Clinical trial NCT03390296
Conditions: Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia
Sponsor: M.D. Anderson Cancer Center
Start date: 2017-12-27; Completion date: 2022-02-04
Enrollment: 50 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase Ib/II trial studies the side effects and best dose of anti-OX40 antibody PF-04518600 (OX40) and how well it works alone or in combination with venetoclax, avelumab, glasdegib, gemtuzumab ozogamicin, and azacitidine in treating patients with acute myeloid leukemia that has come back or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as OX40, avelumab, and gemtuzumab ozogamicin, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Glasdegib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as venetoclax and azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving OX40, venetoclax, avelumab, glasdegib, gemtuzumab ozogamicin, and azacitidine may work better in treating patients with acute myeloid leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the safety of multiple combination regimens of IO-agents (PF04518600 \[Ox40 agonist monoclonal antibody (mAb)\], avelumab \[PD-L1 antagonist mAb\], hypomethylator therapy (azacitidine), anti CD33 mAb (gemtuzumab ozogamycin, GO), Bcl-2 inhibitor (venetoclax) and smoothened pathway inhibitor (glasdegib) in patients with relapsed/refractory (RR) acute myeloid leukemia (AML).

II. To evaluate the composite complete response (CRc) defined as complete response (CR) + complete response with incomplete recovery of platelets (CRp) + complete response with incomplete recovery of counts (CRi) within 3 months of therapy initiation in patients with RR AML of: Arm A. PF-04518600 alone, Arm B. azacitidine + venetoclax + GO, Arm C. azacitidine + aveluma + GO, Arm D. azacitidine + venetoclax + avelumab, Arm E. Azacitidine + avelumab + PF-04518600, Arm F. GO + glasdegib.

SECONDARY OBJECTIVES:

I. To assess the morphologic leukemia free survival (MLFS), partial response (PR), hematologic improvement (HI) rate of patients with RR AML treated on arms A-F.

II. To assess relapse-free survival (RFS), time to next therapy (TNT), 4-week and 8-week mortality, and overall survival (OS) of patients with RR AML treated on arms A-F.

III. To assess minimal residual disease (MRD) by multiparametric flow-cytometry at response (+/- 1 month) and assess correlation of MRD to OS in arms A-F.

EXPLORATORY OBJECTIVES:

I. To study immunological and molecular features at baseline and at predefined time-points on-therapy with each combination in the peripheral blood and bone marrow to include quantification of immune ligand expression by the AML/myelodysplastic syndrome (MDS) blasts and AML/MDS stromal components (myeloid-derived suppressor cell \[MDSC\]s, monocytes and mesenchymal stem cell \[MSC\]s) including galectin 9, 4-1BBL, ICOSL, PD-L1, PD-L2, OX-40L, CD137L, others.

II. To study immunological and molecular features at baseline and at predefined time-points on-therapy with each combination in the peripheral blood and bone marrow to include determination of the quantitative expression of positive and negative co-stimulatory molecules including 4-1BB, CTLA-4, ICOS, PD-1, OX40, LAG-3, TIM-3, HLA-DR, Ki67, others on T-lymphocyte subsets.

III. To study immunological and molecular features at baseline and at predefined time-points on-therapy with each combination in the peripheral blood and bone marrow to include identification of the immunophenotype of tumor-infiltrating T-lymphocytes (TILs) pre- and post-therapy including CD8+, CD4+ effector, CD4+ regulatory TILs and central memory, effector memory, and naive T-cell subsets among the CD4 and CD8 populations.

IV. To develop a micro-array based gene expression profile (GEP) predictor of response to the immune combinations using either baseline ribonucleic acid (RNA) sequencing and/or nanostring.

V. To perform a validated next generation sequencing (NGS)-based analysis for the detection of somatic mutations in the coding sequences of 28 genes commonly mutated in AML at baseline and on treatment to identify baseline predictors and clonal evolution on treatment and/or whole exome sequencing (WES) in selected cases.

VI. To identify clonal T-cells by performing T-cell repertoire analysis at baseline and longitudinally on therapy on the peripheral blood and/o bone marrow samples.

VII. To assess levels of cytokines at baseline and longitudinally on therapy in peripheral blood and/or bone marrow.

OUTLINE: This is a phase I, dose escalation study of anti-OX40 antibody PF-04518600 followed by a phase II study. Patients are assigned to 1 of 6 arms.

ARM A: Patients receive anti-OX40 antibody PF-04518600 intravenously (IV) over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive azacitidine IV over 10-40 minutes or via injection subcutaneously (SC) on days 1-7 or 1-5 and 8-9. Patients also receive venetoclax orally (PO) on days 1-28 and GO IV over 2 hours on day 8. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive azacitidine and GO as in Arm B. Patients also receive avelumab IV over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM D: Patients receive azacitidine and venetoclax as in Arm A and avelumab as in Arm C. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM E: Patientss receive azacitidine and avelumab as in Arm C and anti-OX40 antibody PF-04518600 as in Arm A. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM F: Patients receive GO IV over 2 hours on days 1, 4, and 7, and glasdegib PO on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After conclusion of study treatment, patients are followed up at 30 days, then every 3-6 months for up to 5 years.

Arms: arm 1: Patients receive anti-OX40 antibody PF-04518600 IV over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive azacitidine IV over 10-40 minutes or via injection SC on days 1-7 or 1-5 and 8-9. Patients also receive venetoclax PO on days 1-28 and GO IV over 2 hours on day 8. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive azacitidine and GO as in Arm B. Patients also receive avelumab IV over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 4: Patients receive azacitidine and venetoclax as in Arm A and avelumab as in Arm C. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 5: Patients receive azacitidine and avelumab as in Arm C and anti-OX40 antibody PF-04518600 as in Arm A. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 6: Patients receive GO IV over 2 hours on days 1, 4, and 7, and glasdegib PO on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Anti-OX40 Agonist Monoclonal Antibody PF-04518600 intervention 2: Avelumab intervention 3: Azacitidine intervention 4: Gemtuzumab Ozogamicin intervention 5: Glasdegib intervention 6: Glasdegib Maleate intervention 7: Venetoclax intervention 8: Azacitidine
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV or SC intervention 4: Given IV intervention 5: Given PO intervention 6: Given PO intervention 7: Given PO intervention 8: Given IV or SC

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2017-0337 
11/10/2020 
 
Page 1 of 103 
 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2017-0337 
Protocol Title 
An Open-label Phase IB/II Multi-arm Study of OX40 agonist monoclonal 
antibody (mAb), anti-PDL1 mAb, smoothened inhibitor, anti-CD33 
mAb, Bcl-2 inhibitor, and azacitidine as single-agents and/or 
combinations for the Treatment of Patients with Acute Myeloid 
Leukemia (AML) 
Protocol Phase 
IB/II 
Protocol Version 
20 
Version Date 
11/10/2020 
 
Protocol PI 
Naval Daver, M.D. 
Department 
Leukemia 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
136570 
 
 
 


Protocol 2017-0337 
11/10/2020 
 
Page 2 of 103 
 
 
 
 
An Open-label Phase IB/II Multi-arm Study of OX40 agonist 
monoclonal antibody (mAb), anti-PDL1 mAb, smoothened 
inhibitor, anti-CD33 mAb, Bcl-2 inhibitor, and azacitidine as 
single-agents and/or combinations for the Treatment of Patients 
with Acute Myeloid Leukemia (AML) 
 
 
 
 
 
Principal Investigator: Naval Daver, M.D.  
Co-Chairs: Hagop Kantarjain, M.D and Nicholas Short, M.D 
Sponsor: University of Texas, MD Anderson Cancer Center 
IND number: 136570 
 
 
 
University of Texas 
 
 
MD Anderson Cancer Center 
Leukemia Department, Unit 428 


 
 
Page 3 of 103 
 
1.0 
OBJECTIVES 
 
1.1 
Primary Objectives  
1. To evaluate the safety of multiple combination regimens of IO-agents [PF04518600 
(Ox40 agonist mAb), avelumab (PD-L1 antagonist mAb)], hypomethylator therapy 
(azacitidine), anti CD33 mAb (gemtuzumab ozogamycin, GO), Bcl-2 inhibitor 
(venetoclax) and smoothened pathway inhibitor (glasdegib) in patients with 
relapsed/refractory (RR) AML. 
 
2. To evaluate the composite complete response (CRc) defined as CR + complete 
response with incomplete recovery of platelets (CRp) + complete response with 
incomplete recovery of counts (CRi) within 3 months of therapy initiation in patients with 
RR AML of:  
Arm A. PF-04518600 alone,  
Arm B. Azacitidine + venetoclax + GO 
Arm C. Azacitidine + avelumab +GO 
Arm D. Azacitidine + venetoclax + avelumab 
Arm E.  Azacitidine + avelumab + PF-04518600, 
Arm F. GO + glasdegib  
 
1.2 
Secondary Objectives: 
 
-To assess the morphologic leukemia free survival (MLFS), partial response (PR), 
hematologic improvement (HI) rate of patients with RR AML treated on arms A – F 
-To assess relapse-free survival (RFS), time to next therapy (TNT), 4-week and 8-week 
mortality, and overall survival (OS) of patients with RR AML treated on arms A – F. 
-To assess minimal residual disease (MRD) by multiparametric flow-cytometry at 
response (+/- 1 month) and assess correlation of MRD to OS in arms A – F.  
 
1.3 
Exploratory Objectives: 
1. To study immunological and molecular features at baseline and at predefined time-
points on-therapy with each combination in the peripheral blood and bone marrow to 
include: (a) quantification of immune ligand expression by the AML/MDS blasts and 
AML/MDS stromal components (MDSCs, monocytes and MSCs) including galectin 9, 
4-1BBL, ICOSL, PD-L1, PD-L2, OX-40L, CD137L, others and (b) determination of the 
quantitative expression of positive and negative co-stimulatory molecules including 4-
1BB, CTLA-4, ICOS, PD-1, OX40, LAG-3, TIM-3, HLA-DR, Ki67, others on T-
lymphocyte subsets  and (c) identification of the immunophenotype of tumor-infiltrating 
T-lymphocytes (TILs) pre- and post-therapy including CD8+, CD4+ effector, CD4+ 
regulatory TILs and central memory, effector memory, and naïve T-cell subsets among 
the CD4 and CD8 populations. These analysis will be done using multiparametric flow-
cytometry (MFC) or multi-stain immunohistochemistry (IHC)  
 
2. To develop a micro-array based gene expression profile (GEP) predictor of response 
to the immune combinations using either baseline RNA sequencing and/or nanostring.  
 
3. To perform a validated NGS-based analysis for the detection of somatic mutations in 
the coding sequences of 28 genes commonly mutated in AML at baseline and on 
treatment to identify baseline predictors and clonal evolution on treatment and/or 
whole exome sequencing (WES) in selected cases.  


 
 
Page 4 of 103 
 
 
4. To identify clonal T-cells by performing T-cell repertoire analysis at baseline and 
longitudinally on therapy on the peripheral blood and/o bone marrow samples. 
 
5. To assess levels of cytokines at baseline and longitudinally on therapy in peripheral 
blood and/or bone marrow. 
 
2.0 
BACKGROUND 
 
2.1 RELAPSED/REFRACTORY AML 
 
Therapy for AML has improved only modestly over the last four decades. Traditional 
induction chemotherapy produces cure rates of 30% in adults with AML1-3. Patients with 
relapsed AML have an overall survival of 1 to 4 months with standard salvage therapy 4,5. 
We have previously reported a dismal median OS (3.8 months) for patients with AML who 
are refractory to high-dose cytarabine (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 group6 and from others 7,8 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 myelodysplastic syndrome 
(MDS).  
 
2.2 IMMUNOTHERAPY IN LEUKEMIA 
 
Although the role of antibodies that target PD-1 and other checkpoint pathways has 
been established in solid tumor malignancies and FDA approved for melanoma and non-
small cell lung cancer, there remains a very limited experience in incorporating immune 
checkpoint modulating agents in the therapy of leukemias. This is surprising for many 
reasons. First, leukemias are the quintessential immune responsive tumor type, as 
proven by the success of allogeneic stem cell transplantation (allo-SCT). Second, having 
an immune cell lineage, leukemias often express immune checkpoint molecules that are 
absent in solid tumor cells thereby offering direct targets for immune checkpoint 
inhibition. Third, a number of studies have demonstrated encouraging results with 
immune checkpoint inhibition in other hematologic malignancies including: Hodgkin’s 
lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and multiple myeloma9,10 
 
2.2.1 Role of PD-1/PD-L1 interactions in AML 
            A major anti-tumor inhibitory mechanism is up-regulation of programmed death-ligand 1 
(PD-L1) on tumor or stromal cells or tumor infiltrating lymphocytes (TILs), which binds to 
programmed death-1 (PD-1) on activated CD8+ T cells 11-14. The PD-1/PD-L1 pathway has 
been shown to play a major role in immune evasion and cytotoxic T-cell exhaustion in 
hematologic malignancies including AML and MDS and may be associated with AML 
progression 7,8,15,16. Activation of PD-1 results in in immune evasion and exhaustion of 
tumor-infiltrating CD8+ cytotoxic T-lymphocytes (CTLs) in human and murine AML 7. 
Zhang et al. noted that elevated PD-1/PD-L1 expression significantly blunted the anti-
leukemic effects of CD8+ CTLs in murine AML models 7. Anti-PD1 and/or anti-PD-L1 
antibodies augmented anti-tumor CD8+ CTL responses by preventing CD8+ exhaustion, 
resulting in decreased AML burden in the blood and other organs, and increased 
survival in mice. Zhou et al have demonstrated that AML progression in a murine model 


 
 
Page 5 of 103 
 
is associated with elevated PD-1 expression on CTLs and increased T-regulatory cells at 
the tumor site8. 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. 
 
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) 6. Patients with a greater degree of up regulation of these checkpoint molecules 
had a higher propensity for resistance to epigenetic therapy. Bone marrow samples from 
healthy donors were used as control for these studies. 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 AML17 . Another confirmation of the negative impact of 
PD-L1 overexpression in patients with AML was obtained by interrogating the NEJM 
TCGA data by cBioportal. Patients with AML with increased PD-L1 mRNA had an 
inferior OS. Thirdly, in leukemia, PD-1 and CTLA4 have been shown to play a role in 
leukemia, and graft versus host disease (GvHD), and their overexpression was clearly 
associated with a more aggressive leukemia16  
 
The role of other checkpoint pathways including OX40 in AML/MDS has not been 
published in functional studies. However, we have developed expression data for these 
checkpoint pathways in 75 AML patients in collaboration with the immunotherapy-
platform at MDACC (Pam Sharma, Jim Allison). 
 
            2.2.2 PD1, PD-L1, OX40, 4-1BB and other immune checkpoint receptor expression 
in AML (Data from Department of Leukemia and Immunotherapy Platform, 
MDACC)  
To define the immune landscape of AML we performed 17-color multi-parametric flow-
cytometry (MFC) on BM aspirates from 36 patients with untreated AML and 39 patients 
with relapsed AML to assess the expression of costimulatory ligands (4-1BBL, B7-1, B7-
2, ICOSL, PD-L1, PD-L2, 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+ (Williams P, et al ASH 2017 Oral presentation, 
abstract # 185): see updated data in section 2.6.1. Eight healthy human BMs were used 
as controls. Blasts and T-cells were evaluated at the same time-point. OX40 and PD-1 
positive TILs were significantly higher in untreated AML BM as well as relapsed AML BM 
as compared to healthy donor BM. AML patients had significantly increased OX40+ TILs 
as compared to healthy control marrow across all three lymphocyte subsets interrogated 
including CD4 effector, T regs, and cytotoxic CD8+ cells. Similarly AML patients had 
significantly increased PD-1+ TILs as compared to healthy control BMs across these 
three lymphocyte subsets. Furthermore, PD-1+ and OX40+ TILs were significantly higher 
in relapsed AML BM as compared to newly diagnosed untreated AML15 There was 
significant variability in BM expression of costimulatory receptors and ligands between 
individual patients. The expression of costimulatory receptors and ligands differed 
significantly between BM and PB from the same time-point in the same patient with 
higher expression in the BM T-cells on most occasions. A larger sample size is needed 


 
 
Page 6 of 103 
 
to confirm these data and find additional associations, and this is currently underway at 
our institution. 
 
Thus, clinically targetable checkpoint receptors including PD-1, OX40 and potentially 
others are overexpressed in the BM of patients with AML. These findings in baseline BM 
samples from AML patients (especially in relapsed AML) support the proposed clinical 
trials of OX40 and/or PD-L1 checkpoint blockade with avelumab combinations in AML. 
 
Figure 1: PD-1 expression in AML T-lymphocyte subsets 
 
 
Figure 2: OX40 expression in AML T-lymphocyte subsets 
 
 
 
 
 
2.2.3 CD33 monoclonal antibodies in AML (GO, Mylotarg) 
0
10
20
25
30
35
40
45
50
50
60
70
80
90
100
% cells expressing marker indicated
CD4+Teff
Treg
CD8+
**
**P < 0.006
New
Relapse
Normal
* P < 0.05
*
*
*
**
**
****
***
**
**P < 0.006
New
Relapse
Normal
0
1
2
3
4
5
5
10
15
20
25
30
50
100
150
% cells expressing marker indicated
*
*
* P < 0.05
***P < 0.0005
CD4+Teff
Treg
CD8+
***


 
 
Page 7 of 103 
 
 
CD33 is a member of the sialic acid-binding immunoglobulin-like lectins (Siglecs) and is 
a myeloid differentiation antigen 18 primarily expressed at very early stages on myeloid 
progenitors. CD33 is highly (>90%) expressed on AML blasts 19. Conjugated antibodies 
were engineered with the intention of improving the anti-tumor efficacy of CD33 
antibodies by leveraging the endocytolytic property of CD33.  
 
Thus far the largest clinical experience with a monoclonal antibody in AML has been with 
GO, a humanized CD33-directed antibody drug conjugate (ADC) covalently linked to a 
semisynthetic derivative of a potent DNA-damaging toxin calicheamicin. In 2000, GO 
was granted accelerated approval by the United States FDA 20 on the basis of a 30% 
overall response rate (CR + CRi) in phase II clinical trials 21 in patients with AML in first 
relapse 22. Response duration was difficult to determine due to the high prevalence of 
post-remission therapies, however, responses were relatively short.  
 
However, no difference in OS was observed in the subsequent phase III SWOG S0106 
trial designed to meet FDA post-approval requirements 23. The lack of clear clinical 
benefit, concerns about increased side effects, and slightly increased early death rate 
with GO in this SWOG trial 23, led to voluntary withdrawal of the drug from United States 
markets.  
 
Particular concerns were related to life-threating sinusoidal obstruction syndrome or 
veno-occlusive disease, which was more likely to occur when the drug was used in 
higher concentration, in combination with hepatotoxic agents, or within three months of 
allogeneic stem cell transplant (SCT) (incidence rate 9-14%) 24. The postulated 
mechanisms included either dissociation of calicheamicin from the anti-CD33 antibody 
causing direct toxic effect to hepatocytes or uptake of GO by CD33(+) cells residing in 
the hepatic sinusoids 25. The potential benefits of GO in this trial might have been 
masked due to a suboptimal dosing schema as well as failure to perform patient 
subgroup analysis.  
 
Subsequently, large randomized trials investigated GO in addition to standard induction 
chemotherapy in adults with newly diagnosed AML. These studies 26-28 showed 
statistically improved OS when GO was added to standard induction, particularly in 
younger patients with intermediate and/or favorable risk cytogenetics,  
 
In older patients, the addition of GO to cytotoxic induction regimens improved the 
relapse risk, event-free survival and overall survival without improving the response rate 
or early mortality rate28,29. In a meta-analysis of these randomized clinical trials, the 
addition of GO significantly reduced the risk of relapse (HR 0.8; 95%CI 0.72-0.89, 
p<0.001), improved relapse free (HR 0.8; 95%CI 0.76-0.94, p=0.001) and overall 
survival (HR 0.89; 95%CI 0.82-0.97, p=0.01), particularly in patients without adverse 
cytogenetics 30. These data led to the reassessment of the role of GO in AML 31,32. These 
multiple datasets con- firmed the clinical benefit of GO in patients with AML and led to its 
FDA approval in September 2017 for the treatment of newly diagnosed or relapsed/ 
refractory CD33þ AML in adults, and pediatric patients 2 years of age and older.  
  
 
Currently, clinical trials are ongoing to evaluate the efficacy and toxicity of GO either as a 
monotherapy or in combination with chemotherapy in frontline (France) and relapsed 
(United States) patients with AML, including its addition to standard conditioning prior to 


 
 
Page 8 of 103 
 
ASCT [ClinicalTrials.gov: NCT01869803, NCT02473146, NCT02221310].  
 
The leukemic cell lysis by CD33 directed payload will result in the release of intracellular 
products that may serve as neoantigens to prime the T-cells.  GO is being filed with the 
FDA for approval in July, 2017 and it is expected that it will be favorably reviewed by the 
ODAC resulting in re-introduction of GO to the US market. Combination strategies with 
GO are being developed to further enhance the single-agent response. Inhibition of 
smoothened hedgehog signaling by cyclopamine induced monocytic differentiation in 
AML (HL-60) cell lines33. The CD33 expression is preserved in cell lines after 
smoothened inhibition. Furthermore, GO and glasdegib have independent modes of 
action and non-overlapping toxicities making them suitable for combination approaches. 
 
 
2.2.4 Hedgehog signaling in AML 
 
The hedgehog (Hh) protein family is a group of secreted intercellular signaling molecules 
34. This pathway plays critical role in proliferation, differentiation and migration of 
embryonic cells during embryonic development 35-37. The hedgehog pathway also plays 
a key role in primitive and adult hematopoesis 38-40 and regulates entry of cells into cell 
cycle 41, inhibition of apoptosis 42 and maintenance of self-renewal of stem-cells in 
various tissues 43. In humans, the Hh family consists of three distinct ligand, Sonic (Shh), 
Indian (Ihh) and Desert (Dhh). Ihh is found most specifically within hematopoietic cells 39. 
In absence of Hh ligand Patched (Ptch) suppresses the Hh pathway by inhibiting the 
activation of Smoothened (Smo) – a constitutively activated 7-transmembrane receptor 
44-46. When Hh ligand binds the Ptch receptor, the latter is deactivated, resulting in 
Smoothened (Smo) being released into the cytoplasm. Smo can then initiate a signaling 
cascade that activates members of the Glioma associated oncogene homologs (Gli) 
family of zinc-finger transcription factors. Activated Gli translocates to the nucleus and 
regulates transcription of Hh target genes which act as regulators of cell proliferation, 
survival and apoptosis 47. Mutations in genes encoding proteins involved in the Hh 
pathway such as Ptch and Smo (ligand independent mechanism) have been reported in 
basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma 48,49. In addition to 
mutations in components of Hh signaling, several cancers have been shown to 
abnormally express the Hh ligand; including small cell lung cancer, pancreatic, colon, 
gliomas, multiple myeloma, Chronic Myeloid Leukemia (CML) and B-cell lymphoma 50-53. 
Conversely, inhibition of Hedgehog signaling by cyclopamine (a steroid alkaloid that 
inhibits Hh signaling via Smo) can induce significant tumor regression, as demonstrated 
in human engrafts of medulloblastoma 54, human xenografts of prostate cancer 55 and 
pancreatic adenocarcinoma cell lines 56 
 
Ihh and its receptor molecules have been shown to be highly expressed in cord blood 
CD 34+ stem cells 43.  Hh components Ptch and Smo are expressed in several leukemic 
cell lines; including Jurkat cells 57. Similarly, Shh and Gli are expressed in human 
Promyelocytic leukemia (HL-60) and KG-1 cells. Interestingly, these components were 
detectable in primary acute leukemic cells, but not acute lymphoblastic cells 58. Kobune 
et. al. studied the function of Hh signaling in acute leukemic cells including CD 34+ cells 
using both reverse transcription-polymerase chain reaction (RT-PCR) for Hh pathway 
components and a Gli- responsive receptor assay 34. They found that Ihh was expressed 
in six out of seven leukemic cell lines; except for NB4. Similarly; Gli1 was detected in six 
out of seven cell lines and Gli2 was detected in all seven cell lines. It has been 
demonstrated that Gli1 and Gli2 are the prime transcriptional factors involved and 


 
 
Page 9 of 103 
 
constitutive activation of at least one of them is of critical importance in cancer 
development 59-61. It is known that Ihh contributes to the proliferation of cord blood 
CD34+ stem progenitor cells 62. To study the effect of Ihh signaling in leukemic cell lines, 
CD34+ leukemic stem cells were exposed to chemical inhibitor cyclopamine. They 
observed a dose-dependent decrease in percent survival of all leukemic cell lines, 
although no changes were observed on exposure to control compound tomatidine. Thus, 
Ihh signaling plays an important role in growth and survival of these leukemic cells. 
Similarly, they were able to show that blockage of Ihh signaling by cyclopamine 
increased the expression of annexin V+: a marker of apoptosis. Thus, Ihh signaling 
induces apoptosis in CD34+ leukemic stem cells. 
 
