A Phase 1 Study of MLN4924 (Pevonedistat) and Belinostat in Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
Phase: PHASE1
Conditions: Recurrent Acute Myeloid Leukemia, Recurrent Myelodysplastic Syndrome, Refractory Acute Myeloid Leukemia, Refractory Myelodysplastic Syndrome
Sponsor: National Cancer Institute (NCI)

NCT03772925
Phase 1 Study of MLN4924 (Pevonedistat) and Belinostat in Relapsed/Refractory 
Acute Myeloid
Leukemia or Myelodysplastic Syndrome
2/16/2022

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Version Date:  02/16/2022 
 
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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................3 
1.1 
Primary Objectives...................................................................................................6 
1.2 
Secondary Objectives...............................................................................................6 
2. 
BACKGROUND .................................................................................................................6 
2.1 
Study Diseases .........................................................................................................6 
2.2 
CTEP IND Agents ...................................................................................................7 
2.3 
Rationale ................................................................................................................13 
2.4 
Correlative Studies Background ............................................................................14 
2.5 
Pharmacokinetic Studies Background ...................................................................16 
3. 
PATIENT SELECTION ....................................................................................................16 
3.1 
Inclusion Criteria (all of the following criteria must be met for enrollment) ........16 
3.2 
Exclusion Criteria (none of the following may be present for enrollment) ...........17 
3.3 
Inclusion of Women and Minorities ......................................................................20 
4. 
REGISTRATION PROCEDURES ...................................................................................20 
4.1 
Investigator and Research Associate Registration with CTEP ..............................20 
4.2 
Site Registration .....................................................................................................22 
4.3 
Patient Registration ................................................................................................24 
4.4 
General Guidelines.................................................................................................25 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................27 
5.1 
Biomarker Plan ......................................................................................................27 
5.2 
Specimen Tracking System Instructions ................................................................30 
5.3 
Integrated Correlative Studies................................................................................33 
5.4 
Exploratory Correlative Studies .............................................................................41 
6. 
TREATMENT PLAN ........................................................................................................48 
6.1 
Agent Administration.............................................................................................48 
6.2 
Definition of Dose-Limiting Toxicity ....................................................................49 
6.3 
Dose Escalation ......................................................................................................51 
6.4 
Dose Expansion Cohorts ........................................................................................51 
6.5 
General Concomitant Medication and Supportive Care Guidelines ......................52 
6.6 
Duration of Therapy ...............................................................................................55 
6.7 
Discontinuation of Protocol Therapy .....................................................................56 
6.8 
Duration of Follow Up ...........................................................................................57 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................57 
7.1 
Dose Reduction Steps ............................................................................................57 
7.2 
Dose Modifications ................................................................................................58 
7.3 
Initiation of a New Cycle .......................................................................................67 
7.4 
Resumption of Treatment Within a Cycle .............................................................67 
7.5 
Dose Re-escalation.................................................................................................67 
7.6 
Dose Modifications Requiring Discontinuation of Protocol Therapy ...................67 

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8. 
PHARMACEUTICAL INFORMATION ..........................................................................67 
8.1 
CTEP IND Agent(s) ...............................................................................................67 
9. 
STATISTICAL CONSIDERATIONS...............................................................................72 
9.1 
Study Design/Endpoints.........................................................................................72 
9.2 
Sample Size/Accrual Rate ......................................................................................73 
9.3 
Evaluability for DLT, Toxicity, and Response ......................................................74 
9.4 
Statistical Analysis .................................................................................................75 
10. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................76 
10.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................76 
10.2 
Adverse Event Characteristics ...............................................................................82 
10.3 
Expedited Adverse Event Reporting ......................................................................83 
10.4 
Routine Adverse Event Reporting .........................................................................86 
10.5 
Pregnancy ...............................................................................................................86 
10.6 
Secondary Malignancy...........................................................................................86 
10.7 
Second Malignancy ................................................................................................87 
11. 
STUDY CALENDAR .......................................................................................................87 
12. 
MEASUREMENT OF EFFECT........................................................................................91 
12.1 
Hematologic Tumors .............................................................................................91 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................92 
13.1 
Study Oversight .....................................................................................................92 
13.2 
Data Reporting .......................................................................................................93 
13.3 
Data Quality Portal ................................................................................................95 
13.4 
CTEP Multicenter Guidelines ................................................................................95 
13.5 
DLT Reports ..........................................................................................................96 
13.6 
Safety Updates .......................................................................................................96 
13.7 
Real Time Summary and Communication from Coordinating Study Team to 
Participating Sites ..................................................................................................96 
13.8 
Collaborative Agreements Language .....................................................................96 
14. 
REFERENCES ..................................................................................................................99 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................106 
APPENDIX B 
NEW YORK HEART ASSOCIATION CLASSIFICATION 
OF HEART FAILURE. ...................................................................................................107 
APPENDIX C: PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD ..............................................................................................................................108 
APPENDIX E: PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD ..............................................................................................................................111 

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agent therapy generally have a very poor outcome, and no approved interventions exist for these 
individuals (Garcia-Manero et al., 2014).  
 
2.2 
CTEP IND Agents 
 
2.2.1 Belinostat 
 
2.2.1.1 Background 
 
Histone Deacetylase Inhibitors  
DNA is wrapped around histone octamers known as nucleosomes, thereby forming a “beads on a 
string” structure, which folds into higher-order chromatin. Chromatin structure modifications are 
important modulators of the transcriptional activity of specific genes. Acetylation is one of the main 
histone modifications associated with the regulation of gene expression. Acetylation of the N-
terminal lysine residues of histones leads to a more open chromatin configuration (euchromatin), 
which makes it more accessible to the transcription machinery (Bhalla, 2005). The 4 classes of 
human histone deacetylases (HDACs) mediate histone deacetylation, but also have several other 
substrates, including transcription factors (e.g., p53, E2F, c-Myc, NF-κB, HIF-1α, RelA, GATA1, 
FoxO3A, YY1, Mad/Max, TFIIE, TFIIF), signaling mediators (e.g., β-catenin, STAT 1 and 3), 
steroid receptors, chaperone proteins (e.g., Hsp90), DNA repair enzymes (e.g., Ku70, WRN), the 
nuclear import protein importin-α7, and the cytoskeletal protein α-tubulin (Bhalla, 2005; Lane and 
Chabner, 2009; Quintas-Cardama et al., 2011). 
 
HDAC inhibitors (HDACi) exert multiple biological effects in cancer cells, including induction of 
differentiation/apoptosis, cell cycle/mitotic arrest, and autophagic cell death. Malignant cells 
possess higher levels of HDACs than normal tissues, and normal cells are relatively resistant to 
DNA damage and cell death induced by HDACi (Ungerstedt et al., 2005; Lee et al., 2010). As 
noted above, HDACi can modify gene expression secondary to acetylation of histones and by 
altering the acetylation status of transcription factors and other proteins involved in transcription. 
One of the most important HDACi-induced genes is the cyclin-dependent kinase inhibitor 
CDKN1A (p21WAF1/CIP1) (Richon et al., 2000). HDACi-induced increases in the level of this 
protein (Rosato et al., 2003), as well as that of p16 (CDKN2 or INK4) and p27, decreased 
expression of cyclins A and D, and dephosphorylation of retinoblastoma (Rb) protein, all contribute 
to HDACi-induced cell cycle arrest. HDACi also induce telomerase activity (Bhalla, 2005). HDACi 
acetylate histone H3K9 in pericentromeric chromatin, thus interfering with assembly of the 
kinetochore. This leads to mitotic arrest at prometaphase, followed by aberrant mitosis with 
chromosome segregation defects and ultimately apoptosis (Quintas-Cardama et al., 2011). 
Furthermore, HDACi lethality has been related to disruption of various cell cycle checkpoints 
(Warrener et al., 2003) as well as induction of mitotic slippage (Stevens et al., 2008). 
 
HDACi activate both the intrinsic and extrinsic pathways of apoptosis. They increase levels of both 
Fas/Fas ligand and DR5/TRAIL (Insinga et al., 2005, Nebbioso et al., 2005) and down-regulate c-
FLIP (Aron et al., 2003) in leukemic cells, but not in normal cells. HDACi increase levels of the 
pro-apoptotic Bcl-2 family proteins Bax, Bak, Bim (Chen et al., 2009), and Bmf; down-regulate the 
anti-apoptotic proteins Bcl-2, Bcl-xL, Mcl-1, XIAP (Rosato et al., 2006), and survivin; induce 
conformational change of Bax, and enhance the cleavage and subsequent activation of Bid (Bhalla, 

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2005; Quintas-Cardama et al., 2011; Ruefli et al., 2001). 
 
HDACi induce DNA damage through increased generation of reactive oxygen species (ROS) 
(Rosato et al., 2003, Ruefli et al., 2001) and by impairing mechanisms of DNA repair (Bose et al., 
2014). HDAC3 is essential for the maintenance of chromatin structure and genome stability 
(Bhaskara et al., 2010). HDACi decrease levels of the non-homologous end-joining (NHEJ) 
proteins Ku80 and Rad50 and acetylate Ku70 (Subramanian et al., 2005), thereby decreasing its 
DNA binding. HDACi-mediated apoptosis is, in part, dependent on ROS generation, with 
subsequent DNA and mitochondrial damage and activation of the intrinsic apoptotic pathway (Bose 
et al., 2014). In addition, HDACi inhibit homologous recombination (HR) DNA repair (Kachhap et 
al., 2010). Recently, hypoacetylation of histone H3 lysine 56 has been shown to be necessary for 
efficient NHEJ (Miller et al., 2010), raising the possibility that HDACi may also disable this repair 
mechanism. Our group has shown that disabling certain cytoprotective pathways (e.g., NF-κB) 
promotes HDACi-mediated DNA damage and cell death in human leukemia cells (Dai et al., 2005).  
 
Induction of autophagy is another important mechanism of cell death in response to HDACi (Robert 
et al., 2011; Shubassi et al., 2012). Finally, HDACi, particularly HDAC6 inhibitors (Bali et al., 
2005), abrogate chaperone protein (Hsp90) function via hyperacetylation (Bhalla, 2005; Lane and 
Chabner, 2009; Quintas-Cardama et al., 2011). This leads to down-regulation, via 
polyubiquitinylation and proteasomal degradation, of misfolded Hsp90 client proteins such as Bcr-
Abl (Nimmanapalli et al., 2003), FLT3, Akt, Raf (Bali et al., 2005) and checkpoint kinase 1 (Chk1) 
(Arlander et al., 2003; Brazelle et al., 2010). HDACi may also affect tumor cell survival by 
blocking tumor angiogenesis, and by inhibiting intracellular stress-response pathways (Lane and 
Chabner, 2009). 
 
2.2.1.2 Clinical Experience with Belinostat 
 
Belinostat (PXD101, Beleodaq, Spectrum Pharmaceuticals, Inc.), FDA-approved in 2014 for 
relapsed/refractory peripheral T-cell lymphoma (PTCL), is a hydroxamate derivative that inhibits 
both class I and II HDACs (pan-HDACi) (Molife et al., 2011). In preclinical studies, it suppresses 
the growth of and induces apoptosis in a variety of tumor types, both in vitro and in vivo (Plumb et 
al., 2003; Qian et al., 2006; Qian et al., 2008; Buckley et al., 2007; Ma et al., 2010). Although the 
drug has mostly been administered intravenously (IV) in clinical trials, an oral formulation has also 
been tested (Steele et al., 2011). IV belinostat displays linear PKs with respect to the maximum 
concentration (Cmax) and the area under the “concentration time” curve (AUC) (Steele et al., 2008), 
without significant accumulation (Yeo et al., 2012). The intermediate elimination half-life is 0.3 to 
1.3 hrs and independent of dose (Steele et al., 2008). Belinostat PKs are unaltered by concurrent 
administration with carboplatin and paclitaxel (Lassen et al., 2010). Glucuronidation by UGT1A1 is 
by far the major route of belinostat elimination in humans (Wang et al., 2013). The drug has 5 
major metabolites, which are not expected to have anticancer effects, and the parent drug and 
metabolites can be quantified in human plasma by means of a validated liquid chromatography-
tandem mass spectrometry assay (Kiesel et al., 2013). In vitro studies indicate that belinostat is a 
weak/moderate inhibitor of cytochrome P450 family 2 subfamily C member 8 (CYP2C8) and a 
moderate to strong inhibitor of CYP2C9.  
 
