A Proof-of-Concept Study for Ilorasertib (ABT-348) Activity in Patients With CDKN2A-Deficient Advanced Solid Cancers: a Phase II Basket Trial
Phase: PHASE2
Conditions: Advanced Cancers
Sponsor: M.D. Anderson Cancer Center

Protocol 2014-0920 
August 3, 2016 
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A Proof-of-Concept Study for Ilorasertib (ABT-348) Activity in Patients with 
CDKN2A-Deficient Advanced Solid Cancers: a Phase II Basket Trial 
Short Title:  Ilorasertib (ABT-348) in Patients with CDKN2A-Deficient Advanced Solid 
Cancer 
Principal Investigator: David S. Hong, MD 
Coordinating Center: The University of Texas, MD Anderson Cancer Center 
Department: Investigational Cancer Therapeutics 
Phone: 713-792-4964 
Unit: 455 
Protocol Type: Standard Protocol  
Protocol Phase: Phase II basket trial 
Protocol Number: 2014-0920 
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Table of contents 
Table of contents ................................................................................................................. 2 
1.      Objectives .................................................................................................................. 3 
1.1.   Primary objectives ..................................................................................................... 3 
1.2.   Secondary objectives ................................................................................................. 3 
2.      Background ................................................................................................................ 3 
2.1.   Outline of research hypothesis ................................................................................... 3 
2.2.   Background drug information: Ilorasertib (ABT-348) .............................................. 6 
3.
 Eligibility Criteria .................................................................................................... 15 
3.1.   Inclusion criteria ...................................................................................................... 15 
3.2.  Exclusion criteria ..................................................................................................... 16 
4.
 Treatment Plan ......................................................................................................... 17 
4.1.   Criteria for removal from the study ......................................................................... 17 
4.2.   Dose delays and modifications ................................................................................ 18 
5.
  Pretreatment and Treatment Evaluation .................................................................. 18 
6.
  Concomitant Medication ......................................................................................... 19 
7.      Measurement of Response ....................................................................................... 20 
7.1    Response criteria ...................................................................................................... 20 
7.2.   Methods of evaluation.............................................................................................. 20 
8.      Evaluation of Toxicity ............................................................................................. 20 
9.      Reporting and Regulatory Requirements ................................................................. 22 
10.    Statistical Considerations ......................................................................................... 24 
10.1. Study design and endpoints ..................................................................................... 25 
10.2. Sample size .............................................................................................................. 25 
10.3. Expansion cohorts .................................................................................................... 26 
11.    Pharmacodynamic Analysis of Skin Biopsy ............................................................ 27 
12.    Follow-up Period ..................................................................................................... 28    
13.    Confidentiality ......................................................................................................... 28 
14.    Study Calendar ......................................................................................................... 28 
15.
References ................................................................................................................ 30
         Appendix I. Cautions with Coadministration of Medications ................................. 31 
         Appendix II. Performance Status Criteria   .............................................................. 32 
         Appendix III. Management Guidelines for Toxicities   ........................................... 33 
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1. Objectives
1.1 Primary objectives 
a) In Part I: To evaluate the response rate (partial response, complete response)
of Ilorasertib (ABT-348) (Aurora kinase inhibitor) in patients with cancers
harboring CDKN2A deletion or mutation as tumor response.
b) In Part I: To identify tumor types for further development.
c) In Part 2 (expanded cohort): To determine the antitumor activity of Ilorasertib
(ABT-348)  in specific tumor type harboring CDKN2A deletion or mutation.
1.2 Secondary objectives 
a) To evaluate the safety and tolerability of Ilorasertib (ABT-348) in this
patient population.
b) To assess pharmacodynamics by immunohistochemistry for phospho-Histone
H3 (P-HH3).
2. Background
2.1. Outline of research hypotheses 
Aurora Kinase 
Uncontrolled cell proliferation is a characteristic of tumor cells, and alterations in the 
genes involved in cell cycle control are frequent in human cancers. Aurora kinases1 and 
CDKN2A play a major role in cell cycle checkpoint regulation. Aurora kinases are a 
family of serine/threonine kinases. Humans have 3 Aurora kinases, Aurora A, B, and C 
that are expressed in multiple tissues, but only in the G2 and mitotic phases of the cell 
cycle.1 Aurora A regulates centrosome function and is required for spindle assembly and 
the entry of cells into mitosis.1-3 Aurora B is a chromosomal passenger protein that is an 
integral part of the spindle assembly checkpoint that ensures proper chromosomal 
segregation and cytokinesis.1-3 Aurora C's cellular function is redundant with Aurora B.1-3 
Based on the role of Aurora kinases in centrosome duplication and the proper alignment 
of chromosomes on mitotic spindles, their abnormal expression is thought to contribute to 
tumorigenesis by increasing chromosomal instability.1-3 Inhibition of Aurora kinases 
causes cells to enter aberrant mitosis resulting in aneuploidy or polyploidy cells, and 
ultimately leading to death.1-3  
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Figure 1. Cell cycle and aurora kinases (Giet et al, Trends in Cell Biology 2005) 
CDKN2A 
CDKN2A encodes p16INK4A and p19ARF.4 p16INK4A blocks cell cycle progression 
by binding CDK4/Cyclin D complex. This leads to accumulation of hypophosphorylated 
Rb, which plays a major inhibitory role at the G1-S restriction point. p19ARF blocks cell 
cycle progression by binding p53/Mdm2 complex and preventing p53 degradation at the 
G1-S and G2-M points.5, 6 Therefore loss of CDKN2A contributes to tumorigenesis by 
driving uncontrolled cell cycles.  
Figure 2. CDKN2A pathway 
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Many tumor types show CDKN2A deletion more commonly in bladder cancer (43.8%), 
brain tumor (29.1%), melanoma (27.6%), pancreatic cancer (24.1%), and esophageal 
cancer (21.3%) from the CGH data with the criteria less than 1.2 copies (Table 1). Germ 
line mutations in the CDKN2A gene are known to predispose individuals to familial 
pancreatic cancer and melanoma.7 
Table 1. CDKN2A Deletion Frequency (<1.2 Copies) from CGH data 
General Cancer Type 
Frequency 
# Deleted 
# Tested 
Bladder Cancer 
43.80% 
14 
32 
Brain and CNS Cancer 
29.10% 
423 
1455 
Melanoma 
27.60% 
32 
116 
Pancreatic Cancer 
24.10% 
14 
58 
Esophageal Cancer 
21.30% 
13 
61 
Gastric Cancer 
13.80% 
31 
224 
Head and Neck Cancer 
9.40% 
26 
278 
Sarcoma 
8.40% 
19 
227 
Lung Cancer 
6.50% 
69 
1054 
Ovarian Cancer 
4.70% 
40 
859 
Leukemia 
3.80% 
9 
239 
Breast Cancer 
2.90% 
26 
890 
Kidney Cancer 
1.90% 
12 
635 
Other Cancer 
1.80% 
7 
399 
Liver Cancer 
0.80% 
2 
241 
Cervical Cancer 
0.80% 
1 
120 
Colorectal Cancer 
0.60% 
5 
849 
Myeloma 
0.60% 
3 
530 
Prostate Cancer 
0.50% 
2 
365 
Normal 
0.00% 
0 
3735 
Ilorasertib (ABT-348) activity 