2.3 DRUG INFORMATION 
 
2.3.1 PF-04518600 (OX40 mAb): Drug Information summary 
PF-04518600 is a fully human IgG2 agonistic mAb specific for human OX40. PF-
04518600 binds with high affinity to human OX40 protein. On human T cells in culture, 
PF-04518600 promoted T-cell proliferation and cytokine secretion only when T cells 
were activated and PF-04518600 was plate bound. PF-04518600 binds cynomolgus 
monkey OX40 with a lower affinity. With high concentration of anti-CD3 activation, 
similar downstream signaling of monkey OX40 by PF-04518600 was observed, such as 
activation of NFκB and IL-2 secretion. In addition, a mouse surrogate antibody (OX86 
mIgG1) demonstrated anti-tumor activity in a syngeneic CT26 tumor model. 
 
Treatment with a combination of OX86 mIgG1 and a mouse anti-4-1BB IgG1 surrogate 
antibody further inhibited tumor growth compared to single antibody treatment or an 
isotype control in the CT26 murine colon carcinoma model. In a less immunogenic B16-
F10 murine melanoma model, combination treatment significantly enhanced tumor T-cell 
infiltration and T-cell proliferation. 
 
After single IV dosing of PF-04518600 to cynomolgus monkeys, mean CL values ranged 
from 0.003 to 0.009 mL/min/kg, and mean Vss ranged from 0.042 to 0.123 L/kg resulting 
in mean t½ values ranging from 8 to 15 days. In the repeat-dose toxicity study, there 
were no apparent sex-related differences in systemic exposure (as assessed by Cmax 
and AUC168) within a dose group for all dose groups. In addition, mean systemic 
exposure increased with increasing dose and was higher on Study Day 22 compared to 
Study Day 1. ADA was detected in all dose groups. 
 
Based on the PK observed in cynomolgus monkeys, the PK of PF-04518600 in humans 
is expected to have a CL of 1.55 mL/kg/day, a Vc of 31.3 mL/kg, and t½ of 
approximately 25 days.  
 
In the pivotal 1-month repeat-dose toxicity study in cynomolgus monkeys, no direct 
organ toxicities were observed as would be expected for a target that is only minimally 
expressed on a small number of immune cells. Minimal evidence of pharmacology, 
(increases in proliferating Ki67+, CD4+ and CD8+ effector memory T cells and in HLA-
DR+ monocytes) was seen at all dose levels (1-100 mg/kg/week) in the 1-month monkey 
study and exposure margins ranged from approximately 24-3800-fold (based on AUC) 
over the proposed clinical starting dose of 0.01 mg/kg. In addition, PF-04518600 was 
well tolerated at doses up to the highest dose tested, with an NOAEL established at 100 
mg/kg, administered weekly by IV injection. At the end of the dosing phase in the 1-
month study, Cmax and AUC associated with this dose were 5360 μg/mL and 537000 


 
 
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 
g•h/mL, following repeated weekly administration. The exposure margin (based on 
AUC) at the NOAEL was approximately 3800-fold and was calculated based on 
estimated human exposures at the proposed starting dose of 0.01 mg/kg in the planned 
FIP clinical study (B0601002). 
 
No effects on inflammatory cytokines (IL-1, IL-2, IL-4, IL-6, IFN-g, and TNF) were 
observed in the single dose exploratory monkey study within the first 48 hours postdose. 
Furthermore, in in vitro cytokine release assays, PF-04518600 did not induce production 
of  IFN-γ, IL-6, or TNF in human whole blood or non-stimulated PBMC’s. Based on these 
data, the overall risk from PF-04518600-induced cytokine release in humans is low. In 
addition, combination of PF-04518600 and UTOMILUMAB (anti-4-1BB mAb) did not 
induce cytokine secretion from either non-stimulated or stimulated T cells, which 
supports further exploration of the combinatorial treatment in patients. 
 
In the first-in-patient study (FIP), Protocol B0601002, PF-04518600 monotherapy (Part 
A) is being studied in cancers that are considered to be amendable to immunotherapy, 
including advanced or metastatic hepatocellular carcinoma (HCC), melanoma, clear cell 
renal cell carcinoma (RCC), and head and neck squamous cell carcinoma (HNSCC). 
PF-04518600 will also be studied in combination with UTOMILUMAB (anti-4-1BB mAb, 
see UTOMILUMAB Investigator Brochure) in Protocol B0601002 Part B in patients with 
advanced or metastatic melanoma, head and neck squamous cell carcinoma (HNSCC), 
non-small cell lung cancer (NSCLC), bladder, gastric or cervical cancers, who are 
unresponsive to existing therapies, for whom no standard treatment is available, or who 
have declined standard therapy. Preliminary clinical data from 9 patients in Part A1 
indicate that PF-04518600 is well tolerated. 
 
Overall, the nonclinical package and the preliminary clinical experience with PF- 
04518600 support the safety and design of Protocol B0601002 for both single agent 
treatment and in combinations.. 
 
For further details on preclinical toxicity and safety, dosage, and clinical information 
please see the latest version of the PF-04518600 IB attached as Appendix. 
 
2.3.2 Avelumab (PDL1 mAb): Drug information summary 
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 (company code: MSB0010718C) 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. 
 
Physical, chemical, and pharmaceutical properties and formulation 
The active pharmaceutical ingredient in avelumab drug product is a fully human antibody 
(calculated molecular weight of 143832 Dalton) of the immunoglobulin G (IgG) 1 isotype 
that specifically targets and blocks PD-L1, the ligand for PD-1. 
 
Avelumab drug product is a sterile, clear, and colorless concentrate for solution intended 
for intravenous (iv) infusion. The drug is presented at a concentration of 20 mg/mL in 
single-use glass vial containing 200 mg of avelumab. 


 
 
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Avelumab drug product must be stored at 2°C to 8°C until use, and it must not be frozen. 
Rough shaking of avelumab product must be avoided. Avelumab drug product must be 
diluted with 0.9% saline solution; alternatively a 0.45% saline solution can be used if 
needed. It is recommended that the diluted avelumab solution is used immediately. 
 
Nonclinical pharmacology 
The nonclinical pharmacology studies have shown that avelumab functionally enhances 
T cell activation in vitro and significantly inhibits the growth of PD-L1 expressing tumors 
in vivo.  
 
Avelumab binds to human PD-L1 with a high affinity of 0.7 nM and not to any other B7 
family proteins, and competitively blocks the interaction of PD-L1 with PD-1. The in vitro 
study results have shown that by binding to PD-L1, avelumab effectively enhances T cell 
activation as measured by interleukin (IL)-2 or interferon-gamma (IFN-g production. In 
addition, as a fully human IgG1 antibody, avelumab has the potential to trigger the 
antibody-dependent cell-mediated cytotoxicity (ADCC) against target cells expressing 
PD-L1. 
 
As a monotherapy, avelumab has demonstrated anti-tumor activity against murine MC38 
colon carcinoma tumors that are characterized by a high level of PD-L1 expression. A 
dose-dependent trend was observed, and 400 μg per dose (20 mg/kg, approximately) 
was identified as the optimally effective dose when given every third day for 3 total 
doses. 
 
The in vivo anti-tumor effects were found to be primarily mediated by CD8+ T cells as 
evidenced by the observation that in vivo depletion of this cell type completely abrogated 
the anti-tumor efficacy of avelumab. The contribution of ADCC as a potential mechanism 
of anti-tumor activity was further demonstrated in vivo using a deglycosylated version of 
avelumab to abrogate fragment crystalline (Fc) receptor binding or via the systemic 
depletion of natural killer (NK) cells. In both settings, loss of in vivo ADCC potential 
significantly reduced the anti-tumor activity. 
 
The combination of avelumab with commonly used cancer treatments, such as cytotoxic 
agents and radiation therapy, resulted in an improved anti-tumor activity. Chemotherapy 
with combination therapy (with folinic acid, 5-fluorouracil, and oxaliplatin [FOLFOX], and 
radiation therapy showed the better tumor growth inhibition. In particular, radiation 
therapy was found to be a highly synergistic combination with avelumab capable of 
causing complete regression of established tumors probably through generating anti-
tumor immune memory. 
 
Various immunomonitoring assays were incorporated into the in vivo studies. Treatment 
with avelumab resulted in a consistent increase in the percentage of CD8+PD-1+ T cells 
and an increased frequency of CD8+ T cells with an effector memory (TEM) phenotype 
as determined by flow cytometry. Furthermore, these changes correlated with the anti-
tumor effect. Increases in tumor antigen-specific T cell responses, as measured by 
enzyme-linked immunosorbent spot and pentamer immunoassays, were evident 
following treatment with avelumab and these responses were enhanced when combined 
with FOLFOX or radiation. Hence, increases in CD8+PD-1+ T cells, CD8+ TEM cells, 
and antigen-specific T cell responses, may be leveraged as pharmacodynamics (PD) 
biomarkers with translational relevance to the clinical setting. 


 
 
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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.  
 
Initial CRA in human and cynomolgus monkey whole blood and PBMCs revealed no 


 
 
Page 13 of 103 
 
clear-cut evidence for release of pro-inflammatory cytokines. However, a subsequent, 
optimized CRA demonstrated evidence of potential cytokine release in PHA pre-
stimulated PBMCs. 
 
Clinical safety 
Avelumab is currently in clinical development across Phases I, II, and III. The attached 
updated version of the IB (Appendix) includes safety data from the following 4 clinical 
trials: 
 EMR 100070-001: A Phase I, open-label, multiple ascending dose trial to investigate 
the safety, tolerability, pharmacokinetics, biological and clinical activity of avelumab in 
subjects with metastatic or locally advanced solid tumors and expansion to selected 
indications 
 EMR 100070-002: A Phase I trial to investigate the tolerability, safety, 
pharmacokinetics, biological and clinical activity of avelumab in Japanese subjects with 
metastatic or locally advanced solid tumors, with expansion part in Asian subjects with 
gastric cancer 
 EMR 100070-003: A Phase II, single arm, open-label, multicenter trial to investigate 
the clinical activity and safety of avelumab in subjects with Merkel cell carcinoma (MCC) 
 EMR 100070-004: A Phase III open-label, multicenter trial of avelumab versus 
docetaxel in subjects with non-small cell lung cancer that has progressed after a 
platinum-containing doublet 
 
EMR 100070-001 is a Phase I, open-label, multiple ascending dose trial to investigate 
the safety, tolerability, PK, biological and clinical activity of avelumab in subjects with 
metastatic or locally advanced solid tumors and expansion to selected indications. This 
trial consists of 2 parts. In the dose escalation part, sequential cohorts of subjects were 
enrolled at progressively higher dose levels (ranging from 1.0, 3.0, 10.0, and 20.0 mg/kg 
once every 2 weeks) with a 3 + 3 algorithm design for determination of the maximum 
tolerated dose (MTD) of avelumab; in the treatment expansion phase, subjects in 
different tumor cohorts are being treated with 10 mg/kg of avelumab once every 2 weeks 
until, confirmed progression, unacceptable toxicity, or any reason for withdrawal occurs. 
More than 1500 subjects have been enrolled in the EMR 100070-001 trial. The 
3 + 3 dose escalation algorithm to determine the MTD is complete and a dose of 10 
mg/kg once every 2 weeks was determined for the tumor expansion cohorts on the basis 
of safety, PK, and PD observations. The treatment expansion part of the trial consists of 
16 tumor treatment cohorts. As of 05 November 2015 (data cutoff for a pre-planned 
safety data review by the study Safety Monitoring Committee [SMC]), 53 subjects in the 
dose escalation part had received avelumab (4, 13, 15, and 21 subjects had received 
1.0, 3.0, 10.0, and 20.0 mg/kg of avelumab, respectively) and 1300 subjects in the 
pooled expansion part had received 10 mg/kg avelumab and were followed up for at 
least 4 weeks. 
 
The safety summary for this Investigator’s Brochure summarizes data from 1300 
subjects treated in the pooled treatment expansion cohort from the ongoing Phase I Trial 
EMR 100070-001 (as of 05 November 2015). The pooled data included subjects treated 
in all tumor expansion cohorts, including non-small cell lung cancer (NSCLC), metastatic 
gastric cancer, breast cancer, colorectal cancer, castrate-resistant prostate cancer, 
adrenocortical carcinoma, melanoma, mesothelioma, urothelial 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 


 
 
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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 the IB (appendix) 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 median PFS of this group was 11.9 weeks (95% CI: 6.0 to 12.3 weeks). 
 
For further details on preclinical toxicity and safety, dosage, and clinical information 
please see the latest version of the PF-04518600 IB attached as Appendix. 
 


 
 
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2.3.3 Azacitidine (Vidaza®): Drug Information Summary  
Azacitidine, 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, azacitidine 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 azacitidine in the treatment of AML. Clinical studies 
subsequently evaluated the effects of 5-azacitidine 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 azacitidine in patients with MDS. These studies, in 
addition to other supportive data, led to the approval of Vidaza® (azacitidine) in May 
2004 for the treatment of MDS.  
 
Azacitidine inhibits the methylation of newly synthesized DNA by inhibiting DNA 
methyltransferase (DNMT).66-68 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.69 It is now widely recognized 
that hypermethylation of DNA is frequently associated with myelodysplastic syndromes 
and other cancers,70-72 such as renal,73 melanoma,74 breast,75 colorectal,76 non-small cell 
lung77 and hematologic malignancies.78 Azacitidine is believed to exert its antineoplastic 
effects through hypomethylation and cytotoxicity on abnormal hematopoietic cells in the 
bone marrow.79-83 Hypomethylation may restore normal function to genes that are critical 
for differentiation and proliferation.69,84,85 The cytotoxic effects of azacitidine cause the 
death of rapidly dividing cells, including cancer cells that are no longer responsive to 
normal growth control mechanisms.79,86-88  
 
The cytotoxicity of azacitidine is proportional to dose and exposure time.79,80 Although 
the mechanisms of cytotoxicity are complex and multifaceted, there is general 
agreement that incorporation of azacitidine into DNA and ribonucleic acid (RNA), and 
inhibition of protein synthesis, are critically important.89 Cytotoxicity is greatest in cells 
that are proliferating (S phase) and metabolically active.79 Cytotoxic effects may also be 
mediated through induction of the DNA damage response pathways.88 Nonproliferating 
cells are relatively insensitive to azacitidine.79  
 
Toxicology studies have been conducted in mice, rats, dogs, and Rhesus monkeys.90 
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 azacitidine.90 In single-dose studies, 
the lethal dose of azacitidine after intravenous (IV) administration in mice, rats, and dogs 
was approximately 250 mg/m2. Repeated daily dosing appears to increase the toxicity of 
5-azacitidine.90 The genotoxicity of azacitidine is consistent with that of other nucleoside 
analogs that interact with nucleic acids.90 Likewise, similar to other agents with cytostatic 
properties, azacitidine was embryotoxic and reduced the reproductive performance in 
mice and rats.90 
 
Limited azacitidine pharmacokinetic data are currently available. Based on human 
plasma concentrations of total radioactivity (which represents parent drug plus 
circulating metabolites), azacitidine is rapidly absorbed when given subcutaneously 


 
 
Page 16 of 103 
 
(SC), with maximum plasma concentrations found 0.5 to 2 hours after dosing.90 
Azacitidine 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 azacitidine have not been studied.90 A single dose (75 mg/m2) SC 
versus IV crossover study in 6 MDS subjects91 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 
azacitidine 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 azacitidine 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 azacitidine. In addition, azacitidine 
75 mg/m2 was generally well-tolerated after single SC injection or IV infusion over 
10 minutes.91  
 
A number of studies have looked at different parenteral doses and schedules of 
azacitidine, finding maximum tolerated doses of up to 500 mg/m2 when administered 
weekly.92 
 
During the two decades between the start of the CALGB studies and the approval of 
azacitidine, 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.93 Using the IWG 
response criteria in MDS patients, response rates were between 40% and 70% in 
azacitidine 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 azacitidine was 19.3 
months compared with 12.9 months for the 25 patients assigned to observation.93 
 
A randomized international Phase III trial (Study azacitidine 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.94 Patients were randomized to azacitidine (75 mg/m2/day x 
7days in 28 day cycles) or conventional care regimens (CCR), where CCR was pre-
selected by 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 azacitidine or CCR. This trial did not 
allow erythropoietin. Three hundred fifty eight patients (70% male) were randomized at 
79 centers to azacitidine (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 azacitidine 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. 
Azacitidine was administered for a median of 9 cycles; low-dose cytarabine for 4 cycles. 


 
 
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Median follow-up for the survival analysis was 21.1 months. Azacitidine 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 azacitidine arms compared to CCR: 51% 
vs. 26% (p<0.0001). Azacitidine was well tolerated with safety data consistent with 
previous reports.  
 
Further details can be found in the azacitidine drug information (Appendix), which 
contains comprehensive pharmacology, toxicology, pharmacokinetics, 
pharmacodynamics, metabolism, preclinical, and clinical efficacy and safety data 
information. 
 
2.3.4 Gemtuzumab Ozogamicin (Mylotarg®, CD33 mAb): Drug Information 
Summary 
Please see the updated GO INVESTIGATOR BROCHURE 2016 (Appendix), which 
contains comprehensive pharmacology, toxicology, pharmacokinetics, 
pharmacodynamics, metabolism, preclinical, and clinical efficacy and safety data 
information. 
 
2.3.5 Glasdegib: Drug Information Summary 
PF-04449913 (Glasdegib) is a potent and selective inhibitor of Hedgehog (Hh) signaling 
in vitro and has demonstrated significant antitumor efficacy in vivo. In a mouse model of 
Hh pathway-driven tumor (medulloblastoma), glasdegib inhibits pathway activation(Gli1 
expression) and produces rapid and complete tumor regression. Glasdegib also reduced 
leukemic burden in a blast crisis chronic myeloid leukemia mouse model, and inhibited 
tumor formation in secondary recipients. Preclinical pharmacokinetic/ pharmacodynamic 
(PK/PD) modeling suggests a target human dose of 15 mg/day is projected to yield at 
least 50% of tumor Gli1 mRNA inhibition from baseline levels. 
 
Absolute oral bioavailability of glasdegib following single dose oral administration was 
33% in rats and 68% in dogs. Plasma protein binding of glasdegib in mouse, rat, dog, 
and human plasma ranged from 85% to 93%. After repeat dose administration in rats 
and dogs, glasdegib Cmax and AUC24 values increased in a greater than dose-
proportional manner with no sex differences in drug exposure. Following oral 
administration of [14C]glasdegib to pigmented rats, distribution of [14C]glasdegib-
derived radioequivalents was widespread in most tissues with no quantifiable levels of 
radioequivalents detected after 8 hours in most tissues, except in the uveal tract and the 
eye. 
 
The in vitro metabolic profiles of glasdegib was consistent across evaluated preclinical 
species and humans; all metabolites observed in human in vitro incubations were 
present in one or more of the evaluated preclinical species. Glasdegib appeared to be 
metabolized to several oxidative metabolites in vitro as well as in vivo. In vitro, CYP3A is 
the predominant enzyme mediating the oxidative metabolism of glasdegib. An N-
glucuronide conjugate of glasdegib was also identified in the plasma and urine of human 
subjects following single dose administration of [14C]glasdegib. In vitro, UGT1A9 
mediates the formation of this N-glucuronide. 
 
In vitro, glasdegib has a low risk to inhibit and/or induce various evaluated CYP and 
UGT enzymes and drug transporters at clinically relevant concentrations, but may have 
the potential to inhibit MATE1 and MATE2K. 


 
 
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Glasdegib was evaluated in rat and dog repeat dose toxicity studies up to 3-month in 
duration. Glasdegib was well tolerated up to 100 mg/kg/day in the rat and 10 mg/kg/day 
in the dog. In both the rat and dog, a non-proportional increase in exposure occurred 
with increasing dose. Deaths and/or moribund euthanasia occurred in the 10-day rat and 
1-month dog studies at 500 or 30/15 mg/kg/day, respectively. Cause of death/morbidity 
in both species was attributed to kidney toxicity. The target organs in the rat included 
kidney (tubular degeneration/necrosis, cytomegaly, inflammation, regeneration), bone 
(decreased/disorganized chondrocytes in epiphysis), tooth 
(degeneration/necrosis/absence of the apical portion) and peripheral nerve (axonal 
degeneration); the NOAEL was 10 mg/kg/day in the 3-month rat study, corresponding to 
<1x the projected human Cavg(ss) at steady state. In the 1-month rat study, the kidney 
changes showed signs of reversibility but did not entirely reverse, while the bone 
changes persisted. Reversibility of the tooth and peripheral nerve changes could not be 
evaluated as these changes were present only in the 3-month rat study, which did not 
include a recovery period. 
 
The target organs in the 3-month toxicity study in the dog were the kidney (tubular 
necrosis, granular/mineralized casts, dilated tubules) and liver (mild mixed cell 
inflammation, Kupffer cell pigment accumulation); the NOAEL was 1 mg/kg/day in the 3-
month dog study, corresponding to <1x the projected human Cavg(ss) at steady state. In 
the 1-month dog study, the kidney changes were completely reversed in males and 
partially reversed in females after a 6-week reversal period. Reversibility of the liver 
changes could not be evaluated as the changes were present only in the 3-month dog 
study, which did not include a recovery period. 
 
In the acute CNS and respiratory studies in the rat no effects were observed at the high 
dose of 50 mg/kg (6x above the projected human efficacious Cmax at steady state). 
Increases in QT, QTc75 were noted after single doses of >5 mg/kg to dogs which is 
>4.2x above the projected human efficacious Cmax at steady state. Glasdegib was 
negative in the definitive in the in vitro bacterial mutagenicity assay, human lymphocyte 
assay and the in vivo rat micronucleus. The molar extinction coefficient for glasdegib at 
290 nm is 9,622 L/mol/cm; therefore, glasdegib has the potential to be phototoxic. 
 
Clinical studies in healthy subjects: 
As of 15 July 2015, 4 healthy volunteer studies have been completed (B1371009, 
B1371010, 
B1371014, and B1371015). 
 
1. B1371009: A Phase 1 single-dose study in healthy subjects to evaluate the mass 
balance and pharmacokinetics of glasdegib. Six (6) healthy male subjects were dosed. 
This study has completed. 
 
2. B1371010: A Phase 1 2-sequence, 3-period, 3-treatment, single-dose crossover study 
in healthy subjects to evaluate the effect of food and CYP3A4 inhibition by ketoconazole 
on single- dose plasma pharmacokinetic. Fourteen (14) healthy male subjects were 
dosed. This study has completed. 
 
