the lead-in phase IB portion, the length of the cycle will be at least 28 
days to evaluate DLT. Subsequently, cycles will be repeated approximately every 28 days 
(+/-5 days), and therapy will be continued until clinically significant disease progression or 
documentation of unacceptable toxicity. 
 
 Patients will receive therapy with avelumab IV infusion on Day 1 and day 14 (+/-3 days) of 
each 5-azacyidine cycle for first 4 cycles or until CR (whichever occurs earlier) followed 
by a maintenance regimen (one dose of avelumab on day 1 of each cycle of 5-azacytdine). 
Patients who have evidence of budding relapse or seem to have clinical benefit may 
continue or revert back to receiving avelumab on Day 1 and day 14 (+/-3 days) of each 
cycle of 5-azacytidine. Patients may receive avelumab more or less frequently during the 
maintenance regimen at the discretion of the treating physician only after discussion with 
the PI.  
 
 The historical experience in relapsed/refractory AML patient population is that historical 
responses (CR/CRi/PR/HI with >50% blast reduction) with single agent hypomethylator 
therapy (5-azacytidine or decitabine) or with hypomethylator combinations 
(azacytidine+revlimid, decitabine+myelotarg, azacytidine+vorinostat, 
decitabine+valproate) investigated at MDACC over the last 10 years are 10% (Daver N, 
Kantarjian H et al., European Hematology Association Conference, June 2016). In many 
instances (e.g., patients with relapsed/refractory AML beyond first salvage) no standard 
therapy is available. Thus, an overall response rate (CR/CRi/PR) of 30% will be considered 
significant 
 
4.0 
PATIENT SELECTION 
 
4.1 
Inclusion Criteria 
 
4.1.1    Patients with AML who are refractory (up to salvage 2) or relapsed (up to 2nd relapse). 
For patients with prior MDS or chronic myelomonocytic leukemia (CMML) or MPN 
who transformed to AML, therapy received for MDS, CMML, or MPN is NOT 
considered as prior therapy for AML. 
 
4.1.2    Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy (e.g. 


 
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FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is allowed. 
 
4.1.3 Age >/=18 years 
 
4.1.4 Eastern Cooperative Oncology Group (ECOG) Performance Status </=2  
 
4.1.5 Adequate organ function: total bilirubin </= 1.5 times upper limit of normal (x ULN) 
(</= 3 x ULN if considered to be due to leukemic involvement or Gilbert’s syndrome); 
aspartate aminotransferase or alanine aminotransferase </= 2.5 x ULN (</= 5.0 x ULN 
if considered to be due to leukemic involvement) 
 
4.1.6 Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min 
according to the Cockcroft-Gault formula (or local institutional standard method) 
 
4.1.7 Patients must provide written informed consent. 
 
4.1.8 In the absence of rapidly progressing disease, the interval from prior treatment to time 
of initiation of 5-azacytidine and avelumab will be at least 14 days OR at least 5 half-
lives for cytotoxic/noncytotoxic agents, whichever is longer. The toxicity from prior 
therapy should have resolved to Grade </= 1, however alopecia and sensory neuropathy 
Grade </=2 is acceptable. The half-life for the therapy in question will be based on 
published pharmacokinetic literature (abstracts, manuscripts, investigator brochure’s, or 
drug-administration manuals) and will be documented in the protocol eligibility 
document. Since the effect of both avelumab and 5-azacytidine may be delayed, use of 
hydroxyurea for patients with rapidly proliferative disease is allowed before the start of 
study therapy and will not require a washout. Concurrent therapy for CNS prophylaxis 
or continuation of therapy for controlled CNS disease is permitted. Patients with CNS 
disease or leukemic brain metastasis must have been treated locally and be clinically 
stable for at least 2 weeks prior to enrollment and have no ongoing neurological 
symptoms that are related to the CNS disease (sequelae that are a consequence of the 
treatment of the CNS disease are acceptable). 
 
4.1.9 Females must be surgically or biologically sterile or postmenopausal (amenorrheic for 
at least 12 months) or if of childbearing potential, must have a negative serum or urine 
pregnancy test within 72 hours before the start of the treatment. 
 
4.1.10 Women of childbearing potential must agree to use an adequate method of 
contraception during the study and until 3 months after the last treatment. Males must 
be surgically or biologically sterile or agree to use an adequate method of contraception 
during the study until 3 months after the last treatment. 
 
            Adequate methods of contraception include: 
 Total abstinence when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 Female sterilization (have had surgical bilateral oophorectomy with or without 


 
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hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment 
 Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient 
 Combination of any of the two following (a+b or a+c or b+c) 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository 
In case of use of oral contraception, women should have been stable on the same pill 
before taking study treatment. 
Note: Oral contraceptives are allowed but should be used in conjunction with a 
barrier method of contraception due to unknown effect of drug-drug interaction. 
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 
 
4.2 Exclusion Criteria 
 
4.2.1    Patients with a known allergy or hypersensitivity to avelumab, 5-azacytidine, or any of 
their components. Known severe hypersensitivity reactions to monoclonal antibodies 
(Grade ≥ 3 NCI-CTCAE v 4.03), any history of anaphylaxis, or uncontrolled asthma 
(that is, 3 or more features of partially controlled asthma). 
 
4.2.2    Patients with a known history of severe interstitial lung disease or severe pneumonitis 
or active pneumonitis/pneumonia or pulmonary pathology that is not well controlled in 
the opinion of the treating physician and/or PI. 
 
4.2.3 Patients who have previously been treated with avelumab (or another PD1/PDL1 
inhibitor) in combination with 5-azacytidine will be excluded.  
 
4.2.4 Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; however, 
alopecia and sensory neuropathy Grade ≤ 2 is acceptable 
 
4.2.5 Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent: 
a. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease 
not requiring immunosuppressive treatment are eligible 


 
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b. Subjects requiring hormone replacement with corticosteroids are eligible if the 
steroids are administered only for the purpose of hormonal replacement and at 
doses ≤ 10 mg or 10 mg equivalent prednisone per day 
c. Administration of steroids through a route known to result in a minimal 
systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable 
 
4.2.6 Patients with organ allografts (such as renal transplant) are excluded 
 
4.2.7 Patients who are <90 days post allogeneic stem cell transplant will be excluded. Patients 
beyond 90 days post-allogeneic stem cell transplant with uncontrolled active GVHD > 
grade 1 will be excluded. Patients who are on a stable dose of immunosuppressive 
therapy (tacrolimus, cyclosporine, or other) for > 2 weeks will be eligible but those with 
recent increase in the immunosuppressive medication dose within last 2 weeks to 
control GVHD will not be included. Note: Subjects may be using systemic 
corticosteroids or topical or inhaled corticosteroids post allogeneic stem cell transplant 
(inclusion based on post stem cell transplant activity and tolerability of checkpoint 
inhibitor by Matthew D, et al., ASH 2015 Annual Conference abstract # 860).  Patients 
requiring >/= 1 mg/kg prednisone for GVHD management at the time of screening will 
not be eligible until the prednisone can be weaned to <1 mg/kg. Such patients should be 
monitored for at least 14 days and if no flare of GVHD requiring re-escalation of 
steroids or additional interventions for the GVHD they will be eligible.   
 
4.2.8 Patients with symptomatic CNS leukemia or patients with poorly controlled CNS 
leukemia.  
 
4.2.9 Active and uncontrolled disease/(active uncontrolled infection, uncontrolled 
hypertension despite adequate medical therapy, active and uncontrolled congestive 
heart failure NYHA class III/IV, clinically significant and uncontrolled arrhythmia) as 
judged by the treating physician. 
 
4.2.10 Patients with known Human Immunodeficiency Virus seropositivity will be excluded.  
 
4.2.11 Known to be positive for hepatitis B by surface antigen expression. Known to have 
active hepatitis C infection (positive by polymerase chain reaction or on antiviral 
therapy for hepatitis C within the last 6 months) 
 
4.2.12 Any other medical, psychological, or social condition that may interfere with study 
participation or compliance, or compromise patient safety in the opinion of the 
investigator  
 
4.2.13 All other significant diseases (for example, inflammatory bowel disease, uncontrolled 
asthma), which, in the opinion of the Investigator, might impair the subject’s tolerance 
of trial treatment 
 
4.2.14 Patients unwilling or unable to comply with the protocol. 
 


 
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4.2.15 Pregnant or breastfeeding 
 
4.2.16 Known alcohol or drug abuse within the last 1 year 
 
4.2.17 Vaccination within 4 weeks of the first dose of avelumab and while on trial is 
prohibited except for administration of inactivated vaccines  
 
4.2.18 Acute promyelocytic leukemia (APL). 
 
4.2.19 Subject has a history of other malignancies prior to study entry, with the exception of: 
 
a. Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of 
breast; 
b. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the 
skin; 
c. Previous malignancy confirmed and surgically resected (or treated with other 
modalities) with curative intent or completed definitive therapy (chemotherapy, 
radiation, others) for the malignancy at least 1 year prior to the date of 
screening. 
 
5 
TREATMENT PLAN 
 
5.1 
General 
            All patients will be registered through CORe. We will first treat 6 patients at dose level 
-1.  
 
5.2 
Schedule  
            The Investigator is responsible for completing the cohort summary template and 
submitting to the IND office Medical Monitor for review and approval prior to 
advancing subjects to the next protocol specified cohort/dose level. A copy of the 
cohort summary should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. This should be submitted after the first six patients. 
 
5.2.1    Patients will be treated according to the following schedule: 
 
• 
5-azacytidine will be administered subcutaneously (SQ) or intravenously (IV) for 7 
days of every cycle with daily schedule of 7 consecutive days (Days 1-7) or for days 5-
2-2 which is 5 consecutive weekdays (Days 1-5) with rest on the 2 weekend days (Days 
6 and 7) and then dosing the first two weekdays of the next week (Days 8 and 9) of 
each 28-day cycle as determined by treating physician. Alternative dosing schedules 
such as 4-2-3 which is 4 consecutive weekdays (Days 1-4) with rest on the 2 weekend 
days (Days 5 and 6) and then dosing the first three weekdays of the next week (Days 7, 
8, and 9) of each 28-day cycle or other schedules allowing the 2 day weekend 
interruption may be applied as long as we make every attempt to give the 7 days of 
azacytidine as consecutively as possible. This must be clearly documented in the 
medical record as determined by treating physician after approval from the PI. Both SQ 


 
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and IV forms of administration are FDA approved and considered interchangeable. 
Patients may start receiving 5-azacytidine by one route and changed to the other, and 
also administration schedules from one schedule and changed to the other at any time as 
needed based on patient and/or physician preference. 
 
• 
Avelumab will be administered as an approximately 60 minute (+/- 30 minutes) IV 
infusion on Day 1 and day 14 (+/-3 days) of each 5-azacyidine cycle for the first 4 
cycles or until CR (whichever occurs earlier) followed by a maintenance regimen (one 
dose of avelumab on day 1 of each cycle of 5-azacytdine). Patients who have evidence 
of budding relapse or seem to have clinical benefit may continue or revert back to 
receiving avelumab on Day 1 and day 14 (+/-3 days) of each cycle of 5-azacytidine. 
Patients may receive avelumab more or less frequently during the maintenance regimen 
only after discussion with the PI. Avelumab will be administered every cycle with no 
interruptions unless there are adverse events as described in Section 5.3. 
 