Ilorasertib (ABT-348) is a potent, novel, adenosine triphosphate (ATP)-competitive, pan-
Aurora kinase inhibitor (IC50 < 120 nM and < 10 nM for Aurora A and Aurora B/C, 
respectively) with a unique kinase selectivity profile that includes potent activity against 
the VEGF receptor (VEGFR)/PDGF receptor (PDGFR) family of kinases. Ilorasertib 
(ABT-348) exhibited sub-micromolar cellular activity against multiple human tumor cell 
lines derived from broad range of tumor types including colorectal, ovarian, pancreatic as 
well as lymphoid malignancies. In vivo, Ilorasertib (ABT-348) was broadly efficacious in 
several established murine xenografts with complete inhibition or regression observed by 
a once weekly dosing regimen. The inhibition of VEGF signaling was also observed as 
measured by changes in tumor vascular permeability and contributed to the broad 
antitumor activity. Based on exposure parameters from nonclinical efficacy studies, 
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plasma concentrations of Ilorasertib (ABT-348) exhibited low susceptibility to resistance 
due to poor multidrug resistant (MDR) affinity of Ilorasertib (ABT-348) ranging from 0.5 
to 1.0 μg/mL for up to 16 hours are sufficient for robust antitumor activity. Current 
pharmacokinetic modeling predicts that an oral dose of 400 mg in humans will maintain 
Ilorasertib (ABT-348) plasma concentrations above the 1.0 μg/ml target for ~17 hours 
with a projected maximum observed plasma concentration (Cmax) of 2.4 μg/mL. 
In two phase I dose escalation studies (solid tumor, hematologic malignancy), 102 
patients with advanced solid tumors and 50 with hematologic malignancies were treated 
with Ilorasertib (ABT-348). In solid tumors, 9 of 102 patients showed response (8 PRs 
and 1 CR). Two of 9 responders were tested for CDKN2A and these patients were found 
to be CDKN2A-deleted. In the hematologic study, three of 50 patients responded (2 CRs, 
1 PR). Of the 3 patients with response, there were one patient with homozygous deletion 
and two with wild types for CDKN2A. In terms of estimating the rate of CDKN2A 
deletion, two of 10 solid tumor patients and one of 11 hematologic patients tested for 
CDKN2A showed deletion. The results provide potential association between CDKN2A 
deletion and sensitivity of cancer cells to Ilorasertib (ABT-348).  
We hypothesize that CDKN2A deficiency may confer sensitivity to Ilorasertib 
(ABT-348) (Aurora kinase inhibitor) based on that inhibition of aurora kinases leads 
polyploid cells induced by CDKN2A deficiency through  loss of G1-S checkpoint to 
mitotic catastrophe, thus increasing cell death.6 In this phase II trial, we will evaluate the 
efficacy and safety profile of Ilorasertib (ABT-348) in patients with advanced cancer 
with CDKN2A deletion or mutation. 
2.2. Background drug information: Ilorasertib (ABT-348)
Ilorasertib (ABT-348) [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-
c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted
kinase inhibitor with nanomolar potency (IC50) for inhibiting binding and cellular
autophosphorylation of Aurora B, C, and A. It has the molecular formula C25H21FN6O2S
and molecular weight of 488.54. Ilorasertib (ABT-348) is practically insoluble in water,
and sparingly soluble in lipid excipient blends at 25°C (per United States Pharmacopeia
criteria). Ilorasertib (ABT-348) has been formulated as either a tablet or a concentrate for
infusion solution, 30 mg/vial. In this protocol, only tablet forms will be used
Ilorasertib (ABT-348) is in clinical development. That is, phase I trials have been 
completed to test monotherapy and combination therapy in solid tumors and hematologic 
malignancies.  
2.2.1. Mechanism of action 
Ilorasertib (ABT-348) is a potent, novel, adenosine triphosphate (ATP)-competitive, pan-
Aurora kinase inhibitor (IC50 < 120 nM and < 10 nM for Aurora A and Aurora B/C, 
respectively) with a unique kinase selectivity profile that includes potent activity against 
the VEGF receptor (VEGFR)/PDGF receptor (PDGFR) family of kinases (Table 2). 
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Regarding main targets of Ilorasertib (ABT-348), based on the role of Aurora kinases in 
centrosome duplication and the proper alignment of chromosomes on mitotic spindles, 
their abnormal expression is thought to contribute to tumorigenesis by increasing 
chromosomal instability.1-3  
Evaluation of Ilorasertib (ABT-348) for inhibitory activity across 128 kinases 
revealed a unique kinome profile "signature."17 In addition to the potent activity against 
the VEGFR and PDGFR families, Ilorasertib (ABT-348) also potently inhibits the SRC 
family of cytoplasmic tyrosine kinases. Inhibition of members of the SRC family has 
translated into therapeutics such as Sprycel® (dasatinib) for the treatment of Gleevec® 
(imatinib mesylate)-resistant CML.18 Therefore, this unique kinome "signature" inherent 
to Ilorasertib (ABT-348) has the potential to distinguish it from the other Aurora kinase 
inhibitors. 
Table 2. In vitro potencies of Ilorasertib (ABT-348) 
Kinase 
Biochemical IC50 (nM)a 
Cellular PD Marker IC50 (nM) 
Aurora A 
120 
189b 
Aurora B 
7 
13b 
Aurora B (Y156H)c 
12 
NA 
Aurora C 
1 
13b 
VEGFR1 (FLT-1) 
1 
0.3d 
VEGFR2 (KDR) 
2 
5d 
VEGFR3 (FLT-4) 
43 
2d 
FLT-3  
1 
2d 
CSF-1R 
3 
3d 
c-KIT
20 
45d 
PDGFR-α
11 
16d 
PDGFR-β
13 
11d 
NA = not available; PD = pharmacodynamic 
a. Enzyme assays were conducted in homogeneous time-resolved fluorescence format using 1
mM ATP.
b. Aurora A, B, and C auto-phosphorylation was performed in nocodazole-arrested HeLa cells by
Western analysis using phospho – A, B, and C specific antibodies.
c. Aurora B kinase Y156H mutant.
d. Cellular phosphorylation assays for KDR, CSF-1R, KIT, PDGFR-α, and PDGFR-β are ligand
stimulated for 5 to 20 minutes for optimal phosphorylation depending on receptor type. FLT-3 is
constitutively phosphorylated in SEM cells; inhibition was determined after 60 minutes of
exposure to the compound. FLT-1 activity was determined in BaF3 cells expressing the
TEL:FLT1 catalytic domain fusion using proliferation as a surrogate readout.
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2.2.2. Preclinical studies     
Ilorasertib (ABT-348) exhibited sub-micromolar cellular activity against multiple human 
tumor cell lines derived from a broad range of tumor types including colorectal, ovarian, 
pancreatic as well as lymphoid malignancies. In vivo, Ilorasertib (ABT-348) was broadly 
efficacious in several established murine xenografts with complete inhibition or 
regression observed by a once weekly dosing regimen. The inhibition of VEGF signaling 
was also observed as measured by changes in tumor vascular permeability and 
contributed to the broad antitumor activity. 
2.2.3. Clinical experience with Ilorasertib (ABT-348) 
Phase 1 clinical trials conducted with Ilorasertib (ABT-348) suggest a possible 
association of clinical activity and CDKN2A alteration  (detailed below) that warrants 
further investigation.  
In two phase I dose escalation studies (solid tumor, hematologic malignancy), 102 
patients with advanced solid tumors and 50 with hematologic malignancies were treated 
with Ilorasertib (ABT-348). In solid tumors, 9 of 102 patients showed response (8 PRs, 1 
CR). Two of 9 responders were tested for CDKN2A and these patients were found to be 
CDKN2A-deleted. In the hematologic study, three of 50 patients responded (2 CRs, 1 
PR). Of the 3 patients with response, there were one patient with homozygous deletion 
and two with wild types for CDKN2A. In terms of estimating the rate of CDKN2A 
deletion, two of 10 solid tumor patients and one of 11 hematologic patients tested for 
CDKN2A showed deletion. The results provide potential association between CDKN2A 
deletion and sensitivity of cancer cells to Ilorasertib (ABT-348).  
2.2.4. Pharmacokinetics and pharmacodynamics 
Across multiple species > 99% protein binding was observed for Ilorasertib (ABT-348). 
Therefore, functional aspects of protein binding were evaluated in the histone H3 
phosphorylation assay and demonstrated a 100-fold shift in the IC50 value for Ilorasertib 
(ABT-348) in the presence of mouse plasma (IC50 value of 21 nM without plasma versus 
3,300 nM in the presence of 50% mouse plasma). Based on exposure parameters from 
preclinical efficacy studies, plasma concentrations of Ilorasertib (ABT-348) ranging from 
0.5 to 1.0 μg/mL for up to 16 hours are sufficient for robust antitumor activity. Current 
pharmacokinetic modeling predicts that an oral dose of 400 mg in humans will maintain 
Ilorasertib (ABT-348) plasma concentrations above the 1 μg/mL target for ~17 hours 