3. B1371014: A Phase 1 study in healthy subjects to estimate the bioavailability of two 
new glasdegib formulations relative to the current formulation and to evaluate the 
potential effect of food and a proton-pump inhibitor on glasdegib plasma 


 
 
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pharmacokinetics. Thirty five (35) healthy male subjects were dosed. This study has 
completed. 
 
4. B1371015: A Phase 1 fixed sequence study in healthy subjects to investigate the 
effect of multiple doses of the strong enzyme inducer rifampin on glasdegib 
pharmacokinetics. Twelve (12) healthy male subjects were dosed. This study has 
completed. 
In all clinical studies in healthy volunteers a total of 38 treatment-related TEAEs were 
reported; all were mild or moderate in severity. 
 
Clinical studies in patients: 
As of 15 July 2015, 6 clinical studies have been conducted in cancer patients. Two (2) 
studies in cancer patients have completed (B1371001, B1371002), and 4 studies are 
ongoing (B1371003, B1371005, B1371012, and B1371013). 
 
1. B1371001: A Phase 1 dose-escalation, single-agent study in patients with select 
advanced hematologic malignancies. Forty-seven patients were dosed. This study has 
completed. 
 
2. B1371002: A Phase 1 dose-escalation, single-agent study in patients with advanced 
solid tumors. Twenty-three patients were dosed. This study has completed. 
 
3. B1371003: A Phase 1b/2 study of glasdegib in combination with low-dose cytarabine 
(Ara-C), decitabine, or intensive chemotherapy (cytarabine/daunorubicin), in patients 
with acute myeloid leukemia or high-risk myelodysplastic syndrome. Two-hundred 
nineteen (219) patients have been enrolled and treated in this study. 
 
4. B1371005: A Phase 1 dose-finding study of single-agent glasdegib in Japanese 
patients with select advanced hematologic malignancies, or glasdegib in combination 
with intensive chemotherapy (cytarabine and daunorubicin) or low-dose cytarabine 
(LDAC) in patients with previously untreated AML or high-risk MDS. Thirteen (13) 
patients have been enrolled and treated in this study. 
 
5. B1371012: A Phase 1b/2 study of glasdegib in combination with azacitidine versus 
placebo in patients with previously untreated Intermediate-2 or High-Risk MDS, AML 
with 20% to 30% blasts and multi-lineage dysplasia, and CMML. Six (6) patients have 
been enrolled and treated in this ongoing study. 
 
6. B1371013: A Phase 2 study of single-agent glasdegib versus placebo in patients with 
primary or secondary myelofibrosis who have been previously treated with a Janus 
kinase inhibitor. Eleven (11) patients have been enrolled and treated in this ongoing 
study. 
 
Study B1371001 was a first-in-patient Phase 1 trial with a 3+3 dose escalation design in 
patients with refractory, resistant or intolerant select advanced hematologic 
malignancies. Patients received single agent glasdegib orally once daily (QD) 
continuously in 28 day cycles. Ten dose levels were evaluated in this study, ranging 
from 5 mg QD to 600 mg QD. The median age was 69 years (range 25-89 years). Other 
patient characteristics are detailed in the IB. The safety profile appeared favorable with 
the most common treatment-related AEs being Grades 1/2. The most frequently 
reported treatment-related AE was dysgeusia (27.7%). Two (2) patients developed dose 


 
 
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limiting toxicities (DLTs) during Cycle 1. One (1) patient dosed at the 80 mg QD dose 
level with AML that evolved from chronic myelomonocytic leukemia (CMML) developed 
DLTs of Grade 3 hypoxia and pleural effusion. This patient had an underlying 
pneumonia prior to coming on study. A second patient dosed at 600 mg QD developed a 
DLT of edema of inferior limbs. Regarding the MTD determination, changes in QTc 
values from baseline were seen in some patients, with some pronounced increases at 
the highest dose levels. Because of this observation, only 5/6 patients were enrolled at 
the 600 mg dose level and the next lower dose was expanded successfully to 6 patients. 
The MTD was subsequently determined to be 400 mg QD. The recommended Phase 2 
dose (RP2D) in patients with select advanced hematologic malignancies was 
determined to be </=200 mg QD by comparing the tolerability, PK, and 
pharmacodynamic profile of glasdegib at doses ranging from 5 to 600 mg QD. 
 
In Study B1371001, PK data indicate that glasdegib is absorbed following oral dosing 
with a median Tmax of 1- 4 hours after single and multiple dose administration. 
Following attainment of Cmax, glasdegib plasma concentrations showed a bi-
exponential decline with a mean terminal half-life ranging from 17.4 to 34.3 hours. 
Following repeated daily dosing, glasdegib steady state was achieved by Day 8 and 
showed a median drug accumulation ratio ranging from 1.2 to 2.5, which is consistent 
with the estimated half-life. The geometric mean for the percentage of administered dose 
excreted unchanged in the urine over the dosing interval of 24 hours ranged from 5.89% 
to 16.8%. 
 
Study B1371002 had a similar 3+3 dose escalation design in patients with select 
advanced/metastatic solid tumors. The starting dose of glasdegib in this study was 80 
mg QD and additional dose levels of 160 mg QD, 320 mg QD and 640 mg QD were 
evaluated. Twenty three (23) patients were enrolled. Two (2) patients dosed at 640 mg 
QD developed DLTs during Cycle 1. One (1) patient developed DLTs of Grade 3 
nausea, vomiting, and dehydration that persisted despite optimal supportive care. A 
second patient developed a DLT of inability to administer 80% of the planned dose of 
glasdegib during Cycle 1 due to glasdegib related Grade 2 fatigue, dehydration, and 
dizziness, and Grade 1 dyspepsia and dysgeusia. Therefore, the protocol-defined MTD 
of glasdegib in patients with advanced solid tumors was 320 mg QD. The most 
frequently reported treatment-related AEs of any grade were dysgeusia (65.2%), fatigue 
(52.2%), nausea and decreased appetite (34.8% each), dizziness (30.4%), diarrhea and 
dehydration (26.1% each), vomiting muscle spasms, and alopecia (21.7% each). 
 
In study B1371002, following repeated daily dosing, steady-state was achieved by Cycle 
1/Day 8 based on comparison of Ctrough values across PK days in Cycle 1. Following 
multiple dosing, glasdegib was absorbed with a median time to first occurrence of Cmax 
(Tmax) of 1-4 hours. The mean terminal plasma half-life (t½) for glasdegib ranged from 
17.7 to 20.7 hours. glasdegib accumulated following repeated dosing with a median Rac 
ranging from 1.35 to 1.75 which was consistent with the observed t½. 
 
Study B1371003 is a Phase 1B/2, open-label, multicenter safety and efficacy study of 
glasdegib in combination with low dose Ara-C, decitabine, or intensive chemotherapy in 
patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. For each 
Ph1B arm separately, a 3+3 dose escalation design in 3-6 patient cohorts was employed 
to determine the MTD of glasdegib in combination with each standard therapy. The 
starting dose of glasdegib is 100 mg QD administered orally in 28-day (+/- 4 days) cycles 
on a continuous basis. Fifty two (52) patients were enrolled in Phase 1B portion of the 


 
 
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study (23 patients treated with glasdegib plus low dose Ara-C [Arm A], 7 patients treated 
with glasdegib plus decitabine [Arm B], and 22 patients treated with glasdegib plus 
cytarabine/daunorubicin. 
 
Of the 52 patients treated with glasdegib in Phase 1b, 1 patient in Arm C reported a DLT 
of polyneuropathy (Grade 4 SAE) on Study Day 18 , which resolved on Day 34. The 
most frequently reported treatment-related AEs in patients who received glasdegib 100 
mg +LDAC (Phase 1b Arm A) were nausea (n = 6, 35.3%), diarrhea and neutropenia (n 
= 5, 29.4% each), and muscle spasms and dysgeusia (n = 4, 23.5% each). The most 
frequently reported treatment-related AEs in patients, who received glasdegib 100 mg + 
decitabine (Phase 1b, Arm B) of any grade were nausea (n=3, 75%), diarrhea, 
thrombocytopenia, and neutropenia (n=2, 50% each). The most frequently reported 
treatment-related AEs in patients who received glasdegib 100 mg + cytarabine + 
daunorubicin of any grade were nausea (n = 13, 81.3%), diarrhea, febrile neutropenia 
and muscle spasms (n = 7, 43.8% each), dysgeusia (n = 6, 37.5%), stomatitis, 
headache, fatigue and pyrexia (n = 5, 31.3% each), constipation, dyspepsia, vomiting, 
anemia, neutropenia, white blood cell count decreased, hypocalcaemia, hypokalemia 
and alopecia (n = 4, 25% each). 
 
For the Phase 2 portion of the B1371003 study, glasdegib 100 mg QD was selected as 
the RP2D based on the observed tolerability profile for the combination with LDAC or 
intensive chemotherapy, and the increase in glasdegib exposures observed with a 
strong CYP3A4 inhibitor such as ketoconazole (and potential with other azoles/CYP3A4 
inhibitors). Phase 2 consists of 2 components: Phase 2 randomized component in unfit 
patients (P2 Unfit) enrolled to receive either LDAC in combination with glasdegib or 
LDAC alone, and Phase 2 single arm component in fit patients (P2 Fit) who received 
glasdegib in combination with cytarabine/daunorubicin. As of the data cutoff date, data 
were available for 98 patients in the P2 Unfit randomized portion of the study, and 69 
patients in the P2 Fit arm. The median age was 70.0 years (range 27-85). 
 
Study B1371005 is an open-label, multi-center, Phase 1B study designed to evaluate the 
safety, tolerability, PK, PD, and preliminary signs of efficacy of glasdegib administered 
orally as a single agent in Japanese patients with select advanced hematologic 
malignancies, or in combination with intensive chemotherapy (cytarabine and 
daunorubicin) or low-dose cytarabine (LDAC) in patients with previously untreated AML 
or high-risk MDS. 
 
Study B1371012 is a multi-center, randomized (1:1), double-blind, placebo-controlled 
Phase1B/2 study to compare the safety, efficacy, PK, and PD of glasdegib or placebo 
when combined with azacitidine in patients with previously untreated Intermediate-2 or 
High-Risk MDS, AML with 20-30% blasts and multi-lineage dysplasia, and CMML. 
 
Study B1371013 is a Phase 2, randomised, double-blind, 2-arm study of oral single 
agent glasdegib versus placebo in a continuous daily regimen of 28-day cycles (+/- 4 
days), with defined best supportive therapy allowed in both arms in symptomatic primary 
or secondary myelofibrosis (MF) patients with a spleen palpable >/=5 cm below the LCM 
who have previously been treated with >/=1 licensed or experimental JAK inhibitors 
(JAKi). 
 
As of 01 September 2015, 126 treatment-related SAEs were reported in 64 patients. The 
most frequently reported treatment-related SAEs (≥2 events) included febrile 


 
 
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neutropenia (15 events), pneumonia (6 events), anemia, fatigue and gastrointestinal 
hemorrhage (4 events each), nausea, vomiting, device related infection, sepsis, acute 
kidney injury, acute myocardial infarction and pyrexia (3 events each), abdominal pain, 
death, edema peripheral, Clostridium difficile infection, dehydration, hyponatremia, 
presyncope, bacteremia, neutropenia, syncope and electrocardiogram QT prolonged (2 
events each). 
 
As of 01 September 2015, 56 deaths were reported in clinical studies of glasdegib. The 
most frequently reported cause of death was disease progression. Three (3) deaths (1 in 
Study B1371001 and 2 in Study B1371003) were considered related to study treatment 
(narratives included in the Section 6.2.4). One (1) additional treatment related death 
occurred on Study B1371003 (narrative is included in the Section 6.2.4) although this 
event was not listed as death in the Safety Database at the time of the data cutoff. 
 
In summary, glasdegib appears to be clinically manageable and generally well tolerated 
in all types of diseases studied to date. Several patients with aggressive hematologic 
malignancies remained on single agent glasdegib for a prolonged duration. 
 
Further details can be found in the glasdegib information (Appendix), which contains 
comprehensive pharmacology, toxicology, pharmacokinetics, pharmacodynamics, 
metabolism, preclinical, and clinical efficacy and safety data information. 
 
2.3.6 Venetoclax Drug Information Summary 
See the Venetoclax Prescribing Label (Appendix) for additional details on nonclinical and 
clinical studies. 
 
Bcl-2 overexpression has been implicated in maintaining the survival of AML cells and 
has been associated with resistance to chemotherapy and inferior overall survival 95. 
Venetoclax (VEN) is a potent and selective small-molecule inhibitor of Bcl-2 that has 
demonstrated cell-killing activity against a variety of leukemia cell lines, primary patient 
samples and leukemia stem/progenitor cells 96,97. VEN also has been found to synergize 
with agents known to down-regulate Mcl-1, including azacitidine. 98  
 
Based on the mechanism of action and nonclinical and clinical data available to date, the 
safety profile of venetoclax is well described.  The most common adverse drug reactions 
across all indications are nausea, diarrhea, hematological effects, and serious and/or 
opportunistic infections.  Hematologic effects include neutropenia/febrile neutropenia, 
thrombocytopenia, anemia, and lymphopenia.  Upper respiratory tract infections are 
among the most common infections.  TLS is an important identified risk and is 
predominantly seen in the CLL population with high tumor burden.  Based on pre-clinical 
data, decreased spermatogenesis has been identified as a potential risk for venetoclax. 
 
Summary of Venetoclax Nonclinical Pharmacology 
Venetoclax is a potent, selective and orally bioavailable small molecule inhibitor of Bcl-2 
that binds with > 1,000-fold higher affinity for Bcl-2 (dissociation constant [Ki] < 0.010 
nM) than for Bcl-XL (Ki - 48 nM or Mcl-1 (Ki > 444 nM).96  In vitro, venetoclax has 
demonstrated cell killing activity against patient-derived chronic lymphocytic leukemia 
(CLL) cells and a variety of lymphoma and leukemia cell lines96. Venetoclax has 
demonstrated potent killing of AML cell lines, primary patient samples, and leukemic 
stem/progenitor cells ex vivo, and has also exhibited anti-tumor efficacy in vivo, inhibiting 
the growth of AML cells systemically engrafted into immunocompromised mice. 


 
 
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Summary of Venetoclax Nonclinical Pharmacokinetics 
The pharmacokinetics of venetoclax was evaluated in mice, rats, monkeys, and dogs.  
Venetoclax pharmacokinetic (PK) profile was characterized by low plasma clearance 
and low to moderate volumes of distribution.  Half-lives ranged from 2.2 hours in 
monkeys to 12 hours in dogs.   
 
Venetoclax demonstrated high protein binding to human, rat, dog, and monkey plasma 
proteins ( 99.9%).  Blood to plasma ratios showed that venetoclax does not partition 
preferentially into the red blood cells.  Following oral administration of venetoclax to 
nonclinical species and humans, parent compound and metabolites were mainly cleared 
via biliary excretion and fecal elimination, with minimal renal clearance. 
 
Venetoclax is predominantly metabolized by cytochrome P450 (CYP) 3A4 (CYP3A4) in 
vitro; UDP-glucuronosyltransferases (UGTs) are not involved in the metabolism of 
venetoclax.  In addition, venetoclax is also a substrate for P-gp and BCRP. Active 
uptake of venetoclax was not observed in cells overexpressing OATP1B1, OATP1B3 or 
OCT1.  In vitro studies indicated that venetoclax is not an inhibitor or inducer of 
CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 at clinically relevant concentrations. 
Venetoclax is a weak inhibitor of CYP2C8, CYP2C9, and UGT1A1 in vitro, but it is not 
predicted to cause clinically relevant inhibition due to high plasma protein binding.  
Venetoclax is a P-gp and BCRP inhibitor and weak OATP1B1 inhibitor in vitro.  In vitro, 
venetoclax is metabolized by CYP3A4 and is a moderate inhibitor of CYP2C8.  Definitive 
in vitro experiments showed that venetoclax is not predicted to be an inducer or inhibitor 
of the metabolism of CYP2C9 substrate compounds.  Venetoclax is not a reversible 
inhibitor of CYP1A2, CYP2B6, CYP2D6, CYP2C19 or CYP3A4 (IC50  30 µM) in vitro 
and does not induce CYP3A4 or CYP1A2 at concentrations up to 10 M.  
 
Summary of Nonclinical Toxicology 
Venetoclax has been assessed in repeated-dose general toxicology studies and in 
genetic, developmental/reproductive, and safety pharmacology studies.  The primary 
toxicities associated with venetoclax administration included effects on the hematologic 
system (decreased lymphocytes and erythrocytes) in mice and dogs, the male dog 
reproductive system (testicular germ cell depletion), and embryo-fetal toxicity in mice. 
 
Summary of Venetoclax Clinical Data 
Clinical Efficacy Data for Venetoclax: Preliminary efficacy results are available for 
subjects with a variety of hematological neoplasms; the drug is approved for the 
treatment of CLL patients whose cells have a 17p chromosomal deletion. Preliminary 
data indicate that venetoclax shows promising efficacy in AML. 
• 
In Study M14-212 the ORR for subjects treated with venetoclax monotherapy was 
19%.99 
• 
In Study M14-358 the ORR for AML subjects (given venetoclax plus azacitidine or 
decitabine) was 68%.100 
• 
In Study M14-387 the ORR for AML subjects (given venetoclax plus low dose ara-
C)  was 75%.101 
 
Venetoclax Clinical Pharmacology and Pharmacokinetics: Venetoclax clinical 
pharmacology is being evaluated in several Phase I to III clinical trials, and data are 
available from three Phase I studies (M12-175, M13-367, M12-630), four Phase Ib 


 
 
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studies (M13-365, M12-901, GO29440, GP28331), one Phase II study (M14-212) and 
five dedicated clinical pharmacology studies (Study M13-364, M14-497, M13-363, M14-
253 and M15-101). 
 
In the Phase 1 Study M14-358, preliminary pharmacokinetic results in 31 treatment-
naïve AML subjects were available for venetoclax doses ranging from 400 mg to 800 mg 
when given in combination with decitabine (Arm A) or azacitidine (Arm B) and with or 
without posaconazole (Arm C). For Arm A and Arm B, venetoclax steady-state mean 
Cmax and AUC24 (Cycle 2 Day 5) ranged from 1.77 – 3.36 μg/mL and 24.7 – 59.5 
μg/mL, respectively. Based on the limited preliminary pharmacokinetic data, there was 
no evidence to suggest a marked effect of the co-administration of decitabine and 
azacitidine on the pharmacokinetics of venetoclax. In Arm C of this study, preliminary 
pharmacokinetic results from 6 subjects were available on Cycle 1 Day 20 (venetoclax 
400 mg alone QD until Day 20) and Cycle 1 Day 28 (venetoclax 100 mg QD with 
posaconazole given from Day 21 to Day 28). Venetoclax Cmax and AUC following co-
administration of venetoclax 100 mg with posaconazole were 2.1- and 2.7-fold higher 
respectively, compared to venetoclax 400 mg alone. 
 
Preliminary pharmacokinetic results of venetoclax are available from 12 treatment-naïve 
subjects with AML in Cohorts 1 (600 mg) and 2 (800 mg) from the ongoing Phase 1 
combination study of venetoclax and low dose cytarabine (Study M14-387). On Cycle 1 
Day 10 (with cytarabine), venetoclax mean Cmax and AUC24 values ranged from 2.25 – 
2.56 μg/mL and 34.7 – 44.6 μg•hr/mL, respectively. On Cycle 1 Day 18 (venetoclax 
alone), mean Cmax and AUC values of venetoclax ranged from 2.38 – 2.89 μg/mL and 
37.9 – 45.3 μg•hr /mL. Dose-normalized Cmax and AUC24 of venetoclax on Cycle 1 
Day 10 (with cytarabine) were comparable to dose normalized Cmax and AUC24 on 
Cycle 1 Day 18 (venetoclax alone), suggesting that co-administration of cytarabine did 
not markedly affect venetoclax exposures. 
 
Clinical Safety Data for Venetoclax: As of 05 June 2017, three Phase 1/2 studies have 
been conducted in the AML indication as described below. 
 
Overview of Phase 2 Study M14-212: Venetoclax Monotherapy in AML 
This is a completed study with single agent venetoclax in subjects with R/R AML and 
those unfit for intensive therapy.  A total of 32 subjects were dosed.  Exposure, safety, 
and efficacy data are available for this study.99  The most common adverse events 
observed in ≥ 30% of the subjects in Study M14-212 were nausea (59.4%); diarrhea 
(56.3%); hypokalemia, vomiting (40.6% each); fatigue, headache (34.4% each); 
hypomagnesemia (37.5%); febrile neutropenia (31.3%); abdominal pain, cough, 
hypophosphatemia (28.1% each); epistaxis, hyperphosphatemia, hypocalcemia, 
malignant neoplasm progression (25.0% each); dyspnea, hypotension, peripheral 
edema, pyrexia, and pneumonia (21.9% each).  Serious adverse events were reported 
in 27 subjects (84.4%), the most common being febrile neutropenia (28.1%), malignant 
neoplasm progression (25.0%), and pneumonia (15.6%).  Three serious adverse events 
were considered to have a reasonable possibility of being related to venetoclax (i.e., 1 
event each of diarrhea, febrile neutropenia, and pseudomonal bacteremia).  No cases of 
TLS occurred during venetoclax treatment. 
 
In this phase II multicenter trial single agent VEN produced an overall response in 5/32 
relapsed/refractory AML patients (CR in 1 patient, CRi in 4 patients) 102. Of the 5 patients 
with CR/CRi, 3 had IDH mutations suggesting that patients with IDH mutations may be 


 
 
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particularly sensitive to VEN. 
 
Two ongoing trials are evaluating VEN combination regimens in treatment naïve patients 
with AML who are ≥65 years of age and who are not eligible for standard induction: (a) 
to evaluate the efficacy and tolerability of the combination of VEN with a 
methyltransferase inhibitor (azacytidine or decitabine) (ClinicalTrials.gov Identifier: 
NCT02203773); (b) to evaluate VEN with low-dose cytarabine (ClinicalTrials.gov 
Identifier: NCT02287233).  
 
Overview of Ongoing Phase 1b Study (M14-358): Venetoclax in Combination with 
HMA in Treatment Naïve AML 
As of 09 March 2016, a total of 45 subjects ≥ 65 years of age with treatment naïve AML 
ineligible to receive standard induction therapy were enrolled into the escalation stage at 
3 dose levels of venetoclax at 400 mg, 800 mg, and 1200 mg. Venetoclax was 
administered daily during the 28-day cycles in combination with decitabine (20 mg/m2 
intravenously on Days 1 – 5 once every 28 days) or azacitidine (75 mg/m2 intravenously 
or subcutaneously on Days 1 – 7 once every 28 days). Preliminary safety and efficacy 
data are available from the ongoing dose escalation stage of this trial.101,103 
 
The most common adverse events for all subjects in Study M14-358 were nausea 
(53.3%), diarrhea (44.4%), febrile neutropenia (40.0%), neutrophil count decreased 
(31.1%), platelet count decreased, cough, and fatigue (28.9% each), edema peripheral 
and hypokalemia (26.7% each). Events grade 3 and above were reported for the 
majority (91.1%) of subjects; the most common event was febrile neutropenia (40.0%). 
Serious adverse events were reported for 27 (60.0%) subjects, including febrile 
neutropenia (11 subjects), malignant neoplasm progression (3 subjects) atrial fibrillation, 
abdominal pain, non-cardiac chest pain, pyrexia, pneumonia, sepsis, bone pain (2 
subjects each). All other events occurred in 1 subject each. The combination of 
venetoclax with decitabine and azacitidine demonstrates a tolerable safety profile.  
 