• 
5-azacytidine at a dose of 75 mg/m2 on days 1-7 or days 5-2-2 has been shown to be 
safe in combination with multiple agents including lenalidomide[60], bortezomib[60], 
and vorinostat[61, 62]. We have proposed the starting dose level -1 of 5-azacytidine 75 
mg/m2 x 7 days and avelumab 3.0 mg/kg on days 1 and 14 of each cycle. The lead-in 
phase is to ensure that the combination is well tolerated with no unexpected side effects 
and to identify the MTD of the combination. Avelumab infusion should begin right 
after the administration of 5-azacytidine on day 1, as described above, whenever 
possible. The dosing calculations should be based on the body weight. All doses should 
be rounded to the nearest milligram. There will be no dose reductions (only 
interruptions when indicated) allowed for avelumab on this trial.  
 
• 
Avelumab administration: Subjects will receive avelumab by IV infusion following 
pretreatment with H1 blockers and acetaminophen on day 1 and 14 of each cycle.  
Premedication with an antihistamine and with paracetamol (acetaminophen) (for 
example, 25 50 mg diphenhydramine and 500-650 mg paracetamol [acetaminophen] IV 
or oral equivalent) approximately 30 to 60 minutes prior to each dose of avelumab is 
mandatory.  This regimen may be modified based on local treatment standards and 
guidelines as appropriate provided it does not include systemic corticosteroids. 
 
5.2.1.1 The starting dose will be dose level -1(Table 1). 
  
Table 1. Dose levels of 5-azacytidine and avelumab during the lead-in phase (phase 
IB) 
Dose level              5-azacytidine 
(mg/m2/d, Days 1-7) 
Avelumab (mg/kg, 
                day 1 and 14) 
-3 
         25 
          3.0 
-2 
         50 
          3.0 
-1 
         75 
          3.0 (starting dose) 


 
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 0 
         75 
10.0 (target dose) 
 
5.2.1.2 The goal of the lead-in phase IB is to identify the dose at which <2/6 patients 
experience DLT. During the lead-in phase the doses of 5- azacytidine and 
avelumab may not be reduced if 2 or more patients experience DLT at any 
given dose. After the lead-in phase IB is completed and the MTD dose of 
avelumab is established the dose of avelumab may not be reduced in the phase 
II portion of this study. For potential avelumab related AEs only dose 
interruptions will be permitted. Dose reductions or escalations of 5-azacytidine 
are permitted in the phase II portion of the study and dose reductions or 
escalations of 5-azacytidine beyond those mentioned in Table 1 or different to 
the doses specified should be discussed with the PI and documentation of the 
justification recorded in the chart. The escalation will in no circumstance 
exceed the established MTD for this trial. 
 
5.2.1.3 The dose and /or schedule of administration is subject to modification pending 
information from ongoing clinical trials of avelumab as a single agent and in 
combination with other drugs. 
 
              DLT is defined as clinically significant non-hematologic adverse event or 
abnormal laboratory value assessed as unrelated to disease progression, 
intercurrent illness, or concomitant medications and occurring during the first 
cycle on study that meets any of the following criteria: 
 
• 
CTCAE Grade 3 AST (SGOT) or ALT (SGPT) for >/= 7 days or grade 3 
hyperbiliribunemia for >/= 7 days 
 
• 
CTCAE Grade 4 AST (SGOT) or ALT (SGPT) of any duration 
 
• 
All other clinically significant non-hematological adverse event that is 
Grade 3 or 4 according to the NCI common terminology criteria version 4.0 
with the following exceptions: 
 
• 
Grade 3 or 4 nausea, vomiting and diarrhea will be considered DLT only if 
not controlled by optimal therapy. 
  
• 
Grade 3 biochemical abnormalities (e.g., lipase or bilirubin elevation) will 
only be considered DLT if accompanied by clinical consequences.  Grade 3 
or 4 electrolyte abnormalities will only be considered DLT if possibly 
related to study drug and not corrected by optimal replacement therapy. 
 
 Any treatment-related death;  
 
 Grade 4 neutopenia lasting ≥ 42 days from start of cycle in absence of evidence 


 
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of active AML. 
 
5.2.1.4 We will first treat 6 patients at dose level -1 in the lead-in phase IB. If DLT 
occurs in >/=2/6 patients, this dose level would exceed the MTD, and 6 patients 
will be treated at the next lower dose level (i.e. dose level -2). If DLT occurs in 
< 2/6 patients, this dose level would not exceed the MTD, and 6 patients will 
be treated at the next higher dose level (i.e. dose level 0). The dose de-
escalation (Table 1) will continue in cohorts of 6 until we reach the maximum 
dose level at which <2/6 patients experience a DLT in the first 28 days. The 
maximum dose level at which 0-1/6 patients experience a DLT in the first 28 
days of treatment will be the MTD in this study and will be used to treat an 
additional 40 patients in the phase II portion of the study. If >/=2/6 patients 
experience DLT at dose level -3, the study will be revised to consider 
additional lower dose levels (based on potential synergistic toxicity). 
 
5.2.1.5 If DLT is observed in the first 28 days of treatment in 0 or 1/6 at dose level 0, 
then dose level 0 will be used for the phase II portion of the study. 
 
5.2.1.6 Patients must receive a total of 7 doses of azacytidine and 2 doses of avelumab 
during the first 28 days on trial (i.e. during cycle 1) to be evaluated for DLT. 
Patients may have up to a total of 7 days interruption in the azacytidine dosing 
during the first 28 days and still be evaluable for DLT if the interruption is for 
complications or hospitilizations NOT related to the azacytidine or the 
avelumab. Patients who receive less than 7 doses of azacytidine and/or less 
than 2 doses of avelumab during the first 28 days on trial will NOT be 
evaluable for DLT. Patients not evaluable for DLT will be replaced. These 
patients may continue therapy on trial after discussion with the PI if they are 
having clinical benefit or if in the best interest of the patient and the reasons for 
continuation and potential benefit/risk profile for the patient must be clearly 
documented in the medical records.  
 
 
5.2.1.7 Once MTD is defined, the RP2D will be selected based on efficacy and safety 
result from the phase I in discussion with the PI and the sponsor. The 
Investigator is responsible for completing the cohort summary template prior to 
advancing subjects to the phase II portion. Any patients still on study from the 
phase I portion at a dose lower than RP2D can be dose escalated up to RP2D. 
However, the dose for any patient may never exceed the RP2D. 
 
5.2.1.8 Once MTD is defined, the RP2D will be selected based on efficacy and safety 
result from the phase I in discussion with the PI and the sponsor. The 
Investigator is responsible for completing the cohort summary template prior to 
advancing subjects to the phase II portion. Any patients still on study from the 
phase I portion at a dose lower than RP2D can be dose escalated up to RP2D. 
However, the dose for any patient may never exceed the RP2D. 
 


 
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5.2.2 One cycle of therapy is defined as 28 days. Patients will receive one cycle of therapy 
every 28 days (+/- 5 days). 
 
5.2.2.1 In the phase II portion of the study (once the MTD dose has been defined) 
cycles may be started early (but not earlier than day 23) for patients with active 
disease if judged in the best interest of the patient. 
              For the lead-in cohort, DLT defining period is 28 days. As such, cycle 2 should 
not be started before 28 days for the patients being treated on the lead-in 
cohort. 
 
5.2.2.2 Subsequent cycles may be delayed for recovery of toxicity or other medical 
conditions (e.g. infections). Delays in start of subsequent cycles greater than 8 
weeks will be acceptable only for patients who are deriving clinical benefit and 
after discussion with the principal investigator of potential risk/benefit ratio and 
clear documentation in the medical record of the reason for continuation and 
perceived benefit to the patient from continuation of this therapy. 
  
5.2.2.3 In instances where one drug has to be discontinued transiently because of 
safety, the administration of the other drug may continue as scheduled. 
 
5.2.2.4 Azacitidine and avelumab will be held during phase II of the study, for grade 4 
neutropenia or grade 4 thrombocytopenia lasting ≥ 42 days from the start of 
each cycle, in the absence of evidence of active AML. If prolonged grade 4 
neutropenia (more than 42 days) WITH evidence of a hypocellular marrow 
(marrow cellularity less than 5% without evidence of leukemia) is observed, 5-
azacytadine and avelumab will be discontinued. Delays in start of subsequent 
cycles greater than 42 days will be acceptable only for patients who are 
deriving clinical benefit and after discussion with the principal investigator of 
potential risk/benefit ratio.   
If the  peripheral  counts  do  not  recover (ANC <0.5 x109/L and/or platelets 
<25 x109/L) but there is evidence of residual leukemia by morphology or flow-
cytometry in the bone marrow, subsequent cycles can be administered at the 
discretion of the treating physician not earlier than 23 days after the prior cycle 
in the phase II portion of the study. For the lead-in cohort, DLT defining period 
is 28 days. As such, cycle 2 should not be started before 28 days for the 
patients being treated on the lead-in cohort. 
 
5.2.2.5 For patients who discontinue therapy, the reason for treatment discontinuation 
will be captured. 
 
5.3 
Dose Adjustments 
 
5.3.1 
Avelumab and 5-azacytidine dose adjustments for hematological drug- 
related adverse events (AE): 
 
              Dose reduction/interruption/discontinuation decisions should be based on the 


 
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CTCAE version 4.03 (Appendix E) and the guidelines provided below. 
              Patients with acute leukemia’s usually present with abnormal peripheral blood 
counts at the time therapy is started and myelosuppression is an expected event 
during the course of therapy for acute leukemia. Thus, no dose adjustments or 
treatment interruptions for myelosuppression will be planned for the first 4 
cycles and/or in the presence of residual leukemia. After that, treatment 
interruptions and dose adjustments may be considered according to the 
following guidelines only when there is no evidence of active leukemia (e.g., 
only if <5% blasts in the bone marrow or cytopenias not considered to be 
related to leukemia). 
 
➢ 
Patients with a response (no marrow evidence of leukemia) and pre-cycle 
counts of neutrophils >1x109/L and platelets >50 x109/L who have sustained 
low counts of neutrophils <0.5 x109/L or a platelet count <20 x 109/L for more 
than 2 consecutive weeks in the current cycle, may have the treatment with 5-
azacytidine interrupted at the discretion of the treating physician after 
discussing with the PI until neutrophils recover to ≥1 x109/L and platelets to 
≥50 x109/L.  
 
➢ 
If there are persistent peripheral blood blasts, or the bone marrow shows >5% 
blasts or evidence of residual leukemia, treatment may be continued regardless 
of neutrophil and platelet count with supportive care as needed. Dose-
interruptions of 5- azacytidine in these patients should be considered on an 
individual case-by-case basis and discussed with the PI. 
 
➢ 
Investigators should, whenever possible, determine which medication is 
causing the toxicity and interrupt or dose reduce 5-azacytidine and/or interrupt 
avelumab, as applicable. No dose reductions (only dose interruptions as 
needed) are permitted for avelumab in the phase II portion after RP2D has been 
established. Avelumab has not ben associated with neutropenia and/or 
thrombocytopenia in prior studies and should generally not be interrupted or 
discontinued for myelosuppression. 
 
5.3.2 5-azacytidine dose adjustments for non-hematologic drug- related AEs 
Investigators should, whenever possible, determine which medication is causing 
the toxicity and interrupt or dose reduce 5-azacytidine and/or interrupt 
avelumab, as applicable. No dose reductions (only interruptions) are permitted 
for avelumab in the phase II portion after RP2D has been established.  
 