with a projected Cmax of 2.4 μg/mL. Studies in the GA-10 lymphoma model provided 
valuable insight into the minimal plasma (threshold) concentration required for antitumor 
activity. Pharmacokinetic analysis of plasma levels of Ilorasertib (ABT-348) resulting 
from efficacious doses (6.25 and 12.5 mg/kg) demonstrated a dose-dependent increase in 
Cmax. These results indicate that in this xenograft a steady-state level of 0.5 μg/ml for 16 
hours is sufficient for tumor stasis. Administration of 12.5 mg/kg, a dose that was broadly 
efficacious in other tumor models, resulted in tumor regression in the GA-10 model (30% 
cures) at a steady state concentration of 1.0 μg/mL. Based on these results, 0.5 μg/mL is 
considered to be the threshold concentration required for antitumor activity. This further 
validates the prediction that an oral dose of 400 mg in humans will maintain efficacious 
plasma concentrations. Pharmacokinetic studies revealed sustained, reproducible plasma 
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concentrations of Ilorasertib (ABT-348) in dogs after the compound was dosed orally as a 
lipid solution. This data also supports oral dosing of Ilorasertib (ABT-348). 
2.2.4.1. Absorption 
The sum of urinary and biliary excretion following a single 10 mg/kg oral dose of 
[14C]Ilorasertib (ABT-348) in bile duct-cannulated male Sprague-Dawley rats indicated 
that at least 37.5% of the dose was absorbed; overall recovery of radioactivity 48 hours 
postdose was 70.6% of the dose. Approximately 4.1% to 24.9% of radioactivity was 
recovered in the carcass 48 hours postdose from rats treated PO and IV, indicating 
incomplete dose recovery in excreta. 
2.2.4.2. Distribution  
2.2.4.2.1. Plasma protein binding, binding site, red blood cell distribution 
Preliminary data revealed that Ilorasertib (ABT-348) (1 μM) has high binding to rat 
(99.8%), dog (99.9%), monkey (99.6%), and human (99.9%) plasma proteins. 
Preliminary data suggested [3H]Ilorasertib (ABT-348) distributed preferentially into the 
plasma compartment, with a blood-to-plasma concentration ratio ranging between 0.75 
and 1.08 in human independent of the 0.5 to 5 μM concentration evaluated. 
2.2.4.2.2. Tissue distribution studies 
Evaluation of tissue distribution in male Long-Evans rats (10 mg/kg, PO) at 3, 6, and 
24 hours postdose showed relatively slow uptake of radiolabeled drug and generally low 
tissue-to-plasma (t/p) ratios (< 1 at 6 hours postdose for heart, lungs, muscle, testes, 
brain, eyes, skin, pigmented skin, and spinal cord). Radioactivity reached maximum 
concentrations at 6 hours postdose in all tissues except liver, which showed maximum 
concentrations at 3 hours postdose. From 6 to 24 hours, the t/p ratio in eye and kidney 
increased to 2.56 and 1.70, respectively, suggesting potential retention of drug or 
metabolites in these tissues. 
2.2.4.2.3. Placental and lacteal transfer 
Placental and lacteal transfer studies have not yet been conducted with Ilorasertib (ABT-
348). 
2.2.4.3. Metabolism 
2.2.4.3.1. In Vitro metabolism 
Ilorasertib (ABT-348) showed high microsomal intrinsic clearance (mCLint) in the rat 
and mouse (97 and 86 μL/min/mg, respectively) and moderate to high mCLint in the 
human, monkey, and dog (34, 44, and 54 μL/min/mg proteins, respectively). M2 
(carboxylic acid) was the only metabolite found in rat liver microsomal incubations and it 
was also the most significant metabolite in other species, representing 13.7% and 7.1% of 
the drug-related material in the rat and monkey, but less than 2% in the other species. The 
M4 metabolite (N-dealkylation on the pyrazole) was detected only by tandem mass 
spectrometry (i.e., below radiochemical detection limit) and was found in human, dog, 
monkey, and mouse liver microsomal incubations. Metabolite M2 was also detected in 
rat, monkey, and mouse hepatocytes. Metabolite M6 (N-acetylglucosamine conjugate) 
was observed in monkey hepatocytes, but not found in other species. Formation of 
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metabolites M1, M2, M3, and M4 was catalyzed by recombinant CYP3A isoforms. M1 
was formed by CYP1A1; other CYP isoforms did not appear to be involved in Ilorasertib 
(ABT-348) metabolism. 
2.2.4.3.2. In Vivo metabolism 
Chromatographic evaluation of the radiochemical profile in bile from rats treated PO 
showed that approximately 19.3% of the dose was recovered as intact parent drug, 
indicating biliary clearance was largely by metabolic transformation of [14C]Ilorasertib 
(ABT-348). M5 (proposed as hydroxylation on benzene ring) and M10 (direct 
glucuronidation) represented 3.6% and 3.3% of dose, respectively. Other products of 
metabolism included M1 (hydroxylation on benzene ring), M9 (direct glucuronide 
conjugate), and M7 and M8 (secondary glucuronide conjugates). In circulation, parent 
drug represented approximately 69% of plasma radioactivity (oral) and M2, M5, and 
M11 (hydroxylation on benzene ring) represented approximately 7%, 9%, and 14%, 
respectively, of plasma radioactivity at 3 hours postdose. 
2.2.4.3.3  Elimination  
Chromatographic evaluation of the biliary metabolite profile from rats treated IV showed 
the parent drug represented approximately 19.3% of the dose and the major metabolite 
M2 (carboxylic acid) represented approximately 35.4%, indicating biliary clearance was 
largely by metabolic transformation of [14C]Ilorasertib (ABT-348). Mean total recovery 
in urine was 1.65% for IV administration and 1.0% for oral administration. For rats 
treated PO, mean2.2.5. Dosage and administration recovery was 33.5% in feces and 
28.9% from bile. Approximately 4.1% to 24.9% of radioactivity was recovered in the 
carcass 48 hours postdose from rats treated PO and IV, indicating incomplete dose 
recovery in excreta. 
2.2.5.1. Recommended dose 
The recommended dose of Ilorasertib (ABT-348) is 200mg PO twice a day on D1, 8, and 
15.  
2.2.5.2. Duration of treatment 
It is recommended that patients are treated with Ilorasertib (ABT-348) until disease 
progression or unacceptable toxicity occurs.  
2.2.5.3. Dosage forms and strengths 
2.2.5.4. Tablet 
1) Dosage Form: Tablets
2) Strength: 50 mg
3) Excipients: Microcrystalline cellulose, povidone, hypromellose 2910, crospovidone,
macrogolglycerol hydroxystearate, polysorbate 20, citric acid, colloidal silicon
dioxide, magnesium stearate
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2.2.6 Study Drug Compliance and Disposal 
Study drug will be administered or dispensed only to eligible patients under the 
supervision of the investigator or identified sub-investigator(s). Ilorasertib will be 
dispensed one cycle at a time. The appropriate study personnel will maintain records of 
study drug receipt and dispensing. The used and expired study drug will be disposed of 
per MD Anderson Cancer Center policy. 
2.2.7. Drug abuse and dependence 
No studies on the potential for Ilorasertib (ABT-348) to cause dependence have been 
performed. However, there is no evidence from the available data that Ilorasertib (ABT-
348) treatment can result in dependence.
2.2.8. Adverse reactions/toxicities 
Preliminary aggregate data for Ilorasertib (ABT-348) monotherapy are summarized 
separately for subjects administered the drug PO (Arms A and B in Study M10-943 and 
Arms A and D in Study M10-944, 96 total subjects) and IV (Arm D of Study M10-943 
and Arm E of Study M10-944, 11 total subjects). 
Adverse events were reported in 93 of 96 (96.9%) subjects across both studies 
received Ilorasertib (ABT-348) monotherapy administered PO as shown in Table 3. The 
most frequently reported treatment-emergent adverse events (> 10%) in subjects treated 
with Ilorasertib (ABT-348) PO monotherapy are presented in Table 3. As expected based 
on the mechanism of action of Ilorasertib (ABT-348), gastrointestinal disorders and 
hypertension were some of the most common adverse events in the study. In addition, 
thrombocytopenia, fatigue, peripheral edema, pyrexia, decreased appetite, hypokalemia, 
hypomagnesemia, arthralgia, headache, and proteinuria were also commonly observed 
among subjects treated with Ilorasertib (ABT-348) monotherapy. 
Grade 3 or 4 adverse events were reported by 65 of 96 subjects (67.7%) treated 
with Ilorasertib (ABT-348) PO monotherapy; the most common of these were 
hypertension (20 subjects), hypokalemia (8 subjects), anemia (6 subjects), and 
pneumonia (5 subjects). The most common grade 3 or 4 adverse events considered 
causally related to ilorasertib by the investigator included hypertension (14 subjects); 
diarrhea 
(3 
subjects); 
neutropenia, 
thrombocytopenia, 
pancreatitis, 
fatigue, 
hyperuricemia, and proteinuria (2 subjects each). 