In a phase 1 study in patients with advanced solid tumors, the MTD of belinostat was 1000 mg/m2 

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IV daily, administered over 30 minutes on Days 1-5 of a 21-day cycle (Steele et al., 2008). Dose-
limiting toxicities (DLTs) included grade 3 fatigue, diarrhea, and atrial fibrillation, as well as grade 
2 nausea/vomiting resulting in inability to complete a full 5-day cycle. A phase 1 study in patients 
with advanced hematologic neoplasms reported the same MTD (Gimsing et al., 2008). The most 
common treatment-related adverse events (AEs) (all grades) were nausea (50%), vomiting (31%), 
fatigue (31%), and flushing (31%). There was one case of grade 3 lymphopenia and two cases of 
grade 4 renal failure in the context of tumor lysis syndrome (TLS). The only related grade 3 events 
in more than one patient were fatigue and neurologic symptoms, and no cardiac events were noted. 
Oral belinostat was studied in 15 patients who were included in the phase 1 trial of IV belinostat in 
second or subsequent treatment cycles (Steele et al., 2011). High doses, up to 1000 mg/m2 orally 
twice daily for 5 consecutive days, were found tolerable in this small study. In a phase 1 trial of oral 
belinostat in patients with lymphoma, the drug was found to be safe (no DLTs) at daily doses of 
750-1250 mg on Days 1-14 every 3 weeks (Zain et al., 2009). In a phase 2 clinical trial, belinostat 
was administered IV at 1000 mg/m2 daily on Days 1-5 every 21 days in patients with 
relapsed/refractory AML or newly diagnosed patients with AML over the age of 60 (Kirschbaum et 
al., 2015). Belinostat was well tolerated; however, only 4 patients displayed SD for at least five 
cycles. A similar trial of belinostat at the same dose and schedule showed similar activity in 
myelodysplastic syndrome (MDS), with only one confirmed response (Cashen et al., 2012). 
 
Belinostat has been found to be well tolerated in combination with carboplatin and paclitaxel in 
patients with solid tumors; in a phase 1 study, the maximal administered dose of belinostat was 
1000 mg/m2/d IV on Days 1-5 every 21 days, with carboplatin (AUC 5) and/or paclitaxel (175 
mg/m2) administered on Day 3 after belinostat (Lassen et al., 2010). Belinostat has also been 
evaluated in combination with 5-FU; cisplatin, doxorubicin, and cyclophosphamide (PAC, in 
advanced or recurrent thymic malignancies); cisplatin and etoposide; and 13-cis retinoic acid in 
phase 1 studies in patients with advanced solid tumors (Northfelt et al., 2007; Thomas et al., 2012; 
Balasubramaniam et al., 2013; Luu et al., 2013). In combination with a 96-hr infusion of 5-FU, 500 
mg/m2/d on Days 2-5, belinostat was well tolerated at doses up to 1000 mg/m2 IV daily on Days 1-5 
of a 21-day cycle (Northfelt et al., 2007). In combination with PAC (50/50/500 mg/m2 IV every 3 
weeks), the RP2D of belinostat was 1000 mg/m2 over a 48-hr continuous IV infusion (Thomas et 
al., 2012). The RP2D of belinostat in combination with cisplatin 60 mg/m2 on Day 1 and etoposide 
80 mg/m2/d on Days 1-3 of a 3-week cycle was 500 mg/m2/24 h when administered by 48-hr 
continuous IV infusion (Balasubramaniam et al., 2013). In contrast, when combined with the non-
cytotoxic 13-cis retinoic acid, 100 mg/m2 daily on Days 1-14, the MTD of belinostat was not 
reached even at 2000 mg/m2 daily on Days 1-5 every 21 days (Luu et al., 2013). The combination 
of belinostat, 1000 mg/m2/d IV and azacytidine, 75 mg/m2/d subcutaneously on Days 1-5 every 28 
days has been found to be feasible and active in patients with advanced myeloid malignancies 
(Odenike et al., 2011). This dose of belinostat, administered on Days 1-5 and 8-12 of a 3-week 
cycle in conjunction with bortezomib (1.3 mg/m2 on Days 1, 4, 8, and 11) was found to be tolerable 
and active (1 complete response [CR], 2 partial responses [PRs], and 8 who have stable disease 
[SD] of 22 evaluable patients) in a phase 1 trial in patients with relapsed/refractory acute leukemia 
or MDS (Holkova et al., 2012). In this trial, the CR was attained in a heavily pretreated patient with 
MLL-rearranged AML, while another patient with AML arising from JAK2-mutated myelofibrosis 
maintained SD for 2.5 years (Holkova et al., 2012).  
 

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2.2.2 MLN4924 (pevonedistat) 
 
2.2.2.1 Background 
 
2.2.2.1.1 
Neddylation Inhibitors 
 
The coordinated balance between synthesis and degradation of proteins is important in most cellular 
processes, and the ubiquitin-proteasome system (UPS) is responsible for much of the regulated 
protein turnover in the cell (Pevonedistat Investigator’s Brochure, 2017). The UPS maintains 
cellular homeostasis and impacts many signaling pathways including cell cycle progression and 
regulation of transcription. This complex, multiprotein system involves distinct enzyme classes that 
coordinate ubiquitination and mediate ubiquitin-dependent degradation through the proteasome. 
The proteasome inhibitor (PI) bortezomib (Velcade; Millennium Pharmaceuticals, Inc.) has utility 
in the treatment of multiple myeloma and mantle cell lymphoma (Velcade Package Insert, 2015), 
suggesting that compounds targeting other components of the UPS could prove useful in the 
treatment of malignancies. 
 
The polyubiquitination reaction involves the coordination of 3 classes of enzymes, E1 (ubiquitin 
activating), E2 (ubiquitin conjugating), and E3 (ligases) (Pevonedistat Investigator’s Brochure, 
2018). The E3 ligases are multiprotein complexes whose specificity is established by the members 
of the protein complex and whose activity is regulated by post-translational modification that 
include the addition of the ubiquitin-like molecule, neural precursor cell expressed, 
developmentally down-regulated 8 (NEDD8). NEDD8-activating enzyme (NAE) has been 
identified as an essential component of the NEDD8 conjugation pathway. The NEDD8 conjugation 
pathway controls the activity of a subset of UPS E3 ligases. Specifically, NEDD8 conjugation to 
cullin-dependent ubiquitin E3 ligases (CDLs) is necessary for their activity. These ligases control 
the timely ubiquitination and subsequent degradation of many proteins important for cell cycle 
progression (p27, cyclin E), DNA damage (Cdt-1), stress response (NRF-2, HIF1α), and signal 
transduction (phosphorylated IĸBα). 
 
MLN4924 (pevonedistat) (TAK-924, formerly MLN4924) is a first-in-class small molecule 
inhibitor of NAE under development for the treatment of malignancies (Pevonedistat Investigator’s 
Brochure, 2018). Consistent with the inhibition of NAE, MLN4924 (pevonedistat) treatment of 
cultured tumor cells resulted in a decrease in NEDD8-cullin levels and a reciprocal increase in the 
levels of known CDL substrates, including NRF2 and CDT1, followed by cell death through 
apoptosis (Pevonedistat Investigator’s Brochure, 2018). In vitro experiments with MLN4924 
(pevonedistat) administered in combination with the hypomethylating agents azacitidine and 
decitabine demonstrated synergistic activity in AML cell lines. In nonclinical studies, treatment of 
cells with MLN4924 (pevonedistat) resulted in the accumulation of CDL substrates, followed by a 
DNA damage response and cell death. MLN4924 (pevonedistat) treatment resulted in tumor growth 
inhibition (TGI) in mouse tumor xenograft models of solid tumors, lymphoma, and acute myeloid 
leukemia (AML). These data indicate that inhibitors of NAE activity may be of therapeutic value in 
the treatment of various cancers, by preventing neddylation and activation of the CDLs, thus 
disrupting proteasomal degradation of a variety of critical regulatory proteins integral to tumor cell 
growth, proliferation, and survival.  
 

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2.2.2.2 Clinical experience with MLN4924 (pevonedistat) 
 
There are 38 clinical studies of MLN4924 (pevonedistat) in patients with advanced malignancies.  
 
To date, seven phase 1 MLN4924 (pevonedistat) studies have been completed: Study C15009 with 
azacitidine in patients with AML, Study C15010 with docetaxel, gemcitabine, or in combination 
with carboplatin and paclitaxel in patients with solid tumors, Study Pevonedistat-1012 assessing 
MLN4924 (pevonedistat) as a component of regimens with azacitidine in adult East Asian patients 
with AML or MDS, Study Pevonedistat-2001 with azacytidine in patients with HR MDS, CMML, 
and AML. Additionally, absorption, distribution, metabolism, and excretion properties of 
MLN4924 (pevonedistat) are being studied in Study Pevonedistat-1013 and two supportive phase I 
studies Pevonedistat-1014 (QTc interval) and Pevonedistat-1015 (effects of rifampin on PK of 
pevonedistat in patients with advanced solid tumors) (Pevonedistat Investigator’s Brochure, 2021). 
A phase 1 study evaluating the effects of CYP3A-mediated inhibition on MLN4924 (pevonedistat) 
(Study C15011) has also completed enrollment. There are currently three ongoing studiesassessing 
MLN4924 (pevonedistat) as a component of regimens with azacitidine, in patients with HR MDS, 
CMML, or low-blast AML (Pevonedistat-3001) and in patients with newly diagnosed AML 
(Pevonedistat-2002), and HR MDS, CMML, and solid tumors (Pevonedistat-1016) (Pevonedistat 
Investigator’s Brochure, 2021).  
 
Study Pevonedistat-3001 is a phase 3, randomized, controlled, open-label study of pevonedistat and 
azacytidine versus single-agent azacitidine as first-line treatment for patients with HR MDS, 
CMML, or low-blast AML.  Patients were randomized to the combination arm (pevonedistat and 
azacytidine) or single-agent azacytidine. Each cycle of treatment is 28 days. In the combination 
arm, patients received MLN4924 (pevonedistat) on Days 1, 3, and 5 at 20 mg/m2. Azacitdine was 
administered in either the combination or single-agent arm on Days 1-5, 8, and 9 at 75 mg/m2. A 
total of 443 patients have been treated. The study did not achieve statistical significance for the 
primary endpoint of event-free survival.    
 
 
In a phase 1 study (C15001), MLN4924 (pevonedistat) was administered in four different dosing 
schedules to patients with non-hematological malignancies. Patients received MLN4924 
(pevonedistat) on either 1) Days 1-5 at starting dose 25 mg/m2 (Schedule A), 2) Days 1, 3, and 5 
(with dexamethasone) at starting 50 mg/m2 (Schedule B), 3) Days 1, 3, and 5 (without 
dexamethasone) at starting 50 mg/m2 (Schedule C) or 4) Days 1, 8, and 15 at starting dose 147 
mg/m2 (Schedule D). Cycles were repeated every 21 days. A total of 62 patients were treated and 
DLTs included elevated LFTs, elevated bilirubin, elevated creatinine, hyperbilirubinemia, acute 
renal failure, and acute hepatic failure. The MTD for Schedule A & B was 50 mg/m2 and the MTD 
was 67 mg/m2 for Schedule C. The MTD for Schedule D was not determined.   
 