Dose reductions of azacytidine to be implemented in the phase II portion of the 
study will be as follows: dose level -1 of azacytidine: 50 mg/m2, dose level -2: 
37.5 mg/m2, dose level -3: 25 mg/m2. 
 


 
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Table 2   Dose adjustments of azacytidine for non-hematologic drug-related AEs, 
clinically significant in the opinion of the investigator 
Grade 
Occurrence Dose modification 
1 or 2 
Any time 
No dose reduction 
3 or 4 
 
(Persistent grade 2: 
Consider similar 
dose adjustments if 
persistent and not 
responding to 
optimal 
management in the 
opinion of PI and 
treating physician) 
1st and 
2nd time 
Hold 5-azacytidine. 
Resume 5-azacytidine at prior dose if recovery to ≤ Grade 1 occurs 
within 14 days. 
If toxicity persists for 15-28 days, hold therapy and resume 5-
azacytidine at prior dose if recovery to ≤ Grade 1 OR resume 5-
azacytidine at ONE dose level below current dose if recovery to ≤ 
Grade 2. 
Dose re-escalation to prior dose of 5-azacytidine is permitted in 
accordance with the dose-escalation guidelines in section 5.3.6. 
3rd. and 4th 
time 
Hold 5-azacytidine. 
Follow until toxicity ≤ Grade 2. 
Resume 5-azacytidine at ONE dose level below current dose. 
Dose re-escalation of 5-azacytidine to prior dose is permitted in  
accordance with the dose-escalation guidelines in section 5.3.6.. 
5th time 
Discontinue therapy 
 
5.3.3 Avelumab dose delay/interruption for immune-oncology drug-related AEs, 
clinically significant in the opinion of the investigator 
 
Avelumab administration should be delayed for the following drug-related AEs, 
clinically significant in the opinion of the investigator: 
• Any Grade >/=2 non-skin AE, except that 
– Grade 2 fatigue or laboratory abnormalities do not require delay, however 
 
 Patients with ALT or AST > 3 and up to 5 x ULN or total bilirubin 
greater > 2.0 mg/dL and up to 3 x ULN or creatinine >2.0 mg/dL and 
up to 3 x ULN should have avelumab treatment withheld. 
 
Avelumab administration should be delayed for the following drug-related AEs, 
clinically significant in the opinion of the investigator: 
• Any Grade 3 skin AE, or Grade 3 laboratory abnormality, with the following 
exceptions: 
− Grade 3 lymphopenia or leukopenia does not require dose delay. 
− However, patients with ALT or AST >5 x ULN or total bilirubin greater > 3 x 
ULN or creatinine >3 x ULN should have avelumab treatment interrupted. 
• Any AE, laboratory abnormality, or intercurrent illness, which in the judgment of the 
investigator, warrants delaying the dose of study medication. 
• Avelumab dose reductions are not permitted in this study (only dose delays when 
indicated). 
 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions: 


 
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• Subjects may resume treatment in the presence of Grade 2 fatigue 
• Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity 
• Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline 
or at least </= grade 1 before treatment is resumed 
• Drug-related endocrinopathies adequately controlled may resume treatment 
 
If the criteria to resume treatment are met, the subject should restart treatment at the 
next scheduled time point per protocol. However, if the treatment is delayed past the 
next scheduled time point per protocol, the next scheduled time point will be delayed 
until dosing resumes. Patients who receive combination therapy in whom continuation 
of 5-azacytidine is considered to be inadequate, or inappropriate (e.g., because of 
pancytopenia) can discontinue 5-azacytidine and continue with avelumab only. 
 
If treatment is delayed > 8 weeks, the subject must be permanently discontinued from 
study therapy, except as specified in discontinuation section. 
 
5.3.4 Avelumab Discontinuation Criteria 
The following ADRs require permanent treatment discontinuation of avelumab: 
 
---Any Grade 4 AEs require treatment discontinuation with avelumab except for 
single laboratory values out of normal range that are unlikely related to study 
treatment as assessed by the Investigator, do not have any clinical correlate, and 
resolve within 7 days with adequate medical management 
---Any Grade 3 AEs require treatment discontinuation with avelumab except for 
any of the following:  
 
- 
Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with 
medical management 
 
- 
Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis 
that resolves to Grade ≤ 1  
 
- 
Single laboratory values out of normal range (excluding Grade ≥ 3 liver function 
test increase) that are unlikely related to study treatment according to the 
Investigator, do not have any clinical correlate, and resolve to Grade ≤ 1 within 7 
days with adequate medical management 
 
- 
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites 
of known or suspected tumor 
 
- 
Change in ECOG PS to ≥ 3 that does not resolve to  2 within 14 days (infusions 
should not be given on the following cycle, if the ECOG PS is ≥ 3 on the day of 
study drug administration) 
 


 
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Any Grade 2 AEs should be managed as follows: 
 
- 
If a Grade 2 AE resolves to Grade ≤ 1 by the last day of the current cycle, 
treatment may continue. 
 
- 
If a Grade 2 AE does not resolve to Grade ≤ 1 by the last day of the current cycle, 
infusions should not be given on the following cycle.  If at the end of the 
following cycle the event has not resolved to Grade 1, the subject should 
permanently discontinue treatment with a avelumab AE (except for hormone 
insufficiencies, that can be managed by replacement therapy; for these hormone 
insufficiencies, up to 2 subsequent doses may be omitted).  
 
- 
Upon the second occurrence of the same Grade 2 AE (except for hormone 
insufficiencies that can be managed by replacement therapy) in the same subject, 
treatment with avelumab has to be permanently discontinued. 
 
- 
Infusion-related reactions, hypersensitivity reactions (Grades 1 to 4), and tumor 
lysis syndrome should be handled according to guidelines provided. 
 
•  Any dosing interruption lasting > 8 weeks with the following exceptions: 
o Dosing interruptions to allow for prolonged steroid tapers to manage drug- 
related adverse events are allowed. Prior to re-initiating treatment in a subject 
with a dosing interruption lasting > 8 weeks, the PI must be consulted. 
Tumor/Leukemia assessments should continue as per protocol even if dosing is 
interrupted. 
 
o Dosing interruptions > 8 weeks that occur for non-drug-related reasons may be 
allowed if approved by the PI. Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 8 weeks, the PI must be consulted. 
Tumor/Leukemia assessments should continue as per protocol even if dosing is 
interrupted. 
 
o Delays in start of subsequent cycles greater than 8 weeks will be acceptable only 
for patients who are deriving clinical benefit and after discussion with the PI of 
potential risk/benefit ratio  and documentation of this discussion in the patents 
medical record. 
 
5.3.5 
Detailed management algorithms for immune-oncology drug-related adverse 
events (including gastrointestinal, renal, pulmonary, hepatic, endocrine, skin and 
neurological) are provided in Table 3 below. These general guidelines constitute 
guidance to the Investigator and may be supplemented by discussions with the 
PI and IND Office in specific cases. 
Since inhibition of PD-L1 stimulates the immune system, immune-related AEs 
(irAEs) may occur.  Treatment of irAEs is mainly dependent upon severity 
(NCI-CTCAE grade): 


 
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Grade 1 to 2:  treat symptomatically or with moderate dose steroids, more 
frequent monitoring 
Grade 1 to 2 (persistent):  manage similar to high grade AE (Grade 3 to 4) 
Grade 3 to 4:  treat with high dose corticosteroids 
Table 3. Management of Immune-Related Adverse Events 
Gastrointestinal irAEs 
Severity of Diarrhea / Colitis 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue avelumab 
therapy 
Symptomatic treatment 
(for example, loperamide) 
Close monitoring for worsening 
symptoms 
Educate subject to report worsening 
immediately 
If worsens: 
Treat as Grade 2 or 3/4  
Grade 2 
Diarrhea:  4 to 6 stools per day 
over Baseline; IV fluids 
indicated < 24 hours; not 
interfering with ADL 
Colitis:  abdominal pain; blood 
in stool  
Delay avelumab therapy 
Symptomatic treatment 
If improves to Grade 1:  
Resume avelumab therapy 
If persists > 5 to 7 days or recur: 
0.5 to 1.0 mg/kg/day methylprednisolone 
or equivalent  
When symptoms improve to Grade 1, 
taper steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume 
avelumab therapy per protocol. 
If worsens or persists > 3 to 5 days with 
oral steroids: 
Treat as Grade 3 to 4 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools 
per day over Baseline; 
incontinence; IV fluids ≥ 24 hrs; 
interfering with ADL 
Colitis (Grade 3):  severe 
abdominal pain, medical 
intervention indicated, peritoneal 
signs 
Grade 4:  life-threatening, 
perforation 
Discontinue avelumab 
therapy per protocol 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
equivalent 
Add prophylactic 
antibiotics for 
opportunistic infections  
Consider lower endoscopy  
If improves:  
Continue steroids until Grade 1, then 
taper over at least 1 month 
If persists > 3 to 5 days, or recurs after 
improvement: 
Add infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab 
should not be used in cases of perforation 
or sepsis  


 
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Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 to 2  
Covering ≤ 30% body surface 
area  
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
Continue avelumab 
therapy 
If persists > 1 to 2 weeks or recurs:  
Consider skin biopsy  
Delay avelumab therapy 
Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent. Once improving, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy 
If worsens:  
Treat as Grade 3 to 4  
Grade 3 to 4 
Covering > 30% body surface 
area; life threatening 
consequences  
Delay or discontinue 
avelumab therapy 
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent  
If improves to Grade 1:  
Taper steroids over at least 1 month and 
add prophylactic antibiotics for 
opportunistic infections  
Resume avelumab therapy 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 
Radiographic changes only  
Consider delay of 
avelumab therapy  
Monitor for symptoms 
every 2 to 3 days  
Consider Pulmonary and 
Infectious Disease 
consults  
Re-image at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4  
Grade 2 
Mild to moderate new symptoms  
Delay avelumab therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily, 
consider hospitalization  
1.0 mg/kg/day methyl-
prednisolone IV or oral 
equivalent  
Consider bronchoscopy, 
lung biopsy  
Re-image every 1 to 3 days  
If improves:  
When symptoms return to near Baseline, 
taper steroids over at least 1 month and 
then resume avelumab therapy and 
consider prophylactic antibiotics 
If not improving after 2 weeks or 
worsening:  
Treat as Grade 3 to 4  


 
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Grade 3 to 4 
Severe new symptoms; New / 
worsening hypoxia; life-
threatening  
Discontinue avelumab 
therapy 
Hospitalize  
Pulmonary and Infectious 
Disease consults 
2 to 4 mg/kg/day 
methylprednisolone IV or 
IV equivalent  
Add prophylactic 
antibiotics for 
opportunistic infections  
Consider bronchoscopy, 
lung biopsy  
If improves to Baseline:  
Taper steroids over at least 6 weeks  
If not improving after 48 hours or 
worsening:  
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, 
IV immunoglobulin, or mycophenolate 
mofetil)  
Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 
Grade 1 AST or ALT > ULN to 
3.0 x ULN and / or total bilirubin 
> ULN to 1.5 x ULN  
Continue avelumab 
therapy 
Continue liver function monitoring  
If worsens:  
Treat as Grade 2 or 3 to 4  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN 
and / or total bilirubin > 1.5 to ≤ 
3 x ULN  
Delay avelumab therapy 
Increase frequency of 
monitoring to every 3 days  
If returns to Baseline:  
Resume routine monitoring, resume 
avelumab therapy 
If elevations persist > 5 to 7 days or 
worsen:  
 0.5 to 1 mg/kg/day methylprednisolone 
or oral equivalent and when LFT returns 
to Grade 1 or Baseline, taper steroids 
over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy 
Grade 3 to 4 
AST or ALT > 5 x ULN and / or 
total bilirubin > 3 x ULN  
Discontinue avelumab 
therapy  
Increase frequency of 
monitoring to every 1 to 
2 days  
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
Add prophylactic 
antibiotics for 
opportunistic infections  
Consult gastroenterologist 
If returns to Grade 2:  
Taper steroids over at least 1 month  
If does not improve in > 3 to 5 days, 
worsens or rebounds:  
Add mycophenolate mofetil 1 gram (g) 
twice daily  
If no response within an additional 3 to 5 
days, consider other immunosuppressants 
per local guidelines  