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Table 3. Most frequently reported (>10%) treatment-emergent adverse events in all 
subjects treated with Ilorasertib (ABT-348) PO monotherapy 
A summary of serious adverse events reported in 2 or more subjects treated with 
Ilorasertib (ABT-348) PO monotherapy is presented in Table 4. Serious adverse events 
were reported by 56 of 96 subjects (58.3%). The most common serious adverse events 
were febrile neutropenia, small intestinal obstruction, pneumonia, and acute myeloid 
leukemia (in 4 subjects each, 4.2%), and fungal pneumonia (in 3 subjects, 3.1%). 
Pancreatitis (in 2 subjects) was the most common serious adverse event considered 
causally related to Ilorasertib (ABT-348).  
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Table 4. Treatment-emergent serious adverse events reported in 2 or more subjects 
treated with Ilorasertib (ABT-348) PO monotherapy 
2.2.9. Specific safety issues/events (known, potential and unknown risks)  
Ilorasertib (ABT-348) is a novel orally bioavailable ATP-competitive inhibitor of Aurora 
A, Aurora B, and Aurora C. In addition, Ilorasertib (ABT-348) is a potent inhibitor of all 
members of the VEGF and PDGF family of RTKs. Thus, the safety profile of Ilorasertib 
(ABT-348) is expected to share some safety profile characteristics of RTK inhibitors, 
particularly, those inhibiting VEGF and PDGF effects and some safety characteristics 
associated with antimitotic chemotherapeutic agents. The known and potential risks listed 
below in the table are considered areas of enhanced focus for surveillance. In addition, 
single cases and aggregate safety data are reviewed as described below to identify new 
potential safety issues. Discontinuations, dose reductions or interruptions because of 
safety issues or AEs also are monitored according to the SRP for each clinical study. 
Important identified and potential risks for Ilorasertib (ABT-348) are summarized 
in the Table 5. These risks were identified on the basis of data from Ilorasertib (ABT-
348) clinical studies, and preclinical toxicity studies and other VEGF and PDGF RTK
inhibitors and Aurora kinase inhibitors.8, 9
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Table 5. Identified and potential risks for Ilorasertib (ABT-348) 
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3. Eligibility Criteria
To be eligible for this trial, patients must meet all of the following criteria. 
3.1. Inclusion criteria 
1) Patients with histologically confirmed, advanced or metastatic cancer for which
standard curative or palliative measures do not exist or are no longer effective.
2) Patients must have CDKN2A-deficient tumor (deletion or mutation). Status will
be determined from archived tissue.
Definition of CDKN2A deficient tumor:
   #1. CDKN2A deletion or mutation by any CLIA-certified sequencing OR 
   #2. ≥ 30% of tumor cells with (at least) hemizygous deletion by FISH  
3) Patients must have measurable disease by RECIST 1.1.10
4) Patients must be ≥18 years of age.
5) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
6) Subject has adequate renal function as demonstrated by serum creatinine value of
≤ 1.5 times the upper limit of normal (ULN) and either an estimated creatinine
clearance value of ≥ 50 mL/min as determined by the Cockcroft-Gault formula or
a creatinine clearance value of ≥ 50 mL/min based on a 24 hour urine collection.
7) Subject has adequate liver function as demonstrated by serum bilirubin </= 2 x
ULN and AST and ALT ≤ 2.5 x ULN. For subjects with liver metastasis,
adequate liver function is demonstrated by serum bilirubin ≤ 2 x ULN and
AST/ALT ≤ 5.0 x ULN.
8)
Subject has adequate bone marrow as demonstrated by absolute neutrophil count
(ANC) ≥ 1,500/mm3 (1.5 x 109/L); Platelets ≥ 100,000/mm2 (100 x 109/L);
Hemoglobin ≥ 9.0 g/dL (1.4 mmol/L).
9)
Subject has QTc interval < 500 msec on baseline electrocardiogram.
10) The subject has a documented Left Ventricular Ejection Fraction > 50%.
11) Women of child-bearing potential and men must agree to use adequate
contraception (one of the following listed below) prior to the study entry, for the
duration of study participation and up to 3 months following completion of
therapy. Women of child-bearing potential must have a negative pregnancy test
within 7 days prior to initiation of treatment and/or post menopausal women must
be amenorrheic for at least 12 months to be considered of non-childbearing
potential.
•
Total abstinence from sexual intercourse (minimum one complete
menstrual cycle)
•
Vasectomized male subjects or vasectomized partner of female subjects
•
Intrauterine device
•
Double-barrier method (condoms, contraceptive sponge, diaphragm or
vaginal ring with spermicidal jellies or cream)
•
Additionally, male subjects (including those who are vasectomized) whose
partners are pregnant or might be pregnant must agree to use condoms for
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the duration of the study and for 3 months following completion of 
therapy. 
12) Ability to understand and willingness to sign informed consent form prior to
initiation of the study and any study procedures.
13) Signed informed consent approved by the Institutional Review Board prior to
patient entry
3.2. Exclusion criteria 
1. Patients with CDKN2A wild type by a CLIA-certified laboratory
2. Subject has known active CNS involvement. The subject has untreated brain or
meningeal metastases. CT scans are not required to rule out brain or meningeal
metastases unless there is a clinical suspicion of central nervous system disease.
Subjects with treated brain metastases that are radiographically or clinically stable for
at least 4 weeks after therapy and have no evidence of cavitation or hemorrhage in
the brain lesion(s) are eligible, providing that they are asymptomatic, and do not
require corticosteroids (must have discontinued steroids at least 1 week prior to study
drug administration).
3. Subject has received anti-cancer therapy including chemotherapy, immunotherapy,
radiotherapy, hormonal, biologic or any investigational therapy within a period of 21
days or 5 half-lives (whichever is shorter) prior to Study Day 1.
4. Subject has unresolved toxicities from prior anti-cancer therapy, defined as any
Common Terminology Criteria for Adverse Events (NCI CTCAE v 4.0) grade 2 or
higher clinically significant toxicity (excluding alopecia).
5. Subject has had major surgery within 28 days prior to Study Day 1.
6. Subject currently exhibits symptomatic or persistent, uncontrolled hypertension
defined as diastolic blood pressure > 90 mmHg or systolic blood pressure > 140
mmHg. Subjects may be re-screened if blood pressure is shown to be controlled with
or without intervention.
7. Subject has proteinuria defined by the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE v 4.0) grade > 1 at baseline
as measured by a urine dipstick (2+ or greater) and confirmed by a 24 hour urine
collection (≥ 1 g/24 hrs). Subjects may be re-screened if proteinuria is shown to be
controlled with or without intervention.
8. Subject is receiving therapeutic anticoagulation therapy. Low dose anti-coagulation
(e.g., low dose heparin or warfarin) for catheter prophylaxis will be permitted. Use of
Aspirin for treatment of Atrial Fibrillation will also be permitted.
9. Patients with another primary malignancy within 3 years prior to starting study
treatment with the exception of adequately treated basal cell carcinoma, squamous
cell carcinoma or other non-melanomatous skin cancer, or in-situ carcinoma of the
uterine cervix.
10. Clinically significant uncontrolled condition(s) including but not limited to:
•
Active uncontrolled infection,
•
Symptomatic congestive heart failure,
•
Unstable angina pectoris or cardiac arrhythmia (subjects with stable atrial
fibrillation are not excluded),
•
History of adrenal insufficiency,
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11. Psychiatric illness/social situation that would limit compliance with study 
requirements. 
12. Subject has a known infection with HIV, Hepatitis B or Hepatitis C. 
13. Subject is known to have poorly controlled diabetes mellitus defined as HbA1c > 7%; 
subjects with a history of transient glucose intolerance due to corticosteroid 
administration are allowed in this study if all other inclusion/exclusion criteria are 
met. 
14. Any medical condition which in the opinion of the study investigator places the 
subject at an unacceptably high risk for toxicities. 
15. Subject is unable to swallow or absorb oral tablets normally. 
16. Female subject who is lactating or pregnant. 
17. Subject takes CYP3A Inhibitors/Inducers (see Appendix I) within 7 days prior to the 
study drug administration.  
 