In another phase 1 study (C15002), MLN4924 (pevonedistat) was administered IV to patients with 
lymphoma or multiple myeloma on 5 different dosing schedules (Schedule A: Days 1, 2, 8, and 9 at 
starting dose 25 mg/m2; Schedule B: Days 1, 4, 8, and 11 at starting dose 110 mg/m2; Schedule C: 
Days 1 and 8 at starting dose 110 mg/m2; Schedule D: Days 1, 8, and 15 at starting dose 110 
mg/m2; Schedule E: Days 1, 4, 8, and 11 at starting dose 100 mg/m2). Cycles were repeated every 
21 days. A total of 56 patients were treated and DLTs experienced included febrile neutropenia, 

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elevated LFTs, muscle spasms, thrombocytopenia, and acute renal failure. The MTD for Schedule 
A was 110 mg/m2 and for Schedule B the MTD was determined to be 196 mg/m2. The MTD was 
not determined for Schedules C-E.  
 
A phase 1 dose escalation study (C15003) of MLN4924 (pevonedistat) treated patients with acute 
myelogenous leukemia, high-grade myelodysplastic syndrome or acute lymphoblastic leukemia on 
4 different dosing schedules (Schedule A: Days 1, 3, and 5 at starting dose 25 mg/m2; Schedule B: 
Days 1, 4, 8 and 11 at starting dose 147 mg/m2; Schedule C: Days 1, 8, and 15 at starting dose 44 
mg/m2; Schedule D: [MLN4924 (pevonedistat) starting dose of 45 mg/m2 and azacytidine dose of 
75 mg/m2] Cycle 1: Days 1, 4, 11 and 15, with azacytidine on Days 8-12 and 15-16 of a 35-day 
cycle, Cycles 2+: Days 1, 4, 8, and 11, with azacytidine on Days 1-5 and 8-9 of a 28-day cycle; 
Schedule E: Days 1, 3, and 5, expansion cohort at a fixed dose of 50 mg/m2). A total of 72 patients 
were treated and DLTs observed included elevated LFTs, hypotension, cardiac failure, GI necrosis, 
lactic acidosis, myocardial ischemia, renal failure and rash morbilliform. The MTD was established 
at 59 mg/m2 for Schedule A and 83 mg/m2 for Schedule B. The MTD was not determined for 
Schedules C-E. 
 
A phase 1 study (C15005) assessing MLN4924 (pevonedistat) in adult patients with melanoma 
administered MLN4924 (pevonedistat) in 2 dosing schedules; Schedule A: Days 1, 4, 8, and 11 at 
starting dose of 50 mg/m2 and Schedule B: Days 1, 8, and 15 at starting dose 157 mg/m2. Cycles 
were repeated every 21 days. A total of 37 patients were treated but the study was closed early by 
the study sponsor. DLTs observed included hypophosphatemia, elevated creatinine, myocarditis, 
acute renal failure, and hyperbilirubinemia. The MTD determined for Schedule A was 209 mg/m2 
and the MTD was not determined for Schedule B. 
 
A phase 1b dose escalation study (C15009) of MLN4924 (pevonedistat) plus azacitidine in naïve 
patients with acute myelogenous leukemia assessed safety and tolerability of the drug combination. 
Patients were dosed with (MLN4924) pevonedistat on Days 1, 3, and 5 at a starting dose of 20 
mg/m2 and azacitidine on Days 1-5, 8, and 9 at 75 mg/m2. Cycles were repeated every 28-days. A 
total of 64 patients were treated and responses of CR, CRi and PR were observed in 58% of 
patients. The overall response rate in evaluable patients was 58% with a median response duration 
of 8.3 months. Responses were identified in all cytogenetic risk groups, TP53 mutations, low and 
high marrow blast counts and in de novo as well as secondary AML.  
 
A phase 1 dose escalation study of MLN4924 (pevonedistat) in advanced solid tumors administered 
MLN4924 (pevonedistat) in 3 dosing schedules: Schedule A: Days 1-5 at 50 mg/m2 in a 21-day 
cycle, this schedule was subsequently discontinued due to severe hepatotoxicity. Schedule B: Days 
1, 3, and 5 in a 21-day cycle at 50 mg/m2 with 8 mg oral dexamethasone before each MLN4924 
(pevonedistat) dose and Schedule C: Days 1, 3, and 5 in a 21-day cycle at 67 mg/m2. On Schedule 
B and C, no Grade 3 or greater serious adverse events were noted.  
 
There are 19 ongoing phase 1/1b studies assessing MLN4924 (pevonedistat) in patients with 
advanced solid tumors and hematologic malignancies. 
 
In view of its single-agent activity and complementary mechanisms of action, MLN4924 
(pevonedistat) may prove to be superior to PIs such as bortezomib in disabling NF-κB and 

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2.5 
Pharmacokinetic Studies Background 
 
PK analysis of MLN4924 (pevonedistat) and belinostat will be performed with three goals: 1) to 
gain preliminary insights into potential PK interactions between the two agents; 2) to determine 
whether plasma drug levels can be achieved that mimic concentrations shown to be active in 
previous in vitro studies; and 3) to obtain preliminary information concerning correlations between 
PK parameters (e.g., drug exposure) and results of pharmacodynamic studies and/or responses, if 
the latter occur. 
 
See Section 5 for further details on operational characteristics of PK studies. 
 
 
3. 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria (all of the following criteria must be met for enrollment) 
 
3.1.1 Patients must have one of the following, histologically or cytologically confirmed: 
 
• AML (non- acute promyelocytic leukemia [APL] AML) 
o AML that is relapsed or refractory to at least one prior line of therapy 
• MDS, must meet all of the following at the time of enrollment: 
o Higher risk MDS (intermediate-2 or high risk by the original IPSS) (Greenberg et 
al., 1997), and  
o Relapsed, refractory, or intolerant to at least one prior line of therapy containing a 
hypomethylating agent (DNA methyltransferase inhibitor). 
 
3.1.2 Age ≥18 years.  
 
Because no dosing or adverse event data are currently available on the use of MLN4924 
(pevonedistat) in combination with belinostat in patients <18 years of age, children are 
excluded from this study, but will be eligible for future pediatric trials. 
 
3.1.3 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.4 Patients must have adequate organ and marrow function as defined below: 
− 
total bilirubin 
 
≤upper limit of normal (ULN) for the laboratory 
except in patients with Gilbert’s syndrome. Patients 
with Gilbert’s syndrome may enroll if direct bilirubin 
≤1.5 x ULN for the laboratory of the direct bilirubin. 
− 
AST(SGOT)/ALT(SGPT) 
 
≤3 × institutional ULN. 
− 
creatinine clearance 
 
Within normal limits for the laboratory 
OR  
− 
estimated glomerular filtration  
rate (GFR)  
 
 
≥60 mL/min/1.73 m2 appropriate to race for patients 

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with creatinine levels above institutional normal. 
 
3.1.5 Known human immunodeficiency virus (HIV) positive patients who meet the following 
criteria will be considered eligible: 
 CD4 count >350 cells/mm3 
 Undetectable viral load 
 Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents 
 No history of Acquired Immune Deficiency Syndrome (AIDS)-defining opportunistic 
infections 
 
3.1.6 If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be 
undetectable on suppressive therapy, if indicated. 
 
3.1.7 If history of hepatitis C virus (HCV) infection, patients must be treated and have an 
undetectable HCV viral load. 
 
3.1.8 The effects of belinostat and/or MLN4924 (pevonedistat) on the developing human fetus are 
unknown. For this reason and because histone deacetylase inhibitors and NAE inhibitory 
agents are known to be teratogenic, women of child-bearing potential and men must use 1 
highly effective method and 1 additional (barrier) method of contraception at the same time, 
from the time of signing the informed consent through 4 months after the last dose of study 
drug (female and male condoms should not be used together). Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately. Men treated or enrolled on this protocol 
must also agree to use adequate contraception prior to the study, for the duration of study 
participation, and 4 months after completion of MLN4924 (pevonedistat) and belinostat 
administration. 
 
3.1.9 Ability to understand and the willingness to sign a written informed consent document. 
Participants with impaired decision-making capacity (IDMC) who have a legally-authorized 
representative (LAR) and/or family member available will also be eligible. 
 
3.2 
Exclusion Criteria (none of the following may be present for enrollment) 
 
3.2.1 Clinical picture indicative of leukostasis or evidence of disseminated intravascular 
coagulopathy. 
 
3.2.2 Uncontrolled coagulopathy or bleeding disorder. 
 
3.2.3 Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 
days before the first dose of any study drug, except for hydroxyurea. 
 
3.2.4 Uncontrolled high blood pressure (i.e., systolic blood pressure >180 mm Hg, diastolic blood 
pressure >95 mm Hg). 
 

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3.2.5 Female patients who intend to donate eggs (ova) during the course of this study or 4 months 
after receiving their last dose of study drug(s). 
 
3.2.6 Male patients who intend to donate sperm during the course of this study or 4 months after 
receiving their last dose of study drug(s). 
 
3.2.7 Ongoing toxicities ≥grade 2 from prior therapy, except those related to hydroxyurea (which 
is permitted through the first 5 days of study treatment).  
 
3.2.8 APL (M3). 
 
3.2.9 Active central nervous system (CNS) leukemia. 
 
3.2.10 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MLN4924 (pevonedistat) or belinostat. 
 
3.2.11 Stem cell transplant within previous 3 months prior to initiation of study therapy. 
 
3.2.12 Major surgical procedures <28 days before beginning study treatment or minor surgical 
procedures <7 days before beginning study treatment. No waiting required after placement 
of a vascular access device. 
 
3.2.13 Uncontrolled intercurrent illness or infection. 
 
3.2.14 Circulating blast count >50,000 mm3 within 7 days preceding enrollment. 
 
3.2.15 Current candidacy for a potentially curative allogenic stem cell transplant, unless declined. 
 
3.2.16 Left ventricular ejection fraction (LVEF) <50% as assessed by echocardiogram or 
radionuclide angiography. 
 
3.2.17 Prolongation of the heart-rate corrected QT (QTc) interval ≥450 ms (i.e., grade 1 or higher) 
on electrocardiogram (ECG) prior to initiation of study treatment. 
• If baseline QTc on screening ECG is ≥450 ms (i.e., grade 1 or higher): 
o Check potassium and magnesium serum levels, and 
o Correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to 
confirm QTc interval. 
• For patients with baseline heart rate <60 bpm or >100 bpm, manual measurement of QT 
interval by cardiologist is required, with Fridericia correction applied to that manual 
measurement to determine the QTc for eligibility consideration. 
 
Note: For patients with a heart rate of 60-100 bpm, manual measurement of QT interval 
and use of the Fridericia formula to determine QTc is NOT required. 

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19 
3.2.18 Known cardiopulmonary disease defined as: 
• Unstable angina; 
• Congestive heart failure (New York Heart Association [NYHA] Class III or IV; see 
Appendix B);  
• Myocardial infarction (MI) within 6 months prior to first dose (patients who had 
ischemic heart disease such as ACS, MI, and/or revascularization greater than 6 months 
before screening and who are without cardiac symptoms may enroll); 
• Symptomatic cardiomyopathy; 
• Clinically significant pulmonary hypertension requiring pharmacologic therapy 
• Clinically significant arrhythmia defined as any of the following: 
o History of polymorphic ventricular fibrillation or torsade de pointes 
o Permanent atrial fibrillation (a fib), defined as continuous a fib for ≥ 6 months 
o Persistent a fib, defined as sustaining a fib lasting > 7 days and/or requiring 
cardioversion in the 4 weeks before screening 
o Grade 3 a fib defined as symptomatic and incompletely controlled medically, or 
controlled with device (e.g., pace maker), or ablation in the past 6 months 
o Patients with paroxysmal a fib or < Grade 3 a fib for a period of at least 6 months are 
permitted to enroll provided that their rate is controlled on a stable regimen 
o Known congenital long QT syndrome. 
o Second degree atrioventricular (AV) block type II or third degree AV block 
o Ventricular rate <50 bpm or > 120 bpm. 
 