As of 09 March 2016, the ORR, as assessed by the investigators for the subjects 
enrolled into the 3 dose levels, was 62.2% (28 of 45), with CR in 12 (26.7%), CRi in 15 
(33.3%), and PR in 1 (2.2%). Four subjects (8.9%) were reported to have morphologic 
leukemia-free state (less than 5% blasts in bone marrow aspirate sample with at least 
200 nucleated cells) after completion of Cycle 1. Eight patients (17.8%) had resistant 
disease. However, all of the patients with resistant disease had evidence of blast 
reduction at completion of Cycle 1. The patients enrolled into the 1200 mg dose level 
had a shorter follow-up at the time of this analysis.  
 
The maximum tolerated dose has not been reached in either arm and dose escalation 
stage has completed enrollment. Enrollment into safety expansion at 400 mg and 800 
mg dose of venetoclax in combination with both HMAs is ongoing. 
 
Study M14-387: Study M14-387 titled, "A Phase 1/2 study of venetoclax in combination 
with low-dose cytarabine in treatment naïve subjects with acute myeloid leukemia who 
are ≥ 65 years of age and who are not eligible for standard anthracycline-based 
induction therapy," is an ongoing, open-label, multicenter safety and pharmacokinetics 
study. The primary objectives of the Phase 1 portion are to assess the safety profile, 
characterize pharmacokinetics, and determine the dose schedule, the MTD, and the 
RPTD of venetoclax in combination with low-dose cytarabine (LCD) in treatment-naïve 
AML subjects. The primary objectives of the Phase 2 portion of the study are to evaluate 


 
 
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preliminary estimates of efficacy (including ORR and TTP) and to characterize the 
toxicities of the combination at RPTD. Secondary objectives of the Phase 2 portion 
include evaluating leukemia response (rates of CR, CRi, PR, RD, and HR including 
transfusion support needs) and DOR. An additional exploratory objective includes the 
evaluation of biomarkers that may serve as surrogate or predictors for clinical outcomes 
for future studies. 
Of the 25 subjects in Study M14-387, 24 (96.0%) experienced at least 1 treatment-
emergent adverse event. The most common adverse events for all subjects in Study 
M14-387 were: nausea (54%), febrile neutropenia (41%), diarrhea (44%), decreased 
appetite (33%), and peripheral edema (31%). Adverse events leading to study drug 
discontinuation occurred in 4 (16.0%) subjects, including 1 event each of disease 
progression, acute hepatic failure, Candida pneumonia, and subdural hemorrhage. Fatal 
adverse events occurred in 5 (20.0%) subjects: 2 events of malignant neoplasm 
progression and 1 event each of acute hepatic failure, Candida pneumonia, and lung 
infection.100  
 
For further details of venetoclax preclinical studies, clinical studies, toxicities, 
pharmacokinetics, and adverse events please see the venetoclax Prescribing Label 
(attached). 
 
2.4 RATIONALE FOR THE PROTOCOL 
Evaluation of multiple costimulatory receptors from BM aspirates and peripheral blood in 
75 AML patients (frontline and relapsed AML) as well as at baseline and every 4-8 
weeks on our ongoing PD1/PD-L1 based clinical trials by 17-color flow-cytometry in the 
Leukemia Department in collaboration with the Immunotherapy Platform (Dr James 
Allison and Pam Sharma) at MDACC revealed that a number of checkpoint pathways 
beyond PD1/PDL1 play a role in AML, with our data supporting increased expression of 
OX40 and limited but identifiable expression of 4-1BB on CD4+Teffector phenotype, 
CD8+ phenotype, and CD4+ Treg phenotype T-cells in bone marrow aspirates of patients 
with AML15 (Williams P, et al ASH 2017 Oral presentation, abstract # 185): see updated 
data in section 2.6.1. These PD-1, PD-L1, OX40 expression data, the association 
between high PD-1/PD-L1 and poor outcome in AML, and the synergistic (often multifold 
improved) benefit seen with combined or sequential checkpoint blockade in multiple 
solid tumors supports our planned clinical trials of checkpoint blockade therapies in 
patients with AML. If appropriately identified, a percentage of AML and MDS patients 
may benefit from immunotherapy approaches targeting AML and MDS-specific immune 
checkpoints.  
 
Preclinical data from PF-04518600 (OX40 mAb) suggest that it has limited efficacy as 
monotherapy but may have synergistic efficacy when combined with standard 
cytotoxic/radiation therapy or immunotherapy (e.g. OX40 + PD-L1).  
 
Furthermore, the clinical exigency of AML requires that chemotherapy and/or targeted 
therapy must be used as well. Azacitidine is approved in the US and Europe for patients 
with MDS, and is approved in Europe and commonly used in the US to treat older 
patients with newly diagnosed AML. Hypomethylating agents (HMAs), azacitidine and 
decitabine, promote anti-tumor immune signaling by up regulation of interferon-gamma 
pathway genes, increased expression of HLA class 1 antigens, and activation of viral 
defense pathways.106 The HMAs concurrently dampen anti-tumor immunity by increasing 
the expression of PD-1 and PD-L1 in solid tumors107 and in myelodysplastic syndrome 
(MDS)/AML.104 Up regulation of these immune checkpoint molecules may be a 


 
 
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mechanism of resistance to HMAs. Recent data shows that hypomethylating agents 
increase the expression of natural killer (NK)-cell activating receptors and enhanced 
antibody dependent cellular toxicity (ADCC) when administered in combination with a 
CD33-targeting ADCC inducing antibody108. Furthermore, prior studies from MD 
Anderson and others have suggested that immune checkpoints such as PD-1, PD-L1, 
PD-L2 and CTLA-4 are upregulated by hypomethylating agent exposure.104,105 These 
preclinical data support the rationale for combination of anti-PD-L1 antibodies such as 
avelumab with hypomethylating agents such as azacitidine. 
 
Following discussion and recommendations from the MDACC Department of Leukemia 
and Immunotherapy Platform, we propose a multi-arm study to evaluate checkpoint 
modulating therapies in combination with each other, and with epigenetic agents, 
antibody drug conjugates, and BCL-2 inhibitors in R/R AML. A combination of the 
glasdegib will additionally be tested in combination with an anti-CD33 monoclonal (GO) 
in relapsed AML.  
 
This basket trial approach will enable the evaluation of safety, and pharmacodynamics 
activity of immune checkpoint modulating therapies in combination with each other, 
epigenetic agents, antibody drug conjugates, BCL-2 inhibitors, and other novel therapies 
in AML allowing rapid identification and expansion of promising arms and early closure 
of underperforming or excessively toxic arms. It will be of independent significance to 
achieve a better understanding of the tumor immunology of AML, how that is changed by 
immune checkpoint therapies and non-immune checkpoint therapies, and how both of 
these are related to clinical response, and to identify other checkpoint pathways and 
immune agonists that dominate the immune response in AML and develop predictive 
biomarkers for immunotherapies in AML. These goals will be achieved using a 
prespecified in-depth immune monitoring plan on bone marrow aspirate/biopsy and 
peripheral blood samples as specified in the correlatives section portion of this protocol. 
The development and execution of such master trials will hopefully help accelerate the 
development, identification, and selection of the most active and tolerable combinations 
in AML.  
 
2.5 Clinical experience with immune checkpoints in RR AML 
We treated 53 patients on the azacitidine + PD1 inhibitor (nivolumab) for 
relapsed/refractory AML15 (see updated data from this trial submitted to ASH 2018, in 
section 2.6.2). N=35 patients were evaluable for response: N=6 (18%) achieved 
complete remission (CR)/ complete remission with insufficient recovery of counts (CRi) 
(3 CR, 3 CRi), N=5 (15%) had hematologic improvement (HI), N=9 (26%) had ≥50% BM 
blast reduction, N=3 patients (9%) had stable disease >6 months, and 12 (34%) had 
progression. The CR/CRi/HI (N=11) have been durable, with only one relapse in a 
patient who achieved CR/CRi/HI [CR duration; not reached (NR)]. The 4- and 8-week 
mortality were 0% and 6%, respectively. The median overall survival for the 35 evaluable 
patients was 9.3 months (range, 1.8 – 14.3) (Fig 1), and this compares favorably to 
historical survival with Aza-based salvage protocols in similar patients treated at MDACC 
(Figure 3 – Part 1 and 2).  
 
Grade 3/4 and Grade 2 immune mediated toxicities were observed in N=7 (14%) and 
N=6 (12%) patients, respectively. These included 8 episodes of pneumonitis, 2 nephritis, 
2 transaminitis, and 1 skin rash. In almost all cases the toxicities responded rapidly to 
steroids, and 12 of the 13 patients were successfully rechallenged with nivolumab 
without recurrence of immune toxicities. One patient has come off study due to immune 


 
 
Page 28 of 103 
 
toxicity (pneumonitis). Baseline and end of cycle 1 bone marrow was evaluated on 25 of 
the 35 evaluable patients, including 6 responders (CR/CRi/HI) and 19 non-responders. 
Patients who achieved a CR/CRi/HI had a baseline higher live total CD3 (P=0.10), CD8+ 
T-cells (P=0.02), and lower live CD4+Foxp3+PD1+ T-regulatory (T-reg) cells (P=0.01) 
infiltrate in the bone marrow suggesting potential biomarkers of response. On further 
evaluation of post cycle 1 and post cycle 2 BM the responders demonstrate a 
progressive increase in the live CD3+ and CD8+ BM infiltrate and an increase in CD8+ 
ICOS+ activated phenotype cells. On the other hand non-responders did not have an 
increase in the live CD3+ or T-cell subsets.  
 
Our conclusion based on this data was that full dose azacitidine and nivolumab are 
tolerable and produce an encouraging response rate with durable responses in relapsed 
AML with poor risk features. However, combination checkpoint blockade or simultaneous 
blockade of inhibitory checkpoints and activation of stimulatory checkpoints may be 
needed to further improve the response rate and durability has been observed in many 
solid tumor types. 
 
To confirm the efficacy of a hypomethylator and PD-1/PD-L1 inhibition, we activated 
another study of azacitidine in combination with avelumab in patients with salvage 1 or 2 
AML (NCT02953561). The study includes a dose escalation run in phase to identify the 
MTD/DLT for the combination followed by an expansion phase to define the CRc within 
3 months of initiation of the combination. This study has recently started accrual at 
MDACC (N=6 accrued) and the dosing, safety, and efficacy data obtained from this 
study will provide further background and guidance for some of the combination arms 
included in this study.  
 
Figure 3: Aza+PD-1 inhibition in AML 
 
Figure 3, Part 1 
 
 
Figure 3, Part 2 


 
 
Page 29 of 103 
 
 
2.6 Update as of August 1, 2018 
 
2.6.1 Immune checkpoint expression in AML  
 
We have performed flow cytometry on bone marrow aspirates and peripheral blood 
mononuclear cells from 107 patients with AML (38 previously untreated, 69 
relapsed/refractory) and 8 healthy donors to evaluate the distribution of T cell subsets, 
their expression of inhibitory (PD1, CTLA4, LAG3, TIM3) and activating (GITR, OX40, 
41BB, ICOS) immune receptors, and their ligands (41BBL, B7-1, B7-2, ICOSL, Galectin 
9, PD-L1, PD-L2, OX40L) on AML blasts.109 PD1+ CD8+ T cells were significantly less 
frequent in bone marrow specimens from healthy donors (12.1%) than in the bone 
marrows from patients with newly diagnosed (27.3%), first relapsed (25.5%), and >1 
relapsed AML (34.7%)(P<0.01; Figure 4). A similar but less pronounced trend was seen 
for the frequency of OX40+ CD8+ T cells (healthy donors versus new AML versus first 
relapsed AML versus >1 relapsed AML: 0.6%, 0.9%, 2.3%, and 2.1%, P=0.08). 
Compared with healthy donors, patients with relapsed and newly diagnosed AML had 
significantly higher percentage of CD8+ T cells co-expressing the inhibitory markers PD1 
with TIM3 (P=0.02) and PD1 with LAG3 (P<0.01). Overall, 4-1BBL was not significantly 
increased in samples from either previously untreated or relapsed/refractory patients 
with AML, suggesting this may not be an ideal marker to target in patients with AML. 
 
Figure 4: Increased frequency of PD1 and OX40 positive CD8 T cells in AML 
(N=107) 


 
 
Page 30 of 103 
 
 
 
 
2.6.2 Updated clinical experience with hypomethylating agent in combination with 
immune checkpoint antibodies in AML (submitted to ASH 2018) 
Patients were eligible for the azacytidine with nivolumab (AZA+Nivo) trial if they had R/R 
AML, ECOG ≤ 2, and adequate organ function. The recommended phase 2 dose was 
established as azacytidine 75mg/m2 Days 1-7 with nivolumab 3mg/kg Day 1 and 14. 
Courses were repeated approximately every 4-5 weeks indefinitely. 70 R/R AML patients 
with median age 70 years (range, 22-90), secondary AML (44%), poor risk cytogenetics 
(34%), median salvage 2 (range, 1-7) were enrolled. The overall response rate was 33% 
including 15 CR/CRi (22%) (4 CR, 11 CRi), 1 PR, and 7 HI maintained on study >6 
months (10%) without ASCT. Additionally, 6 patients (9%) remained on study with stable 
disease (SD) >6 months. The remaining 41 patients (58%) had no response. 8-week 
mortality was 10%. Patients who achieved a CR/CRi/PR/HI/SD (n=29; 42%) had 
significantly improved overall survival (OS) compared with NRs (n=41; 58%) (16.1 
versus 4.1 months; p<0.001) (Figure 5A). By univariate analysis (UVA) improved ORR 
was seen in patients with pretherapy BM blast <20%, circulating WBC 
</=10,000/mL, ASXL1 mutation, and no prior HMA-based therapy. By UVA improved OS 
was seen in patients who achieved any response or SD (CR/CRi/PR/HI/SD), were 
salvage 1 status, and had ASXL1 mutation. The med OS with Aza+Nivo compared 
favorably to historical med OS with azacytidine-based protocols in salvage 1 or 2 
patients at MDACC (6.0 versus 4.7 months; p=0.03), most prominent improvement seen 
in salvage 1 patients (11.1 versus 4.1 months; P<0.001) (Figure 5B). Grade 3/4 immune 
related adverse events were observed in 8 (11%) patients, including pneumonitis (n=3), 
colitis (n=2), and nephritis, skin rash, and hypophysitis (1 each). The majority (12 of 16; 
75%) of these occurred in the first 8 weeks after nivolumab initiation. These responded 
rapidly to steroids. 
 
As of 10/4/18, we have treated a total of 19 patients with relapsed/refractory AML in a 
phase Ib/II study of the combination of azacitidine and avelumab (NCT02953561). In the 
phase Ib portion of the study, 6 patients received avelumab at a dose of 3 mg/kg on 
Days 1 and 14 in combination with azacitidine 75 mg/m2 on Days 1-7, followed by 6 


 
 
Page 31 of 103 
 
patients who received avelumab at a dose of 10 mg/kg on Days 1 and 14 (the maximum 
planned dose) in combination with azacitidine 75 mg/m2 on Days 1-7. No DLTs were 
observed and the MTD was not reached.  The phase II portion of the study is now 
ongoing with the 10 mg/kg dose of avelumab in combination with standard 7-day dosing 
of azacitidine. Eight-four serious adverse events have occurred, including 5 serious 
advents at least possibly related to the azacitidine and/or avelumab (grade 2 
pneumonitis, n=1; grade 3 pneumonitis, n=1; grade 3 syncope, n=1; grade 3 lung 
infection, n=1; grade 3 renal insufficiency, n=1). Five patients have died during the study 
due to sepsis (n=2), lung infection (n=1), sepsis (n=1) and unknown cause (n=1), none 
of which were considered related to the study treatment. One patient dropped out of the 
study due to sepsis, which was considered unlikely related to the study treatment. Grade 
3-4 adverse events (any cause) are shown in the table below: 
 
Adverse event 
Grade 3 
Grade 4 
Alanine aminotransferase increased 
3 
  
Anemia 
12 
  
Anorectal infection 
3 
  
Anorexia  
3 
  
Blood bilirubin increased  
3 
  
Colitis 
3 
  
Diarrhea 
3 
  
Dysphagia 
3 
  
Dyspnea 
6 
  
Fatigue 
6 
  
Febrile neutropenia 
24 
  
Gastrointestinal disorders - (Other) 
3 
  
Generalized muscle weakness 
6 
  
Hematuria 
3 
  
Hypercalcemia  
3 
  
Hyperglycemia 
3 
  
Hypokalemia 
3 
  
Hyponatremia 
6 
  
Hypotension 
3 
  
Hypoxia 
3 
  
Infections and infestations - (Other) 
24 
  
Left ventricular systolic dysfunction 
3 
  
Lung infection 
24 
  
Lymphocyte count decreased 
6 
4 
Metabolism and nutrition disorders 
3 
  
Nail infection 
3 
  
Nausea 
3 
  
Neutrophil count decreased  
3 
8 
Pain 
3 
  
Platelet count decreased 
- 
8 


 
 
Page 32 of 103 
 
Pleural effusion  
6 
  
Pneumonitis 
3 
  
Respiratory failure 
- 
12 
Sepsis 
- 
8 
Skin infection 
3 
  
Soft tissue infection 
3 
  
Syncope 
9 
  
Tracheostomy site bleeding 
3 
  
Urinary tract infection 
6 
  
Weight loss 
3 
  
 
 
Translational biomarkers for AZA+PD1 in R/R AML  
Flow-cytometry (MFC) was performed on pre- and post-therapy BMAs, after 2 doses 
(end of cycle 1 or EOC1) and 4 doses (EOC2) of nivolumab in 19 of 23 responders (R) 
(CR/CRi/PR/HI) (83%) and 28 of 41 NRs (68%). 36 parameter CyTOF was performed at 
same time-points in 5 responders and 5 non-responders. On pretherapy BMAs, 
responders had a higher frequency of CD3+ (p=0.04) and CD8+ cells (p=0.09) on MFC. 
CD3+ in the pretherapy BMA with a cut-off of 13.2%, had a sensitivity of 74% and a 
specificity of 65% for predicting response. CD3+ was >13.2% in 26 of 47 patients (55%) 
who had an evaluable pretherapy BMA. Immunohistochemistry confirmed that CD3+ 
cells were increased in pretherapy BMs in responders. PhenoGraph clustering of all 
CD3-gated cells revealed 24 meta-clusters. The frequency of an effector CD8+ T cell 
cluster (C2) expressing CD45RA+PD1loTbethiEomeslo was significantly higher in the 
pretherapy BMAs of responders versus non-responders (11.2% versus 2.5%; p=0.002), 
and was further expanded in responders but not in non-responders in the EOC1, EOC2, 
and EOC4 BMAs. 
 
Figure 5A: Overall survival in patients with response/stable disease versus non-
responders (N = 70) 
 
 
Figure 5B. Overall survival among patients who were salvage 1 versus >salvage 1 
at enrollment 


 
 
Page 33 of 103 
 
 
2.6.3 Hypomethylating agents (HMAs) in combination with GO in AML: 
The combination of HMAs with GO has been evaluated in two prospective phase II 
clinical trials. At MD Anderson, we treated 110 patients with myeloid malignancies with 
decitabine and GO.110 The patient populations, including relapsed/refractory AML with 
complete remission duration (CRD) <1 year (N=28, 25%); group 2: relapsed/refractory 
AML with CRD ≥1 year (N=5, 5%); group 3: untreated AML unfit for intensive 
chemotherapy or untreated myelodysplastic syndrome (MDS) or untreated myelofibrosis 
(MF; N=57, 52%); and group 4: AML evolving from MDS or relapsed/refractory MDS or 
MF (N=20, 18%). Treatment consisted of decitabine 20 mg/m2 daily for 5 days and GO 
3 mg/m2 on day 5. Post-induction therapy included five cycles of decitabine+GO 
followed by decitabine alone. CR or CRi was achieved in 39 (35%) patients; group 1= 
5/28 (17%), group 2=3/5 (60%), group 3=24/57 (42%) and group 4=7/20 (35%). The 8-
week mortality in groups 3 and 4 was 16% and 10%, respectively. In another phase II 
study, 142 older patients with newly diagnosed AML were treated with azacitidine and 
GO.111 Treatment consisted of azacitidine, 75 mg/m2 for 7 days, and gemtuzumab 
ozogamicin, 3 mg/m2 on day 8. The patients were stratified into good-risk (age 60-69 
years or performance status 0-1) and poor-risk (age ≥70 years and performance status 2 
or 3) groups. Of the 83 patients in the good-risk group, 35 (44%) achieved a CR. The 
median RFS and OS were 8 and 11 months, respectively. The 30-day mortality rate was 
8%. In the poor-risk group, 19 (35%) achieved CR. The median RFS and OS were 7 and 
11 months, respectively. The 30-day mortality rate was 14%. There were no cases of 
VOD in either group.  
 
2.6.4 Venetoclax in AML 
 
Bcl-2 inhibition: Bcl-2 overexpression has been implicated in maintaining the survival of 
AML cells and has been associated with resistance to chemotherapy and inferior overall 
survival 95 Venetoclax (formerly ABT-199/GDC-0199 is a potent and selective small-
molecule inhibitor of Bcl-2 that has demonstrated cell-killing activity against a variety of 
leukemia cell lines, primary patient samples and leukemia stem/progenitor cells 96,97. 
Venetoclax also has been found to synergize with agents known to down-regulate Mcl-1, 
including azacitidine.98 


 
 
Page 34 of 103 
 
 
Venetoclax monotherapy in R/R AML: A phase II study has been completed 
evaluating single agent venetoclax in subjects with R/R AML and those unfit for intensive 
therapy.  A total of 32 subjects were dosed.  Exposure, safety, and efficacy data are 
available for this study.99  The most common adverse events observed in ≥ 30% of the 
subjects were nausea (59.4%); diarrhea (56.3%); hypokalemia, vomiting (40.6% each); 
fatigue, headache (34.4% each); hypomagnesemia (37.5%); febrile neutropenia 
(31.3%); abdominal pain, cough, hypophosphatemia (28.1% each); epistaxis, 
hyperphosphatemia, hypocalcemia, malignant neoplasm progression (25.0% each); 
dyspnea, hypotension, peripheral edema, pyrexia, and pneumonia (21.9% each).  
Serious adverse events were reported in 27 subjects (84.4%), the most common being 
febrile neutropenia (28.1%), malignant neoplasm progression (25.0%), and pneumonia 
(15.6%).  Three serious adverse events were considered to have a reasonable 
possibility of being related to venetoclax (i.e., 1 event each of diarrhea, febrile 
neutropenia, and pseudomonal bacteremia).  No cases of TLS occurred during 
venetoclax treatment. In this phase II multicenter trial single agent venetoclax produced 
an overall response in 5/32 R/R AML patients (CR in 1 patient, CRi in 4 patients). Of the 
5 patients with CR/CRi, 3 had IDH mutations suggesting that patients with IDH mutations 
may be particularly sensitive to venetoclax. 
 
Venetoclax plus HMA in older patients with newly diagnosed AML: An ongoing 
phase Ib study has reporting promising safety and efficacy of venetoclax in combination 
with either azacitidine or decitabine in patients ≥65 years of age with previously 
untreated AML and who are ineligible for chemotherapy.113,114  At the most recent 
update, 145 patients were treated with a median age of 74 years (range, 65-86 years). 
Cytogenetics were poor risk in 49% of patients. The 30-day and 60-day mortality rates 
were 3% and 8%, respectively.  Tumor lysis syndrome was not observed. The CR/CRi 
rate for the entire cohort was 66% with a median duration of CR/CRi of 11.0 months. 
The median overall survival for the entire cohort was 17.5 months. These results 
represent the best survival data for older, unfit patients with newly diagnosed AML yet 
reported.  Emerging clinical and exposure response data have suggested that the 
400mg dose of venetoclax has the best risk-benefit profile, and a phase III study of 
venetoclax 400mg with azacitidine in the frontline setting is ongoing. 
 