 
4. Treatment Plan 
Drug administration will take place as per protocol schedule as shown in Figure 3 unless 
patient/logistical/medical reasons intervene. A 2-day window is allowed for all 
assessments. Response evaluation will be performed every 2 cycles between day 43 and 
day 50. 
 
 
 
 
 
Figure 3. Treatment plan 
200 mg ilorasertib will be administered by mouth twice daily on days 1, 8, and 15 of each 
28-day cycle. All study visits will take place at MD Anderson Cancer Center. Participants 
may have labs performed at outside facilities. 
Each morning dose of ABT-348 will be taken with 4 ounces of water. Patients should fast 
for 8 hours before taking this dose. Patients will be allowed to have a light snack 2 hours 
after the dose, and then may resume normal eating 4 hours after the dose. 
4.1. Criteria for removal from the study:  
Patients will continue treatment until their disease progresses per RECIST 1.1 or other 
objective tumor measurements, their side effects become too severe, an inter-current 
illness that prevents further administration of treatment, patient withdraws consent, or the 
physician or patient feels it is not in the patient’s best interest to continue. Patients will be 
200mg PO 
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treated beyond their disease progression (as described by RECIST 1.1) at the discretion 
of the PI if they are deriving clinical benefit from the treatment. 
4.2. Dose delays and modifications: 
If an individual patient experiences any new grade 3 or greater toxicity that is considered 
to be related to treatment, treatment will be held until recovery to </= grade 1 or to the 
baseline level. Ilorasertib (ABT-348) will be supplied as 50 mg tablets.  Dose may be 
reduced in increments of 50 mg. All dose delays and reductions are up to physician’s 
discretion. Dose may also be re-escalated based on physician’s discretion when toxicities 
recover to grade 1 or to the baseline level. To stay eligible for the study, treatment can be 
delayed up to 4 weeks and dose can be reduced down to 50mg BID. For suggested dose 
reductions, see Appendix III. Patients requiring more than 2 dose reductions during the 
course of the study will be permanently discontinued.  
Patients who experience Grade 4 non-hematologic adverse events will be permanently 
discontinued form the study unless the patients are experiencing clear clinical benefit and 
meet the proposed recovery criteria. 
4.3. All participants who receive treatment will be considered in the response analysis. In 
particular, objective response rates will be analyzed in any tumor types with CDKN2A 
deletion or mutation and subgroup expansion cohort with specific tumor type and CDKN2A 
deletion or mutation, separately.  Response will be evaluated with RECIST 1.1.  
4.4. Patient will begin a new cycle if toxicity grade 2 or less; ECOG 2 or less; and no 
pregnancy. 
5. Pretreatment and Treatment Evaluation
•
The following treatment evaluations will be conducted as part of this study. If
CDKN2A status is not known, tumor tissue will be tested in a CLIA-certified lab
prior to initiating treatment.
•
Physical examinations including BP measurement at screening and on Day 1, Day
8 and 15 of cycle 1 and 2, then at least once per cycle (28 days).
•
Labs should be performed on each dosing day for the first 2 cycles and at least
once per cycle (at screening and at Day 1 of subsequent cycles) and on Day 15 of
Cycles 1 and 2, including CBC with differential, electrolytes, BUN/creatinine,
magnesium, glucose, phosphorus, uric acid, AST, ALT, Alkaline Phosphatase,
total bilirubin, albumin, calcium, total protein. PT/PTT at screening only.
•
Dipstick urinalysis at screening and Day 1 of every cycle.
•
Serum pregnancy test in women of childbearing potential at screening (within 7
days prior to initiating treatment). Serum or urine pregnancy test in women of
childbearing potential on Day 1 of Cycle 2 and beyond.
•
ECHO/MUGA at screening.
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•
Skin punch biopsy (optional) of 3mm and hair follicle collection will be collected
on Cycle 1 Day 1 at up to 72 hours prior to the first dose and 2–4 hours post the
second dose.
•
Radiologic evaluations will be obtained at screening and repeated after every 2
cycles of treatment.
•
EKGs should be performed at screening, Day 1 of Cycles 2 and 3,
followed by every 3 months thereafter or more often as clinically
indicated.
•
Concomitant medications should be assessed at each visit.
6. Concomitant Medication
All concomitant medications will be documented in the electronic medical record. They 
will be captured from day 1 (pre-dose) through the safety reporting period. 
Premedication: National Comprehensive Cancer Network (NCCN) or American Society 
of Clinical Oncology (ASCO) approved prophylactic antiemetics may be given as 
appropriate. 
Anti-cancer Agents: No anti-cancer agents or investigational agents may be taken 
concurrently with Ilorasertib (ABT-348).  
Supportive Care: Best supportive care and treatment will be given as appropriate to 
each subject (antiemetics, antibiotics, transfusions, nutritional support, palliative 
treatment for pain, etc.). 
CYP3A Inhibitors/Inducers: CYP3A inhibitors (strong, moderate and weak) and 
CYP3A inducers should be used with caution when used concurrently with Ilorasertib 
(ABT-348) . Subjects will be provided with a list of CYP3A inhibitors/inducers and must 
bring the list with them to all appointments with any physician or other healthcare 
provider. Refer to Appendix I for a sample list of  medications which should be used with 
caution.  
Substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6: Sensitive substrates of 
CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 should be used with caution. Refer to package 
insert of co-administered drug to determine if the drug is a sensitive substrate of 
CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6. 
Growth Factors: Biologic response modifiers administered for erythropoiesis (e.g., 
erythropoietin, darbepoetin alpha) and colony stimulating factors (e.g., G-CSF, GM-CSF, 
etc.) may be administered according to the ASCO guidelines.  
Radiation: Radiation therapy is not allowed during the study. If radiation therapy is 
needed to treat the symptoms due to underlying cancer, it will be considered clinical 
progression (as defined in Section 5.4.1). 
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Surgery: If the subject requires surgery during the study then this needs to be 
discussed with the Principal Investigator (David Hong, MD). 
7. Measurement of Response
The primary objective of this protocol is to determine response rate.  Patients will be 
evaluated every 2 cycles. Confirmatory scans will also be obtained 4 weeks following 
initial documentation of an objective response. 
7.1. Response criteria 
Response and progression will be evaluated in this study using the new international 
criteria proposed by revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline version 1.1. Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used 
in the RECIST criteria. If patients with Gastrointestinal Stromal Tumors (GIST) are 
included in this study, we will use the Choi criteria11 as parameters of response.  
Evaluation of lesions based on photographs and clinical measurements will also 
be allowed for Head and Neck Squamous Cell tumors with superficial or skin lesions. 
These clinical pictures offers difficulties for precise monitoring of lesions based 
exclusively on CTs.  
Patients with bone metastasis will be classified as having classic measurable 
disease if they met the criteria for on new RECIST 1.1 recommendations.   
7.2. Methods of evaluation 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. The following image 
methods will be accepted as methods to evaluated response: 
•
Conventional CT (preferred method)
•
Magnetic Resonance Image (MRI)
•
Chest x-ray
•
Bone scan
•
PET CT
8. Evaluation of Toxicity
The secondary objective of this protocol is to determine the safety. Toxicities are will be 
described 
according 
to 
the 
NCI-CTCAE 
Version 
4.03 
(available 
at 
http://ctep.cancer.gov/reporting/ctc.html).  
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The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events, and assigning attribution for each event on all 
subjects enrolled on this study. 
Molecular and Clinical Data Integrated Platform (MOCLIP) will be used as the electronic 
case report form for this protocol and adverse events and protocol specific data will be 
entered into MOCLIP. 
If an adverse experience increases in frequency or severity during a study period, a new 
record of the experience will be started.   
Assessment of Intensity 
Maximum intensity should be assigned to an adverse experience.  Intensity will be 
assigned a Grade of 1-5. Final arbitration of intensity in cases of differing assessments by 
different practitioners will be the attending physician. Day to day fluctuations of intensity 
may not be recorded but rather the worst grade over the longest time period. Adverse 
events will be recorded in the Adverse Event log utilizing the recommended AE 
recording guidelines for Phase II studies, below: 
Assessment of Causality 
Every effort should be made by the investigator to explain clinically significant adverse 
experience and to assess its relationship, if any, to the study medication.   
Statement of Good Clinical Practices 
Phase I 
Phase II 
Phase III
Phase I 
Phase II 
Phase III
Definitive Phase I 
Phase II
Phase I 
Phase II 
Phase III
Phase I 
Phase II 
Phase III
Phase I 
Phase II 
Phase III
Phase I 
Phase II 
Phase III
Phase I 
Phase II 
Phase III
Phase I 
Phase II 
Phase III
Phase I 
Phase II
Phase I 
Phase II 
Phase III
Phase I 
Phase II 
Phase III
Phase I 
Phase II 
Phase I 
Phase II 
Phase III
Phase I 
Phase II 
Phase III
Phase I 
Phase II 
Phase III
Phase I 
Phase II 
Phase III
Phase I 
Phase II 
Phase III
Unlikely
Possible
Phase I 
Phase II
Probable
Grade 4
Phase I
Phase I
Phase I
Phase I
Phase I 
Phase II 
Grade 5
Recommended Adverse Event Recording Guidelines 
Unrelated
Phase I 
Phase II 
Phase III
Attribution
Grade 1
Grade 2
Grade 3
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This trial will be conducted in adherence to the study protocol, Good Clinical Practices as 
defined in Title 21 of the US Code of Federal Regulations Parts 50, 54 56, 312 and Part 
11 as well as ICH GCP consolidated guidelines (E6) and applicable regulatory 
requirements. http://www.fda.gov/cder/guidance/index.htm 
 