 
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Consider obtaining 
MRI/CT scan of liver and 
liver biopsy if clinically 
warranted  
Endocrine irAEs 
Endocrine Disorder 
Management 
Follow-up 
Asymptomatic TSH abnormality  
Continue avelumab therapy   
 If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range 
in 2 subsequent measurements: include T4 at subsequent cycles as 
clinically indicated; consider endocrinology consult  
Symptomatic endocrinopathies  
Evaluate endocrine 
function  
Consider pituitary scan  
Symptomatic with 
abnormal lab / pituitary 
scan:  
Delay avelumab therapy 
1 to 2 mg/kg/day 
methylprednisolone IV or 
by mouth equivalent  
Initiate appropriate 
hormone therapy  
No abnormal lab / 
pituitary MRI scan but 
symptoms persist:  
Repeat labs in 1 to 3 
weeks / MRI in 1 month  
If improves (with or without hormone 
replacement):  
Taper steroids over at least 1 month and 
consider prophylactic antibiotics for 
opportunistic infections  
Resume avelumab therapy  
Subjects with adrenal insufficiency may 
need to continue steroids with 
mineralocorticoid component  
Suspicion of adrenal crisis (for 
example, severe dehydration, 
hypotension, shock out of 
proportion to current illness)  
Delay or discontinue avelumab therapy  
Rule out sepsis  
Stress dose of IV steroids with mineralocorticoid activity  
IV fluids  
Consult endocrinologist  
If adrenal crisis ruled out, then treat as above for symptomatic 
endocrinopathies  
ADL = activities of daily living; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CT = computed tomography; irAE = immune-related adverse event; IV=intravenous; LFT = liver 
function test; LLN = lower limit of normal; MRI = magnetic resonance imaging; NCI-CTCAE = 
National Cancer Institute-Common Terminology Criteria for Adverse Event; T4 = free thyroxine; TSH 
= thyroid-stimulating hormone; ULN = upper limit of normal. 
 
5.3.6 Intra-patient dose re-escalation for patients who have had dose-reductions due to 
hematological or non-hematological toxicity: 
Once the MTD/RP2D has been established in the lead-in, the avelumab dose 


 
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will not be reduced or escalated during the phase II portion. Intra-patient dose re-
escalation of 5-azacytidine (in accordance with the dosing schema in table 1) will be 
permitted provided: 
  
• Patient has completed >/=1 cycle at their current dose level 
 
• Patient has not experienced any grade 3 or higher non-hematologic drug-related 
toxicity, and 
 
• Patient has not experienced drug-related hematologic DLT, and 
 
• At least 6 patients have been treated at the next higher dose level and followed for at 
least 28 days without experiencing DLT. 
 
• The dose may be escalated by one dose level per cycle (per table 1) provided such 
dose level does not exceed the established MTD/RP2D, whichever is lower. Dose 
level 0 is the maximum dose to be evaluated on this study. No dose escalation 
beyond dose level 0 will be permitted at any time on this study. 
 
5.3.7 Modifications of dose schedules other than the above will be allowed within the 
following guidelines: 
 
5.3.7.1 Dose adjustments by more than 1 dose level at a time (e.g., from 5-azacytidine 75 
mg/m2 to 25 mg/m2) can be considered when judged in the best interest of the 
patient (e.g. severe myelosuppression) when toxicity has resolved. The reason for 
this reduction will be discussed with the PI or Co-PI and documented in the medical 
record. 
 
5.3.7.2 A patient who has had a dose reduction because of any of the reasons mentioned 
above may have their dose escalated provided the patient has remained free of 
toxicity requiring dose adjustments as defined above for at least 1 month. Escalation 
will be made by 1 dose-level increment only, and not more frequent than every 
month. 
 
5.3.7.3 Treatment interruptions and dose modifications other than the ones mentioned above 
can be considered after discussion with the PI and proper documentation of the 
rationale. Dose adjustment/delay of only one of the agents is permissible if the 
toxicity is most likely judged to be related to one of the agents by the investigator 
(e.g., in patients with autoimmune thyroiditis or autoimmune hepatitis this would be 
likely secondary to avelumab, in patients with cytopenia’s this would be likely 
secondary to 5-azacytidine). 
 
5.4       Duration of Therapy 
In  the  absence  of  treatment  delays  due  to  adverse  events,  treatment  may 
continue until one of the following criteria applies: 


 
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1. Clinically significant progressive disease, or 
 
2. Intercurrent illness that prevents further administration of either treatment agent, or 
 
3. Patient request, or 
 
4. General or specific  changes  in  the  patient's  condition  render  the  patient 
unacceptable for further treatment in the judgment of the investigator, or 
 
5. Unacceptable toxicity that in the opinion of the investigator makes it unsafe to 
continue therapy. 
 
5.4.1    It is planned that up to a total of 24 cycles of therapy will be administered for 
patients deriving benefit from this regimen. Continuation of therapy for patients 
completing 24 cycles of therapy may be considered on a case- by-case basis 
after discussion with the principal investigator and IND Office. 
 
5.4.2. A minimum of 1 full course (defined as the  administration  of  5- azacytidine for 
7 days and one dose of avelumab) will be required for a patient to be considered 
as having received an adequate trial to evaluate efficacy. All patients receiving 
at least one dose of any of the two drugs will be considered evaluable for 
toxicity. 
 
5.5 
Supportive Care: 
Supportive care measures including blood products, infection prophylaxis and 
growth factors will be administered according to institutional and MDACC Leukemia 
Department guidelines. 
 
Management Algorithms for Treatment of Avelumab Related Adverse Events 
Immuno-oncology (I-O) agents are associated with AEs that can differ in 
severity  and   duration   than   AEs   caused   by  other   therapeutic   classes. 
Avelumab is considered an immuno-oncology agent in this protocol. Early recognition 
and management of AEs associated with immuno-oncology agents such as avelumab 
may mitigate severe toxicity. Avelumab has a known safety profile however, a general 
principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non- inflammatory etiologies should be considered and 
appropriately treated. Corticosteroids are a primary therapy for immuno-oncology drug-
related adverse events, and avelumab is no exception. The oral equivalent of the 
recommended IV doses may be considered for ambulatory patients with low-grade 
toxicities. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.


 
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Management Algorithms have been developed to assist investigators in 
assessing and managing the following groups of adverse events: 
Endocrinopathies, Gastrointestinal, Hepatic, Neurological Pulmonary, Renal 
and Skin. These algorithms are found in the “Avelumab Investigator Brochure” 
(Appendix C) and “Table 3. Management of immune related adverse events” of 
this protocol. The guidance provided in these algorithms should not replace the 
Investigator’s medical judgment but should complement it. 
 
Finally, consultation with a medical or surgical specialist, especially prior to an 
invasive diagnostic or therapeutic procedure, is highly recommended. 
 
5.6 
 Concomitant Medications 
Consistent with subject safety and comfort, administration of any prescription 
or over-the-counter drug products other than study medication should be minimized 
during the study period. Subjects should be discouraged from use of street drugs, 
herbal remedies, self-prescribed drugs, tobacco products, or excessive alcohol 
during the clinical study. 
 
If considered necessary for the subject’s wellbeing, drugs for concomitant medical 
conditions or for symptom management may be given at the discretion of the 
investigator. The investigator’s decision to authorize the use of any drug other than 
study drug should take into account subject safety, the medical need, the potential 
for drug interactions, the possibility for masking symptoms of a more significant 
underlying event, and whether use of the drug will compromise the outcome or 
integrity of the study. 
 
Subjects should be instructed about the importance of the need to inform the clinic 
staff of the use of any drugs or remedies (whether prescribed, over-the- counter, or 
illicit) before and during the course of the study. 
 
Recommendations with regard to specific types of concomitant therapies, 
supportive care; diet and other interventions are as follows: 
 
Concomitant medications are recommended as prophylaxis for nausea, vomiting, 
and infections, and are allowed for managing myelosuppression as shown in Table 
3. Myelosuppression is expected in patients with AML due to underlying disease, 
as well as due to chemotherapy (such as 5-azacytidine), or both. Most patients have 
neutropenia, thrombocytopenia, or both at study entry. Significant or life-
threatening myelosuppression may be managed with growth factor support and 
blood transfusion according to institutional standard of care, American Society of 
Clinical Oncology (ASCO) Practice Guidelines, and/or NCCN Practice Guidelines. 
 
Infections secondary to myelosuppression are common in patients with AML, and 
may be related to underlying disease, chemotherapy, or both. Therefore, the use of 
prophylactic antibiotics, antifungal agents, and antiviral agents is recommended 
according to institutional standards. 


 
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Since the effect of both avelumab and 5-azacytidine may be delayed, patients with 
high WBC counts may receive hydroxyurea prior to study entry. Hydroxyurea is 
allowed before the start of study therapy and during the study treatment. 
Hydroxyurea use would be recorded in the case report form (CRF). Concurrent 
therapy for CNS prophylaxis or continuation of therapy for controlled CNS disease 
is permitted. With the exception of these agents, concomitant systemic 
chemotherapy or radiation therapy is not permitted. Subjects are not allowed to 
participate concurrently in any other therapeutic clinical study. 
 
Subjects may be receiving systemic corticosteroids (daily doses ≤10 mg of 
prednisone or equivalent if indicated for adrenal replacement or antiemetic 
therapy), topical, or inhaled corticosteroids at study enrollment. They may receive 
systemic, topical, inhaled, or enteric corticosteroids while on study without 
limitation if they develop conditions that require corticosteroid therapy; such 
subjects are not required to discontinue study participation. 
 