Venetoclax plus HMA in R/R AML: Several retrospective studies have been published 
evaluating the safety and efficacy of venetoclax plus an HMA in patients with R/R AML. 
A study from MD Anderson evaluated the outcomes of 43 patients with R/R myeloid 
malignancies (n=39, 91% with AML) who received venetoclax in combination with other 
agents.115 Thirty-one of the evaluated patients (72%) received venetoclax with an HMA. 
Most patients (84%) were treated in salvage 2 or later (range 2-8) with a median of 3 
prior treatment regimens. Objective response rate (ORR) was achieved in 9 (21%) 
patients, including 2 (5%) with CR, 3 (7%) with CRi, and 4 (9%) with morphologic 
leukemia‐free state (MLFS). Of the 9 responding patients, all responded within 1 cycle of 
venetoclax combination therapy. These nine responding patients included eight (26%) of 
the patients treated with an HMA combination. With a median follow-up of 3 months, the 
estimated 6-month OS rate was 24%. In another study of venetoclax in combination with 
HMAs in R/R AML from City of Hope, 33 patients were treated.116 The median number of 
prior therapies was 2 (range, 1-8). Twenty patients (61%) had failed HMA therapy 
previously and 13 patients (39%) had prior allogenic stem cell transplantation. The ORR 
was 64% (N=21), with 10 patients (30%) achieving CR, 7 (21%) achieving CRi and 4 
(12%) achieving MLFS. With a median follow-up of 6.5 months, the 1-year OS rate was 


 
 
Page 35 of 103 
 
53%. The group at Memorial Sloan Kettering Cancer Center has also reported their 
experience with venetoclax in combination with either low-dose cytarabine or an HMA in 
patients with R/R myeloid malignancies.117 A total of 24 patients were treated (n=8 with 
HMA; N=16 with low-dose cytarabine). Twenty-three patients (96%) had a diagnosis of 
AML. The median number of prior treatments was 3 (range, 1-8); 6 patients (29%) had 
prior stem cell transplantation. Of 21 patients evaluable for efficacy, the ORR was 29%, 
including a CR rate of 24% (n=5) and PR rate of 5% (n=1). With a median follow-up of 
4.1 months, the 3-month OS rate was 72%. 
 
Pre-clinical rationale for combination of venetoclax with immune checkpoint 
inhibitors 
 
In a series of human in vitro and in vivo syngeneic tumor model studies, venetoclax does 
not appear to antagonize anti-PD-1 therapy with nivolumab (Matthew R et al. ASH 2018, 
abstract #3704). Venetoclax was shown to decrease naïve but not memory T cells in in 
vitro studies of human lymphocytes. In a mixed lymphocyte reaction assay, venetoclax 
did not affect IFN-gamma secretion by itself or when co-treated with the checkpoint 
inhibitor nivolumab. Similar findings were observed in a cytomegalovirus recall assay, 
suggesting that venetoclax does not impair immune response to infections. In an in vivo 
experiment with the murine syngeneic tumor model MC38, venetoclax did not impair the 
efficacy of anti-PD-1 therapy with nivolumab, and in some studies, increased efficacy 
compared to either venetoclax or nivolumab monotherapy.  These findings suggest that 
venetoclax does not impair anti-PD-1 anti-tumor therapy and may synergize with 
immune checkpoint therapy. 
 
2.6.5 Rationale for protocol amendment and proposed changes 
 
Given the emerging preclinical and clinical data outlined above, we propose an 
amendment to remove the 4-1BB mAb inhibitor arms and doublet arms containing IO 
only agents. We would instead like to add combinations that build on the doublets that 
have shown encouraging response rates and OS in R/R AML in recent years and have 
emerged as our priority regimens for patients with R/R AML, namely HMA+venetoclax 
and HMA+PD1/PDL1 antibody.  
Specifically, we proposed the following changes: 
• 
Removal of arms evaluating checkpoint modulating doublets: 1) OX40 mAb + 
avelumab, 2) OX40 mAb + azacitidine, 3) OX40 mAb + 4-1BB mAb, and 4) 
avelumab + 4-1BB mAb 
• 
These arms will be replaced with arms built on a backbone of either 
HMA+venetoclax or HMA+avelumab: 1) azacitidine + venetoclax + GO, 2) 
azacitidine + avelumab + GO, and 3) azacitidine + venetoclax + avelumab 
 
Previous arms that will be continued include: 1) OX40 mAb single-agent, which will 
confirm the safe dose of OX40 in AML for use in combination arms, 2) the triplet regimen 
of azacitidine + avelumab + OX40 mAb, and 3) GO + glasdegib. 
 
The primary goal of this amendment is to shift to triplet regimens incorporating agents 
with established efficacy in AML (e.g. combination of azacitidine, GO and/or venetoclax) 
and to improve on commonly used doublets in RR AML such as HMA+venetoclax and 
HMA+PD1/PDL1 antibody. 
 
 


 
 
Page 36 of 103 
 
2.7 Update as of 6/4/2019: amendment to open azacitidine + avelumab + OX40 
mAb arm 
 
To date, 4 patients have been treated with the OX40 mAb (PF-04518600) in this clinical 
trial. All patients were treated at the 0.3 mg/kg dose level.  The number of cycles 
received prior to progression were 1 (n=2), 2 (n=1) and 3 (n=1).  No DLTs, immune-
related AEs or grade 3+ related AEs were observed.  The following grade 3-5 AEs were 
observed all of which were attributed as unrelated to the OX40mAb: grade 3 confusion 
(n=1), grade 3 stroke (n=1), grade 4 sepsis (n=1), grade 4 hypotension (n=1), grade 4 
ileus (n=4), grade 3 febrile neutropenic fever (n=3) and grade 5 multi-organ failure.  
 
In a parallel phase I/II study in patients with advanced solid tumors (NCT03217747), 51 
patients have been treated with OX40 mAb combinations as of 5/9/19. All patients 
received the OX40 mAb at a dose of 0.3 mg/kg. Twenty-two patients received 
avelumab + OX40 mAb, 22 received avelumab + OX40 mAb + 4-1BB mAb, 3 
received avelumab + OX40 mAb + irradiation, and 4 received avelumab + OX40 
mAb + 4-1BB mAb + irradiation. No DLTs have been observed in any of these 
cohorts.  A total of 9 AEs (in 6 total patients) were attributed as at least possibly 
related to the OX40 mAb, and all were grades 1 or 2.  These AEs included: grade 1 
fatigue (n=1), grade 1 alkaline phosphatase elevation (n=1), grade 1 rash (n=2), 
grade 2 rash (n=1), grade 2 pruritus (n=1), grade 2 mucositis (n=1), grade 1 anorexia 
(n=1), grade 2 lipase elevation (n=1). Two patients died within 30 days of the first 
treatment dose (1 patient on avelumab + OX40 mAb + 4-1BB mAb arm, and 1 
patient on the OX40 mAb + 4-1BB mAb arm).  Both patients were taken off study 
prior to death (1 for progressive disease and 1 for withdrawal of consent).  Both 
deaths were attributed to underlying disease and assessed as unrelated to the study 
treatment. 
 
In sum, the OX40 mAb appears safe in these ongoing clinical trials, with no DLTs or 
related grade 3-5 AEs observed to date, with 55 patients treatment with OX40 mAb as a 
single-agent or in combinations to date. Given the rapidly changing treatment landscape 
of AML and the established safety of OX40 mAb (PF-04518600) alone and in 
combinations, we propose an amendment to close cohort A (i.e. OX40 mAb as single 
agent) and open cohort E (i.e. combination of azacitidine + avelumab + OX40 mAb). 
 
2.8 Update as of 3/18/20: amendment to close OX40 mAb monotherapy, GO + 
glasdegib, and azacitidine + avelumab + OX40 mAb arms 
 
Since the last update (see section 2.7 above), no additional patients have been treated 
on the OX40 mAb (PF-04518600) single-agent arm (Arm A). Although this agent was 
safe in this trial and in other studies in solid tumors, given the limited clinical activity in 
solid tumors and the changing landscape of AML therapy with encouraging therapies 
becoming available and focus transitioning to safe doublets and triplet based therapies, 
we propose to close this arm. Given the lack of single-agent activity of the OX40 mAb, 
we also propose to close the azacitidine + avelumab + OX40 mAb arm (Arm E) as the 
other triplets are of higher clinical interest. 
 
To date, 5 patients have been treated with GO + glasdegib (Arm F). Three patients were 
evaluable for response and none responded after one cycle. The other 2 patients were 
not evaluable for response due to death prior to response assessment (considered 


 
 
Page 37 of 103 
 
unrelated to the study drug). Overall, no DLTs were observed in the 3 evaluable 
patients. However, due to the apparent lack of clinical activity and similarly availability of 
other doublets and triplets with encouraging activity and stronger clinical/preclinical 
rationale at our center, we propose to close this arm and focus on patient accrual in the 
arms containing of triplet regimens with venetoclax and/or GO (i.e. Arms B-D). 
 
 
3.0 STUDY DESIGN 
 
• 
This will be a phase IB, multiple, parallel, and sequential arm, open-label, non-
randomized study with no crossover permitted between the arms. 
 
3.1 Study Design Overview (Table 1) 
 
Table 1: Study Schema and Schedule Overview  
 
Indication 
Treatment 
Arm 
Treatment 
Dosing 
Escalation/ 
de-
escalation 
Major 
Endpoints 
Fixed N 
(Apply 
stopping 
rules) 
Salvage  
AML 
A 
OX40 (PF-
04518600) 
alone 
D1 and D14 of 
a 4 wk cycle 
4 patients  
RP2D/MTD 
Closed 
(as of 
6/4/19) 
 
4 treated 
B 
Azacitidine 
+ venetoclax 
+ GO 
-Aza D1-7 of a 
4wk cycle 
-Ven D1-28 
-GO D8 
 
1. 
CR/CRp/PR 
per IWG2003 
 
30 
C 
Azacitidine 
+ GO + 
avelumab 
-Aza D1-7 of a 
4wk cycle 
-GO D8 
-Avelumab D1 
and D14 
  
1. 
CR/CRp/PR 
per IWG2003 
 
24 
D 
Azacitidine 
+ venetoclax 
+ avelumab 
 
-Aza D1-7 of a 
4wk cycle 
-Ven D1-28 
Avelumab D1 
and D14 
 
1. 
CR/CRp/PR 
per IWG2003 
 
24 
E 
Azacitidine 
+ avelumab 
+ OX40  
-Aza D1-7 of a 
4wk cycle 
-Both OX40 
and avelumab 
D1 and D14 
 
1. 
CR/CRp/PR 
per IWG2003 
 
 
Closed 
(as of 
3/18/20) 
 
0 treated 
F 
 GO + 
Glasdegib 
Glasdegib po 
daily in 4 wk 
cycle 
-GO D1, D4 
and D7 
 
1. 
CR/CRp/PR 
per IWG2003 
 
 
Closed 
(as of 
3/18/20) 
 
5 treated 
 
 


 
 
Page 38 of 103 
 
 
3.2 Safety evaluation for Arm A (OX40 mAb alone in RR AML): 
 
DLT is defined in section 3.4. A maximum of 4 patients will be enrolled in one dose level.  
 
Only the 0.3 mg/kg dose of OX40 will be evaluated as this was the dose selected to 
move forward from the solid tumor OX40 single agent dose finding study (B0601002, 
ClinicalTrials.gov NCT02315066). Up to four patients will be enrolled at the dose level of 
0.3mg/kg of OX40. If no more than 1 out of the 4 patients experienced a DLT, then this 
dose of OX40 will be established as the RP2D for AML and used in the subsequent 
combinations incorporating OX40 mAb. 
 
3.3 DLT monitoring in each arm (B-F): 
Each arm in the study will accrue up to 21 patients (Arms E-F) or up to 24 patients (Arms 
C-D) and 30 patients (Arm B) with pre-defined toxicity stopping rules to be implemented 
for early DLT evaluation as per following plan:  
Evaluation of the first 6 patients in each treatment arm will occur after all patients have 
completed two cycles of treatment (or at least 56 days from the first day of treatment).  
Enrollment will be halted while the first 6 patients in each treatment arm are evaluated 
for safety. The treatment combination will be considered as safe, and continue to enroll 
to a total of 21 patients (Arms E-F) or 24 patients (Arms C-D) or 30 patients (Arm B) 
when there are no more than 1 out of 6 patients with DLTs in the first cycle of treatment. 
If any patients in the first 6 of each treatment arm withdraw from the study without a DLT 
event prior to completing the first cycle of treatment, they will be replaced for the 
assessment of DLT rate. This will allow for early identification of significant toxicities and 
early stoppage in potentially toxic arms. If 2 or more out of 6 patients have DLTs in the 
first cycle of treatment in any arm, then an additional 6 patients will enroll at a next lower 
dose level to be determined by the PI, sponsor (MDACC IND office), and Pfizer team 
after reviewing the safety, efficacy, and PD data from the first 6 patients enrolled. If no 
more than 1 out of the additional 6 patients treated with the lower dose level experience 
DLTs, this treatment combination will be considered as safe and continue to enroll to a 
total of 21 patients (Arms E-F) or 24 patients (Arms C-D) or 30 patients (Arm B). If 2 or 
more out of these 6 additional patients experienced DLTs, then this arm will be halted.  
 
The Investigator is responsible for completing the cohort summary template and 
submitting to the IND office Medical Monitor for review and approval prior to continuing 
accrual beyond each set of 6 patients in each arm of the study. 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.  
 
3.4 DLT Definition 
              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 (28 days) 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 


 
 
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• 
CTCAE Grade 3 AST (SGOT) or ALT (SGPT) accompanied by grade 
2 bilirubin increase 
 
• 
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 within 72 hours. 
 
➢ 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 within 72 hours. 
 
• 
Results in discontinuation of therapy 
 
• 
Any treatment-related death;  
 
Grade 4 neutopenia lasting ≥ 42 days from start of cycle in absence of evidence 
of active AML. 
For patients in venetoclax-containing arms (i.e. Arms B and D) who do not receive 
venetoclax on day 1 due to logistical and/or financial reasons, the DLT period will be 
extended to 28 days from the first dose of venetoclax.  For evaluation of neutropenia-
related DLT, the DLT period will be 42 days from the first dose of venetoclax. Evaluation 
of the first 6 patients in each of the venetoclax containing treatment arms (arms B and D) 
will occur after all patients have completed two cycles of treatment (or at least 56 days 
from the first dose of venetoclax).  Enrollment will be halted while the first 6 patients in 
each of these treatment arms are evaluated for safety. 
 
Please see statistics section (section 11.0) for efficacy and toxicity stopping rules to be 
applied independently to each cohort. 
 
3.5 Cohort enrollment schema 
 
 
(A) Arms B-E (Azactidine + venetoclax + GO; azacitidine + avelumab + GO; 
azacitidine + venetoclax + avelumab; azacitidine + avelumab + PF-
04518600) 
Arms B-E will commence enrollment in parallel with the OX40 arm (namely Arm 
A). If multiple are open to enrollment the patient allocation will generally follow a 
rotating sequence between arms unless the PI (or Co-PI) decide to allot a patient 
to a particular arm. There will be no separate escalation/dose finding cohorts for 


 
 
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these combination arms, but predefined toxicity stopping rules have been built in 
to monitor for grade 3/4 drug-related toxicities and to stop or de-escalate dose if 
>30% grade 3/4 drug-related toxicity is observed in any of the combination arms 
at any given time as outlined in section 3.3 (DLT monitoring in each arm).  
 
 
(B) Arm F (GO + Glasdegib) 
Arm F is the combination of GO + glasdegib. This arm will commence enrollment 
in parallel with the OX40 arm (namely Arm A). There will be no separate 
escalation/dose finding cohorts these combination arms but we have built in 
predefined toxicity stopping rules to monitor for grade 3/4 drug-related toxicities 
and to stop or de-escalate dose if >30% grade 3/4 drug-related toxicity is 
observed in any of the combination arms at any given time as outlined in section 
3.0 (DLT monitoring in each arm). 
 
4.0 PATIENT SELECTION 
 
4.1 
Inclusion Criteria 
 
4.1.1    Patients with AML who are refractory or relapsed (any salvage) with no available 
therapies or not candidates for available therapies. 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 with the exception of MDS or CMML treated with HMAs. Patients with 
MDS or CMML treated with HMA therapies who progress to AML, and have no 
available therapies or are not candidates for available therapies, will be eligible at 
the time of progression to AML. 
  
4.1.2    Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy 
(e.g. FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is 
permitted. 
 
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 ≤2.0 times upper limit of normal (x ULN); 
aspartate aminotransferase or alanine aminotransferase ≤2.5 x ULN  (aspartate 
aminotransferase or alanine aminotransferase ≤5.0 x ULN if deemed related to 
leukemia by the treating physician) 
 
4.1.6 Adequate renal function defined by an estimated creatinine clearance ≥ 
40 mL/min according to the Cockcroft-Gault formula (or local institutional 
standard method) 
 
4.1.7 Patients must provide written informed consent. 
 


 
 
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4.1.8 In the absence of rapidly progressive disease, the interval from prior treatment to 
the time of initiation of protocol therapy will be at least 14 days for prior anti-
leukemic therapy with the exception of hydroxyurea as noted below, OR at least 
5 half-lives for cytotoxic/noncytotoxic agents, whichever is shorter. 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. The toxicity from 
prior therapy should have resolved to Grade ≤1, however alopecia and sensory 
neuropathy Grade ≤2 not constituting a safety risk based on investigators 
judgement is acceptable. Since the effect of most IO-agents, HMA-therapies, 
SMO-inhibitors, venetoclax 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.  
 
4.1.9 Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled 
CNS disease is permitted. Patients with a known history of CNS disease or 
leukemic brain metastasis must have been treated locally, have at least 3 
consecutive LPs with no evidence of CNS leukemia, and must be clinically stable 
for at least 4 weeks prior to enrollment and have no ongoing neurological 
symptoms that in the opinion of the treating physician are related to the CNS 
disease (sequelae that are a consequence of the treatment of the CNS disease 
are acceptable). 
 
4.1.10 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. 
 
4.1.11 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 
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) 


 
 
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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 the protocol therapies or any 
of their components to be used in the arm the patient is to be enrolled on. 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 Clinically significant (i.e., active) cardiovascular disease: acute cerebral vascular 
accident/stroke (< 6 months prior to enrollment) excluding TIA, myocardial 
infarction (< 6 months prior to enrollment), unstable angina, congestive heart 
failure (≥ New York Heart Association Classification Class II), or serious cardiac 
arrhythmia requiring medication. 
 
4.2.4 Ejection fraction < 50% on screening ECHO or MUGA for patients in glasdegib-
containing arm 
 
4.2.5 Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; 
however, alopecia and sensory neuropathy Grade ≤ 2 is acceptable 
 


 
 
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4.2.6 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 
b. Current use of immunosuppressive medication, EXCEPT for the 
following: a. intranasal, inhaled, topical steroids, or local steroid injection 
(e.g., intra-articular injection); b. Systemic corticosteroids at physiologic 
doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as 
premedication for hypersensitivity reactions (e.g., CT scan 
premedication). 
 
4.2.7 Prior organ transplantation including allogenic stem-cell transplantation within 3 
months prior to planned enrollment. 
 
4.2.8 Patients with symptomatic CNS leukemia or patients with poorly controlled CNS 
leukemia.  
 
4.2.9 Active and uncontrolled disease (active infection requiring systemic therapy, 
fever likely secondary to infection within prior 48 hours, uncontrolled 
hypertension despite adequate medical therapy as judged by the treating 
physician. 
 
4.2.10 Known history of testing positive for HIV or known acquired immunodeficiency 
syndrome  
 
4.2.11 Known history of Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at 
screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody 
screening test positive  
 
4.2.12 Vaccination within 4 weeks of the first dose of avelumab and while on trials is 
prohibited except for administration of inactivated vaccines 
 
4.2.13 Other severe acute or chronic medical conditions that is active and not well 
controlled including colitis, inflammatory bowel disease, or psychiatric conditions 
including recent (within the past year) or active suicidal ideation or behavior; or 
laboratory abnormalities that may increase the risk associated with study 
participation or study treatment administration or may interfere with the 
interpretation of study results and, in the judgment of the investigator, would 
make the patient inappropriate for entry into this study. 
  
4.2.14 Patients unwilling or unable to comply with the protocol. 
 
4.2.15 Pregnant or breastfeeding 
 
4.2.16 Known alcohol or drug abuse within the last 1 year 
 


 
 
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4.2.17 Acute promyelocytic leukemia (APL). 
 
4.2.18 Cardiac exclusions specific to Glasdegib and OX40 containing arms: Any one of 
the following ongoing or in the previous 6 months: congenital long QT syndrome, 
Torsades de pointes, sustained ventricular tachyarrhythmia, right or left bundle 
branch block and bifascicular block, unstable angina, coronary/peripheral artery 
bypass graft, CVA, transient ischemic attack or symptomatic pulmonary emboli, 
as well as bradycardia defined as <50 bpms. Active cardiac dysrhythmias of NCI 
CTCAE grade >/= 2 (eg, atrial fibrillation) or QTcF interval > 470 msec 
 
 
5.0 TREATMENT PLAN 
 
5.1 
General 
            All patients will be registered through CORe.  
 
5.2 
Schedule  
            The Investigator is responsible for completing Safety/Efficacy Monitoring 
summary reports and submitting to the IND office Medical Affairs and Safety 
Group for review and approval. These should be submitted as follows: 
 
• 
Arm A: 
Every 4 evaluable subjects, after completion of 28 days of study treatment.  
Study enrollment of this arm must be held until IND approval is obtained. 
 
• 
Lead-In and Phase II for Arms B to F: 
o Safety monitoring 
▪ 
Lead-in: After the first 6 evaluable subjects, per arm, complete 2 
cycles of therapy and every 3 evaluable subjects, per arm, 
thereafter.  Enrollment must be halted for that individual arm while 
the first 6 patients of that arm are evaluated for safety (i.e. after all 
patients have received 2 cycles of therapy, or been followed for at 
least 56 days from the start of treatment or at least 56 days from 
the first dose of venetoclax in the venetoclax containing arms B 
and D). 
▪ 
Phase II:  After the first 6 evaluable subjects, per arm, complete 2 
cycles of therapy and every 3 evaluable subjects, per arm, 
thereafter.   
o Futility monitoring 
▪ 
Futility summary will be submitted after the first 10 evaluable 
subjects, per arm, complete 3 cycles of therapy and every 5 
evaluable subjects, per arm, thereafter. 
 
The dosing calculations should be based on the body weight. All doses should be 
rounded to the nearest milligram for all agents. There will be no dose reductions (only 
interruptions when indicated) allowed for avelumab and PF-04518600 on this trial. 
 
Patients will be treated according to the following schedules that are specific to each 
arm: 


 
 
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(A) Arm A (PF-04518600 alone in RR AML) (6 patient dose-finding cohort):  
PF-04518600 will be administered as an intravenous infusion over 60 minutes (+/- 30 
minutes) on Day 1 and 14 (+/- 2 days) of each 28-day (+/- 4 day) cycle. This regimen 
may be modified based on local treatment standards and guidelines. If the patient 
develops an infusion-related reaction, prophylactic premedications can be added for 
future infusions, at the discretion of the PI and/or treating physician. PF-04518600 
should be administered in a setting that allows for immediate access to an intensive care 
unit or equivalent environment and administration of therapy for anaphylaxis, such as the 
ability to implement immediate resuscitation measures.  Steroids (e.g. dexamethasone 
10 mg), epinephrine (1:1,000 dilution), allergy medications (IV antihistamines), 
bronchodilators, or equivalents, and oxygen should be available for immediate access. 
Following completion of the infusions, patients must be observed for 2 hours 
post-infusion for potential infusion-related reactions. The ambulatory treatment 
center/inpatient nurse will use the institutional flowsheet to document observation of the 
patient as per institutional standards. If the patients tolerate the first two infusions of PF-
04518600 without any reactions the observation period for potential infusion-related 
reactions can be reduced to 1 hour for subsequent infusions.  
The dose level of 0.3 mg/kg selected for PF-04518600 monotherapy portion of this study 
was the dose levels found to be of interest and selected for further evaluation in the solid 
tumor PF-04518600 monotherapy dose-finding study (Study B0601002).  
 