 
9. Regulatory and Reporting Requirements 
Adverse Event Monitoring and Reporting 
The principal investigator is responsible for monitoring the safety of patients who enroll 
in the study.  All drug-related AEs occurring after any administration of the study drug 
will be followed until resolution, stabilization, death, loss to follow up, or 
commencement of new therapy.  The descriptions and grading scales found in the revised 
NCI CTCAE version 4.0 will be used for adverse event reporting.  A copy of the CTCAE 
version 
4.03 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
(http://ctep.cancer.gov/reporting/ctc.html).  
Serious Adverse Event Reporting (SAE)    
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32). 
 Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, 
IND Office. 
 All events occurring during the conduct of a protocol and meeting the definition of a 
SAE must be reported to the IRB in accordance with the timeframes and procedures 
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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 study treatment/intervention, 
unless the participant withdraws consent. Serious adverse events must be 
followed until clinical recovery is complete and laboratory tests have returned to 
baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 
 Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This 
may include the development of a secondary malignancy. 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure that serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review 
Board policy. 
Adverse Events: Pregnancy 
Principal Investigator shall comply with all FDA reporting requirements pursuant to 21 
C.F.R. § 312.   
In addition to compliance with all FDA reporting requirements pursuant to 21 C.F.R. § 
312, the Principal Investigator shall: 
a. report all serious adverse events experienced by a study subject receiving an 
AbbVie product within 24 hours of learning of the event regardless of the 
relationship of the event to the AbbVie product.  Principal Investigator shall make 
available to AbbVie promptly such records as may be necessary and pertinent to 
investigate any such event, if specifically requested by AbbVie; and 
b. copy AbbVie on the submission to the FDA of events meeting the definition of 
IND safety reports at the time of submission to the Agency; and 
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c.
notify AbbVie upon any subject receiving an AbbVie Product whose pregnancy
has resulted in a negative outcome or untoward event during the course of
pregnancy or upon delivery.
AbbVie’s contact for reporting serious adverse drug experiences and pregnancy 
experiences shall be  PPDINDPharmacovigilance@abbvie.com  
Subjects who become pregnant during the study must be discontinued. 
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected. Male subjects should be informed that contraceptive 
measures should be taken by their female partners.  If the subject's partner should become 
pregnant during the study, this should also be reported and data may be collected. 
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to (847) 938-0660 within 24 
hours of the site becoming aware of the event. 
Data Collection 
All patients who meet eligibility criteria and are enrolled in this trial will be registered in 
Clinical Oncology Research Database at the University of Texas MD Anderson Cancer 
Center at Houston.   
Data Protection and Confidentiality 
All patients who meet eligibility criteria and are enrolled in this trial will be registered in 
Clinical Oncology Research Database (CORe) at the University of Texas MD Anderson 
Cancer Center at Houston. All protocol participants must be registered in the CORE. The 
date in the current informed consent document is displayed to ensure only the most 
current IRB approved version is used.  Consent date, registration date, off study date, and 
evaluability data are required for all registrants. 
The principal investigator agrees to keep all information and results concerning 
the study confidential. The confidentiality obligation applies to all personnel involved 
with this clinical trial.  The Investigator must ensure that each participant’s anonymity 
will be maintained in accordance with applicable laws.  The principal investigator should 
keep a separate log of ID numbers and names.  Documents that contain the names 
associated with these ID numbers (e.g., written consent/assent forms), should be 
maintained by the Investigator in strict confidence except to the extent necessary to allow 
auditing by regulatory authorities, auditing or monitoring by the IRB. 
The Principal Investigator shall obtain all such permissions and authorizations as 
may be necessary or desirable to allow the collection and use of information protected 
under federal privacy laws and state privacy laws, including permission/authorization for 
monitoring and analysis (including re-analysis in combination with results of other 
studies), for regulatory submission purposes and for applicable reporting (if any). 
10. Statistical Considerations
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10.1. Study design and endpoints 
This is an open-label, single-center, phase II study exploring the efficacy and safety of 
Ilorasertib (ABT-348) monotherapy in a diverse population of patients with advanced 
cancers with CDKN2A deletion or mutation for whom Ilorasertib (ABT-348) is deemed 
the best treatment option in the opinion of the Investigator. 
Primary endpoint is to evaluate the tumor response rate (partial response, 
complete response) by Response Evaluation Criteria In Solid Tumors, Version 1.1 
(RECIST, v1.1) in solid tumors. Secondary endpoints are the safety and tolerability and 
pharmacodynamics. For safety and tolerability, toxicities will be evaluated according to 
the NCI-CTCAE Version 4.0 (available at http://ctep.cancer.gov/reporting/ctc.html). For 
pharmacodynamics, phospho-Histone H3 on biopsied skin tissues will be analyzed with 
immunohistochemistry. 
10.2. Sample size 
Sample size calculations are based on single arm, Phase II design with early stopping 
rules for futility. Early stopping rules will be applied. Accrual in a cohort will stop if 
>25% overall response rate (ORR) is unlikely. Prior to advancing to the next cohort, an
Efficacy/Toxicity Summary will be completed and submitted to the IND Medical
Monitor after 10 evaluable patients, and every 10 patients thereafter. The summary will
contain aggregating information.
We assume that the targeted level of activity is 25% ORR or greater. ORR is 
defined as complete response or partial response.  
We used the program MultcLeanDesktop Version 2.0.0 to generate an appropriate 
Bayesian design targeting a clinical benefit rate of 25%. We suppose that: θE = 
probability of ORR on the experimental arm ~ beta (aE, bE) and θS = probability of ORR 
for standard treatment in the historical data ~ beta (aS, bS) whereas = 250, bS = 750, aE = 
0.5, and bE = 1.5. This specifies an informative prior for the standard with mean 0.25 and 
a non-informative prior for the experimental arm also with mean 0.25. We stop the trial 
early if Prob (θS>θE | data) > 0.925. The maximum sample size is set to 40, and we 
choose to monitor in cohorts of size 10. The stopping boundaries are 0/10, 2/20, 4/30, and 
6/40 (where m/n indicates that we stop early if after n patients, we see m or fewer 
successes). If the true success probability is 5% then the probability of stopping early 
with these stopping boundaries is 0.99; for 10% it is 0.86; for 15%: 0.59; for 20%: 0.33; 
for 25%: 0.16; for 30%: 0.07; and for 35%: 0.03. 
We will set the maximum sample size to 40 for the cohort in part 1 of the study, 