All ongoing medications and therapies (including herbal products, nutritional 
supplements, and nontraditional medications) at screening will be considered prior 
medications. Concomitant medication data will not be collected or entered into the 
case report form other than hydroxyurea as mentioned above; however, the 
subject’s medication record will contain a list of concomitant medications. If a 
prohibited medication is inadvertently administered/ taken by the patient, the 
patient may remain on study as long as the prohibited medication is discontinued as 
soon as feasible. If a prohibited medication is considered essential for the patient 
well being, continuation on study with concomitant administration of such 
medication(s) will need to be discussed with and approved by the principal 
investigator and medical monitor 
 
Table 4: Instructions for the use of concomitant medications and therapies 
Category of Use 
Medication 
Comment on Use 
Restriction on Use 
Recommended 
Prophylactic 
antibiotics, 
antifungal agents, 
and antiviral agents 
Strongly encouraged 
None 
 
Antiemetic agents 
According to 
standard of care at 
MDACC 
None 
Allowed 
Oral allopurinol or 
rasburicase 
At investigators 
discretion 
 
None 
 
Leukapheresis 
According to 
standard of care at 
MDACC 
 
Before induction 1 
day 1 only 
 
Red blood cell 
None 
None 


 
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Category of Use 
Medication 
Comment on Use 
Restriction on Use 
transfusion 
 
 
 
Platelet transfusion 
None 
 
 
None 
 
White blood cell 
transfusion 
At investigators 
discretion according 
to standard of care at 
MDACC 
 
None 
 
Myeloid growth 
factors or platelet 
growth factor 
At investigators 
discretion according 
to standard of care at 
MDACC 
 
None 
 
Erythropoietin or 
darbepoetin 
 
At investigators 
discretion according 
to standard of care at 
MDACC 
 
None 
 
Any other 
medication for 
supportive care 
At investigators 
discretion according 
to standard of care at 
MDACC  
None 
 
 
6.0      STUDY MEDICATIONS 
 
6.1 Avelumab (Anti-PD1) 
Avelumab is a fully human, monoclonal antibody of the IgG1 isotype that 
specifically targets and blocks the ligand (PD-L1) for PD-1 and has a preserved Fc 
domain. Avelumab is a sterile solution intended for intravenous (IV) infusion. 
Avelumab will be available as a sterile, clear, colorless, and non-pyrogenic solution 
for intravenous infusion. Each single-use vial contains 200 mg of avelumab, 
formulated as a 20 mg/mL preservative free acetated buffered solution at pH 5.2 in 
presence of Polysorbate 20 and Mannitol. It will supplied in Type I glass vials filled 
with 10 mL of liquid (200mg/vial), closed with a rubber septum and sealed with an 
aluminium flip off seal. The vials are not subject specific although there will be 
specific vial assignments by subject distributed by the Pharmacy in order to track 
drug usage and re-supply. 
 
6.1.1 Dose Calculation of Avelumab 
The determined dose is based on the patients bodyweight at each visit.  
 
# of assigned vials for a patient = (Current weight x dose level)/ 200 (mg/vial) 


 
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For example, a subject weighing 70 kg who is scheduled receive a dose of 10 mg/kg 
would require 700 mg/ 200 (mg/vial) = 3.5 vials i.e. 4 vials have to be used for this 
patient. 
 
6.1.2 Preparation and Dispensing of Avelumab 
The product storage manager should ensure that the study drug is stored in 
accordance with the environmental conditions (temperature, light, and humidity) as 
determined by the Investigator Brochure for avelumab (Appendix C). If concerns 
regarding the quality or appearance of the study drug arise, do not dispense the study 
drug and contact the supporting company (Pfizer) immediately. To prepare the 
dilutions, subsequent preparation steps must be accomplished by adequate trained 
personnel to guarantee the sterility of the product to be injected. Preferred method is 
to prepare the solution under laminar flow box using aseptic techniques.  
 
Investigational product documentation must be maintained that includes all 
processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage 
temperatures, reconstitution, and use of required processes (e.g. required diluents, 
administration sets). 
 
Avelumab vials must be stored in the original packaging at a refrigerated conditions 
2°C to 8°C until use with a temperature log maintained daily and should be 
protected from light. Avelumab stored at room temperature 15-25°C or higher 
temperatures for extended periods of time might be subject to degradation. 
Avelumab must not be frozen. Recommended safety measures for preparation and 
handling of avelumab include laboratory coats and gloves. 
 
For details on prepared drug storage and use time of avelumab under room 
temperature/light and refrigeration, please refer to the Avelumab Investigator 
Brochure section (Appendix C) for “Recommended Storage and Use Conditions”. 
Care must be taken to assure sterility of the prepared solution, as the product does 
not contain any anti-microbial preservative or bacteriostatic agent. No 
incompatibilities between avelumab and polyolefin bags have been observed. 
 
6.1.3 Administration of avelumab 
Patients will receive avelumab as an approximately 60 minute (+/- 30 minutes) IV 
infusion on Day 1 and day 14 (+/-3 days) of a treatment cycle every 28 days for 4 
cycles or until CR (whichever occurs earlier) followed by a maintenance regimen 
(one dose of avelumab on day 1 of each cycle of 5-azacytidine). Dosing calculations 
should be based on the body weight assessed at the start of each cycle as described 
above. All doses should be rounded to the nearest milligram. The screening body 
weight may be used for dosing of cycle 1.  
 
Prior to the preparation of dilution for final infusion, allow each vial to equilibrate to 
room temperature (15-25 C) preferably for 30-50 minutes. Rough shaking of the 


 
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solution must be avoided. The administration must be performed by adequately 
trained personnel. For application in clinical trials, avelumab must be diluted with a 
saline solution (Sodium Chloride for injection). The prepared avelumab dilution for 
infusion is connected to the infusion set equipped with a PES-inline filter and a 22G 
IV standard catheter. Alternatively, a permanent venous catheter or implantable 
PORT may be used. Prior to infusion the assembly is primed with the diluent. The 
administration is to be conducted in approximately 60 minutes by IV infusion. A 
constant infusion rate is achieved by using a microprocessor-controlled infusion 
pump. Variations in infusion times due to minor differences in IV bag overfill/under 
fill and institutional procedure on flushing chemotherapy lines will not result in 
protocol deviation. All infusion times are considered approximate. It is 
recommended (nut not mandatory) that immediately following the infusion of 
avelumab, using the same tubing, 25-100 mL normal saline are flushed and infused 
at the same rate to clear the infusion set of residual drug.  
 
6.1.4  Patient Monitoring During Infusion 
During the first infusion patient vital signs should be monitored prior to dosing, 
approximately 15 minutes after initiation of the infusion (then approximately every 
15-20 minutes as indicated), at approximately 60 and 120 minutes after completion 
of the infusion, or longer if indicated, until the vital signs normalize or return to 
baseline. For subsequent infusions, vital signs should be collected prior to dosing, 
approximately every 30 minutes during dosing, and approximately 1 hour post 
dosing. There is a +/- 30-minute window allowed for all time points that vital signs 
are to be monitored. 
 
6.1.5 Treatment of avelumab Related Infusion Reactions 
Since avelumab contains only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. 
However, if such a reaction were to occur, it might manifest with fever, chills, 
rigors, headache, rash, pruritus, arthralgia’s, hypo- or hypertension, bronchospasm, 
or other symptoms. All Grade 3 or 4 infusion reactions should be reported within 5 
days to the Pfizer Medical Monitor and reported as an SAE if criteria are met. 
Infusion reactions should be graded according to NCI CTCAE (version 4.03) 
guidelines. 
 
Treatment recommendations for avelumab related infusion reactions, including 
severe hypersensitivity reactions and tumor lysis syndrome (TLS) are provided 
below and may be modified based on MD Anderson treatment standards and 
guidelines, as appropriate: 
A. 
Avelumab Infusion Related Reactions 
            Symptoms 
 Fever 
 Chills 
 Rigors 


 
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 Diaphoresis 
 Headache 
            Management 
Table 5. Treatment Modification for Symptoms of Infusion-Related Reactions  
NCI-CTCAE Grade  
Treatment Modification for Study Drug 
Grade 1 – mild 
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated. 
 
Decrease the study drug infusion rate by 50% 
and monitor closely for any worsening. 
The total infusion time for study drug should 
not exceed 120 minutes. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for example, antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic 
medications indicated for  24 h. 
 
Stop study drug infusion. 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any worsening. 
Grade 3 or Grade 4 – severe or 
life-threatening 
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
 
Stop the study drug infusion immediately and 
disconnect infusion tubing from the subject. 
Subjects have to be withdrawn immediately 
from study drug treatment and must not 
receive any further study drug treatment. 
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 
Once the avelumab infusion rate has been decreased by 50% or interrupted due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions.  If 
the subject has a second infusion-related reaction Grade ≥ 2 on the slower infusion 
rate, the event will be reviewed by  and discussed with the PI, and if felt to be in the 
best interest of the pt, and  the pt is receiving benefit, the pt may continue on study 
and receive avelumab at the 50% lower infusion rate for all subsequent cycles. 
If a subject experiences a Grade 3 or 4 infusion-related reaction at any time, the 
subject must discontinue study drug. 
B. Severe Hypersensitivity Reactions and Flu-Like Symptoms  
If hypersensitivity reaction occurs, the subject must be treated according to the best 
available medical practice. Subjects should be instructed to report any delayed 
reactions to the Investigator immediately. 


 
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For prophylaxis of flu-like symptoms, 25 mg of indomethacin or comparable 
nonsteroidal anti-inflammatory drug (NSAID) dose (for example, ibuprofen 600 mg, 
naproxen sodium 500 mg) may be administered 2 hours before and 8 hours after the 
start of each dose of avelumab IV infusion.  Alternative treatments for fever (for 
example, paracetamol) may be given to subjects at the discretion of the Investigator. 
C. Tumor Lysis Syndrome 
In addition, since avelumab can induce antibody-dependent cell-mediated 
cytotoxicity, there is a potential risk of tumor lysis syndrome.  Should this occur, 
subjects should be treated per the local guidelines and the management algorithm 
below (Howard 2011). 
 
 


 
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Assessment and Initial Management of Tumor Lysis Syndrome  
Measure serum potassium,  phosphorus, calcium, creatinine, uric acid, and urine output
No TLS at diagnosis
Assess cancer mass
Laboratory TLS
≥2 abnormal laboratory
test values
No symptoms
Small or resected
localized tumor
Medium‐size 
cancer mass
Large cancer mass
Bulky tumor or organ 
infiltration
Bone marrow replaced
with cancer
Assess cell‐lysis potential
Assess cell‐lysis potential
Low
High
Medium or
unknown
Low
High
Medium or
unknown
Negligible Risk
of Clinical TLS
No prophylaxis
No monitoring
Low Risk or
of Clinical TLS
Intravenous fluids
Allopurinol
Daily laboratory tests
High Risk of
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Laboratory tests every
6‐8 hr 
Established
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Intensive care unit
Laboratory tests every
4‐6 hr 
High Risk of
Clinical TLS
Intravenous fluids
Allopurinol or ras‐
buricase
Inpatient monitoring
Laboratory tests every
8‐12 hr 
Assess patient
presentation
Preexisting nephropathy
Dehydration
Hypotension
Nephrotoxin exposure
No
Yes
Clinical TLS
Acute kidney injury
Symptomatic hypo‐
calcemia
Dysrhythmia
 
TLS = tumor lysis syndrome 


 
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            For further details regarding dose-calculation of avelumab, preparation and 
dispensing of avelumab, administration of avelumab, patient monitoring during 
infusion and treatment of avelumab related infusion reactions please see the 
Avelumab dosing procedure manual (Appendix H). 
 
6.2     Azacytidine:  
5-azacytidine will be commercially obtained. Refer to azacitidine prescribing 
information (appendix D) in addition to institutional standards for preparation and 
administration azacitidine. 
6.3       Variations in infusion times of avelumab or 5-azacytidine due to minor differences 
in IV bag overfill/under fill and institutional procedure on flushing chemotherapy 
lines will not result in protocol deviation. All infusion times are considered 
approximate. 
 
6.4       Unused or expired avelumab and 5-azacytidine will be safely disposed according to 
MD Anderson pharmacy standard guidelines. 
 