3.2.19 Treatment with clinically significant metabolic enzyme inducers within 14 days before the 
first dose of the study drug.  
 
Note: Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated medical reference. As part of the enrollment/informed consent 
procedures, the patient will be counseled on the risk of interactions with other agents, and 
what to do if new medications need to be prescribed or if the patient is considering a new 
over-the-counter medicine or herbal product. 
 
3.2.20 Ongoing or planned treatment with strong inhibitors of UGT1A1. 
 
3.2.21 Any known UGT1A polymorphism, heterozygous or homozygous. 
 
3.2.22 History of prior therapy with belinostat or MLN4924 (pevonedistat). 
 
3.2.23 Active gastrointestinal (GI) conditions that might predispose to drug intolerance or poor 
drug absorption. 
 
3.2.24 Known hepatic cirrhosis. 
 
3.2.25 Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, 
and pulmonary fibrosis. 
 

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20 
3.2.26 No other prior malignancy is allowed except for the following: 
• In situ cervical cancer,  
• Adequately treated basal cell or squamous cell skin cancer,  
• Adequately treated Stage I or II cancer from which the patient is currently in complete 
remission, and 
• Any other cancer from which the patient has been disease-free for at least 1 year. 
 
3.2.27 Medical, psychological, or social condition that, in the opinion of the investigator, may 
increase the patient’s risk, interfere with the patient’s participation in the study, or hinder 
evaluation of study results. 
 
3.2.28 Pregnant or nursing. Women of childbearing potential must have a negative serum 
pregnancy test performed within 7 days prior to the start of study therapy.  
 
Note: Pregnant women are excluded from this study because MLN4924 (pevonedistat) is a 
NEDD8 inhibitor with the potential for teratogenic or abortifacient effects and because 
belinostat may cause teratogenicity and/or embryo-fetal lethality by virtue of targeting 
actively dividing cells. Because there is an unknown but potential risk for AEs in nursing 
infants secondary to treatment of the mother with MLN4924 (pevonedistat) or belinostat, 
breastfeeding should be discontinued if the mother is treated with MLN4924 
(pevonedistat)/belinostat. 
 
3.3 
Inclusion of Women and Minorities 
 
National Institutes of Health (NIH) policy requires that women and members of minority groups 
and their subpopulations be included in all NIH-supported biomedical and behavioral research 
projects involving NIH-defined clinical research unless a clear and compelling rationale and 
justification establishes to the satisfaction of the funding Institute & Center (IC) Director that 
inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. 
Exclusion under other circumstances must be designated by the Director, NIH, upon the 
recommendation of an IC Director based on a compelling rationale and justification. Cost is not an 
acceptable reason for exclusion except when the study would duplicate data from other sources. 
Women of childbearing potential should not be routinely excluded from participation in clinical 
research. 
 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. Every 
attempt will be made to enter all eligible patients in this protocol to address the study objectives in a 
population representative of the population treated by the participating institutions. 
 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 

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24 
 
• Click on Regulatory at the top of the screen, 
• Click on Site Registration, and  
• Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note:  The status shown only reflects institutional compliance with site registration requirements as 
outlined within the protocol.  It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available on 
a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the Lead Protocol 
Organization (LPOs) registration/randomization systems or Theradex Interactive Web Response 
System (IWRS) for retrieval of patient registration/randomization assignment.  OPEN will populate 
the patient enrollment data in NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access:   
 
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Be on an LPO roster, ETCTN 
Corresponding roster, or Participating Organization roster with the role of Registrar.  Registrars 
must hold a minimum of an AP registration type. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, crediting, 
consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in OPEN, the 
IVR or NPIVR must list the IRB number used on the site’s IRB approval on their Form FDA 1572 
in RCR.  If a DTL is required for the study, the IVR or NPIVR must be assigned the appropriate 
OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
 from the OPEN link on the CTSU members’ website.  

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26 
that would cause treatment delays should be discussed with the principal investigator. If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study may 
be canceled. The PI and study coordinator should be notified of treatment delays and/or 
cancelations as soon as possible.

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30 
5.2 
Specimen Tracking System Instructions 
 
5.2.1 Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
 
• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification: Patients must meet all the eligibility requirements listed in Section 3 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID. The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this protocol that uses the ETCTN Specimen Tracking System. The 
UPID contains no information or link to the treatment protocol. IWRS will maintain an 
association between the UPID for ETCTN biobanking and molecular characterization and any 
treatment protocols the patient participates in, thereby allowing analysis of the molecular 
characterization results with the clinical data.  
 
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave. The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial. For newly acquired biopsies, the radiology and operative 
report(s) must also be uploaded into Rave. Important: Remove any personally identifying 
information, including, but not limited to, the patient’s name, initials, medical record number, 
and patient contact information from the institutional pathology report prior to submission. 
 
For questions regarding the Specimen Tracking System, please contact the 
 
at 
 
 
A shipping manifest must be included with all sample submissions 
 
Submitted specimens may be labeled using the label-generation utility in STS or labels generated 
outside STS. Labels generated outside STS must contain information as outlined in applicable 
specimen handling sections.  
 
5.2.2 Specimen Labeling 
 
5.2.2.1 Blood and/or Bone Marrow Aspirate Specimen Labels  
 
Please refer to handling section for each specimen type in Sections 5.3 and 5.4.  

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32 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. The last alpha-numeric code is protocol specific and is only included if the protocol 
requires an additional special code classification 
 
The last line on the example label is for the handwritten date and optional time. 
 
5.2.3 Overview of Process at Treating Site 
 
5.2.3.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system. OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization and any prescribed slot 
assignments. If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration without eligibility specimen analysis:  
 
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal 
Patient ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Registration with eligibility specimen analysis - not applicable for this trial. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.2.4 Specimen Tracking System Overview and Enrollment Instructions 
 
5.2.4.1 Rave Specimen Tracking Process Steps 
 
Step 1: Complete the Histology and Disease form (but do not upload reports until a specimen 
label can be applied to them) and the Baseline forms regarding Prior Therapies. Enter the initial 
clinical specimen data:  
 
• Specimen Tracking Enrollment CRF: Enter Time Point, Specimen Category, Specimen Type, 
Block number, Tissue type, Surgical Path ID, and number of labels needed (include extra 
labels to apply to reports to be uploaded). CRF generates unique Specimen ID.  
 

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35 
5.3.2 RT-PCR of Pharmacodynamic Markers 
 
RT-PCR will be performed to assess pharmacodynamic markers for drug response. The assay 
includes 2 integrated target genes: NQO1 and SLC7A11. Sampling for PD-RTPCR analysis is 
mandatory. 
 
5.3.2.1 Collection of Specimen(s) 
 
• Blood samples will be collected pre-treatment and 6 hr post-treatment. Collect 2.5 mL of 
blood in PAXgene RNA tube (see supply ordering information below). 
• Ensure that the PAXgene tube is at room temperature (18°C–25°C) prior to use and properly 
labeled with patient identification.  
• Using a blood collection set, collect blood into the PAXgene Blood RNA Tube using your 
institution’s recommended standard procedure for venipuncture.  
• Hold the PAXgene blood RNA tube vertically, below the donor’s arm during blood 
collection. 
• Allow at least 10 seconds for a complete blood draw to take place. Ensure that the blood has 
stopped flowing into the tube before removing the tube from the holder.  
5.3.2.1.1 
Asuragen/PAXgene tube supply ordering 
Each participating site will procure PAXgene tubes. Recommended items/vendors include: 
• BD Biosciences Catalog No. 762165: PAXgene® Blood RNA Tube 2.5mL 
• Fisher Scientific Catalog No. 23-021-01 (Manufacturer No. 762165): BD PAXgene™ Blood 
RNA Tube 2.5mL 
• QIAGEN Catalog No./ID 762125: PAXgene® Blood RNA Tube (IVD) 2.5mL 
5.3.2.2 Handling of Specimen(s) 
 
• Gently invert the PAXgene Blood RNA Tube 8 to 10 times. 
• “Slow-freeze” the tube overnight at -20°C. The tube may then be transferred to a -70°C 
freezer for long-term storage. 
 
Samples being submitted to Asuragen will be labeled as follows or labeled using the RAVE 
Specimen Tracking System.  
 
Labels generated outside STS should mimic the STS labeling format as shown below: 
 
• Patient ID: Protocol # (10246) - Treatment ID # (assigned at enrollment) – UPID (assigned in 
STS) 
• Specimen ID: Protocol # (10246) – UPID plus sequentially generated integer (assigned in 
STS) 
• Code: PD-RTPCR 
• Type: Blood  

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37 
• Collect 3 mL of venous blood into a chilled tube containing K2-EDTA (see tube ordering 
information below) at the time points specified below for MLN4924 (pevonedistat) PK 
analysis. 
• GENTLY invert the tube 8-10 times to mix the additive with the collected blood prior to 
centrifugation and place immediately on ice. 
• For MLN4924 (pevonedistat), sample collection will occur at these approximate time points 
on Cycle 1, starting on Day 1, timed from the START of the MLN4924 infusion: 
o pre-MLN4924 (pevonedistat) infusion 
o 30 minutes (±10 min) after the START of the MLN4924 (pevonedistat) infusion, and 
then 
o 1 hr (±10 min) 
o 2 hrs (±10 min) 
o 2.5 hrs (±10 min) 
o 5 hrs (±30 min) 
o 8 hrs (±45 min) 
o and 24hrs (± 4 hrs) after the START of MLN4924 (pevonedistat) infusion. 
 
Note: if samples cannot be obtained within the stated time point window, it’s preferable to 
draw a sample as close to the time point as possible rather than omitting the sample – be sure 
the actual time of collection is recorded 
 
5.3.3.1.1.1 MLN4924 PK supply ordering 
 
Each participating site will procure K2-EDTA tubes. Recommended items/vendors include: BD 
(Becton Dickinson) Catalog No. 02-689-03 (Manufacturer No. BD367835): K2EDTA-
containing plastic lavender-top tubes 3 mL  
• Fisher Scientific Catalog No. 367835: K2EDTA-containing plastic lavender-top tubes 3 mL  
5.3.3.1.2 Handling of MLN4924 (Pevonedistat) Specimen(s) 
 
• Process within 60 minutes of collection. 
• Centrifuge at approximately 1100 to 1300 × g (RCF) for 10 minutes at approximately 4°C in 
a refrigerated centrifuge. Note: If using a collection device other than Becton-Dickinson, 
refer to manufacturer’s instruction for proper centrifugation force and time.  
• Immediately following centrifugation, gently remove plasma from the packed cells and 
transfer into 2 labeled 2 mL cryovials. Each plasma sample will be split into 2 cryovials, 
which should be clearly designated as part of “Set 1” (primary set) or “Set 2” (back-up set).  
• To ensure a more homogeneous sample, transfer all plasma into one cryovial. From there, 
split the plasma evenly between the 2 aliquots. A minimum of 0.6 mL needs to be obtained 
for each aliquot 

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38 
• Samples being submitted to QPS will be labeled as follows or labeled using the RAVE 
Specimen Tracking System. Labels generated outside STS should mimic the STS labeling 
format as shown below: 
 
o Patient ID: Protocol # (10246) - Treatment ID # (assigned at enrollment) – UPID 
(assigned in STS) 
o Specimen ID: Protocol # (10246) - UPID plus sequentially generated integer (assigned in 
STS) 
o Code: PK-PEVO 
o Type: Blood  
o Time Point: pre or post 
o Date/time collected 
o Optional (not included in STS labels): “Set 1” or “Set 2” 
 
• Freeze the plasma samples immediately at approximately -70°C or lower. If a -70°C freezer 
is not available, freeze and store samples at -20°C. No more than 45 minutes should elapse 
between blood collection and freezing the plasma sample. 
• Store samples frozen at approximately -70°C or lower until shipment. 
 