 
• 
The dose and /or schedule of administration is subject to modification pending 
information from other ongoing clinical trials of PF-04518600 as a single agent 
and in combination with other drugs. 
 
• 
DLT definition are provided in section 3.4. Patients that are removed from study 
before day 28 for any reason other than toxicity and have not experienced DLT 
will be replaced. Patients not evaluable for DLT will be replaced. Patients 
experiencing DLT 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.  
 
• 
One cycle of therapy is defined as 28 days (+/- 4 days) or 4 weeks. Patients will 
receive one cycle of therapy every 28 days (+/- 4 days). During the DLT 
evaluation period the cycle must be a minimum 28 days. 
 
(B) Arm B (Azacitidine + venetoclax + GO in RR AML): N= Up to 26 
• 
Azacitidine will be administered subcutaneously (SQ) or intravenously (IV) for the 
first 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 (+/- 4 days) as determined by treating 
physician. Both SQ and IV forms of administration are FDA approved and 
considered interchangeable. Patients may start receiving azacitidine 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. 


 
 
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• 
Venetoclax will be given orally on days 1-28 of cycle 1 and days 1-21 of 
subsequent cycles.  During cycle 1, venetoclax will be dose escalated daily to the 
goal dose of 400mg daily.  Patients will receive 100mg on day 1, 200mg on day 2 
and 400mg on day 3 and onwards. This dosing applies to patients in both Phase 
I and II components of this study. 
 
To minimize the risk of tumor lysis syndrome (TLS), All patients will be 
hospitalized for the entirety of the venetoclax dose escalation starting at least on 
day -1 of treatment initiation and until 24 hours after the completion of venetoclax 
dose escalation. To mitigate the risk for TLS, subjects must be receiving tumor 
lysis prophylaxis, including hydration (oral, intravenous) and treatment with a uric 
acid reducing agent (allopurinol, rasburicase) prior to and during the venetoclax 
ramp up period of Cycle 1. Physicians should leukoreduce with hydroxyurea to 
reduce the peripheral white blood count to below 15,000/μL prior to the 
administration of the first dose of venetoclax. If the WBC is >15,000/μL the 
venetoclax should not be initiated till the white count is brought down to below 
15,000/μL 
As venetoclax is obtained commercially, some patients may have delays in 
beginning venetoclax due to financial or other logistical considerations. Even if 
venetoclax is not yet available, patients may begin azacitidine on day 1.  
Venetoclax should be started when it is obtained and continued as above (i.e. 
through day 28). Failure to begin venetoclax on day 1 will not be considered a 
protocol deviation. 
 
TLS chemistry tests (potassium, uric acid, creatinine, calcium and phosphorus) 
will be obtained prior to dosing and 6-8 hours after each new venetoclax dose. 
TLS chemistry test results will be reviewed by the investigator in real time and 
prior to the subject receiving the next higher dose of venetoclax to ensure 
appropriate and timely management. If a subject meets criteria for clinically 
significant laboratory or clinical TLS, no additional venetoclax should be 
administered until resolution of the TLS. Venetoclax interruption for up to 72 
hours following transient (< 48 hours) chemical changes and laboratory TLS will 
be allowed and will not require a dose reduction. 
 
In cycle 1, patients should undergo a bone marrow aspiration/biopsy on day 21 
(+/- 3 days). Patients who achieve marrow remission (i.e. bone marrow blasts 
<5%) or marrow aplasia/hypoplasia (</=10% cellularity or insufficient sample) 
should discontinue venetoclax and be monitored for count recovery.  
 
a)  If the Day 21 bone marrow shows <5% blasts, the venetoclax should be held 
on Day 21, and cycle 2 should not be initiated till ANC>0.5 and platelets are 
>30K without platelet transfusion support for >5 days.  
 
b)  If the Day 21 bone marrow shows aplasia/hypoplasia (</=10% cellularity or 
insufficient sample), the venetoclax should be held on Day 21, and a repeat 
bone marrow should be performed on Day 28 (+/- 3 days). If the Day 28 bone 
marrow shows >/=5% blasts proceed with cycle 2 if this is in the best interest 
of the patient. If the Day 28 bone marrow shows <5% blasts, the venetoclax 
should continue to be held, and cycle 2 should not be initiated till ANC>0.5 
and platelets are >30K without platelet transfusion support for >5 days. If the 


 
 
Page 47 of 103 
 
Day 28 bone marrow shows persistent aplasia/hypoplasia (</=10% cellularity 
or insufficient sample) continue to hold the venetoclax and repeat a bone 
marrow in 10-12 days. 
 
c)  If a bone marrow remission (<5% blasts) or aplasia/hypoplasia is not 
confirmed on the Day 21 bone marrow, patients should continue venetoclax 
until day 28 and have a repeat bone marrow on Day 28 (+/- 3 days). If the 
Day 28 bone marrow shows >/=5% blasts proceed with cycle 2 if this is in the 
best interest of the patient. If the Day 28 bone marrow shows <5% blasts or 
aplasia/hypoplasia follow steps outlined in “a” and “b” above. 
 
Treatment interruptions and dosing schedules other than the ones mentioned 
above can be considered after discussion with the PI and proper documentation 
of the rationale. 
 
• 
The recommended starting dose of GO in this arm is 3 mg/m2 on Day 8. In order 
to mitigate potential toxicity, the dose may be capped at 4.5 mg at the discretion 
of the treating physician. GO will not be administered for a longer duration or 
repeated beyond the Day 8dosing. The GO solution, following reconstitution and 
dilution in saline, can be infused to deliver the dose over a 2-hour period on Day 
8. During the infusion, only the syringe or IV bag needs to be protected from light. 
GO should never be administered as an IV push or bolus. 
 
In order to lessen the risk of infusion reactions associated with GO, it is 
recommended that patients receive the following prophylactic medications one 
hour before GO administration: diphenhydramine 50 mg PO and acetaminophen 
650-1000 mg PO. Thereafter, two additional doses of acetaminophen 650-1000 
mg PO, one every 4 hours, and additional diphenhydramine may be administered 
as needed. For first infusion, vital signs should be checked prior to the infusion, 
every 15 minutes (+/- 10 minutes) during infusion, at end of infusion (+/- 10 
minutes) and 60 minutes (+/- 30 minutes) after end of infusion. For subsequent 
infusions, vital signs should be checked prior to the infusion, every 30 minutes 
(+/- 15 minutes) during infusion, at end of infusion (+/- 10 minutes) and 60 
minutes (+/- 30 minutes) after end of infusion. The ambulatory treatment 
center/inpatient nurse will use the institutional flowsheet to document observation 
of the patient as per institutional standards. Additionally, methylprednisolone can 
be given prior to GO infusion to further decrease the risk of infusion-related 
symptoms. In case of infusion reactions during administration, study drug 
infusion should be stopped and appropriate medication should be given (e.g., 
diphenhydramine, acetaminophen, and methylprednisolone). Once symptoms 
have resolved, reinfusion at a lower rate (e.g., 50% slower) may be attempted. In 
the event of a serious anaphylactic reaction during administration of GO, the 
infusion should be stopped and the patient treated as clinically indicated. Re-
infusion of GO under these circumstances is NOT recommended. 
 
Physicians should consider leukoreduction with hydroxyurea or leukapheresis to 
reduce the peripheral white blood count to below 30,000/μL prior to 
administration of GO and appropriate measures (e.g., hydration and allopurinol) 
must be taken to minimize hyperuricemia and the potential for renal impairment 
due to tumor lysis. Patients should be closely monitored for signs and laboratory 
changes suspicious for VOD including weight gain, right upper quadrant pain, 


 
 
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lower extremity edema, transaminitis or bilirubin increase. A right upper quadrant 
ultrasound with Doppler flow should be obtained if there is clinical suspicion for 
VOD. Further work-up for VOD may include a liver biopsy at the discretion of the 
treating physician. Therapy with GO should be stopped if there is any clinical 
concern for VOD. 
 
The dose of GO should be held if total bilirubin > 2 x ULN or if AST or ALT > 2.5 
x ULN. If laboratory studies return to acceptable range, then the dose of GO may 
be made up later in the cycle at the discretion of the treating physician after 
consultation with the PI. 
 
• 
Following completion of the infusions, it is recommended to be observed for 2 
hours post-infusion for potential infusion-related reactions. The ambulatory 
treatment center/inpatient nurse will use the institutional flowsheet to document 
observation of the patient as per institutional standards.   
 
(C) Arm C (Azacitidine + avelumab + GO in RR AML): N= Up to 26 
• 
Azacitidine will be administered subcutaneously (SQ) or intravenously (IV) for the 
first 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 (+/- 4 days) as determined by treating 
physician. Both SQ and IV forms of administration are FDA approved and 
considered interchangeable. Patients may start receiving azacitidine 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 infusion at a dose of 10 mg/kg (maximum dose: 2000 mg) should 
begin 30-60 minutes after the completion of azacitidine on day 1, as described 
above, whenever possible. A second dose of avelumab will be administered on 
Day 14 of each 28 day 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) is mandatory 
and recommended to be given approximately 30 to 60 minutes prior to each dose 
of avelumab. This regimen may be modified based on local treatment standards 
and guidelines as appropriate provided it does not include systemic 
corticosteroids.   
 
• 
The recommended starting dose of GO in this arm is 3 mg/m^2 on Day 8. In 
order to mitigate potential toxicity, the dose may be capped at 4.5 mg at the 
discretion of the treating physician. GO will not be administered for a longer 
duration or repeated beyond the Day 8 dosing. The GO solution, following 
reconstitution and dilution in saline, can be infused to deliver the dose over a 2-
hour period on Day 8. During the infusion, only the syringe or IV bag needs to be 
protected from light. GO should never be administered as an IV push or bolus. 
Prevention and monitoring of infusion reactions and tumor lysis syndrome and 
monitoring for VOD and hold parameters will be as outlined in Arm B. 
  
• 
Following completion of the infusions, it is recommended to observed patients for 


 
 
Page 49 of 103 
 
2 hours post-infusion for potential infusion-related reactions. The ambulatory 
treatment center/inpatient nurse will use the institutional flowsheet to document 
observation of the patient as per institutional standards.   
 
(D) Arm D (Azacitidine + venetoclax + avelumab in RR AML): N= Up to 26 
• 
Azacitidine will be administered subcutaneously (SQ) or intravenously (IV) for the 
first 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 (+/- 4 days) as determined by treating 
physician. Both SQ and IV forms of administration are FDA approved and 
considered interchangeable. Patients may start receiving azacitidine 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 infusion at a dose of 10 mg/kg (maximum dose: 2000 mg) should 
begin 30-60 minutes after the completion of azacitidine on day 1, as described 
above, whenever possible. A second dose of avelumab will be administered on 
Day 14 of each 28 day 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) is mandatory 
and recommended to be given approximately 30 to 60 minutes prior to each dose 
of avelumab. This regimen may be modified based on local treatment standards 
and guidelines as appropriate provided it does not include systemic 
corticosteroids.  
 
• 
Venetoclax will be given orally on days 1-28 of cycle 1 and on days 1-21 of 
subsequent cycles.  During cycle 1, venetoclax will be dose escalated daily to the 
goal dose of 400mg daily.  Patients will receive 100mg on day 1, 200mg on day 2 
and 400mg on day 3 and onwards. Prevention of TLS and need for day 21 bone 
marrow aspiration in cycle 1 to decide on continued venetoclax administration will 
be as outlined in Arm B. This dosing applies to patients in both Phase I and II 
components of this study. 
 
As venetoclax is obtained commercially, some patients may have delays in beginning 
venetoclax due to financial or other logistical considerations. Even if venetoclax is not 
yet available, patients may begin the combination of azacitidine and avelumab on day 1.  
Venetoclax should be started when it is obtained and continued as above (i.e. through 
day 28). Failure to begin venetoclax on day 1 will not be considered a protocol deviation. 
 
• 
Avelumab infusion at a dose of 10 mg/kg should begin 30-60 minutes after the 
completion of azacitidine on day 1, as described above, whenever possible. A 
second dose of avelumab will be administered on Day 14 of each 28-day cycle.   
 
• 
Following completion of the infusions, it is recommended to observe patients for 
2 hours post-infusion for potential infusion-related reactions. The ambulatory 
treatment center/inpatient nurse will use the institutional flowsheet to document 
observation of the patient as per institutional standards.   
 


 
 
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(E) Arm E (Azacitidine + avelumab + PF-04518600 in RR AML): N= Up to 21 
• 
Azacitidine will be administered subcutaneously (SQ) or intravenously (IV) for the 
first 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 (+/- 4 days) as determined by treating 
physician. Both SQ and IV forms of administration are FDA approved and 
considered interchangeable. Patients may start receiving azacitidine 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 infusion at a dose of 10 mg/kg (maximum dose: 2000 mg) should 
begin 30-60 minutes after the completion of azacitidine on day 1, as described 
above, whenever possible. A second dose of avelumab will be administered on 
Day 14 of each 28 day 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) is mandatory 
and recommended approximately 30 to 60 minutes prior to each dose of 
avelumab. This regimen may be modified based on local treatment standards 
and guidelines as appropriate provided it does not include systemic 
corticosteroids.   
• 
PF-04518600 will be administered 30-60 minutes after completion of the 
avelumab infusion in absence of infusion reaction on Days 1 and 14 (+/-2 days) 
of each 28 day cycle. Specifics of drug administration and premedications will be 
the same as specified in Arm A. 
• 
Following completion of the infusions, it is recommended to observe patients for 
2 hours post-infusion for potential infusion-related reactions. The ambulatory 
treatment center/inpatient nurse will use the institutional flowsheet to document 
observation of the patient as per institutional standards.   
 
(F) Arm F (GO + Glasdegib in RR AML): N= Up to 21 
• 
The recommended starting dose of GO in this arm is 3 mg/m^2 on Days 1, 4 
and 7. In order to mitigate potential toxicity, the dose may be capped at 4.5 mg at 
the discretion of the treating physician. GO will not be administered for a longer 
duration or repeated beyond the Day 1, 4, 7 dosing. The GO solution, following 
reconstitution and dilution in saline, can be infused to deliver the dose over a 2-
hour period on Days 1, 4, and 7. During the infusion, only the syringe or IV bag 
needs to be protected from light. GO should never be administered as an IV push 
or bolus. Prevention and monitoring of infusion reactions and tumor lysis 
syndrome and monitoring for VOD and hold parameters will be as outlined in Arm 
B. 
• 
Glasdegib will be administered as a 100 mg PO qday to be taken continuously. 
Glasdegib will be self-administered by the patient at home, unless otherwise 
specified. Glasdegib, starting dose of 100mg, will be administered orally with 
approximately 8 ounces (240 mL) of water and should be taken in the morning, at 
the same time each day.  Tablets must not be crushed or cut; they must be 
swallowed whole, not manipulated or not chewed prior to swallowing.  Patients 
should be instructed to self-administer their medication in the morning at 
approximately the same time each day and to not take more than the prescribed 
dose at any time.  If a patient forgets to take their dose at the regularly scheduled 


 
 
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time, and if less than 10 hours have passed since the scheduled dosing time, 
that dose should be taken as soon as possible.  If more than 10 hours have 
passed since the scheduled dosing time, the dose should be skipped and the 
patient should continue on their normal dosing schedule.  If a patient misses a 
day’s dose entirely, they must be instructed not to “make it up” the next day.  If a 
patient vomits any time after taking a dose, they must be instructed not to “make 
it up,” but to resume subsequent doses the next day as prescribed.  If a patient 
inadvertently takes 1 extra dose during a day, the patient should not take the 
next dose of glasdegib.  
• 
Patients requiring glasdegib dose reduction(s) will be administered multiples of 
25 mg tablets and should continue taking the glasdegib at the same time each 
morning at the dose prescribed by the Investigator (i.e., 75 mg QD and 50 mg 
QD in the form of three or two 25 mg tablets respectively). In situations where 
clinical benefit is observed, glasdegib can be reduced below 50 mg QD upon 
Sponsor approval. 
• 
Glasdegib (PF-04449913) will be supplied in strengths of 25mg and 100mg 
tablets. Both strengths will be packaged in bottles of 34 tablets. Full bottles of 
glasdegib will be dispensed to the patient.  
 
5.3  TREATMENT CYCLES 
• 
One cycle of therapy is defined as 28 days (+/- 4 days). Patients will receive one 
cycle of therapy every 28 days (+/- 4 days). 
 
• 
Cycles may be started early (but not earlier than day 24) for patients with active 
disease if judged in the best interest of the patient. 
For the dose finding PF-04518600 monotherapy cohort, the DLT defining period 
is 28 days. As such, cycle 2 should not be commenced before 28 days for the 
patients being treated in the lead-in cohort. 
 
• 
Subsequent cycles may be delayed for recovery of toxicity or other medical 
conditions (e.g. infections). Delays in the 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. 
 
• 
In instances where one drug has to be discontinued transiently because of 
safety, the administration of the other drug/s may continue as scheduled. 
 
• 
Therapy 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 any evidence of active AML in the bone marrow or peripheral blood. 
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 24 days after the prior cycle in 


 
 
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the phase II portion of the study. 
 
• 
For patients who discontinue therapy, the reason for treatment discontinuation 
will be captured. 
 
5.4 DOSE ADJUSTMENTS 
 
5.4.1 Dose adjustments for hematological drug- related adverse events (AE): 
 
• 
Dose reduction/interruption/discontinuation decisions should be based on the 
CTCAE version 4.03 (Appendix) and the guidelines provided below. 
 
Patients with acute leukemias 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 
in patients in whom myelosuppression is due to the presence of residual 
leukemia. After cycle 1, treatment interruptions and dose adjustments may be 
considered according to the following guidelines 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 evidence of any residual leukemia on bone 
marrow and/or peripheral blood) and pre-cycle counts of neutrophils 
>1x109/L and platelets >50 x109/L will have dose modifications for 
hematological toxicities as specified in the azacitidine and gemtuzumab PIs 
and the venetoclax, avelumab, PF-04518600, and glasdegib IBs (Appendix) 
.  
 
➢ 
If there are persistent peripheral blood blasts, or the bone marrow shows 
>5% blasts or any evidence of residual leukemia, treatment may be 
continued regardless of neutrophil and platelet count with supportive care 
as needed. Dose-interruptions of individual drugs 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, as applicable. No dose 
reductions (only dose interruptions as needed) are permitted for the IO-
agents (avelumab and PF-04518600) in the phase II portion.  
 
-        Patients who are experiencing ongoing dose delays >8 weeks due to 
unresolved grade ≥3 adverse events should be taken off treatment. 
 
5.4.2 Dose adjustments for non-hematologic drug- related AEs 
Investigators should, whenever possible, determine which medication is causing the 
toxicity and interrupt or dose reduce azacitidine, venetoclax, glasdegib, GO and/or 
interrupt IO-agents, as applicable (Table 3). No dose reductions (only interruptions) are 
permitted for the IO-agents (avelumab and PF-04518600) in the phase II portion. 
 


 
 
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Dose reductions of azacitidine will be as follows: dose level -1 of azacitidine: 50 
mg/m^2 x 7 days, dose level -2: 37.5 mg/m^2 x 7 days, dose level -3: 25 mg/m^2 x 7 
days. Further reductions beyond what is shown above or alternative reductions (e.g. 
75mg/m2 x 5 days) may be allowed if deemed in the patient’s best interest by the 
treating physician. 
 
Dose reductions of venetoclax will be as follows: dose level -1 of venetoclax: 
200mg, dose level -2: 100mg, dose level -3, 50mg. Alternatively, the duration of 
venetoclax administration can be decreased (e.g. decrease from 21-day to 14-day 
administration) rather the dose being reduced. 
 
The dose of GO is 3mg/m^2 and dose-reductions will not be done. In case of toxicity 
considered to be related to GO the dose/s of GO will be omitted. 
 
Separate dose-modifications for glasdegib are presented in section 5.4.7 and should be 
followed for toxicities considered to be related to the glasdegib. 
 
Table 3.   Dose adjustments of azacitidine 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 suspected drug. 
Resume the held drug at prior dose if recovery to ≤ Grade 1 
occurs within 14 days. 
If toxicity persists for 15-28 days, hold the drug and resume at 
prior dose if recovery to ≤ Grade 1 OR resume the drug at ONE 
dose level below current dose if recovery to ≤ Grade 2. 
Dose re-escalation to prior dose of the drug is permitted in 
accordance with the dose-escalation guidelines in section 
5.4.7. 
3rd.  
Hold suspected drug. 
Follow until toxicity ≤ Grade 2. 
Resume the held drug at ONE dose level below current dose. 
Dose re-escalation of the drug to prior dose is permitted in  
accordance with the dose-escalation guidelines outlined below 
Patients who are experiencing ongoing dose delays >8 weeks 
due to unresolved grade ≥3 adverse events should be taken off 
treatment. 
4th time 
Discontinue therapy 
 
 
5.4.3 IO-agent (avelumab and PF-04518600) dose delay/interruption for immune-
oncology drug-related AEs, clinically significant in the opinion of the investigator 


 
 
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All IO-agent/s 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. 
 
All IO agent/s 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 drug-related 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. 
• 
IO-agent 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: 
• 
Subjects may resume treatment in the presence of Grade 2 drug-related 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 
the non-IO agent(s) (e.g azacitidine, GO and/or venetoclax) is considered to be 
inadequate, or inappropriate (e.g., because of pancytopenia or other considered related 
severe toxicity) can discontinue these agents and continue with IO-agent only. 
 
Patients who are experiencing ongoing dose delays >8 weeks due to unresolved grade 
≥3 adverse events should be taken off treatment, except as specified in discontinuation 
section. 
 
5.4.4 IO-agent Discontinuation Criteria: The following clinically significant, drug-
related ADRs require permanent treatment discontinuation of any IO=agent/s: 
 
---Any Grade 4 drug-related AEs require treatment discontinuation with IO-agent/s 
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 drug-related AEs require treatment discontinuation with IO-agent/s 
except for any of the following:  


 
 
Page 55 of 103 
 
 
- 
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) 
 
Any Grade 2 drug-related 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 IO-agent/s (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 the IO-agent/s has to be permanently discontinued 
unless the patient is deriving clinical benefit in which case the agent may be 
continued after discussion with the PI of potential risk/benefit ratio and 
documentation of this discussion in the patents medical record. 
 
- 
Infusion-related reactions, hypersensitivity reactions (Grades 1 to 4), and 
tumor lysis syndrome should be handled according to guidelines provided. 
 