not including screen failures. If the observed ORR is 25% with a maximum 
sample size of N=40, the true ORR from the drug is between 16% and 38%, 90% 
of the time. Best response will be used for the response evaluation and stable 
patients will be followed for 6 months before declaring them a non-responder for 
the sake of analysis. Biomarker-drug combinations that meet these criteria will be 
recommended for further comparative evaluation in a larger trial. If the lower 
bound of the 90% posterior credible interval is > 16%, the drug will be 
recommended for subsequent independent confirmatory study.  
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10.3. Expansion cohorts 
We propose that cohorts be expanded if predetermined sample size and response rate are 
met in specific tumor types. The objective of expansion cohorts is for patient enrichment 
by virtue of histology which may show better response. To identify tumor types with 
sufficiently convincing data to justify expansion to cohorts, we will use a Bayesian 
approach. We start with a prior distribution on, p, the probability of response, as a 
beta(1,1) (a uniform distribution). For each cohort, we will compute the posterior 
probability that p is greater than 0.5 given the data (i.e., Pr(p > 0.5 | data)). We will 
expand the cohort if this probability exceeds 0.5. 
Below is a table of the probabilities that a cohort will be expanded based on the 
size of the cohort (columns) and the true response probability (rows). The probabilities 
are computed using standard methods associated with the binomial distribution and 
Bayesian updating using the beta-binomial distribution. Probabilities > 0.85 are 
highlighted. These probabilities are computed in the following manner. Suppose we have 
a cohort of size 3 and a true response rate of 0.8. There are four possibilities: 0 responses, 
1 response, 2 responses or 3 responses in these 3 patients. With a true response rate of 0.8 
these possibilities will occur with probabilities of 0.008, 0.096, 0.384 and 0.512. The 
posterior probabilities that p > 0.5 associated with these possibilities are 0.06, 0.31, 0.69, 
and 0.94. Thus expansion would occur only for 2/3 and 3/3 responses. Since these occur 
with probabilities 0.384 and 0.512, the overall probability of expansion is 0.384+0.512 = 
0.896 (which rounds to 0.90).  
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
0.5 
0.25 
0.50 
0.31 
0.50 
0.34 
0.50 
0.36 
0.50 
0.38 
0.50 
0.61 
0.50 
0.40 
0.50 
0.6 
0.36 
0.65 
0.48 
0.68 
0.54 
0.71 
0.59 
0.73 
0.63 
0.75 
0.84 
0.77 
0.69 
0.79 
0.7 
0.49 
0.78 
0.65 
0.84 
0.74 
0.87 
0.81 
0.90 
0.85 
0.92 
0.96 
0.94 
0.91 
0.95 
0.8 
0.64 
0.90 
0.82 
0.94 
0.90 
0.97 
0.94 
0.98 
0.97 
0.99 
1.00 
0.99 
0.99 
1.00 
0.9 
0.81 
0.97 
0.95 
0.99 
0.98 
1.00 
0.99 
1.00 
1.00 
1.00 
1.00 
1.00 
1.00 
1.00 
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Based on the rule defined above, we will expand eligible tumor subtype cohorts to a total 
of 25 patients including those patients enrolled in part 1 of the study. With 25 patients, if 
the observed response probability is 0.7, the 90% credible interval is (0.53, 0.82). This 
means that the true response probability is between 53% and 82%, 90% of the time. 
Screen failures will not count against the maximum accrual number. Specific cohorts 
meeting the response threshold for expansion will be expanded even if part 1 of the study 
is stopped early for overall futility. Tumor type specific expansion will be triggered after 
accrual to part 1 of the study is complete: either after all 40 patients have been enrolled, 
or when part 1 of the study is stopped for overall futility. 
An evaluation of safety data will be performed at the time of the first efficacy assessment 
in this trial (i.e., after 10 patients).  If at any point the toxicities are found to be greater 
than 33% in this safety assessment, enrollment will be stopped for excessive toxicities. 
11. Pharmacodynamic Analysis of Skin Biopsy
Aurora kinase inhibition induces several distinct cellular phenotypes including inhibition 
of histone H3 phosphorylation and the induction of polyploidy. Given the potent 
inhibition of aurora kinases by Ilorasertib (ABT-348), skin punch biopsy may be 
analyzed to determine if modulation of these events can be monitored as a surrogate of 
drug exposure. Analysis may not be limited to histone H3 phosphorylation but may be 
expanded to testing other events that may be predictive of clinical outcome. Skin punch 
biopsy of 3mm (optional) will be collected on Cycle 1 Day 1 at up to 72 hours prior to 
the first dose and 2-4 hours post the second dose on Cycle 1 Day 8. Skin biopsies should 
be fixed in formalin for between 8 to 24 hours then embedded in paraffin following 
institutional procedures. The FFPE blocks will be kept in an IHC slide carrier (or 
equivalent) and stored at 2° to 8°C to maintain the sample integrity until shipment. These 
samples will be shipped at ambient temperature. Phospho-Histone H3 (P-HH3) will be 
evaluated by immunohistochemistry (IHC) at the AbbVie laboratory or any CLIA-
certified laboratory. 
Shipment of Skin Punch Biopsy 
Skin punch biopsy FFPE blocks will be placed in an IHC slide carrier (or equivalent) for 
shipping. Skin punch biopsy blocks slide boxes should be labeled with study drug 
number, sample matrix (tissue), protocol number, subject number, and collection date. 
Samples should be packaged using suitable shipping materials and sent at ambient 
temperature to the following address: 
AbbVie 
Attention: Peter Ansell, PhD 
Cancer Biomarkers 
AP10- Room 114 
1 North Waukegan Road 
North Chicago, IL 60064-6098 
PHONE (847)-935-1222 
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Protocol 2014-0920 
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12. Follow-up Period
All subjects will enter the follow-up period upon discontinuation of study treatment for 
reasons other than withdrawal of consent or death. The subject should be monitored for 
new and ongoing adverse events until 30 days after the last dose of study treatment. All 
serious adverse events should be followed until resolution. Patients removed from the 
study for unacceptable adverse event(s) will be followed until resolution or stabilization 
of the adverse event. 
13. Confidentiality
All laboratory and clinical data gathered in this protocol will be stored in a password-
protected database (MOCLIP/CORe). All patient information will be handled using 
anonymous identifiers. Linkage to patient identity is only possible after accessing a 
password-protected database. Access to the database is only available to individuals 
directly involved in the study. 
Information gathered for this study will not be reused or disclosed to any other 
person or entity, or for other research. Once the research has been completed, identifiers 
will be retained for as long as is required by law and by institutional regulations, and at 
that point will be destroyed. 
14. Study Calendar
Table 6.  Study Calendar
Assessment Tool* 
Baseline 
(within 2 
weeks of 
C1D1) 
Cycle 1 
Cycle 2 
Cycle 3~X 
Day 
Day 
Day 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 15 
22 
History and 
Physical Exam 
including BP 
measurement 
X 
X 
X8 
X 
X 
X8
X 
X 
CDKN2A status 
X6 
CBC with 
differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sodium, 
Potassium, 
Chloride, 
Bicarbonate, BUN, 
Creatinine, 
Glucose, Calcium, 
Magnesium, Uric 
Acid, Phosphorus, 
Total Protein 
X 
X 
X 
X 
X 
X 
X 
X 
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Protocol 2014-0920 
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Albumin, Alkaline 
Phosphatase, Total 
Bilirubin, AST,  
ALT 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
 