5.3.3.1.3 
Shipping of MLN4952 (Pevonedistat) Sample(s) 
 
• Samples should be stored through the duration of the PK study and shipped as a batch by 
patient.  
• The primary set of samples should be shipped using site supplies to the QPS laboratory 
within 3 months of first sample's collection date (i.e., if baseline sample is collected on 
06/01/2019, all of that patient's samples should be at the QPS laboratory by 09/01/2019). If a 
second set of patient samples can be batch shipped by waiting up to 2 weeks (i.e., 3.5 
months), this is allowed.  
• Coordinate shipment with the QPS laboratory (
 via email prior to shipment 
(on the day of shipment or before), providing the shipment tracking information and a copy 
of the sample inventory. 
• All samples will be shipped via overnight express courier in insulated containers with enough 
dry ice to maintain the samples in a frozen state for at least 72 hours (3 days), or up to the 
expected delivery date, whichever is longer.  
• Shipments should occur on Monday through Wednesday (Tuesday is the preferred day) 
except when the following day is a holiday.  
• A sample inventory must accompany all shipments. 
 
*Once receipt of the primary set of samples (SET 1) is confirmed by QPS, the back-up set of 
samples (SET 2) may be shipped. 
 

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5.3.3.2.1.1 Belinostat PK supply ordering 
 
Each participating site will procure sodium heparin tubes. Recommended items/vendors include: 
• BD (Becton Dickinson) Catalog No. 23-021-017 (Manufacturer No. BD 367878): sodium 
heparin-containing plastic green-top tubes 6 mL  
• Fisher Scientific Catalog No. 367878: sodium heparin-containing plastic green-top tubes 
6 mL  
5.3.3.2.2 Handling of Belinostat PK Specimen(s) 
 
• Centrifuge at 2500-3000 rpm for 10 mins in swinging bucket (SW) or 15 mins in a fixed 
angle (FA) rotor at 4°C in a refrigerated centrifuge. Make sure that the centrifuge reaches 
speed and is maintained throughout the entire spin. 
• Using a pipette, transfer equal aliquots of plasma into 2 labeled 2 mL cryovials, not 
exceeding ~1 mL per cryovial. Each plasma sample will be split into 2 cryovials, which 
should be clearly designated as part of “Set 1” (primary set) or “Set 2” (back-up set).  
• Samples being submitted to APC will be labeled as follows or labeled using the RAVE 
Specimen Tracking System. Labels generated outside STS should mimic the STS labeling 
format as shown below: 
 
o Patient ID: Protocol # (10246) - Treatment ID # (assigned at enrollment) – UPID 
(assigned in STS) 
o Specimen ID: Protocol # (10246) - UPID plus sequentially generated integer (assigned in 
STS) 
o Code: PK-BELINOSTAT 
o Type: Blood  
o Time Point: pre or post 
o Date/time collected 
o Optional (not included in STS labels): “Set 1” or “Set 2” 
 
• Freeze the plasma samples immediately at approximately ~70°C or below. 
• Store samples frozen at approximately -70°C or lower until shipment. 
 
5.3.3.2.3 Shipping of Belinostat PK Specimen(s) 
 
• Samples should be stored through the duration of the PK study and shipped as a batch by 
patient (more than one patient/shipment is acceptable if the site has more than one patient on 
study).  
• The primary set of samples should be shipped to the APC laboratory within 3 months of first 
sample's collection date (i.e., if baseline sample is collected on 06/01/2019, all of that 
patient's samples should be at the APC laboratory by 09/01/2019). If a second set of patient 
samples can be batch shipped by waiting up to 2 weeks (i.e., 3.5 months), this deviation is 
allowed.  
• All samples should be shipped via overnight express courier in insulated containers with 

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43 
sample type (blood or bone marrow aspirate) must be used for both samples.  
 
5.4.1.2.1.1 Routine Approach – PD-WB/FC supply ordering 
 
Each participating site will procure K2-EDTA tubes. Recommended items/vendors 
include: 
• BD (Becton Dickinson) Catalog No. 02-689-03 (Manufacturer No. BD367835): 
K2EDTA-containing plastic lavender-top tubes 3mL  
• Fisher Scientific Catalog No. 367835: K2EDTA-containing plastic lavender-top 
tubes 3mL  
 
5.4.1.2.2 
Routine Approach – PD-WB/FC Handling of Specimens(s)  
 
Samples will be processed within 2 hours of collection for isolation of leukemic 
mononuclear cells in a uniform manner, using BD Phosflow lyse/fix red cell lysis 
buffer (BD Bioscience), by dedicated research personnel according to manufacturer-
specified protocol. Briefly, samples will be depleted of red blood cells by incubation 
with the buffer. After washing and counting, the cells will be resuspended in 
FBS/10% DMSO solution (5 x 106 cells/mL) in cryovials, frozen using a controlled-
rate freezing apparatus or isopropanol chamber, and stored at -80°C. 
 
Samples being submitted to VCU CTRL will be labeled as follows or labeled using 
the RAVE Specimen Tracking System. Labels generated outside STS should mimic 
the STS labeling format as shown below: 
 
• Patient ID: Protocol # (10246) - Treatment ID # (assigned at enrollment) – UPID 
(assigned in STS) 
• Specimen ID: Protocol # (10246) - UPID plus sequentially generated integer 
(assigned in STS) 
• Code: PD-WB/FC 
• Type: Blood or Bone marrow 
• Time Point: pre or post 
• Date/time collected 
• Additional field for all labels (STS-generated or generated outside STS): Cell 
count or cell concentration in sample 
 
5.4.1.2.3 
Routine Approach – PD WB/FC Shipping of Specimen(s) 
 
The frozen cell suspension may be temporarily stored, and then shipped by overnight 
courier on dry ice to the Clinical and Translational Research Laboratory (CTRL) at 
the VCU Massey Cancer Center for western blot and/or flow cytometry analysis. 
Based on preliminary experiments, we have concluded that shipping frozen cell 
pellets does not adversely affect western blot or flow cytometry results as compared 
to analyzing fresh samples.  
 

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51 
Only DLTs occurring during Cycle 1 will influence decisions regarding dose escalation, 
expansion of a dose level, or evaluation of intermediate dose levels. Patients will be monitored 
through all cycles of therapy for treatment-related toxicities.  
Patients who for any reason are not evaluable for DLT will be replaced. See Section 9.3.1 for 
DLT Evaluable Population. 
Management and dose modifications for AEs are outlined in Section 7. 
6.3 
Dose Escalation 
Dose escalation will proceed within each cohort according to the following scheme.   
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enroll 3 patients at the next dose level. 
≥ 2 
Dose escalation will be stopped. This dose level will be 
declared the maximally administered dose (highest dose 
administered). Three additional patients will be entered 
at the next lowest dose level if only 3 patients were 
treated previously at that dose. 
1 out of 3 
Enroll at least 3 more patients at this dose level. 
If 0 of these 3 patients experience a DLT, proceed to the 
next dose level (unless MTD has already been exceeded 
at that dose level, in which case, the current dose level is 
the MTD). 
If 1 or more of this group experience DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose. Three additional patients 
will be enrolled at the next lowest dose level if only 3 
patients were treated previously at that dose 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is the MTD and is generally the RP2D. At least 6 
patients must be entered at the RP2D. 
 
6.4 
Dose Expansion Cohorts 
 
The RP2D may be equal to, but may not exceed, the MTD. A RP2D below the MTD may be 
considered given the overall tolerability of the treatment including the frequency of AEs that do 
not qualify as DLTs and the frequency of dose modifications. 
 
Once the RP2D is reached, an additional 12 patients will be treated at this dose. For the 
expansion cohort, patients will continue to be monitored for occurrence of DLT. If 2 of the first 5 

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56 
6.7 
Discontinuation of Protocol Therapy 
 
Study treatment may continue until one of the following criteria applies: 
 
• Disease progression. Note: Patients with progressive disease may remain on the study, 
after discussion with principal investigator, if it is judged that they are deriving a clinical 
benefit from doing so. 
• Toxicity requiring that initiation of a new cycle must be delayed >14 days, unless the 
delay is due to reasons other than toxicity and has been approved by the study principal 
investigator. 
• Toxicity requiring permanent discontinuation of one of the study drugs. 
• Intercurrent illness that prevents further administration of treatment. 
• Unacceptable AEs. 
• Achievement of complete remission followed by the administration of 3-4 additional 
cycles of study treatment as “consolidation”. 
• Stem cell transplantation. 
• Pregnancy 
o All women of child bearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• Patient decides to withdraw from study treatment. 
• Determination by the investigator that discontinuation is in the patient’s best medical 
interest. 
• Termination of the study by sponsor. 
• The drug manufacturer can no longer provide the study agent. 
• Patient non-compliance that, in the opinion of the investigator, warrants study treatment 
discontinuation. 
• Patient meets criteria for permanent discontinuation of either study agent. 
• Subsequent anti-cancer therapy. 
 
Discontinuation of study treatment does not constitute removal from study. Patients who stop 
study treatment prematurely transition directly into follow-up per Section 6.6. A patient may be 
removed from study follow-up and be taken off study for any of the following reasons: 
 
• If in the opinion of the treating physician or principal investigator, it is in the best interest 
of the patient to do so. 
• Patient’s decision to discontinue from study follow-up. 
• Study sponsor’s decision to discontinue the study. 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 

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59 
o MLN4924 (pevonedistat) should be modified only for AEs thought to be related to 
MLN4924 (pevonedistat) 
o If the AE could be related to both drugs or if the relationship of the AE is unclear, 
both study drugs should be modified. 
• If a patient experiences several AEs and there are conflicting recommendations for dose 
modification, the investigator should observe the more cautious modification 
recommendation. Treatment Delays and Omissions: 
o At the beginning of a cycle:  
 All treatment-related toxicities must be resolved to ≤ grade 1 for initiation 
of a new cycle (see Section 7.3).  
 Initiation of a new cycle occurs when both agents meet criteria to be 
given.  
 Delay in initiation of a new cycle by > 14 days requires discontinuation of 
study therapy. 
o Within a cycle:  
 On days when only belinostat is due, if treatment criteria aren’t met 
due to toxicity, then the belinostat dose scheduled on that date will be 
omitted and not made up on a later date. When belinostat is omitted, 
patients should be assessed to determine if dosing may resume on the next 
scheduled dosing day. 
 On days when both study agents are due, if treatment criteria aren’t 
met due to toxicity, for either agent, then both agents will be delayed. 
Dosing days will shift accordingly, allowing delayed treatment to resume 
on a later date in the cycle - with the exception that no dosing may occur 
after Day 12 of any cycle. Doses not delivered on or before Day 12 will be 
omitted for that cycle. When treatment is delayed, patients should be 
evaluated regularly to determine if dosing may resume, with a goal of 
delivering as much of the regimen as possible on or before Day 12.  
• Permanent discontinuation of either study agent requires discontinuation of study 
treatment. 
• Treatment delay of >14 days requires discontinuation of study treatment. 
 
 

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67 
7.3 
Initiation of a New Cycle 
 
See section 7.2 Dose Modifications. Treatment with study drugs will be repeated every 21 days. 
Initiation of a new cycle requires that all toxicity considered related to treatment with study 
drugs must have resolved to grade <1, to the patient’s baseline values, or to a level considered 
acceptable by the treating physician after discussion with the principal investigator.  
If criteria for treatment are not met, initiation of the next cycle of treatment may be delayed for 
up to 2 weeks. If treatment criteria are not met after a 14-day delay, study treatment will be 
discontinued.  
 
In certain circumstances and with agreement from the principal investigator, after Cycle 1, 
consideration may be given to allowing an additional rest week in subsequent cycles thus 
lengthening the cycle to 4 weeks to support the patient’s need for time off between cycles, e.g., 
during holidays. 
 