• Any dosing interruption due to drug-related toxicity lasting > 8 weeks 
 
5.4.5 Detailed management algorithms for immune-oncology drug-related adverse 
events (including gastrointestinal, renal, pulmonary, hepatic, endocrine, skin and 
neurological) are provided in Table 4 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 IO-agent/s stimulates the immune system, immune-related AEs (irAEs) may 
occur.  Treatment of irAEs is mainly dependent upon severity (NCI-CTCAE grade): 
Grade 1 to 2:  treat symptomatically or with moderate dose steroids, more frequent 


 
 
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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 4. Management of Immune-Related Adverse Events (irAEs) (These are to be 
followed for toxicities with all immune agents included in this protocol including 
immune checkpoints and monoclonal antibodies) 
 
Gastrointestinal irAEs 
Severity of Diarrhea / Colitis 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue IO therapy/s 
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 IO therapy/s 
Symptomatic treatment 
If improves to Grade 1:  
Resume IO-therapy/s 
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 IO-therapy/s 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 IO-
therapy/s 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  
Dermatological irAEs 


 
 
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Grade of Rash 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 1 to 2  
Covering ≤ 30% body surface 
area  
Symptomatic therapy 
(for example, 
antihistamines, topical 
steroids)  
Continue IO-therapy/s 
If persists > 1 to 2 weeks or 
recurs:  
Consider skin biopsy  
Delay IO-therapy/s 
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 IO-
therapy/s 
If worsens:  
Treat as Grade 3 to 4  
Grade 3 to 4 
Covering > 30% body surface 
area; life threatening 
consequences  
Delay or discontinue IO-
therapy/s 
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 IO-therapy/s 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 
Radiographic changes only  
Consider delay of IO-
therapy/s  
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 IO-therapy/s 
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 
IO-therapy/s and consider 
prophylactic antibiotics 
If not improving after 2 weeks 
or worsening:  
Treat as Grade 3 to 4  
Grade 3 to 4 
Discontinue IO-
If improves to Baseline:  


 
 
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Severe new symptoms; New / 
worsening hypoxia; life-
threatening  
therapy/s 
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  
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 IO-therapy/s 
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 IO-therapy/s 
Increase frequency of 
monitoring to every 3 
days  
If returns to Baseline:  
Resume routine monitoring, 
resume IO-therapy/s 
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 IO-
therapy/s 
Grade 3 to 4 
AST or ALT > 5 x ULN and / or 
total bilirubin > 3 x ULN  
Discontinue IO-
therapy/s  
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 
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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gastroenterologist 
Consider obtaining 
MRI/CT scan of liver 
and liver biopsy if 
clinically warranted  
Endocrine irAEs 
Endocrine Disorder 
Management 
Follow-up 
Asymptomatic TSH abnormality  Continue IO-therapy/s   
 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 IO-therapy/s 
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 IO-therapy/s  
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 IO-therapy/s  
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  
Cardiac irAEs 
Myocarditis 
Management 
Follow-up 
New onset of cardiac signs 
or symptoms and / or new 
laboratory cardiac biomarker 
elevations (e.g. troponin, 
CK-MB, BNP) or cardiac 
imaging abnormalities 
suggestive of myocarditis.  
Withhold IO therapy 
Hospitalize. In the presence 
of life threatening cardiac 
decompensation, consider 
transfer to a facility 
experienced in advanced 
heart failure and arrhythmia 
If symptoms improve and 
immune-mediated etiology is 
ruled out, re-start IO therapy. 
  
If symptoms do not 
improve/worsen, viral 


 
 
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management.     
Cardiology consult to 
establish etiology and rule-
out immune-mediated 
myocarditis.  
Guideline based supportive 
treatment as appropriate per 
cardiology consult.* 
Consider myocardial biopsy 
if recommended per 
cardiology consult. 
myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed 
following cardiology consult, 
manage as immune-
mediated myocarditis. 
Immune-mediated 
myocarditis 
Permanently discontinue 
avelumab. 
Guideline based supportive 
treatment as appropriate per 
cardiology consult.* 
Methylprednisolone 1-2 
mg/kg/day.  
Once improving, taper 
steroids over at least 1 
month and add prophylactic 
antibiotics for opportunistic 
infections. 
If no improvement or 
worsening, consider 
additional 
immunosuppressions (e.g. 
azathioprine, cyclosporine A) 
*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website:  
https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=
&t=1001 
 
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. 
 
5.4.6 Venetoclax specific dietary recommendations, concomitant medications and 
dose adjustments 
 
Patients should not consume grapefruit or grapefruit products, Seville oranges, or Star 
fruit during treatment with venetoclax due to possible CYP3A mediated metabolic 
interaction. 
 
Moderate and strong CYP3A inducers and inhibitors are discouraged during venetoclax 
administraton. If a patient requires use of CYP3A inducers, use with caution. In many 
instances, such as antifungal prophylaxis with “azole” therapy in neutropenic patients, 
CYP3A inhibitors are required in AML patients. Venetoclax should be administered at 


 
 
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50% dose reduction in the setting of moderate CYP3A inhibitors (e.g. isavuconazole, 
ciprofloxacin, diltiazem) and 50-75% dose reduction in the setting of strong CYP3A 
inhibitors (e.g. posaconazole, voriconazole). The venetoclax dose reduction should 
continue for the duration of co-administration. In the event the co-administered CYP3A 
inhibitor is discontinued, the assigned venetoclax dose should be resumed 3 days after 
discontinuation.  During the venetoclax ramp-up, these agents must be held; however, 
they may be started or resumed 24 hours after the highest planned dose of venetoclax is 
given, along with the appropriate dose reduction of venetoclax as above. 
 
5.4.7 Glasdegib specific dose adjustments 
In the event of significant toxicity, dosing must be interrupted, delayed and/or reduced as 
outlined below. In the event of multiple toxicities, dose modification should be based on 
the worst toxicity observed. Patients must be instructed to notify investigators at the first 
occurrence of any adverse symptom/s. 
 
Dose modifications may occur in three ways: 
• 
Within a cycle: Dosing interruption until adequate recovery followed by dose 
reduction (if required) of glasdegib during a given treatment cycle.  
• 
Between cycles: The next treatment cycle may be delayed if toxicity from the 
preceding cycle persists. 
• 
In the next cycle: Dose reduction may be required based on toxicities 
experienced in the previous cycle. 
 
Dosing Interruptions for glasdegib  
Patients experiencing Grade 3 or 4 toxicities potentially attributable to glasdegib should 
have their glasdegib treatment interrupted regardless of when it occurs in the cycle until 
the toxicity resolves or returns to baseline or </= grade 1. 
Appropriate follow-up assessments should be implemented until adequate recovery 
(toxicity resolves or returns to baseline or </= grade 1) occurs. The criteria that must be 
met prior to resuming treatment with glasdegib are described below. 
Depending on when the adverse event resolved, treatment interruption may lead to the 
patient missing all subsequent planned doses of glasdegib within the cycle. If the AE 
leading to treatment interruption recovers within the same cycle, re-commencement of 
dosing in that cycle is allowed. Glasdegib doses omitted for toxicity will not be replaced 
within that cycle (e.g., cycles will not be prolonged beyond the 28 days in order to make 
up for any missed glasdegib doses during that cycle). 
 
The need for a dose reduction at the time of treatment resumption should be based on 
the criteria outlined below, unless specifically agreed otherwise following discussion 
between the treating physician and the PI. If a dose reduction for glasdegib is applied in 
the same cycle, the patient must return to the clinic to receive a new supply of drug. 
In the event of glasdegib treatment interruption for reasons other than treatment-related 
toxicity (e.g., elective surgery) for a duration >21 days, the details of treatment 
resumption will be determined in consultation with the PI. 
 
Glasdegib treatment should be interrupted for ANC <100/mm3 and /or platelets 
<10,000/mm3 regardless of when it occurs. 
Re-commencement of treatment with glasdegib may not occur until the recovery 
parameters described in Table 6 below are met. 
Patients who are experiencing ongoing dose delays >8 weeks due to unresolved grade 
≥3 adverse events should be taken off treatment. 


 
 
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At the time of glasdegib re-initiation the non-hematologic toxicities listed in Table 7 below 
have returned to baseline or ≤ Grade 1 severity. 
If these conditions are met within ≤21 days of dose interruption, glasdegib may be 
resumed. If these parameters have not been met following >21 days of dose 
interruption, permanent discontinuation of treatment with glasdegib should be 
considered.   
 
QTcF Interval Monitoring and Management: Patients should be closely monitored for 
potential cardiovascular symptoms.  Appropriate monitoring should include clinical 
examinations, vital signs, routine ECGs, and AE monitoring. In case of QTcF 
prolongation, concomitant conditions such as electrolyte imbalances, hypoxia, or use of 
medications affecting the QT interval should be ruled out or corrected. In case of 
clinically significant toxicities, glasdegib administration should be interrupted and the 
dose reduced as indicated in Table 8 below (Glasdegib Dose Modifications for mean 
QTcF (mQTcF) Prolongation). 
 
Concomitant administration of glasdegib with moderate/strong CYP3A4/5 inhibitors and 
drugs with known risk of Torsade de Pointes (TdP) is not recommended due to the 
potential for drug-drug interaction to prolong the QTcF interval. However, if it is medically 
necessary for patients to use these medications please refer to Section below for details 
on required assessments and monitoring procedures. 
 
Investigators must be aware of the QTcF-prolonging potential of all medications that 
patients on study at their site are taking, and should take appropriate action when 
clinically indicated. Given the potential for QTcF prolongation, the measurement and 
immediate correction of electrolyte abnormalities such as potassium and magnesium 
and of other reversible causes of QTcF prolongation such as hypoxia, are especially 
important during the study. In the event that the QTcF interval is prolonged beyond 480 
ms (CTCAE v.4.03  Grade≥ 2), the protocol glasdegib Dose Modifications for mean 
QTcF (mQTcF) Prolongation must be referenced and actioned (Table 9). Throughout the 
study additional ECG and cardiac consultation should be obtained as clinically indicated. 
 
Dose Reductions for glasdegib  
 
Following dosing interruption or cycle delay due to toxicity, the glasdegib dose may need 
to be reduced when treatment is resumed. 
Dose reduction of glasdegib by 1 or if necessary, 2 dose levels will be allowed 
depending on the type and severity of toxicity encountered. In the specific situations 
where clinical benefit is observed, glasdegib can be reduced below 50 mg QD upon PI 
approval.  All dose modifications/adjustments must be clearly documented in the 
patient’s notes and CRF. 
 
Table 5: Glasdegib dose reduction schema 
Glasdegib dose (mg Qday) 
100 
75 
50 
25* 
*Note: If clinical benefit is observed, glasdegib may be reduced below 50 mg Qday 


 
 
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following PI approval. 
 
 
 
 
 


 
 
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Table 9: Evaluation and management of QTcF changes with Glasdegib therapy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Table 10 
 
CYP3A4/5 Inducers: Glasdegib (PF-04449913) metabolism may be induced when 
taking CYP3A4/5 inducers, resulting in reduced plasma concentrations.  The impact of 
CYP3A4/5 inducers on PF-04449913 pharmacokinetics has not been studied in the 
clinic. Therefore co-administration of PF-04449913 with any of the following and other 
moderate/strong CYP3A4/5 inducers is not permitted from study entry until study 
treatment discontinuation (avasimibe, mitotane, phenytoin, enzalutamide, semagacestat, 
bosentan, genistein, thioradazine, nafcillin, modafinil, carbamazepine, phenobarbital, 


 
 
Page 67 of 103 
 
phenytoin, rifampin, rifabutin, rifapentine, St. John’s Wort).  A comprehensive list of 
strong CYP3A4/5 inducers is provided in the Appendix.  
 
Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is 
recommended.  Moderate/strong CYP3A4/5 inhibitors should be used with caution and 
only if considered medically necessary. If a moderate/strong CYP3A4/5 inhibitor is to be 
initiated in addition to glasdegib the guidance provided below requiring additional ECG 
monitoring before, during and after starting the medication, electrolyte monitoring 
(including correction and re-checking values) and dose modifications for QT prolongation 
must be followed. 
The concomitant administration of glasdegib and drugs with a known risk of Torsade de 
pointes should be avoided whenever possible.  A list of such drugs is provided in the 
Appendix.  Use of these drugs is not recommended unless there are no alternatives. If a 
TdP drug is to be initiated in addition to glasdegib the guidance provided below requiring 
additional ECG monitoring before, during and after starting the medication, electrolyte 
monitoring (including correction and re-checking values) and dose modifications for QT 
prolongation must be followed. 
QT prolonging medications (without a risk of TdP) should be avoided whenever possible. 
Concomitant administration of multiple moderate/strong CYP3A4/5 inhibitors, TdP drugs, 
and/or QT prolonging medications (without a risk of TdP) is not recommended and must 
be discussed with the PI. 
 
The acceptable mean on-treatment upper limit of QTcF interval is 480 msec. If any 
patient has a mean pre- or post-dose QTcF value >480 msec, please refer to Table 
‘Dose Modifications for mean QTcF (mQTcF) Prolongation’ (Table 9) for detailed 
instructions on management of QTcF prolongation and handling dose delays and dose 
modifications for glasdegib. 
 
If a moderate/strong CYP3A4/5 inhibitor or TdP drug will be initiated in addition to 
Glasdegib (PF-04449913) the following guidance must be followed: 
 
-Prior to the start of a moderate/strong CYP3A4/5 inhibitor or TdP drug: 
ECGs pre-glasdegib dose, 1 and 4 hours post-glasdegib dose; 
Follow dose modifications for QT prolongation. 
 
-After starting a moderate/strong CYP3A4/5 inhibitor or TdP drug: ECGs on Day 2 or 3 
and on Day 5, 6, or 7: 
 
-Perform additional ECG testing as appropriate; 
 
- Perform routine electrolyte monitoring (Ca, K, Cl, Mg), implement timely electrolyte 
correction, followed by appropriate re-checking of values. 
 
When there is an urgent need to start a moderate/strong CYP3A4/5 inhibitor or TdP 
drug, administration of these medications should not be delayed, the Investigator should 
consider temporarily interrupting glasdegib dosing and should implement these 
additional monitoring procedures as soon as it is reasonably possible. 
  
 
5.4.7 Modifications of dose schedules other than the above will be allowed 
within the following guidelines: 


 
 
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5.4.7.1 Dose adjustments by more than 1 dose level at a time for azacitidine, venetoclax 
or glasdegib (e.g., from azacitidine 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. 
 
5.4.7.2 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. 
The dose of any agent must not exceed the RP2D dose for that agent in this protocol 
(i.e. azacytidine dose cannot exceed 75mg/m2 x 7 days, venetoclax dose cannot exceed 
400 mg/day, and glasdegib dose cannot exceed 100 mg/day). 
 
5.4.7.3 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 or PF-04518600, in patients with cytopenias this would be likely secondary to 
azacitidine and venetoclax, in patients with hepatic congestion or transaminitis this may 
be secondary to the GO). 
 
 
5.4.8 Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until 
one of the following criteria applies: 
 
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. 
 
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. 
 
All patients receiving at least one dose of any of the two/three drugs to be received in 
the combination will be considered evaluable for toxicity and efficacy by intent-to-treat 
analysis. 
 


 
 
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5.5 Supportive Care: 
Management Algorithms for Treatment of immuno-oncology agents 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 and PF-04518600 are considered an immuno-oncology agent in this protocol. 
Early recognition and management of AEs associated with immuno-oncology agents 
may mitigate severe toxicity. These IO-agent/s 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. In cases with slightest 
suspicion of IO-toxicities it is encouraged that the treating physician consult the PI/Co-PI 
or immunotherapy expert in the department as soon as possible. 
 
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 and PF-04518600 Investigator Brochures” (Appendix) and “Table 4- 
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 
Supportive care measures including blood products, infection prophylaxis and 
growth factors will be administered according to institutional and MDACC Leukemia 
Department guidelines (Table 11). 
 
Table 11: 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 


 
 
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Category of Use 
Medication 
Comment on Use 
Restriction on Use 
 
 
Red blood cell 
transfusion 
None 
 
 
None 
 
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 
 
 
 
CYP3A4 inducers, 
inhibitors in patients 
on venetoclax or 
glasdegib, TdP 
drugs, QT 
prolonging drugs in 
patients on 
glasdegib 
At investigators 
discretion 
according to 
standard of care at 
MDACC  
 
Please see section 
5.5.6 and 5.4.7 for 
guidelines on use 
of these agents 
None 
 
 
 
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 


 
 
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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 azacitidine), 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. 
 
Since the effect of IO-agents, azacitidine, smoothened inhibition 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 to treat the underlying disease but are eligible to enroll on 
supportive care clinical trials. 
 
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 


 
 
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study with concomitant administration of such medication(s) will need to be discussed 
with and approved by the principal investigator and medical monitor 
 
 
6.0 DRUG ADMINISTRATION 
 
6.1 IO-agent Patient Monitoring During Infusion (avelumab and PF-04518600) 
Vitals should be checked prior to dosing, at least once during infusion, and at least once 
after completion of infusion. 
 
6.2 Treatment of IO-agent/s Related Infusion Reactions 
Since avelumab and PF-04518600 contains only human immunoglobulin protein 
sequences, they are 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, arthralgias, 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 IO-agent 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. IO-agent Infusion Related Reactions 
            Symptoms 
• 
Fever 
• 
Chills 
• 
Rigors 
• 
Diaphoresis 
• 
Headache 


 
 
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Table 12. 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. 
- Once the 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 
infusion should be stopped and the subject should be removed from study treatment unless the patient 
is deriving clinical benefit in which the agent may be continued after discussion with the PI of potential risk/benefit ratio 
and documentation of this discussion in the patents medical record. 
- If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice.  
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 
 
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. 
 
C. Tumor Lysis Syndrome 
In addition, since IO-agents 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  
 
TLS = 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


 
 
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6.3     Azacitidine:  
Azacitidine will be commercially obtained. Refer to azacitidine prescribing information 
(Appendix) in addition to institutional standards for preparation and administration 
azacitidine. 
 
6.4 GO (Mylotarg) 
Infusion reactions (e.g., fever, chills, flushing, hypotension, and dyspnea) have been 
very commonly encountered in association with GO administration and anaphylaxis has 
also been reported. Therefore, GO should only be administered in a location that is 
equipped to manage serious allergic reactions. The possibility of infusion reactions and 
anaphylaxis should always be anticipated during GO infusions and standard agents for 
the treatment of allergic/anaphylactic reaction should be available (e.g., oxygen, 
bronchodilators, intravenous saline, and emergency drugs including epinephrine 
[adrenaline], diphenhydramine or chlorpheniramine, and methylprednisolone). 
 
Treatment of GO Infusion-Related Reactions (including Anaphylaxis):  
GO administration can result in severe hypersensitivity reactions (including anaphylaxis), 
and other infusion-related reactions which may include severe respiratory symptoms. 
Infrequently, hypersensitivity reactions and associated pulmonary events have been 
fatal.  
 
A post-infusion reaction symptom complex of fever and chills, and less commonly 
hypotension and dyspnea, has been very commonly reported following GO 
administration, with symptoms typically occurring during, or in the first 24 hours after 
infusion. The most commonly reported Grade 3 or 4 non-hematologic infusion-related 
AEs include fever, chills, nausea, vomiting, dyspnea, headache, hyperglycemia, 
hypertension, hypotension, and hypoxia. Infusion-related symptoms generally resolve 
after 2 to 4 hours with supportive therapy of acetaminophen, diphenhydramine, and IV 
fluids. Fewer infusion-related events have been observed after the second dose than 
after the first dose of GO. 
 
Severe pulmonary events (including pulmonary infiltrates, pleural effusions, non-
cardiogenic pulmonary edema, pulmonary insufficiency, and acute respiratory distress 
syndrome), which may be fatal, have been reported infrequently as part of infusion-
related reactions with the use of GO. Patients with an initial WBC count > 30,000/μL may 
be at increased risk of developing these symptoms and physicians should therefore 
consider leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral 
WBC count to < 30,000/μL prior to administration of GO. Patients with symptomatic 
intrinsic lung disease may also be at increased risk of developing severe pulmonary 
reactions. 
 
Most patients have received prophylactic diphenhydramine 50 mg orally (PO) or IV and 
acetaminophen 650 to 1000 mg PO before administration of GO and thereafter, 2 
additional doses of acetaminophen 650 to 1000 mg PO, 1 every 4 hours, and additional 
diphenhydramine may have been administered if required. Methylprednisolone 
administered prior to GO infusion may further ameliorate infusion-related symptoms. For 
first infusion, vital signs should be checked prior to the infusion, every 15 minutes (+/- 10 
minutes) during infusion, at end of infusion (+/- 10 minutes) and 60 minutes (+/- 30 
minutes) after end of infusion. For subsequent infusions, vital signs should be checked 
prior to the infusion, every 30 minutes (+/- 15 minutes) during infusion, at end of infusion 


 
 
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(+/- 10 minutes) and 60 minutes (+/- 30 minutes) after end of infusion.. 
 
GO infusion should be interrupted for patients experiencing dyspnea or clinically 
significant hypotension, fever or chills and patients monitored until signs and symptoms 
completely resolve. Once symptoms have resolved, reinfusion at a lower rate (e.g., 50% 
slower) could be attempted but permanent discontinuation of treatment with GO should 
be strongly considered for patients who develop anaphylaxis, pulmonary edema, or 
acute respiratory distress syndrome. Since patients with high peripheral blast counts 
may be at greater risk for infusion-related pulmonary events, physicians should consider 
leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral WBC count to 
below 30,000/μL prior to administration of GO. 
 
6.5  Venetoclax will be commercially obtained. Refer to venetoclax Prescribing Label 
(Appendix). 
 
6.6       Variations in infusion times of drugs 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. 
 
6.7       Unused or expired drugs will be safely disposed according to MD Anderson 
pharmacy standard guidelines. 
 
6.8       For further details on drug formulation, reconstitution, administration, infusion 
related instructions, concern and plan of management for infusion related topics please 
the respective agents IB and/or Pharmacy Manuals (Appendices) 
 
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 any of the study 
arms, 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, electrolytes, glucose, uric 
acid, creatinine, direct bilirubin, calcium, magnesium, alkaline 
phosphatase, BUN.  
 
7.1.4 Pregnancy test (urine or plasma) in females of childbearing 
potential should be performed within 72 hours before initiation of 
protocol therapy. 
 


 
 
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7.1.5 Bone marrow aspirate during the last 28 days (+/- 7 days) 
preceding study initiation. Cytogenetics will be obtained prior to 
therapy (results from prior analysis can be used for this purpose). 
 
7.1.6 Electrocardiogram EKG at baseline. Cardiac ECHO or MUGA at 
baseline. Troponin-T, CK, CK-MB, NT-proBNP at baseline 
 
7.1.7 Urine for routine urine analysis 
 
7.1.8 TSH, total T3, free T4, serum fasting cortisol, testosterone (in 
males), growth hormone level: GnRHs  
 
7.1.9 Chest X-Ray PA/Lateral 
 
7.1.10 Nasal wash for viral PCR 
 
7.1.11 Pretreatment optional correlative studies (see below) 
 
7.2 
Evaluation During Treatment 
 
7.2.1 Physical exam at the start of each cycle (± 4 days). 
 
7.2.2 CBC, platelet count, differential two times per week (+/- 4days) for 
the first 3 cycles, then one to two times per week (+/- 4 days) in 
subsequent cycles (differential can be omitted if WBC is ≤0.5 
x109/L) 
 
7.2.3 Creatinine, total bilirubin, ALT, or AST, electrolytes, glucose, uric 
acid, creatinine, direct bilirubin, calcium, magnesium, alkaline 
phosphatase, BUN two times per week (+/- 4 days) for the first 3 
cycles, then one to two times per week (+/- 4 days) in subsequent 
cycles 
 
7.2.4 In venetoclax containing arms only (Arms B and D): TLS 
chemistry tests (potassium, uric acid, creatinine, calcium and 
phosphorus) will be obtained daily prior to dosing and 6-8 hours 
on each day after a new venetoclax dose during cycle 1 
 
7.2.5 Cortisol, TSH, Total T3, Free T4 once every cycle for the first 3 
cycles, then once every 3 months. 
 
7.2.6 Troponin-T, CK, CKMB and NT-proBNP once every cycle for 
patients on glasdegib-containing arms. 
 
 
7.2.7 EKG on Day 1 of each cycle of therapy for patients on glasdegib-
containing arms. 
 
 
7.2.8 ECHO or MUGA after every 3 cycles of therapy. 
 


 
 
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7.2.9 Urinalysis day 1 of every cycle 
 
 
7.2.10 Bone marrow aspiration on day 28 (+/- 4 days), then on day 28 
(+/- 4 days) of cycles 2, 4, 8 and progression. 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. Bone marrow examinations can be 
omitted at the discretion of PI and co-PI in patients with no bone 
marrow involvement at the time of screening. Response 
assessment should be instead performed with appropriate 
imaging (e.g. PET CT) as determined by the treating physician, 
depending on the site of disease. 
 