7.0 PATIENT EVALUATION 
         Every effort will be made to adhere to the schedule of events and all protocol 
requirements. Variations in schedule of events and other protocol requirements that do 
not affect the rights and safety of the patient will not be considered as 
deviations.  Such variations may include laboratory assessments completed outside of 
schedule, occasional missed required research samples such as correlative assays. 
 
7.1 
Pre-Treatment Evaluation 
All pretreatment studies should be obtained within 14 days of entry into the 
trial, unless otherwise stated.  
 
7.1.1 A complete history and physical, documentation of all measurable 
disease, concomitant medications and performance status. 
 
7.1.2 CBC, platelet count, differential (differential can be omitted if WBC 
is ≤0.5 x109/L). 
 
7.1.3 Creatinine, total bilirubin, ALT or AST, sodium, potassium, chloride, 
glucose, uric acid, bicarbonate, BUN, calcium, magnesium, alk phos, 
direct bili.  
 
7.1.4 Pregnancy test (urine or plasma) in females of childbearing potential 
should be performed within 72 hours before initiation of protocol 
therapy. 
 
7.1.5 Bone marrow biopsy/aspirate during the last 28 days preceding study 
initiation. Cytogenetics will be obtained prior to therapy (results from 
prior analysis can be used for this purpose). 


 
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7.1.6 Pretreatment optional correlative studies (see below) 
 
7.1.7 Electrocardiogram (EKG) 
 
7.1.8 Routine urinalysis 
 
7.1.9 Chest X-ray 
 
7.1.10 TSH, free T3, free T4, free & total cortisol 
7.1.11 Respiratory PCR panel 
 
7.2 
Evaluation During Treatment 
 
7.2.1 Physical exam at the start of each cycle (± 4 days) and documentation 
of all concomitant medications. 
 
 
7.2.2 CBC, platelet count, differential twice weekly (4 days) for the first 3 
cycles, then every 2-4 weeks (differential can be omitted if WBC is 
≤0.5 x109/L) 
 
7.2.3 Creatinine, total bilirubin, ALT, or AST, calcium, magnesium, 
glucose, BUN, uric acid, fractionated bilirubin, alkaline phosphatase, 
sodium, potassium, chloride, bicarbonate twice weekly (4 days) for 
the first 3 cycles, then every 2-4 weeks.  
 
7.2.4 TSH, free T3, free T4, and free & total cortisol once monthly (4 
days) for the first 3 cycles, then every 3 months (4 days). 
 
7.2.5 Bone marrow aspiration on day 28 (+/- 7 days), then every 1-4 
cycles. Bone marrow tests can be ordered more frequently if 
mandated by development of peripheral blood counts. No repeat bone 
marrow is necessary if nonresponse or progressive disease can be 
unequivocally diagnosed from peripheral blood tests or, in patients 
with a WBC < 0.3 if the bone marrow test is considered 
noncontributory by the investigator at any time point. 
  
7.2.6 Concomitant medication data will not be collected or entered into the 
case report form except for concomitant hydroxyurea; however, the 
subject’s medication record will contain a list of concomitant 
medications. 
 
Correlative Studies relating to immunologic response (Optional):  
Tumor tissue, blood samples and bone marrow aspirate will be collected from patients under 
Z20160444 and will be sent to Dr. Marina Konopleva’s lab at MD Anderson for research 


 
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purposes (described below).  Patients will be consented separately on this  IRB approved 
consent for collection of additional material. Correlative laboratory studies will be 
conducted under this clinical trial protocol as described below.   
7.2.7 Patients may participate in the clinical study protocol irrespective of 
whether they choose to participate in the correlative studies. In tumor 
tissues, immunohistochemical studies will be performed to evaluate 
tumor and immunological cell markers such as CD4 and CD8 T cells. 
In peripheral blood, we will also evaluate tumor and immune cell 
populations including but not limited to CD4 and CD8 T cells in pre 
and post therapy samples. 
Proposed correlative studies to be performed: 
 
  Standard of Care tests done on all AML patients at MDACC: To 
analyze for the presence of common somatic mutations, we routinely 
perform a 53-gene/28-gene panel with validated, next-generation 
platform sequencing on DNA extracted from bone marrow samples in 
the CLIA-certified molecular laboratory at MD Anderson Cancer 
Center at pre-treatment and end of study (if available) assessment for 
all AML patients at MDACC. Multiparametric flow-cytometry for 
minimal residual disease (MRD) assessment in AML by validated 15 
color flow cytometry, cytogenetics, FISH and molecular markers (if 
mutated at baseline) at baseline and on treatment to assess for MRD 
will be done routinely at MDACC Hematopathology lab as standard 
of care. These data will automatically be available for all patients and 
will allow allow exploration of correlations between specific somatic 
mutations and/or cytogenetic aberrations and response in AML 
patients. 
 
 Multi-stain immunohistochemistry and validated immune relevant 
multiparametric flow-cytometry on bone marrow and peripheral 
blood at the above mentioned time-points on all patients to: (a) 
identify the immunophenotype of tumor-infiltrating T-lymphocytes 
(TIL): CD8+, CD4+ effector, or CD4+ regulatory, (b) determine the 
quantitative expression of immune ligands on AML blasts, MSCs and 
(c) determine the quantitative expression of positive and negative co-
stimulatory molecules on TILs pre- and post-therapy with the 
combination. For the analysis of the co-stimulatory ligands on 
leukemic blasts (defined as CD13+HLADR+CD33+CD38+), we 
have developed the “AML tumor ligand panel”: 4-1BBL, B7-1, B7-2, 
ICOSL, PDL-1, PDL-2, OX40L, CD40, CD27L, and CD137L. For 
the analysis of co-stimulatory molecules on T cells (CD4 T effector 
cells defined as CD3+CD4+Foxp3- cells; CD4 T regulatory cells 
defined as CD3+CD4+CD127-Foxp3+ cells, and CD8 T cells defined 
as CD3+CD8+) we have developed the “AML lymphocyte panel”: 4-
1BB, CTLA-4, CD28, ICOS, PD-1, OX40, CD40L, LAG-3 and TIM-
3. These studies may enable identification of prognostic and 


 
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predictive markers and enable the identification of other immune 
checkpoints of significance for future checkpoint based therapeutic 
approaches in AML. These studies may be performed in the 
Department of Leukemia and Immunotherapy platform using 
validated MFC (or Cytof panels that we are currently validating) or 
through Pfizer commercial vendors depending on the more 
financially viable option.  
 
Peripheral blood (up to 45 mL within 24 hours: about 3 tablespoons) 
will be collected in patients who consent to the correlative studies for 
testing of biomarkers at the following time points: 
-Baseline (prior to 5-azacytidine dose), on day 14 (prior to avelumab 
dose #2), and on day 28 (+/- 5) on cycle 1 (done at MD Anderson).  
-In cycle 2 blood sample will be obtained on day 14 (prior to 
Avelumab dose) when possible. 
-In cycle  4, 8, and 12 blood samples will be obtained on day 1 (prior 
to 5-azacytidine dose) and day 14 (prior to avelumab dose) when 
possible. 
All these tests can be +/- 5 days. 
-Samples will be collected at progression whenever possible.  
 
Bone marrow samples will be collected in patients who consent to 
the correlative studies for testing of biomarkers at baseline, at day 28 
(+/-5 days), at day 28 (+/- 5 days) of cycles 3, 7, and 11, and at 
progression (if possible).  
 
All correlative samples are optional. 
 
Missed samples for correlative studies will not constitute protocol 
deviations.  
 
7.2.8 For patients that remain on study with no significant toxicity for more 
than 6 months, subsequent evaluations during study may be modified 
after discussion with the principal investigator.  These include a 
decrease in frequency of bone marrow aspirations to every 6-12 
months (or as clinically indicated), correlative studies to every 6-12 
months (or suspension of sample collection for correlative studies), 
other laboratory tests to once every cycle. 
 
7.2.9 ALL treatments with avelumab must be administered at the MDACC 
outpatient clinic. The first cycle of azacytidine must be administered 
at the MDACC outpatient clinic. Subsequently, patients will have the 
option of receiving 5-azacytidine injections or infusions at the 
MDACC outpatient clinic or local ambulatory treatment center. We 
do not intend for the subjects to receive avelumab at any time at an 
outside physician’s office. During the first cycle all the laboratory 


 
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evaluations will be done at MDACC. Subsequently, the patient may 
have the laboratory work done at a local clinic and the results 
reported and filed by the MDACC research nurse for the study. The 
laboratory work done at the local clinic will be forwarded to the 
patient’s attending physician at MDACC or PI of the study, who will 
sign off on the labs to verify that the results have been reviewed. 
 
7.2.10 EKG beginning Cycle 2 on Day 1 (+/_5 days) for subsequent cycles. 
 
7.2.11 Urinalysis beginning Cycle 2 on Day 1 (+/- 5 days) for subsequent 
cycles. 
 
Outside Physician Participation During Treatment 
 
1. 
MDACC Physician communication with the outside physician is 
required prior to the patient returning to the local physician.  
This will be documented in the patient record. 
2. 
A letter to the local physician outlining the patient's participation in a 
clinical trial will request local physician agreement to supervise the 
patient's care (Appendix F). 
3. 
Protocol required evaluations outside MDACC will be documented 
by telephone, fax or e-mail. Fax and/or e-mail will be dated and 
signed by the MDACC physician, indicating that they have reviewed 
it. Changes in drug dose and/or schedule must be discussed with and 
approved by the MDACC physician investigator, or their 
representative prior to initiation, and will be documented in the 
patient record. 
4. 
A copy of the informed consent, protocol abstract, treatment schema 
and evaluation during treatment will be provided to the local 
physician. 
5. 
Documentation to be provided by the local physician will include 
progress notes, reports of protocol required laboratory and diagnostic 
studies and documentation of any hospitalizations. 
6. 
The home physician will be requested to report to the MDACC 
physician investigator all life threatening events within 24 hours of 
documented occurrence.  
7. 
All follow-up visits will be performed at MDACC.  
8.  
Changes in drug dose and/or schedule must be discussed with and 
approved by the MDACC physician investigator, or their 
representative prior to initiation, and will be documented in the 
patient record. 
 
7.2.12 Patients with an objective response at completion of active study 
treatment will be followed for survival at MD Anderson Cancer 
Center (MDACC) every 3 to 6 months for up to 5 years after 
completion of active treatment and while still on study. If the patient 


 
2016‐0444 
 
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is unable to return to MDACC the follow-up visits may be conducted 
via telephone. Every 3-6 months for up to 5 years after last dose of 
study drug patient will have a physical exam and blood (about 1-2 
teaspoons) will be drawn for routine testing. If the patient is unable to 
return to MD Anderson, they may be called by a member of the 
research staff and asked how they are feeling. 
 