7.4 
Resumption of Treatment Within a Cycle 
 
See section 7.2 Dose Modifications. MLN4924 (pevonedistat) doses must be separated by at 
least one full calendar day. In each cycle, a maximum of 3 doses of MLN4924 (pevonedistat) 
and 5 doses of belinostat should not be exceeded. 
 
7.5 
Dose Re-escalation 
 
If a dose reduction is incurred for a ≤ grade 3 toxicity; and that toxicity is resolved ; and that 
toxicity has not recurred at the reduced dose; then, with approval of the principal investigator (or 
designee), the dose may be re-escalated (to no higher than the enrollment dose) in the next cycle. 
 
7.6 
Dose Modifications Requiring Discontinuation of Protocol Therapy 
 
See section 6.7. 
 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the AEs and potential risks associated with the investigational or commercial agents 
administered in this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 MLN4924 (Pevonedistat-HCL) (NSC # 793435) 
 
Chemical Name: ((1S,2S,4R)-4-{(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d] 
pyrimidin-7-yl}-2-hydroxycyclopentyl) methyl sulfamate hydrochloride 
 
Classification: NEDD8-activating enzyme (NAE) inhibitor 
 
Other Names: TAK924/MLN4924; MLN4924-003 (hydrochloride salt); MLN4924-001 (free base); 

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68 
ML00644807; ML644507 
 
CAS Registry Number: 905579-51-3 (free base); 1160295-21-5 (hydrochloride salt) 
 
Molecular Formula: C21H26CIN5O4S 
 
M.W.: 443.52 (free base); 479.98 (hydrochloride salt) 
 
Mode of Action: MLN4924 (pevonedistat) is an inhibitor of neural precursor cell expressed 
development down-regulated 8 (NEDD8)-activating enzyme or NAE. NAE is essential in the 
NEDD8-conjugation pathway to control the activity of a subset of multiprotein complexes that 
transfer NEDD8 molecules to protein substrates by E3 ligases. NAE inhibitors stop the degradations 
of a subset of proteins that regulated by the proteasomes.  
 
Description: White to off-white solid with an assay value of 96.0% to 103.0% (w/w) on an 
anhydrous basis. Acid dissociation constants of pKa1= 5.16 and = 8.81. 
 
How Supplied: Takeda supplies and PMB distributes MLN4924 (Pevonedistat HCl) formulated 
as 10 mg/mL Concentrate for Solution for Infusion. Each single-use vial contains either 50 mg (5 
mL) or 44 mg (4.4 mL) free base equivalent containing the following excipients: citric acid 
(anhydrous), trisodium citrate dihydrate, and Betadex Sulfobutyl Ether Sodium (Captisol®) at 
pH 3.3. The sterile solution is packaged in USP Type I glass vials with rubber stoppers (latex 
free), aluminum seals with plastic caps.  
 
The current supply is 50 mg (5 mL) with 0.3 mL overfill volume. At a future date, the 44 mg (4.4 
mL) vial configuration will replace the 50 mg (5 mL) vial configuration. The 44 mg (4.4 mL) 
vial contains 0.3 mL overfill volume.  
Preparation: Before use, bring MLN4924 (Pevonedistat HCl) vials to ambient room temperature 
(15°-30°C/59°-86°F) for 15 minutes. Do not use a water bath to warm up the vials. Return vials 
to 2°-8°C (36°-46°F) storage if not used within 6 hours.  
• Use a 250 mL prefilled 5% Dextrose (D5W) or 0.9% Normal Saline (NS) IV bag:  
o Remove excess volume from 250 mL D5W or NS prefilled IV bag  
o Add the calculated dose (mL) of pevonedistat  
o Final volume (250 mL) = drug + D5W or NS  
o Do not shake; gently mix the IV solution by inverting the IV bag several times  
o Inspect the IV solution to ensure it is clear and free of visible particles  
• Alternatively, a 250 mL empty IV bag can be used:  
o Add the required volume of D5W or NS into the empty IV bag  
o Add the calculated dose (mL) of pevonedistat o Final volume (250 mL) = Drug + D5W 
or NS 
o Do not shake; gently mix the IV solution by inverting the IV bag several times  
o Inspect the IV solution to ensure it is clear and free of visible particles 
Materials: PVC or Polyolefin bags; non-DEHP IV bag is preferred but not required     
Storage: Store MLN4924 (Pevonedistat HCl) refrigerated at 2°-8°C (36°-46°F) in its original 

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69 
carton to protect from light. 
If a storage temperature excursion is identified, promptly return MLN4924 (Pevonedistat HCl) to 
2°-8°C (36°-46°F) and quarantine the supplies. Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
 determination of suitability.  
Stability: Stability studies are ongoing. 
 
 
o Once MLN4924 (Pevonedistat) prepared IV solution is complete, the prepared IV 
solution must be used within 6 hours when stored at ambient room temperature. 
Discard the IV bag if it cannot be used within 6 hours.  
o Alternatively, the prepared IV solution is stable up to 18 hours when stored at 20-80C 
(360-460F), after which the IV bag can be used within 3 hours upon removal from          
20-80C storage. The prepared IV solution must be brought up to ambient room 
temperature before administering to patient. If cannot used within 3 hours, the 
prepared IV solution must be discarded. 
 
Route of Administration: Intravenous  
 
Method of Administration: Infuse over 60 minutes (+/- 10 minutes) through peripheral IV-line, 
midline or central venous access. The IV infusion can be slowed or stopped and restarted for any 
associated infusion-related reactions. The total time from the IV preparation to end of IV infusion 
must not exceed 6 hours. Infusion line can be flushed with 5% Dextrose in Water or 0.9% Normal 
Saline immediately after IV administration is complete. Protecting IV bag from light during IV 
infusion is not required. 
 
Potential Drug Interactions: In vitro, pevonedistat is metabolized mainly by hepatic CYP3A4/5 
and to some extent by CYP2D6 (3%). CYP1A1 and 2J2 appear to be involved in extrahepatic 
metabolism, which may explain the lack of drug-drug interaction with CY3A4/5 inhibitors. This 
was demonstrated in an in vivo PK study where a moderate CYP3A inhibitor (e.g., fluconazole) and 
a strong CYP3A4 inhibitor (e.g., itraconazole, which is also a strong P-gp inhibitor) did not result in 
interactions when administered with pevonedistat. Therefore, drugs that are CYP3A/P-gp inhibitors 
can be used in patients receiving MLN4924 (pevonedistat).  
 
In vitro, pevonedistat is not an inhibitor of CYP1A2, 2C9, 2C19, 2D6, or 3A4/5 (IC50 > 100 µM 
and Ki >50 μM) but is a weak inhibitor of CYP2B6 and 2C8 (IC50 = 97.6 and 23.1 μM, 
respectively). Pevonedistat causes concentration-dependent decreases in CYP1A2, 2B6, and 3A4/5 
mRNA expression and/or activities, but is not expected to affect the PK of CYP1A2, 2B6 or 3A4/5 
substrates.  
 
Pevonedistat is a substrate of P-gp and BCRP, and a weak inhibitor of P-gp, OATP and BCRP-
mediated transport. Pevonedistat is unlikely to affect the PK of known P-gp, BCRP or OATP 
substrates.  
 
Because the metabolic and excretion pathways of pevonedistat remain to be fully characterized in 

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70 
humans, the risk of drug-drug interactions between pevonedistat and concomitantly administered 
drugs are currently informed by available nonclinical and clinical data. As a general precaution, 
patients receiving concomitant medications, particularly those with narrow therapeutic indices, 
should be carefully monitored. 
 
8.1.2 
Belinostat (NSC # 726630) 
 
Chemical Name: (E)-N-hydroxy-3-(3-(N-phenylsulfamoyl)phenyl)acrylamide 
Other Names: PXD101; Beleodaq® 
Classification: HDAC inhibitor 
CAS Registry Number: 414864-00-9; 866323-14-0 
Molecular Formula: C15H14N2O4S 
 
M.W.: 318.35 
Approximate Solubility: Water 0.14 mg/mL; ethanol >200 mg/mL;  
polyethylene glycol 400 ~ 1.5 mg/mL; 1,2-propanediol ~ 0.2 mg/mL 
Mode of Action: Histone deacetylases (HDACs) are a family of enzymes that regulate 
chromatin remodeling and gene transcription via the dynamic process of acetylation and 
deacetylation of core histones. Belinostat is a novel and potent HDAC inhibitor of the 
hydroxamate class. It alters acetylation levels of histone and non-histone proteins, thus 
influencing chromatin accessibility and ultimately gene transcription.  
How Supplied: Spectrum Pharmaceuticals supplies and the PMB, CTEP, DCTD distributes 
belinostat in single-use 30 mL clear glass vials with coated stoppers and aluminum crimp seals 
with “flip-off” caps containing 500 mg belinostat for injection. The sterile yellow lyophilized 
product also contains 1000 mg arginine, European Pharmacopoeia/ US Pharmacopoeia (Ph. 
Eur/USP).  
Preparation: Reconstitute the lyophilized product with 9 mL sterile water for injection to yield a 
final belinostat concentration of 50 mg/mL. Before IV administration, further dilute in 250 mL 
0.9 % sodium chloride injection. 
Storage: Store intact vials of belinostat at controlled room temperature (20-25°C; 68-77°F); 
brief excursions permitted (15-30°C; 59-86°F). Leave intact vials of belinostat in the secondary 
packaging until use. 
If a storage temperature excursion is identified, promptly return belinostat to controlled room 
temperature and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
for determination of suitability.  
Stability: Shelf life stability studies of intact vials of belinostat are on-going; once the 
lyophilized product is reconstituted, the vialed solution is stable for up to 12 hours at ambient 
temperature (15-25°C).  
Once further diluted in 250 mL of 0.9% sodium chloride, belinostat may be stored at ambient 
temperature (15-25°C) for up to 36 hours, including the infusion time. 
Route and Method of Administration: Infuse belinostat IV over 30 minutes through a 0.22 

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71 
micron in-line filter. 
Potential Drug Interactions: Belinostat is primarily metabolized by hepatic UGT1A1, and to a 
lesser extent by CYP2A6, CYP2C9 and CYP3A4 enzymes. Avoid concomitant use of strong 
inhibitors of UGT1A1. Use caution when co-administering agents which may compete for 
UGT1A1 metabolism, such as irinotecan. Patients with known UGT1A1 genetic polymorphisms, 
such as UGT1A1*28, can have reduced UGTA1A activity and may be at risk for increased 
belinostat exposure. If subjects with UGT1A1 genetic polymorphisms are not excluded from 
study participation, reduced doses are warranted. 
In vitro studies have shown belinostat and its metabolites are weak to moderate inhibitors of 
CYP2C8 and moderate to strong inhibitors of CYP2C9; however, studies did not demonstrate 
effects when co-administered with warfarin. Avoid CYP2C8 and CYP2C9 substrates during 
belinostat treatment unless deemed medically necessary. 
Belinostat is likely a P-gp substrate but is unlikely to inhibit P-gp. 
Avoid concomitant medications that may cause Torsade de Pointes. 
Availability: Belinostat is an investigational agent supplied to investigators by the DCTD, NCI. 
Belinostat is provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 13). 
 
8.1.3 
Agent Ordering and Agent Accountability 
 
8.1.3.1 
NCI-supplied agents  
NCI-supplied agents may be requested by eligible participating investigators (or their authorized 
designee) at each participating institution. The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents. The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF). If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution. 
 
Confirmation of patient enrollment onto study is required for initial supply. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. 
Access to OAOP requires the establishment of a CTEP IAM account and the maintenance of an 
“active” account status, a “current” password, and active person registration status. For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time. Refer to the 
PMB’s website for specific policies and guidelines related to agent management.  
 

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79 
included in the e-mail. 
 