7.2.11 In venetoclax containing arms only (Arms B and D): Bone marrow 
aspiration will also be performed on day 21 (+/- 3 days) of cycle 1 
and follow the guidelines in section 5.  
 
7.2.12 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. 
 
7.2.13 Correlative Studies relating to immunologic response 
(Optional): Tumor tissue, blood samples and bone marrow 
aspirate for correlative research will be collected in patients who 
consent to participate in the optional procedures. Correlative 
laboratory studies will be conducted under this clinical trial as 
described:  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 


 
 
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(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 
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 aspirate (or slides) and 
peripheral blood at baseline, EOC2, EOC4, progression 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 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. 
 
 
• 
RNA sequencing (Illumina Hi-seq) and Nanostring analysis for IO-gene 
signature and gene expression for “stemness” associated genes [Ng et al, A 
17-gene stemness score for rapid determination of risk in acute leukaemia. 
Nature. 2016 Dec 15;540(7633):433-437.] on bone marrow aspirate (and 
possibly on peripheral blood) at baseline, EOC2, EOC4, and at progression 
 
 
• 
TCR analysis on bone marrow aspirate and peripheral blood at baseline, 
EOC2, EOC4, and progression on all patients 
 
 
• 
Serum cytokine profiling by ELISA panels at baseline, EOC2, EOC4, and 
progression on bone marrow aspirate and peripheral blood on all patients.  
 
 
Peripheral blood up to 40 mL (within 24 hours) will be collected in patients who 
consent to the correlative studies for testing of biomarkers at the following time 
points: 
-Baseline (prior to day 1 dose of drug), and on day 28 (+/- 4) on cycle 1 (done at 
MD Anderson), at day 28 (+/- 4 days) of cycles 2, 4, 8.  


 
 
Page 80 of 103 
 
 
Bone marrow samples will be collected in patients who consent to the 
correlative studies for testing of biomarkers at baseline, on day 28, at day 28 (+/- 
4 days) of cycles 2, 4, 8, and at progression (if possible).  
 
All correlative samples are optional. 
 
Missed samples for correlative studies will not constitute protocol deviations.  
 
• 
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. 
 
• 
ALL treatments with the investigational agents including PF-04518600, 
avelumab, GO must be administered at the MDACC outpatient clinic. The first 
cycle of azacitidine must be administered at the MDACC outpatient clinic, 
when applicable. Subsequently, patients will have the option of receiving 
azacitidine injections or infusions at the MDACC outpatient clinic or local 
ambulatory treatment center. We do not intend for the subjects to receive PF-
04518600, avelumab, or GO at any time at an outside physician’s office. 
During the first cycle for ALL arms A-F all the laboratory evaluations will be 
done at MDACC and the patients must stay locally within easy access of 
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. 
 
 
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 S). 
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 they’re 
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 


 
 
Page 81 of 103 
 
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 they’re 
representative prior to initiation, and will be documented in the patient 
record. 
 
7.2.14 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 is unable to return to MDACC the follow-up visits may be 
conducted via telephone. 
 
 


 
 
Page 82 of 103 
 
 
 
Table 13. 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 
Subsequen
t Cyclesj 
Cycle Day 
 
1 
8 
14 
15 
22 
2
8 
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 
 
57 
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 
Chest X-ray PA/Lateral 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal Wash PCR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Q 3 cycles 
 
 
ECGk 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
TropI, CK, CK-MB, BNPk  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
CBC with differentialb 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 


 
 
Page 83 of 103 
 
 
* Samples collected at screening do not need to be repeated on Day 1 of Cycle 1. 
** For first infusion of GO, vital signs should be checked prior to the infusion, every 15 minutes (+/- 10 minutes) during infusion, at end of infusion (+/- 10 
minutes) and 60 minutes (+/- 30 minutes) after end of infusion. For subsequent infusions of GO, vital signs should be checked prior to the infusion, every 30 
minutes (+/- 15 minutes) during infusion, at end of infusion (+/- 10 minutes) and 60 minutes (+/- 30 minutes) after end of infusion. For avelumab and PF-
04518600, vitals should be checked prior to dosing, at least once during infusion and at least once after completion of infusion. 
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. Differential can be omitted if WBC <0.5x109/L. In venetoclax containing-
arms only (Arms B and D), TLS chemistry tests (potassium, uric acid, creatinine, calcium and phosphorus) will be obtained prior to dosing and 6-8 hours on each 
day after a new venetoclax dose during cycle 1. 
c Cortisol, TSH, total 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. 
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 
 
Urinalysis 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Testosterone (males), 
GnRH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH, total T3, free T4, 
cortisolc 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Pregnancy testd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspirate/ 
biopsye 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Correlative 
Screeni
ng 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent cycles 
EOS 
Optional correlatives 
on bloodf 
X 
 
 
 
Day 28 
 
 
 
Day 28 
 
 
 
 
Day 28 of cycles 2,4,  8, 
prog 
If possible 
Optional correlatives 
on bone marrowg 
X 
 
 
 
Day 28 
 
 
 
Day 28 
 
 
 
 
Day 1 of cycle 2,  4, 8, 
prog 
If possible 


 
 
Page 84 of 103 
 
eBone marrow aspiration must be done within 28-days (+/- 7 days) of initiation of therapy, then Day 28 (+/- 4 days)cycles 2, 4, 8 and progression. Cytogenetics 
may be used from prior bone marrow analysis if these were not reported on the screening bone marrow. In venetoclax-containing arms only (Arms B and D), bone 
marrow aspiration should be performed on day 21 (+/- 3 days) of cycle 1. Follow-up bone marrows may be omitted at the discretion of the PI or co-PI for patients 
with extramedullary disease in whom no bone marrow disease was present at screening. 
fCorrelative studies will be collected on peripheral blood at baseline, 28 on cycle 1. Subsequently, peripheral blood will be obtained on day 28 of cycles 2, 4, and 
8. 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 (+/-4 days), then on day 28 (+/- 4 days) of cycles 4, 8and 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 – 5 days) will be scheduled as a 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 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.k Perform at specified time-
points and repeat as clinically indicatedL ECG on day 1 of every cycle of therapy 
k Only for patients on glasdegib-containing arm 
 


 
 
Page 85 of 103 
 
Data regarding adverse events will be collected during the study. Protocol specific data 
will be entered intothe electronic case report form (eCRF). AEs will be recorded in the 
Case Report Form (eCRF as described under section 10.0).  
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 118. 
Responders are patients who obtain a CR, CRp, CRi, or PR, with or without cytogenetic 
response, hematologic improvements, and morphologic leukemia-free state.  
 
For patients with only extramedullary disease, CR is defined as complete resolution of 
disease by appropriate imaging. PR is defined as at least 50% reduction of disease by 
appropriate imaging. 
 
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% 
 
 
9.0       DISCONTINUATION OF TREATMENT 
 
9.1 Discontinuation Criteria for Individual Patients 
 
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 


 
 
Page 86 of 103 
 
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 
100 days after the last protocol treatment. The 100-day follow-up visit (+ or – 5 days) will 
be scheduled as a 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.  
 
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 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 


 
 
Page 87 of 103 
 
• 
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 
 
10.0 
ADVERSE EVENT REPORTING 
 
10.1 
Monitoring, recording and reporting adverse events 
 
Adverse Event (AE) 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. 
 
All subjects will be monitored for AEs during the study. AEs will be 
recorded in the subject’s source documents from the first dose through 30 
days after the last dose. All Grade 1-4 AEs possibly, probably, likely 
related to study drug(s) will be captured within the eCRF. Grade 3 and 4 
AEs will be captured irrespective of relatedness to study drug(s). 
Hematologic lab abnormalities will not be recorded or reported as adverse 
except for prolonged myelosuppression as defined by the NCI-CTCAE 
criteria specific for leukemia, e.g. marrow hypocellularity on day 42 or 
later (6 weeks) from start of therapy without evidence of leukemia (< 5% 
blasts), or that results in dose modifications, interruptions or meets the 
protocol definition of DLT or SAE.  
 
Serious Adverse Events (SAEs) will be captured starting from the date of 
consent. 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. 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. 
 
The Leukemia-specific Adverse Event Recording and Reporting Guidelines 
will be followed for the recording and reporting of adverse and serious 
adverse events. 
1. Baseline events will be recorded in the medical history section of the 
case report form and will include the terminology event name, grade, 


 
 
Page 88 of 103 
 
and start date of the event.  The medical history section of the case 
report form will serve as the source document for baseline events 
once signed and dated by the principal investigator.   
a. Baseline events are any medical condition, symptom, or 
clinically significant lab abnormality present before the 
informed consent is signed 
i. Hematologic laboratory abnormalities will not be 
recorded as baseline events for patients with acute 
leukemia, myelodysplastic syndrome, chronic 
lymphocytic leukemia, or chronic myeloid leukemia in 
blast phase. 
ii. If exact start date is unknown, month and year or year 
may be used as the start date of the baseline event. 
2. The maximum grade of the adverse event will be captured per course 
or protocol defined visit date. 
3. These adverse events will be recorded in the case report form: 
a. Any grade adverse event that is possibly, probably, or 
definitely related to the study drug(s). 
b. All serious adverse events regardless of attribution to the 
study drug(s). 
c. Any grade adverse event regardless of attribution to the study 
drug(s) that results in any dose modification. 
4. Hematologic adverse events will not be recorded or reported for 
studies in patients with acute leukemia,  myelodysplastic syndrome, 
chronic lymphocytic leukemia, or chronic myeloid leukemia in blast 
phase except for: 
a. Prolonged myelosuppression as defined by the NCI-CTCAE 
criteria specific for leukemia, e.g. marrow hypocellularity on 
day 42 or later (6 weeks) from start of therapy without 
evidence of leukemia (< 5% blasts), or that results in dose 
modifications, interruptions or meets the protocol definition of 
DLT or SAE. 
5. Serious adverse events will be reported according to institutional 
policy. 
6. Protocol specific language regarding the recording and reporting of 
adverse and serious adverse events will be followed in the event of 
discordance between the protocol and Leukemia-specific adverse 
event recording and reporting guidelines. 
 
10.2 
Serious Adverse Events  (SAEs) 
 
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. 


 
 
Page 89 of 103 
 
• 
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. 
 
10.3    Reporting SAEs to the IND Office and MDACC IRB 
 
• 
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 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 


 
 
Page 90 of 103 
 
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. 
 
10.4  Reporting SAEs 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 teams 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 utilizing the provided Pfizer SAE form.  
• 
All SAEs, whether related or unrelated to study drugs 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:  
 
SAE Email Address: USA.AEReporting@pfizer.com 
SAE Fax Number: 1-866-997-8322 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
This is an open-label Phase IB/II multi-arm study. The primary objectives are to determine 
the maximum tolerable dose  (MTD) and identify the dose of PF-04518600 (Arm A), and 
to evaluate the composite complete response (CRc) within 3 months of therapy initiation 
of the combination therapies:  Azacitidine + venetoclax + GO (arm B), Azacitidine + 
avelumab + GO (arm C), Azacitidine + venetoclax + avelumab (arm D), Azacitidine + 
avelumab + PF-04518600 (arm E),  and GO + glasdegib (arm F), in patients with 
relapsed/refractory AML.  A total of up to 87 patients will be enrolled in the study (arms 
with up to 24 patients per arm in arms C-D and 30 patients in arm B, in addition to the 4 
patients enrolled in arm A and 5 patients enrolled in arm F at the time of closing these two 
arms.  
 
 
Dose safety evaluation for Arm A (PF-04518600 alone in RR AML): 
 
The 0.3 mg/kg dose of PF-04518600 will be evaluated as this was the dose selected to 
move forward from the solid tumor PF-04518600 single agent dose finding study 
(B0601002, ClinicalTrials.gov NCT02315066). Up to four patients will be enrolled at the 
dose level of 0.3mg/kg of PF-04518600. This arm will be closed at this time to further 
enrollment due to lack of clinical efficacy and competing options of higher priority at our 
institution.  


 
 
Page 91 of 103 
 
 
Lead-in safety evaluation for Arm B-F 
A lead-in safety evaluation for Arm B-F will be conducted to confirm the safety and 
tolerability of the treatment combination. Up to 30 patients in arm B, 24 patients in arms 
C-D and up to 21 patients in arms E-F will be enrolled.  Enrollment must be halted while 
the first 6 patients in each treatment arm are evaluated for safety (i.e. after all patients 
have received 2 cycles of therapy, or been followed for at least 56 days from the start of 
treatment).  
 
The treatment combination will be considered as safe and continue to enroll a total of 30 
patients (arm B) or 24 patients (arms C-D) or 15 patients (arms E-F) when there are no 
more than 1 out of 6 patients with DLTs in the first cycle (28 days) of treatment. If any 
patients in the first 6 of each treatment arm withdraw from the study without a DLT event 
prior to completing the first cycle of treatment, they will be replaced for the assessment 
of DLT rate. This will allow for early identification of significant toxicities and early 
stoppage in potentially toxic arms. If 2 or more out of 6 patients with DLTs in the first 
cycle of treatment, then additional 6 patients will enroll at a lower dose level. If no more 
than 1 out of the additional 6 patients treated with lower dose level experienced DLTs, 
this treatment combination will be considered as safe and continue to enroll to a total of 
30 patients (arm B), 24 (arms C-D) or 15 patients (arms E-F). If 2 or more out of these 6 
additional patients experienced DLTs, then this arm will be halted.  
Arm F will be closed at this time to further enrollment due to lack of clinical efficacy and 
competing options of higher priority at our institution. 
 
Futility Monitoring for Arms B-F 
The primary endpoint of Arm B-F is the achievement of composite complete response 
(CRc) within 3 months of therapy initiation in patients with RR AML. The method of Thall, 
Simon and Estey (1995) will be used to monitor efficacy and safety. After the lead-in, 
shiny applications were used to generate the operating characteristics for toxicity and 
futility monitoring, respectively (http://qcprlshinypro.mdanderson.edu/postprobtoxicity/; 
http://qcprlshinypro.mdanderson.edu/postprobfutility/). 
 
The historical data suggested a composite complete response (CRc) rate of 30% in 
patients with R/R AML with a variety of different therapies4,110,119-122, and a target 
response rate is 45%. The study arm will be stopped early if the data suggest that:  
Pr(PE > PH + 0.15 | data)<0.05, 
where PE and PH are the CRc rates for experimental and historical treatment, 
respectively. That is, if at any time during the study we determine that there is less than 
5% chance that the CRc rate improves over historical rate by more than 15%, the arm 
will be stopped due to futility. PE is assumed to follow a prior of Beta (0.6, 1.4). The 
futility monitoring will be conducted starting from the 10th patient in cohort size of 5 
patients except the last cohorts with less than 5 patients. The design parameters are set 
the same for arms B-F, while separate futility monitoring analyses were conducted to 
accommodate different numbers of patients among these arms.  
Arm F will be closed at this time to further enrollment due to lack of clinical efficacy and 
competing options of higher priority at our institution. 
 


 
 
Page 92 of 103 
 
 
Arm B 
The stopping boundaries for efficacy based on these assumptions and monitoring 
conditions are provided in Table 14. The operating characteristics are summarized in 
Table 15.    
 
If the study arm is not stopped early and 24 patients have been treated and evaluated in 
the study arm, assuming 8 of the 24 patients achieve CRc under the combination 
treatment, then the 95% credible interval for CRc rate will be (0.17, 0.52). 
 
Table 14.  Stopping boundaries for futility monitoring in Arm B 
# of patients 
evaluated for 
response 
Stop the arm if # of patients with response is less than or 
equal to:  
10 
0-2 
15 
0-3 
20 
0-5 
24 
Always stop with this many patients 
 
Table 15. Operating characteristics for futility monitoring in Arm B-D 
True response rate 
Prob(stop the arm early) 
Average sample size 
0.15 
0.952 
11.7 
0.25 
0.702 
15.6 
0.30 
0.525 
17.8 
0.35 
0.357 
19.8 
0.45 
0.126 
22.5 
0.55 
0.031 
23.6 
0.65 
0.005 
23.9 
 
Arm C-D 
The stopping boundaries for efficacy based on these assumptions and monitoring 
conditions are provided in Table 16. The operating characteristics are summarized in 
Table 17.    
 
If the study arm is not stopped early and 18 patients have been treated and evaluated in 
the study arm, assuming 6 of the 18 patients achieve CRc under the combination 
treatment, then the 95% credible interval for CRc rate will be (0.15, 0.54). 
 
Table 16.  Stopping boundaries for futility monitoring in Arm C-D 
# of patients 
evaluated for 
response 
Stop the arm if # of patients with response is less than or 
equal to:  
10 
0-2 
15 
0-3 
18 
Always stop with this many patients 
 


 
 
Page 93 of 103 
 
Table 17. Operating characteristics for futility monitoring in Arm C-D 
True response rate 
Prob(stop the arm early) 
Average sample size 
0.15 
0.878 
11.3 
0.25 
0.585 
13.6 
0.30 
0.428 
14.8 
0.35 
0.291 
15.8 
0.45 
0.108 
17.2 
0.55 
0.029 
17.8 
0.65 
0.005 
18.0 
 
Arm E-F 
The stopping boundaries for efficacy based on the same assumptions and monitoring 
conditions are provided in Table 18. The operating characteristics are summarized in 
Table 19.  If the study arm is not stopped early and 15 patients have been treated and 
evaluated in the study arm, assuming 5 of the 15 patients achieve CRc under the 
combination treatment, then the 95% credible interval for CRc rate will be (0.13, 0.56). 
Arm F will be closed at this time to further enrollment due to lack of clinical efficacy and 
competing options of higher priority at our institution. 
 
Table 18.  Stopping boundaries for futility monitoring in Arm E-F 
# of patients 
evaluated for 
response 
Stop the arm if # of patients with response is less than or 
equal to:  
10 
0-2 
15 
Always stop with this many patients 
 
Table 19. Operating characteristics for futility monitoring in Arm E-F 
True response rate 
Prob(stop the arm early) 
Average sample size 
0.15 
0.820 
10.9 
0.25 
0.526 
12.4 
0.30 
0.383 
13.1 
0.35 
0.262 
13.7 
0.45 
0.100 
14.5 
0.55 
0.027 
14.9 
0.65 
0.005 
15.0 
 
Toxicity Monitoring for Arm B-F 
The method of Thall, Simon and Estey will be used for toxicity monitoring for this study. 
Denote the probability of DLT by PT. We assume as a priori, PT ~ beta (0.3, 1.7).  Our 
stopping rule is: if 2 or more out of 6 patients with DLTs in the first cycle of treatment, 
then additional 6 patients will enroll at a lower dose level.  If 2 or more out of these 6 
additional patients experienced DLTs, then this arm will be halted.  Otherwise, we will 
stop the arm if Pr(PT > 0.15 | data)>0.80. That is, we will stop the arm for new patient 
enrollment if at any time during the study, we determine that there is more than 80% 


 
 
Page 94 of 103 
 
chance that the toxicity rate is more than 15%. Again, the design parameters are set the 
same for arms B-F, while separate toxicity monitoring analyses were conducted to 
accommodate different numbers of patients among these arms. 
Arm F will be closed at this time to further enrollment due to lack of clinical efficacy and 
competing options of higher priority at our institution. 
 
Arm B 
 
The toxicity stopping rule will be applied starting from the 6th patient, and then in cohort 
size of 3. Stopping boundaries corresponding to the above stopping rule are listed in 
Table 18. The operating characteristics are summarized in Table 19.   
 
Table 18.  Early stopping boundaries for toxicity monitoring arm B 
# of patients ( in cohort 
size of 3, starting from 
the 6th  patient) 
Stop the arm if there 
are this many patients 
with toxicities:  
6 
2-6 
9 
3-9 
12 
4-12 
15 
4-15 
18 
5-18 
21 
5-21 
24 
Always stop 
 
 
Table 19. Operating characteristics for toxicity monitoring arm B 
True toxicity rate 
Prob(stop the arm early) 
Average sample size 
0.10 
0.163 
21.4 
0.15 
0.342 
19.0 
0.20 
0.555 
16.0 
0.25 
0.731 
13.4 
0.30 
0.856 
11.0 
0.40 
0.976 
8.0 
 
Arm C-D 
 
The toxicity stopping rule will be applied starting from the 6th patient, and then in cohort 
size of 3. Stopping boundaries corresponding to the above stopping rule are listed in 
Table 18. The operating characteristics are summarized in Table 19.   
 
Table 20.  Early stopping boundaries for toxicity monitoring arm C-D 
# of patients ( in cohort 
size of 3, starting from 
the 6th  patient) 
Stop the arm if there 
are this many patients 
with toxicities:  
6 
2-6 
9 
3-9 
12 
4-12 


 
 
Page 95 of 103 
 
15 
4-15 
18 
Always stop 
 
 
Table 21. Operating characteristics for toxicity monitoring arm C-D 
True toxicity rate 
Prob(stop the arm early) 
Average sample size 
0.10 
0.137 
16.5 
0.15 
0.290 
15.0 
0.20 
0.485 
13.1 
0.25 
0.653 
11.4 
0.30 
0.771 
10.1 
0.40 
0.936 
7.8 
 
 
Arm E - F 
The toxicity stopping rule will be applied starting from the 6th patient, and then in cohort 
size of 3. Stopping boundaries corresponding to the above stopping rule are listed in 
Table 22. The operating characteristics are summarized in Table 23.   
Arm F will be closed at this time to further enrollment due to lack of clinical efficacy and 
competing options of higher priority at our institution. 
 
Table 22.  Early stopping boundaries for toxicity monitoring arm E-F 
# of patients ( in cohort 
size of 3, starting from 
the 6th  patient) 
Stop the arm if there 
are this many patients 
with toxicities:  
6 
2-6 
9 
3-9 
12 
4-12 
15 
Always stop 
 
Table 23. Operating characteristics for toxicity monitoring arm E-F 
True toxicity rate 
Prob(stop the arm early) 
Average sample size 
0.10 
0.122 
13.9 
0.15 
0.264 
12.8 
0.20 
0.410 
11.6 
0.25 
0.562 
10.3 
0.30 
0.685 
9.3 
0.40 
0.874 
7.6 
 
Statistical Analysis Plan 
 
Demographic/clinical characteristics and safety data will be summarized using 
descriptive statistics such as mean, standard deviation, median and range. The 
composite complete response (CRc) rates, partial response (PR), hematologic 
improvement (HI) rate, 4-week and 8-week mortality will be estimated along with the 


 
 
Page 96 of 103 
 
95% credible intervals. Kaplan-Meier method will be used to estimate the relapse-free 
survival (RFS), morphologic leukemia free survival (MLFS), time to next therapy (TNT) 
and overall survival (OS). The two-sided log-rank tests will be used to assess the 
differences of time to events between groups.  Cox proportional hazards regression 
model will be used to determine associations between MRD and OS. 
 
All patients who received at least one dose of study drug will be included in the intent-to-
treat analysis for efficacy and safety. We will follow standard reporting guidelines for 
adverse events. Safety data will be summarized by category, severity and frequency. 
Paired t-tests will be used to determine the immunological and molecular changes in the 
peripheral blood and bone marrow from baseline to the predefined time-points on-
therapy. 
 
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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