 
 
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Table 6. The study assessment schema is shown in tabular form below 
 
Study Period/Cycle 
Scree
ning* 
Treatment 
End of 
Study 
(EOS)h,i 
Long‐Term 
Follow‐Up 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
Cyclesk 
Cycle Day 
1 
8 
14 
15 
22 
28 
1 
8 
14 
15 
22 
28 
1 
8 
14 
15 
22 
1 
30 Days 
After Last 
Dose 
Every 3‐6 
months 
Study Day 
‐14 to 
0 
1 
8 
 
15 
22 
 
29 
36 
 
43 
50 
 
5
7 
64 
70 
71 
78 
__ 
Complete history 
X 
X 
 
 
X 
 
 
X 
 
X 
 
Physical examinationa 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Vital Signs** 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Performance status 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
Document all 
measurable disease (if 
present) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medicationsa 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
ECGL 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
CBC with differentialb 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
Sodium, Potassium, 
Chloride, glucose, uric 
acid, bicarbonate, BUN, 
Creatinine, total 
bilirubin, direct bilirubin, 
calcium, magnesium, 
ALT, or AST, alk phosb 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
Routine Urinalysis 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
TSH, free T3, free T4c , 
free & total cortisol 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Pregnancy testd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspirate/ 
biopsye 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


 
 
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* Samples collected at screening do not need to be repeated on Day 1 of Cycle 1. 
**During the first infusion patient vital signs should be monitored prior to dosing, approximately 15 minutes after initiation of the infusion (then 
approximately every 15-20 minutes as indicated), at approximately 60 and 120 minutes after completion of the infusion, or longer if indicated, until the 
vital signs normalize or return to baseline. For subsequent infusions, vital signs should be collected prior to dosing, approximately every 30 minutes during 
dosing, and approximately 1 hour post dosing. 
aA complete physical examination and documentation of concomitant medications will be done on day 1 of each cycle (+/- 4 days). 
bThe specified labs must be done at least twice weekly (+/- 4 days) for the first 3 cycles, then every 2-4 weeks on subsequent cycles. The labs may be done 
more frequently than twice a week at the discretion of the treating physician and/or the PI. 
cTSH, free T3, free T4 will be done at least once monthly (+/- 4 days) after the start of therapy for the first 3 cycles, then every 3 months (+/- 4 days) on 
subsequent cycles. 
dPregnancy test either urine or plasma should be done in women of childbearing potential 72 hours before initiation of protocol therapy. 
eBone marrow aspiration must be done within 28-days (+/- 7 days) of initiation of therapy, then Day 28 (+/- 7 days) every 1-4 cycles. Cytogenetics may be 
used from prior bone marrow analysis if these were not reported on the screening bone marrow. 
fCorrelative studies will be collected on peripheral blood at baseline (prior to 5-azacytidine dose), on day 14 (prior to avelumab), and between days 21 to 28 
on cycle 1. Subsequently, peripheral blood will be obtained on days 1 and 14 of cycles 2, 4, 8, 12, and at progression if possible. All these tests can be +/- 5 
days.  Additional samples may be collected if the disease gets worse. 
gCorrelative studies will be collected on bone marrow at baseline, day 28 (+/-5 days), then on day 28 (+/- 5 days) of cycles 3, 7, 11 and at progression if 
possible.  
hEOS visitis include a physical examination, CBC with differential and platelets and a limited chemistry profile (total bilirubin, serum creatinine, SGPT or 
SGOT). A bone marrow aspiration may be done if non-response or progressive disease cannot be unequivocally diagnosed from peripheral blood.   
iSubject will be followed for toxicity for at least 30 days after the last protocol treatment. The 30-day follow-up visit (+ or – 3 days) will be scheduled as a 
Correlative 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent cycles 
EOS 
Optional 
correlatives on 
bloodf 
X 
 
 
Day 14 
Day 21‐28 
 
 
Day 14 
 
No 
 
No 
 
Day 1 and 14 of 
cycles 4, 8, 12 
If possible 
Chest X‐ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory PCR 
panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional 
correlatives on 
bone marrowg 
X 
 
 
 
C#1 Day 28 
 
 
 
C#2 Day 28 
 
 
 
C#3Day 28 
Day 28 of cycle 6, 
12 
If possible 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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clinic visits for clinical evaluation and physical examinations.  If the patient cannot make it to the MDACC clinic for this visit, the required follow up 
treatment procedures may be done with a local physician and the records forwarded to MDACC. The research nurse will contact the patient by telephone 
and get a verbal assessment of the patient’s condition. The phone conversation will then be documented in the patient’s charts. 
 j Every 3-6 months for up to 5 years after last dose of study drug patient will have a physical exam and blood (about 1-2 teaspoons) will be drawn for 
routine testing.  If the patient is unable to return to MD Anderson, they may be called by a member of the research staff and asked how they are feeling.   
k For patients that remain on study with no significant toxicity for more than 6 months, subsequent evaluations during study may be modified after 
discussion with the principal investigator.  These include a decrease in frequency of bone marrow aspirations to every 6-12 months (or as clinically 
indicated), correlative studies to every 6-12 months (or suspension of sample collection for correlative studies), other laboratory tests to once every cycle. 
 
L Perform at specified time-points and repeat as clinically indicated


 
 
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51
 
Data regarding adverse events will be collected during the study. Protocol specific data will 
be entered into PDMS/CORe. PDMS/CORe will be used as the electronic case report form 
for this protocol.. While investigators do not need to report all adverse reactions, they must 
be recorded. The Principal Investigator will sign and date the AE log per each patient at the 
completion of each course. Following signature, the AE log will be used as source 
documentation for the adverse events for attribution. 
 
Treatment may be discontinued for a variety of reasons, including patient withdrawal, 
investigator decision, and reasons specified by the protocol. Reasons for discontinuation of 
treatments are described in section 9.0. 
 
 
8.0 CRITERIA FOR RESPONSE: 
 
Response Criteria for AML 
 
Responses will be assessed by the International Working Group for AML 
[67]. Responders are patients who obtain a CR, CRi, or PR, with or without 
cytogenetic response, hematologic improvements, and morphologic 
leukemia-free state.  
 
Hematologic Improvement (HI): Hematologic response will be assessed by 
the MDS IWG response criteria (Cheson et al., Blood 2006) 
 
 
Erythroid response (E) (pretreatment Hgb <11 g/dL) 
 
Hgb increase by >/=1.5 g/dL 
 
 
Platelet response (P) (pretreatment platelets <100 x109/L) 
 
Absolute increase of >/=30 x 109/L for patients starting with > 
20 x 109/L platelets 
Increase from < 20 x 109/L to > 20 x 109/L and by at least 
100% 
 
 
Neutrophil response (N) (pretreatment ANC <1.0 x109/L) 
 
At least 100% increase and an absolute increase > 0.5 x 109/L 
 
 
Blast response (B) 
>/=50% reduction in peripheral blood or bone marrow blasts 
but still >5% 
 
8 
DISCONTINUATION OF TREATMENT: 
 
8.1 Discontinuation Criteria for Individual Patients 
 


 
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52
9.1.1 Patient Withdrawal 
Patients may voluntarily withdraw consent to participate in the clinical study at any 
time and without giving any reason. Their withdrawal will not jeopardize their 
relationship with their healthcare providers or affect their future care. Patients may 
also choose to withdraw from study treatment, but agree to remain in the study for 
follow-up procedures.  
 
9.1.2 Investigator Discontinuation of Patient 
The investigator may exercise medical judgment to discontinue study treatment if 
clinically significant changes in clinical status or laboratory values are noted. 
 
9.1.3 Criteria for Protocol-Defined Required Discontinuation of Treatment 
The protocol requires discontinuation of study treatment for the following reasons: 
1.  Patient requests discontinuation. 
2.  Unacceptable toxicity that in the opinion of the investigator makes it unsafe to     
continue therapy.  
3.   Clinically significant progressive disease.  
4.   Investigator discretion. 
 
9.1.4 Follow-Up at Treatment Discontinuation or Early Withdrawal 
Patients who discontinue treatment for any reason should complete end-of-treatment 
procedures when possible. End of treatment procedures will include a physical 
examination, CBC with differential and platelets and a limited chemistry profile 
(total bilirubin, serum creatinine, SGPT or SGOT). A bone marrow aspiration may 
be recommended only if non-response or progressive disease cannot be 
unequivocally diagnosed from peripheral blood. Although treatment will be 
discontinued at that time, all patients who do not withdraw consent for follow-up, 
die, or become lost to follow-up, will remain on study for follow-up evaluations. 
Subject will be followed for toxicity for at least 30 days after the last protocol 
treatment. The 30-day follow-up visit (+ or – 3 days) will be scheduled as a clinic 
visits for clinical evaluation and physical examinations. The Subject will then be 
followed every 3-6 months for up to 5 years after the last dose of study drug. If the 
patient cannot make it to the MDACC clinic for this visit, the required follow up 
treatment procedures may be done with a local physician and the records forwarded 
to MDACC. The research nurse will contact the patient by telephone and get a 
verbal assessment of the patient’s condition. The phone conversation will then be 
documented in the patient’s charts.  
 
9.2 Study Stopping Rules 
The principal investigator and MDACC IND office have the right to terminate this 
clinical study at any time. The principal investigator and MDACC IND office, as 
appropriate, will be involved in any decisions regarding terminating the study, 
temporarily suspending enrollment, or stopping ongoing treatment with study 
treatment. 
Reasons for terminating the clinical study or a study site’s participation include, but 


 
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53
are not limited to, the following: 
 
The incidence or severity of an adverse reaction related to treatment in this 
study or other studies indicates a potential health hazard to patients 
 
Data recording is significantly inaccurate or incomplete 
 
Study site personnel are noncompliant with study procedures 
 
Pattern of noncompliance is observed 
 
9.3 Protocol Violations and Deviations 
Protocol violations are defined as significant departures from protocol-required 
processes or procedures that affect patient safety or benefit potential, or confound 
assessments of safety or clinical activity. A protocol deviation is a departure from 
the protocol that does not meet the above criteria. Protocol violations or deviations 
may be grouped into the following classes: 
 
Enrollment criteria 
 
Study activities (missed evaluations or visits) except for those allowed per 
protocol 
 
Noncompliance with dose or schedule, including dose calculation, 
administration, interruption, reduction, or delay; or discontinuation criteria 
 
Investigational product handling, including storage and accountability 
 
Informed consent and ethical issues 
 
 
9 
ADVERSE EVENT REPORTING 
 
9.1 
Adverse event is any untoward medical occurrence that may present during   
treatment with a pharmaceutical product but which does not necessarily have 
a causal relationship with this treatment.  
 
 Adverse drug reaction is a response to a drug which is noxious and 
unintended and which occurs at doses normally used in man for prophylaxis, 
diagnosis, or therapy of disease or for the modification of physiologic 
function.  
 
 Assessing causal connections between agents and disease is fundamental to 
the understanding of adverse drug reactions. In general, a drug may be 
considered a contributory cause of an adverse event if, had the drug not been 
administered, 1) the event would not have happened at all, 2) the event 
would have occurred later than it actually did, or 3) the event would have 
been less severe. 
 
 The Investigator or physician designee is responsible for verifying and 
providing source documentation for all adverse events and assigning the 
attribution for each event for all subjects enrolled on the trial. 
 
9.2 
Serious Adverse Event Reporting (SAE) 


 
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54
 
An adverse event or suspected adverse reaction is considered “serious” if, in 
the view of either the investigator or the sponsor, it results in any of the 
following outcomes: 
 
 Death 
 A life-threatening adverse drug experience – any adverse experience 
that places the patient, in the view of the initial reporter, at immediate 
risk of death from the adverse experience as it occurred. It does not 
include an adverse experience that, had it occurred in a more severe 
form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse (21 CFR 312.32). 
 
 Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should 
be reported as an SAE if deemed appropriate by the Principal 
Investigator or the IND Office. 
 
 All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with 
the timeframes and procedures outlined in “The University of Texas 
M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs 
and Devices”. Unless stated otherwise in the protocol, all SAEs, 
expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the 
event). 
 