Adverse events reported on MLN4924 (Pevonedistat HCl) trials, but for which there 
is insufficient evidence to suggest that there was a reasonable possibility that 
MLN4924 (Pevonedistat HCl) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (pancytopenia); Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; 
Myocarditis 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Ascites; Dyspepsia; Gastrointestinal disorders - Other 
(gastrointestinal necrosis); Gastrointestinal disorders - Other (gastrointestinal hemorrhage); Ileus; 
Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Generalized 
edema; Multi-organ failure; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure 
INFECTIONS AND INFESTATIONS - Bacteremia; Sepsis; Sinusitis; Skin infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall 
INVESTIGATIONS - Investigations - Other (brain natriuretic peptide increased); Neutrophil 
count decreased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperkalemia; Hyperuricemia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Leukemia secondary to oncology chemotherapy; Treatment related secondary 
malignancy 
NERVOUS SYSTEM DISORDERS - Intracranial hemorrhage; Spinal cord compression 
PSYCHIATRIC DISORDERS - Psychiatric disorders - Other (mental status changes) 
RENAL AND URINARY DISORDERS - Dysuria; Renal and urinary disorders - Other (renal 
impairment); Urinary retention 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Nasal congestion; Oropharyngeal pain; Respiratory failure; Rhinorrhea 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Rash maculo-papular 
VASCULAR DISORDERS - Hypertension; Phlebitis; Thromboembolic event 
 
 
Note: MLN4924 (Pevonedistat HCl) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 
 
 
 

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82 
Hypermagnesemia; Hypertriglyceridemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; 
Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back 
pain; Bone pain; Chest wall pain; Generalized muscle weakness; Muscle cramp; Myalgia; Pain 
in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Depressed level of consciousness; Dysesthesia; 
Encephalopathy; Lethargy; Nervous system disorders - Other (apraxia); Nervous system 
disorders - Other (burning sensation); Peripheral sensory neuropathy; Reversible posterior 
leukoencephalopathy syndrome; Seizure; Stroke; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Depression; Insomnia; Psychosis 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - 
Other (azotemia); Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital edema; Vaginal 
inflammation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Hiccups; 
Hypoxia; Nasal congestion; Pneumonitis; Pulmonary hypertension 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Pruritus; Urticaria 
VASCULAR DISORDERS - Hematoma; Hypertension; Hypotension; Phlebitis; 
Thromboembolic event; Vasculitis 
 
Note: Belinostat (PXD-101) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
10.2 Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP website 
 
 
• For expedited reporting purposes only:  
 
o Aes for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
o Other Aes for the protocol that do not require expedited reporting are outlined in 
Section 10.3.4. 
 
• Attribution of the AE: 
o Definite – The AE is clearly related to the study treatment. 
o Probable – The AE is likely related to the study treatment. 

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83 
o Possible – The AE may be related to the study treatment 
o Unlikely – The AE is doubtfully related to the study treatment. 
o Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 Expedited Adverse Event Reporting 
 
10.3.1 Rave-CTEP-AERS Integration 
 
The Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of post-baseline AEs entered in Rave to determine 
whether they require expedited reporting, and facilitates entry in CTEP-AERS for those 
AEs requiring expedited reporting.   
 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period, and used to 
collect AEs that start during the period or persist from the previous reporting period.  The 
Clinical Research Associate (CRA) will enter AEs that occur prior to the start of 
treatment on a baseline form that is not included in the Rave-CTEP-AERS integration.  
AEs that occur prior to enrollment must begin and end on the baseline Adverse Event 
form and should not be included on the standard Adverse Events form that is available at 
treatment unless there has been an increase in grade. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query-free (fields 
added to the form during study build do not need to be query-free for the integration 
call with CTEP-AERS to be a success). 
 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form.  Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting.  A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements.  The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the deep link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU 

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87 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS. Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., AML)  
• MDS  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
10.7 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
11. STUDY CALENDAR 
 
Unless stated otherwise, baseline evaluations are to be conducted within 1 week prior to start of 
protocol therapy. Bone marrow evaluations for disease assessment must be done ≤ 3 weeks prior 
to start of therapy. Scans and X-rays must be done <2 weeks prior to the start of therapy. 
Hepatitis serologies and left ventricular ejection fraction assessment should be done <4 weeks 
prior to the start of therapy. In the event that the patient’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hrs prior to initiation of the next cycle of therapy. 
 

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88 
Study Calendar 
 
 
Baselinea,b,t 
Cycle 1 
Subsequent Cycles 
End of 
Treatmentc 
End of 30-Day 
Safety Follow-
upd 
Extended 
Follow-
upd,e 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
8 
Day 
15 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
8 
Day 
15 
MLN4924 (pevonedistat) 
 
A 
 
A 
 
A 
 
 
A 
 
A 
 
A 
 
 
 
 
 
Belinostat 
 
B 
B 
B 
B 
B 
 
 
B 
B 
B 
B 
B 
 
 
 
 
 
Performance status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LVEF assessment by 
echocardiogram or radionuclide 
angiography  
Xr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and physical exam and 
weight.  
X 
Xa 
 
 
 
 
 
 
Xa 
 
 
 
 
 
 
X 
 
 
Urinalysis f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (T, P, R, BP, pulse 
oximetry) 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent medicationsg 
X 
Xa 
 
 
 
 
 
 
Xa 
 
 
 
 
 
 
X 
 
 
Baseline symptoms and 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE assessment 
 
X---------------------------------------------------------------------------------------------------------X 
X 
X 
 
CBC, differential, platelet count 
X 
X 
 
X 
 
X 
X 
X 
Xa 
 
 
 
 
 
 
X 
 
 
Basic metabolic panelh, eGFR 
X 
X 
X 
X 
 
X 
X 
X 
Xa 
 
Xa 
 
Xa 
 
 
X 
 
 
Uric acid, Mg2+ 
X 
X 
X 
X 
 
 
X 
X 
Xa 
 
 
 
 
 
 
X 
 
 
PT/INR, PTT 
X 
X 
 
 
 
 
X 
X 
Xa 
 
 
 
 
 
 
 
 
 
Hepatic paneli,j 
X 
X 
 
X 
 
X 
X 
X 
Xa 
 
Xa 
 
Xa 
 
 
X 
 
 
LDH, PO4 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 CD4; HIV viral loadu  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serologies (Hep B 
SAg, Hep B S Ab, Hep B c 
Ab;Hep B viral load)k, v 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Baselinea,b,t 
Cycle 1 
Subsequent Cycles 
End of 
Treatmentc 
End of 30-Day 
Safety Follow-
upd 
Extended 
Follow-
upd,e 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
8 
Day 
15 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
8 
Day 
15 
n. Baseline/pre-treatment bone marrow procedure may be done within 3 weeks prior to start of therapy. For patients with AML, baseline assessments should 
also include NPM1, FLT3, and CEBPA. If these markers cannot be assessed at study baseline, markers from bone marrow assessment done at any time 
point prior to study baseline may be reported.  
o. For PK samples time points, see Section 5.3.3. Note: when feasible, Cycle 1, Day 1 treatment should be started in the morning to allow for the timing of PK 
collections. If unforeseen delays occur sample collections may be missed  
p. For pharmacodynamic samples, see Sections 5.3 and 5.4 
q. For PG samples: see Section 5.4 
r. 
LVEF assessment should be done <4 weeks prior to the start of therapy. 
s. 
Scans or x-ray for disease assessment should be done ≤ 2 weeks prior to start of therapy. 
t. 
Unless stated otherwise, baseline evaluations are to be done within 1 week prior to start of therapy. 
u. HIV testing not required for eligibility. Persons with known HIV-positivity must have CD4 and HIV viral load testing <4 weeks prior to the start of therapy.  
v. Hepatitis C testing not required for eligibility. Persons with history of Hepatitis C virus infection must have HCV viral load testing. testing <4 weeks prior 
to the start of therapy.  
 

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12. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of these drugs has not yet been established, the intent of offering 
this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability. Patients 
with measurable disease will be assessed by standard criteria. For the purposes of this study, 
patients should be re-evaluated at the end of every even cycle. Additional bone marrow 
procedures may also be obtained as clinically indicated following initial documentation of a CR.  
 
12.1 Hematologic Tumors 
 
Treatment responses will be classified according to the IWG revised criteria for response 
assessment in AML (Cheson et al., 2003); the ELN recommendations for diagnosis and 
management of AML (Dohner et al., 2010); and the IWG application and proposal for 
modification of response criteria in MDS (Cheson et al., 2006). 
 
Bone marrow blast percentages will be defined by manual differential count on the aspirate. 
 
Morphologic complete remission (CR): <5% bone marrow blasts and no blasts with Auer rods 
with no requirement for bone marrow cellularity, as long as absolute neutrophil count (ANC) 
≥1000/mcL AND platelets ≥100,000/mcL, patient is transfusion-independent, and has no 
residual evidence of extramedullary leukemia. Persistent dysplasia is allowed. 
 
Morphologic complete remission with incomplete blood count recovery (CRi): All criteria 
for morphologic CR must be met, except that the patient has residual neutropenia (ANC 
<1000/mcL) or thrombocytopenia (platelets <100,000/mcL). 
 
Morphologic leukemia-free state (MLPS): <5% bone marrow blasts, no blasts with Auer rods, 
and no persistent extramedullary leukemia, peripheral blood count recovery not required. 
 
Cytogenetic complete remission (CRc): There should be no evidence of a previously present 
cytogenetic abnormality (e.g., t(8;21), inv 16, t(9;22), etc.) by conventional karyotyping or 
Fluorescent in situ hybridization (FISH) (must be specified). 
 
Molecular complete remission (CRm): There should be no evidence of a previously present 
molecular abnormality (e.g., BCR-ABL, mutated FLT3, NPM1, or CEBPA, etc.). The sensitivity 
of the PCR assay must be specified. 
 
Partial remission (PR): All peripheral blood criteria for CR must be met, with a decrease of at 
least 50% in the percentage of blasts to 5% to 24% in the bone marrow aspirate. A value of <5% 
bone marrow blasts will be considered a PR if Auer rods are present.  
 
Stable disease (SD): Patients not meeting criteria for CR, CRi, ML-FS, CRc, CRm, PR, relapse, 
or progressive disease. 
 
Morphologic relapse: Relapse after CR is defined as reappearance of leukemic blasts in the 

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peripheral blood or ≥5% blasts in the bone marrow not attributable to any other cause (e.g., bone 
marrow regeneration). Relapse from PR is defined as ≥25% bone marrow blasts not attributable 
to bone marrow regeneration or use of colony stimulating factors. The appearance of new 
dysplastic changes should also be considered relapse. 
 
Progressive Disease: Any of the following in patients who have not previously met CR, CRi, 
CRc, CRm, ML-FS, or PR criteria while on study therapy: 
 
• ≥50% increase in the bone marrow blasts (by aspirate differential count) over the best 
previous assessment (comparing to a minimum bone marrow blast percentage threshold 
of 20% at baseline or during study at such time as that threshold is met). 
• ≥50% increase in peripheral blood absolute blast count over the best previous assessment 
(comparing to a minimum peripheral blood absolute blast count threshold of ≥1000/mcL 
at baseline or during study at such time as that threshold is met). In some cases, the 
peripheral blood absolute blast count may not accurately reflect disease burden, 
especially with targeted therapies. At investigator discretion, the patient can continue on 
study with close monitoring of peripheral blood absolute blast count and bone marrow 
biopsies to assess bone marrow blast percentage (by aspirate differential count) as 
clinically indicated. 
• Development of new extramedullary disease. 
 
Appearance of new dysplastic changes should be closely monitored for emerging relapse. In a 
patient who has been recently treated, dysplasia or a transient increase in blasts may reflect a 
chemotherapy effect and recovery of hematopoiesis. Cytogenetics should be tested to distinguish 
true relapse from therapy-related MDS/AML. 
 