 
Urinalysis, dipstick 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
PT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (in 
women with 
childbearing 
potential)5 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
12-lead EKG 
X 
 
 
 
 
X 
 
 
 
X
7 
 
 
 
ECHO/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Appropriate 
Radiologic 
Evaluation 
X 
 
 
 
 
 
 
 
X4 
 
 
 
 
Skin punch biopsy 
(optional) 
 
X2 
X3 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
At each visit 
* All assessments to be performed within +/- 2 days of the specified date. 
1. Urinalysis, dipstick every other cycle 
2. Cycle 1 Day 1 at up to 72 hours prior to the first dose. 
3. Cycle 1 Day 1 at 2–4 hours post the second dose. 
4. Subsequent restaging every 2 cycles. If objective response is observed, a confirmatory scan should be 
obtained 4 weeks following initial documentation of response. 
5. Serum pregnancy test at baseline in women of childbearing potential within 7 days prior to initiating 
treatment. Serum or urine pregnancy test in women of childbearing potential on Day 1 of Cycle 2 and 
beyond. 
6. If not already performed, CDKN2A status must be determined in a CLIA-certified lab prior to treatment.  
7. After Cycle 3, EKG may be performed every 3 months or more often as clinically indicated. 
8. Blood pressure measurement only. 
 
 
 
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15. References
1. Giet R, Petretti C, Prigent C. Aurora kinases, aneuploidy and cancer, a coincidence or a real
link? Trends Cell Biol. 2005;15: 241-250.
2. Andrews PD. Aurora kinases: shining lights on the therapeutic horizon? Oncogene. 2005;24:
5005-5015.
3. Fu J, Bian M, Jiang Q, Zhang C. Roles of Aurora kinases in mitosis and tumorigenesis. Mol
Cancer Res. 2007;5: 1-10.
4. Quelle DE, Zindy F, Ashmun RA, Sherr CJ. [1st: CDKN2A encodes p16.p19] Alternative
reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of
inducing cell cycle arrest. Cell. 1995;83: 993-1000.
5. Sherr CJ. Principles of tumor suppression. Cell. 2004;116: 235-246.
6. Okada H, Mak TW. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev
Cancer. 2004;4: 592-603.
7. Whelan AJ, Bartsch D, Goodfellow PJ. Brief report: a familial syndrome of pancreatic cancer
and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med. 1995;333:
975-977.
8. Manfredi MG, Ecsedy JA, Chakravarty A, et al. Characterization of Alisertib (MLN8237), an
investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic
assays. Clin Cancer Res. 2011;17: 7614-7624.
9. Lowenberg B, Muus P, Ossenkoppele G, et al. Phase 1/2 study to assess the safety, efficacy,
and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid
leukemia. Blood. 2011;118: 6030-6036.
10. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45: 228-247.
11. Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron
emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single
institution with imatinib mesylate: proposal of new computed tomography response criteria. J
Clin Oncol. 2007;25: 1753-1759.
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APPENDIX I- Cautions with Coadministration of Medications 
1) Inhibitors of CYP3A4:
•
Antibiotics: clarithromycin, erythromycin, troleandomycin, chloramphenicol
•
HIV: anti-retrovirals (delaviridine), protease inhibitors (ritonavir, indinavir,
saquinavir, nelfinavir, amprenavir, lopinavir)
•
Antifungals: itraconzaole, ketoconazole, voriconazole, fluconazole (>150 mg
daily)
•
Antidepressants: nefazodone, fluvoxamine
•
Miscellaneous: Grapefruit or its juice
2) Inducers of CYP3A4 :
•
HIV: efavirenz, nevirapine
•
Anticonvulsants, mood stabilizers: carbamazepine, phenytoin,
oxcarbamazepine
•
Antibiotics: rifampin (rifampicin), rifabutin, rifapentene
•
Antiretrovirals: efavirenz, nevirapine
•
Miscellaneous: St. John’s Wort, modafinil
3) Drugs with narrow therapeutic window:
•
Phenytoin
•
Digoxin
•
Wafarin
•
Lithium
•
Aminoglycosides
•
Vancomycin
Avoid St John's Wort 
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APPENDIX II- Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percen
t 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without 
restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or sedentary 
nature (e.g., light housework, 
office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry 
out any work activities.  Up 
and about more than 50% of 
waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  Death 
not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to 
bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
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APPENDIX III- Management Guidelines for Toxicities 
Based upon results from the preclinical safety pharmacology evaluation of Ilorasertib 
(ABT-348), and experience with other inhibitors of Aurora kinase and VEGF signaling, 
potential toxicities may include hypertension, proteinuria, gastrointestinal toxicities such 
as nausea, vomiting and/or diarrhea.  For observed toxicities, subjects should be assessed 
for inter-current illness or other causes and treated as appropriate.  While investigator 
discretion should be used for subject management with regards to these toxicities 
(i.e., dose interruptions and/or dose reductions), some suggested guidelines are included 
in the following sections. 
Subject Management for Hypertension 
Toxicity 
Subject Management 
Asymptomatic Grade 2 or 
Grade 3 Hypertension 
Initiate antihypertensive therapy and continue Ilorasertib 
(Ilorasertib (ABT-348)) at same dose level. 
Symptomatic Hypertension 
Interruption of Ilorasertib (ABT-348) and possible 
discontinuation of therapy.  Once blood pressure is 
controlled (≤140/90), the subject may resume Ilorasertib 
(ABT-348) at a dose reduced by 50 mg. 
Systolic BP >200 mm Hg or 
Diastolic BP > 110 mm Hg  
Interruption of Ilorasertib (ABT-348) and possible 
discontinuation of therapy. 
Once blood pressure is controlled, the subject may resume 
Ilorasertib (ABT-348) at a dose reduced by 50 mg. 
 
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Management of Proteinuria 
Subject Management for Proteinuria 
Based on the results of routine laboratory analysis: 
Toxicity 
Subject Management 
Monitoring 
Urine dipstick > 2+ 
Hold until 24 hour urine 
collection confirms 
proteinuria  
< 2 g/24 hrs 
Perform the following tests: 
• 
24 hour urine collection 
for total protein and 
creatinine 
Microscopic examination of 
fresh urine 
Based on the results of the 24-hour urine collection: 
Toxicity 
Subject Management 
Monitoring 
Proteinuria < 2.0 g/24 hours Continue Ilorasertib 
(ABT-348) planned dose. 
Continue urine analysis as 
routinely scheduled. 
Proteinuria > 2.0 g/24 hours Interrupt Ilorasertib 
(ABT-348). 
Resume Ilorasertib (ABT-348) 
at same or reduced dose once 
urine dipstick  
< 1+ or urinary protein levels 
decrease to < 2 g/24 hrs. 
 
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Management of Gastrointestinal Toxicities 
Subject Management for Diarrhea 
Diarrhea 
Occurrence 
Subject Management 
Grade 1 
2 or more 
Subject may continue Ilorasertib (ABT-348) at the same 
dose.  Manage appropriately with an anti-diarrheal agent. 
Grade 2 
2 or more 
Assess and treat as appropriate.  If alternative etiology is 
identified and treatment administered, subject may continue 
on Ilorasertib (ABT-348) at the same dose.  If no other 
cause has been identified, recommend interruption of 
Ilorasertib (ABT-348), per investigator discretion.  If 
interruption deemed necessary, once toxicity has resolved 
to Grade < 1, the subject may resume Ilorasertib (ABT-
348) at the same dose.
Grade 3 
1 
Assess and treat as appropriate.  If alternative etiology is 
identified and treatment administered, subject may continue 
on Ilorasertib (ABT-348) at the same dose.  If no other 
cause has been identified then interrupt Ilorasertib (ABT-
348) therapy if diarrhea continues for greater than 72 hours
despite maximum supportive care.  Once toxicity has
resolved to Grade < 2, the subject may resume Ilorasertib
(ABT-348) at a dose reduced by 50 mg.
Grade 4 
1 
Discontinue Ilorasertib (ABT-348). 
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