 
 All life-threatening or fatal events, that are unexpected, and related 
to the study drug, must have a written report submitted within 24 


 
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55
hours (next working day) of knowledge of the event to the Safety 
Project Manager in the IND Office.  
 
 Unless otherwise noted, the electronic SAE application (eSAE) will 
be utilized for safety reporting to the IND Office and MDACC IRB. 
 
 Serious adverse events will be captured from the time of the first 
protocol-specific intervention, until 30 days after the last dose of 
drug, unless the participant withdraws consent. Serious adverse 
events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event 
has stabilized, or there has been acceptable resolution of the event.  
 
 Additionally, any serious adverse events that occur after the 30 day 
time period that are related to the study treatment must be reported to 
the IND Office. This may include the development of a secondary 
malignancy. 
 
Reporting to FDA: 
 Serious adverse events will be forwarded to FDA by the IND Sponsor 
(Safety Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal 
Regulations, Good Clinical Practices, the protocol guidelines, the IND 
Office guidelines, and Institutional Review Board policy 
 
10.5      Investigator Communications with Pfizer 
All Serious Adverse Events must be reported to Pfizer Clinical 
Trial Department 
 All SAEs, whether related or unrelated to avelumab and all 
pregnancies must be reported to Pfizer (by the investigator or 
designee) within 24 hours.  
 All SAEs should be reported via confirmed facsimile (fax) 
transmission, or scanned and reported via electronic mail to:  
 
SAEs may be submitted directly via email.  
 
SAE Email Address: USA.AEReporting@pfizer.com 
SAE Fax Number: 1-866-997-8322 
 
11.0 
STATISTICAL CONSIDERATIONS 
This will be a single arm, single center, open label study of avelumab in 
combination with 5-azacytidine in patients with refractory, relapsed or untreated 
AML.  
 


 
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56
11.1 Sample Size 
 
Part a. Lead-in phase IB 
The primary objective of the lead-in phase is to determine the MTD and DLT of 
avelumab in combination with 5-azacytidine in patients with refractory/ relapsed 
AML during the first cycle (28 days). 12 - 18 participants will be accrued into lead-in 
part of the study.  
        
 Once safety of the MTD has been established, any patients still on study at a dose 
lower than MTD can be dose escalated up to MTD.  
 
Part b. Phase II  
 
The primary objective of the phase II is to determine the efficacy of avelumab in 
combination with 5-azacytidine in patients with refractory/relapsed or untreated 
AML. The efficacy of the combination will be measured by the overall response rate 
(ORR), defined as CR (complete remission) + CRp (complete remission with 
incomplete platelet recovery) + CRi (complete remission with incomplete count 
recovery) + PR (partial response) + morphologic leukemia fre state (MLFS)+HI 
within 3 months of treatment initiation among adult patients with refractory/ 
relapsed AML. ORR and toxicity will be monitored simultaneously using the 
Bayesian approach of Thall, Simon, Estey (1995, 1996) and the extension by Thall 
and Sung (1998).  
 
Up to 40 additional patients (excluding patients treated at the MTD from the lead-in 
part) will be recruited for the Phase II part.  
 
Total accrual: 12-18 patients from lead-in + 40 Phase II patients (N= 52 - 58 patients) 
 
11.2 
Statistical Design 
 
Part a. Lead-in phase IB 
The MTD is defined as the highest dose level with </= 1 out of 6 patients experience 
a DLT during the first 28 days of treatment. DLT is defined in section 5.2.2. The 
dosing schema for the combination treatment during the lead in phase is shown in 
Table 1 in section 5.2.1. 
A Toxicity Summary will be submitted to the IND Office Medical Monitor, after the 
first three evaluable patients have completed their first cycle, and every three 
evaluable patients thereafter, prior to dose modification, expansion, or phase II 
initiation.   
 
Part b. Phase II 
 
An Efficacy/Toxicity Summary will be submitted every five evaluable patients 
during Phase II.   


 
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57
The historical experience in relapsed/refractory AML patient population is that 
historical responses (CR/CRp/CRi/PR/HI/MLFS with >50% blast reduction) with 
single agent hypomethylator therapy (5-azacytidine or decitabine) or with 
hypomethylator combinations (azacytidine+revlimid, decitabine+myelotarg, 
azacytidine+vorinostat, decitabine+valproate) investigated at MDACC over the last 
10 years are 10% (Daver N, Kantarjian H et al., European Hematology Association 
Conference, June 2016). The target ORR with the experimental treatment is 30%. 
This regimen of the combination treatment will be considered worthy of further 
investigation if it elicits an increase in ORR to 30% with acceptable toxicity.  A 
>30% drug-related grade 3/4 toxicity rate is considered unacceptable.  Thus, interim 
monitoring rules, assuming the prior distributions above, were constructed that meet 
the following two conditions, 
1) 
Stop if   Prob{ p(ORR,E )<p(ORR,H)  + 0.20 | data> 0.975, or 
2) 
Stop if Prob{ p(TOX,E)>0.30| data}>0.975,  
where P(ORR, E) and P(TOX, E) are the true ORR and toxicity rates for the 
combination treatment, and p(ORR, H) is the true ORR rate of the standard treatment. 
The first rule provides for stopping the study if the data suggest that it is unlikely 
(i.e., probability < 2.5%) that ORR rate of the combination treatment is greater than 
the ORR rate of standard treatment by 20.0%. The second condition will stop the 
study early if excessive therapy-related grade 3/4 toxicity (>30%) is highly probable 
(i.e., probability >97.5%) for the combination treatment.  Monitoring for toxicity and 
futility will not begin until 5 patients have been evaluated, and cohort size for future 
evaluations is 5. 
The monitoring rule for the toxicity rate, based on these assumptions and monitoring 
conditions above is found in Table 7. For example, accrual will cease if 4 or more 
patients experience toxicities among the first 5 patients. 
 
Table 7. Stop accrual if the number of drug-related grade 3/4 toxicities is greater than or 
equal to indicated (i.e., # patients with toxicities) among the number of patients evaluated 
# patients evaluated  
5 
10 
15 
20 
25 
30 
35 
40 
# patients with 
toxicities 
4-5 
7-10 
9-15 
11-20 
13-25 
15-30 
17-35 
Always stop 
 
Monitoring the ORR rate, based on the above assumptions and monitoring conditions 
is found in Table 8.  For example, accrual will cease if no patients experience an 
overall response within 3 months of initiation of therapy in the first 10 patients 
treated. 
Table 8. Stop accrual if the number with overall response is less than or equal to indicated 
(i.e., # patients with overall response) among the number of patients evaluated 
# patients evaluated  
5-10 
15 
20 
25 
30 
35 
40 


 
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58
# patients with overall response 
0 
0-1 
0-2 
0-3 
0-4 
0-5 
Always stop 
 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility 
stopping boundaries and the OC table (Table 9). In order to utilize the software for the 
design, a beta (0.2, 1.8) was assumed for the experimental treatment response prior 
distribution and a constant rate of 10% for the standard treatment, respectively. For 
response stopping criterion, the shif parameter delta was 0.20. In addition, a 30% 
toxicity constant rate and beta (0.6, 1.4) priors were assumed for the standard treatment 
toxicity constant rate and experimental treatment toxicity prior distribution, 
respectively. 
The probability of stopping the study early if the true ORR of the combination 
treatment was 30% and the true toxicity rate was 30% was 25%.  Probabilities of 
stopping early for high true toxicity rates (i.e., 50%) were 45% when the true ORR was 
30% and 95% when true ORR rate was 10%. 
 
Table 9.  Operating characteristics for simultaneous monitoring response and toxicity rates 
for patients treated with combination treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.10 
0.10 
0.9294 
 
0.20 
0.5119 
 
0.30 
0.2029 
 
0.40 
0.0817 
 
0.50 
0.0319 
0.20 
0.10 
0.9300 
 
0.20 
0.5156 
 
0.30 
0.2090 
 
0.40 
0.0887 
 
0.50 
0.0393 
0.30 
0.10 
0.9339 
 
0.20 
0.5429 
 
0.30 
0.2535 
 
0.40 
0.1400 
 
0.50 
0.0934 
0.40 
0.10 
0.9512 


 
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59
Table 9.  Operating characteristics for simultaneous monitoring response and toxicity rates 
for patients treated with combination treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
 
0.20 
0.6623 
 
0.30 
0.4486 
 
0.40 
0.3648 
 
0.50 
0.3303 
0.50 
0.10 
0.9803 
 
0.20 
0.8637 
 
0.30 
0.7774 
 
0.40 
0.7436 
 
0.50 
0.7297 
 
Statistical Analysis Plan 
All patients who received any dose of the study agent will be included in the analysis 
for efficacy and safety.  Demographic/clinical characteristics (including duration of 
response) and safety data of the patients will be summarized using descriptive statistics 
such as mean, standard deviation, median and range. For the primary efficacy analysis, 
we will estimate the ORR for the combination treatment, along with the 95% credible 
interval. For the efficacy, a sample size of 40 patients ensures a posterior 95% credible 
interval for ORR of (0.17, 0.43), if the trial is not terminated early, under the 
assumption of a 30% ORR.  Patients who drop out of the study before completing all 
the cycles will be treated as “failures” for the primary analysis. ORR during the study 
period will also be presented with the 95% confidence credible. The association 
between ORR and patient’s clinical characteristics will be examined by Wilcoxon’s 
rank sum test or Fisher’s exact test, as appropriate. Toxicity type, severity and 
attribution will be summarized for each patient using frequency tables.  
The distribution of time-to-event endpoints (DFS and OS) including overall survival 
and progression free survival will be estimated using the method of Kaplan and Meier. 
Comparisons of time-to-event endpoints by important subgroups will be made using 
the log-rank tests. Paired t-tests will be used to determine the immunological and 
molecular changes in the peripheral blood and bone marrow from baseline to the time 
of response, and to the time of disease progression. Correlation analysis (such as 
logistic regression analysis) will be conducted to determine the relationship between 
induction of hypomethylation / DNA damage and clinical response.    
 
A Toxicity Summary will be submitted to the IND Office Medical Monitor, after the 
first three patients have completed their first cycle of study therapy or administration is 


 
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60
discontinued, whichever comes first, and every three evaluable patients thereafter 
during the Lead-in Phase IB. 
 
An Efficacy/Toxicity Summary will be submitted every five evaluable patients during 
Phase II. 
 
Statistical analysis of biomarker data: Descriptive statistics including plots, mean, 
median and standard deviations will be used to summarize data. For continuous 
outcomes, t-test and ANOVA will be used to compare outcome measures across patient 
characteristics. Dunnett’s and Tukey’s test that properly adjust for multiplicity in 
multiple tests will be implemented. Pairwise comparisons will be performed using pre- 
and post-therapy samples from each patient . The chi-square test or Fisher’s exact test 
will be used to test the association between two categorical variables such as disease 
state and performance status. Both univariate and multivariate logistic regressions will 
be performed to model prognostic factors. 
 
12.0 
PROTOCOL ADMINISTRATION 
This study will be monitored by the MD Anderson IND Office and a protocol-specific 
monitoring plan will be followed. 
 
Protocol amendments 
 
Changes to the protocol will be made only when protocol amendments have been 
signed by the principal investigator and approved by Pfizer and the IRB of the study 
center. 
 
Archival of data 
 
MD Anderson-IND study must retain all records indefinitely.   
 
 
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