Duration of remission is defined only for patients who achieve CR, CRi, CRc, or CRm and is 
measured by the interval from the date of CR (by blood count recovery and BM examination), 
until the date of relapse. 
 
Cytogenetic responses: For patients with AML or MDS, a complete cytogenetic response 
requires the disappearance of a previously present cytogenetic abnormality (without appearance 
of new ones), while a partial cytogenetic response requires a ≥50% reduction in the number of 
metaphases positive for the chromosomal abnormality by conventional karyotyping. 
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
AE lists, guidelines, and instructions for AE reporting can be found in Section 10 (Adverse 
Events: List and Reporting Requirements). 
 
13.1 Study Oversight 
 
This protocol is monitored at several levels, as described in this section. The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 

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93 
SAEs; reporting of expedited AEs; and accumulation of reported adverse events from other trials 
testing the same drug(s). The Protocol Principal Investigator and statistician have access to the 
data at all times through the CTMS web-based reporting portal.  
 
For the phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS. In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, 
or more frequently, conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and adverse events and unanticipated problems.  
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study. This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.   
Requirements to access Rave via iMedidata: 
 
• 
A valid account, and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of:  Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.   
Rave role requirements: 
 
o Rave CRA or Rave CRA (Lab Admin) role, must have a minimum of an 
Associate Plus (AP) registration type, 
o Rave Investigator role, must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR), and 
o Rave Read Only role, site staff must have at a minimum an Associates (A) 
registration type. 
• 
 for registration types 
and documentation required. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata.  To accept the invitation, site staff must log in to the Select Login 
g their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page.  Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed.  Trainings will be in the form of electronic learnings (eLearnings), and can be 

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The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
 

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Steele, N.L., J.A Plumb., L. Vidal, et al. (2008). A Phase 1 Pharmacokinetic and 
Pharmacodynamic Study of the Histone Deacetylase Inhibitor Belinostat in Patients with 
Advanced Solid Tumors. Clin Cancer Res. 14(3):804-810. 
 
Steele, N.L., J.A. Plumb., L. Vidal, et al. (2011). Pharmacokinetic and Pharmacodynamic 
Properties of an Oral Formulation of the Histone Deacetylase Inhibitor Belinostat (PXD101). 
Cancer Chemother Pharmacol. 67(6):1273-1279.  
 
Stevens, F.E., H. Beamish., R. Warrener, et al. (2008). Histone Deacetylase Inhibitors Induce 
Mitotic Slippage. Oncogene. 27(10):1345-1354.  
 
Subramanian, C., A.W. Jr. Opipari., X. Bian, et al. Ku70 Acetylation Mediates Neuroblastoma 
Cell Death Induced by Histone Deacetylase Inhibitors. Proc Natl Acad Sci U S A. 102(13):4842-
4847. 
 
Swords, R.T., K.R. Kelly., P.G. Smith, et al. (2010a). Inhibition of NEDD8-Activating Enzyme: 
A Novel Approach for the Treatment of Acute Myeloid Leukemia. Blood. 115(18):3796-3800.  
 
Swords, R.T., H.P. Erba., D.J DeAngelo, et al. (2010b). The Novel, Investigational NEDD8-
Activating Enzyme Inhibitor MLN4924 in Adult Patients with Acute Myeloid Leukemia (AML) 
or High-Grade Myelodysplastic Syndromes (MDS): A Phase 1 Study. Abstract 658, American 
Society of Hematology 2010 Annual Meeting. Blood. 116 (21):658. 
 
Swords, R.T., H.P. Erba., D.J. DeAngelo, et al. (2015). Pevonedistat (MLN4924), a First-in-
Class NEDD8-Activating Enzyme Inhibitor, in Patients with Acute Myeloid Leukaemia and 
Myelodysplastic Syndromes: A Phase 1 Study. Br J Haematol. 169(4):534-543.  
 
Swords, R.T., S. Coutre., M.B. Maris, et al. (2016). Results of a Clinical Study of Pevonedistat 

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(Pev), a First-in-Class NEDD8-Activating Enzyme (NAE) Inhibitor, Combined with Azacitidine 
(Aza) in Older Patients (Pts) with Acute Myeloid Leukemia (AML). Blood. 128(22):98-98.  
 
Taplitz, R. A., E. B. Kennedy., E. J. Bow, et al. (2018). Antimicrobial Prophylaxis for Adult 
Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline 
Update Summary. J Oncol Prac. 14:692-695. 
 
Thomas, A., A. Rajan., S. Khozin, et al. (2012). A Phase (Ph) I/II Study of Belinostat (Bel) in 
Combination with Cisplatin, Doxorubicin, and Cyclophosphamide (Pac) in the First-Line 
Treatment of Advanced or Recurrent Thymic Malignancies. J Clin Oncol. 30(15).  
 
Ungerstedt, J.S., Y. Sowa., W.S. Xu, et al. (2005). Role of Thioredoxin in the Response of 
Normal and Transformed Cells to Histone Deacetylase Inhibitors. Proc Natl Acad Sci U S A. 
102(3):673-678. 
 
Velcade (Bortezomib) for Injection Package Insert. Cambridge, MA: Millennium 
Pharmaceuticals, Inc; 2015. 
 
Wang, L.Z., J. Ramirez., W. Yeo, et al. (2013). Glucuronidation by UGT1A1 Is the Dominant 
Pathway of the Metabolic Disposition of Belinostat in Liver Cancer Patients. PLoS One. 
8(1):e54522.  
 
Warrener, R., H. Beamish., A. Burgess, et al. (2003). Tumor Cell-Selective Cytotoxicity by 
Targeting Cell Cycle Checkpoints. FASEB J. 17(11):1550-1552.  
 
Xu, Y., W. Fang., W. Zeng, et al. (2008). Evaluation of Dried Blood Spot (Dbs) Technology 
Versus Plasma Analysis for the Determination of Mk-1775 by Hilic-Ms/Ms in Support of 
Clinical Studies. Anal Bioanal Chem. 404(10):3037-3048.  
 
Yeo, W., H.C. Chung., S.L. Chan, et al. (2012). Epigenetic Therapy Using Belinostat for Patients 
with Unresectable Hepatocellular Carcinoma: A Multicenter Phase I/II Study with Biomarker 
and Pharmacokinetic Analysis of Tumors from Patients in the Mayo Phase II Consortium and the 
Cancer Therapeutics Research Group. J Clin Oncol. 30(27):3361-3367. 
 
Zain, J.M., F. Foss., W.K. Kelly, et al. (2009). Final Results of a Phase I Study of Oral Belinostat 
(PXD101) in Patients with Lymphoma. J Clin Oncol. 27(15s): Abstract 8580.  
 
Zhou, L., S. Chen., Y. Zhang, et al. (2016). The NAE Inhibitor Pevonedistat Interacts with the 
HDAC Inhibitor Belinostat to Target AML Cells by Disrupting the DDR. Blood. 127(18):2219-
2230. 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
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 hrs. 
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 hrs. 
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 C: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, MLN4924 (Pevonedistat). This clinical trial is sponsored by the 
National Cancer Institute. This form is addressed to the patient but includes important 
information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
MLN4924 interacts with certain specific enzyme in your liver, and certain transport proteins that 
help move drugs in and out of cells. 
 
• The enzymes in question are CYP3A4/5. MLN4924 is broken down by CYP3A4/5 and 
may be affected by drugs that are moderate or strong inducers of CYP3A4/5.  
• The transporter enzymes and proteins in question are P-glycoprotein (P-gp). OATP and 
BCRP. MLN4924 is moved in and out of cells/organs by P-gp, and BCRP. Use caution 
with concomitant drugs that are inhibitors of P-gp . MLN4924 may affect the ability of 
other drugs to be moved in and out of cells by inhibiting P-gp, OATP and BCRP. Use 
substrates of these transport proteins with caution.  
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.  
 
MLN4924 may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial. It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study. When you talk 
about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort. It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions. You must tell all your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical 
trial.  
 
These are the things that you and they need to know:  
 
MLN4924 must be used very carefully with other medicines that use certain liver enzymes or 
transport proteins to be effective or to be cleared from your system. Before you enroll onto the 
clinical trial, your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered moderate or strong inhibitors or inducers 
of CYP3A4/5, P-gp, OATP and BCRP. 
 

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109 
• Please be very careful! Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug. Speak to your doctors or pharmacist 
to determine if there could be any side effects.  
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine. Your study doctor’s name is  
_____________________________________ and he or she can be contacted at  
 
_____________________________________.  
 
 
  
 
 
(08/18) 
 

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110 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
MLN4924.  This clinical trial is sponsored by the NCI.  MLN4924 may 
interact with drugs that are processed by your liver, or use certain 
transport proteins in your body.  Because of this, it is very important to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all your health care providers (doctors, physician assistants, nurse 
practitioners, or pharmacists) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement (e.g., St. John’s Wort) 
MLN4924 interacts with a specific liver enzyme called CYP3A4/5 and 
transport proteins called P-gp, OATP and BCRP and must be used very 
carefully with other medicines that interact with these enzymes and 
transport proteins. 
 
 
 
 
 
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong 
inhibitors/inducers of CYP3A4/5, P-gp, and OATP  
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for 
a list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

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APPENDIX E: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, Belinostat. This clinical trial is sponsored by the National Cancer 
Institute. This form is addressed to the patient but includes important information for others who 
care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
• Belinostat has potential drug interactions of concern 
o Drugs that may cause Torsade de Pointes should be avoided. 
o Belinostat is broken down in the liver mostly by UTG1A1, and, to a lesser extent, 
by CYP2A6, CYP2C9 and CYP3A4 enzymes.  
 Strong inhibitors of UGT1A1 should be avoided.  
 Drugs that compete for UGT1A1 for metabolism, such as irinotecan, 
should be used with caution.  
 Patients with known UGT1A1 genetic polymorphisms, such as 
UGT1A1*28, can have reduced UGT1A1 activity, placing them at risk for 
belinostat overexposure.  
 CYP2C8 and CYP2C9 substrates should be avoided during treatment with 
belinostat unless deemed medically necessary.  
o Belinostat is likely a substrate of the transporter enzymes and proteins P-
glycoprotein (P-gp) but is unlikely to inhibit P-gp. There are no specific 
interactions of concern based on P-gp. 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.  
 
Belinostat may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial. It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study. When you talk 
about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort. It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions. You must tell all your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical 
trial.  
 
These are the things that you and they need to know:  
 
Drugs known to cause Torsade de Pointes should be avoided. 

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112 
Belinostat must be used very carefully with other medicines that use certain liver enzymes to be 
effective or to be cleared from your system. Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care providers to review any medicines and herbal 
supplements that are considered strong inhibitors of UGT1A1 or substrates of CYP2C8 and 
CYP2C9.   
 
 
• Please be very careful! Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug. Speak to your doctors or pharmacist 
to determine if there could be any side effects.  
 
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  
 
Your study doctor’s name is _____________________________________ and he or she can 
be contacted at _____________________________________.   
 
   
 
 
 

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113 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
Belinostat.  This clinical trial is sponsored by the NCI.  Belinostat may 
interact with drugs that are processed by your liver or that can cause a 
condition of the heart known as Torsade de Pointes.  Because of this, it is 
very important to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all your health care providers (doctors, physician assistants, nurse 
practitioners, or pharmacists) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement (e.g., St. John’s Wort) 
Belinostat interacts with liver enzyme called UGT1A1, CYP2C8 and 
CYP2C9 and must be used very carefully with other medicines that 
interact with these enzymes and transport proteins. 
 
Belinostat should not be used at the same time with drugs that can cause 
Torsade de Pointes. 
 
 
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered  
o 
strong inhibitors of UTG1A1 or  
o 
substrates of CYP2C8 or CYP2C9 or 
o 
drugs that can cause Torsade de Pointes 
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for 
a list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _______________________________.