The PRIME Trial: PARP Inhibition in IDH Mutant Effectiveness Trial. A Phase II Study of Olaparib in Isocitrate Dehydrogenase (IDH) Mutant Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome
Phase: PHASE2
Conditions: Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, Acute Myeloid Leukemia Post Cytotoxic Therapy, Recurrent Acute Myeloid Leukemia, Recurrent Myelodysplastic Syndrome, Refractory Acute Myeloid Leukemia, Refractory Myelodysplastic Syndrome
Sponsor: National Cancer Institute (NCI)

NCI Protocol #: 10264 
Version Date:  December 11, 2024 
i 
 
 
 
To: 
Cancer Therapy Evaluation Program 
From: Rory Shallis, M.D. 
Date: 
 December 11, 2024 
Re: 
Response to Request for Amendment from Melissa M. McKay-Daily, Ph.D.  
dated 10/1/2024: Amendment  6, Revision 11: “The PRIME Trial: PARP 
Inhibition in IDH Mutant Effectiveness Trial. A Phase II Study of Olaparib in 
Isocitrate Dehydrogenase (IDH) Mutant Relapsed/Refractory Acute Myeloid 
Leukemia and Myelodysplastic Syndrome.” 
 
SUMMARY OF CHANGES – Protocol 
 
I. 
CTEP Request for Amendment dated 10/1/2024 from Melissa M. McKay-
Daily, Ph.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
II. 
Additional Changes by Principal Investigator 
 
# 
Section 
Comments 
1. 
All 
Updated Version Date in Header 
2. 
  Protocol 
Type/Vers
ion Date  
Updated Protocol Type / Version Date 
 
3.  
 TOC 
  5.1 
  5.2.2 
  5.4.3 
  5.5 
  5.5.2 
  5.10.2.1 
   
  
ETCTN Biorepository updated to EET Biobank 
4. 
  5.5.2 
  5.5.3 
Address and contact information updated for EET Biobank.  
# 
Section 
Comments 
5. 
Title 
Page 
Added Jan Bewersdorf as Co-Principal Investigator  
6. 
Study 
Coordin
ator 
Removed Laura Leary and replaced with Anne Caldwell.  
7. 
Data 
Manager 
Removed GraceAnne Valentin and replaced with Anne Caldwell. 

NCI Protocol #: 10264 
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Protocol #: 
10264 
Local Protocol #: 
2000027686 
 
ClinicalTrials.gov Identifier: NCT03953898 
 
TITLE: The PRIME Trial: PARP Inhibition in IDH Mutant Effectiveness Trial. A Phase II 
Study of Olaparib in Isocitrate Dehydrogenase (IDH) Mutant Relapsed/Refractory Acute 
Myeloid Leukemia and Myelodysplastic Syndrom 
 
Corresponding Organization: LAO-CT018 / Yale University Cancer Center LAO 
 
Principal Investigator: 
Rory Shallis, M.D. 
Yale University Cancer Center 
Section of Hematology 
37 College Street 
New Haven, CT 06520 USA 
203-785-6074 
203-785-3023 (fax) 
Rory.Shallis@yale.edu 
 
Co-Principal Investigator:        Jan Bewersdorf, M.D. 
Yale University 
333 Cedar Street 
PO Box 208028 
New Haven, CT  06520-8028 
203-785-4144 
203-737-3401 (fax) 
Jan.bewersdorf@yale.edu  
 
 
Participating Organizations 
 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 

NCI Protocol #: 10264 
Version Date:  December 11, 2024 
2 
 
 
LAO-NCI / National Cancer Institute LAO 
EDDOP / Early Drug Development Opportunity Program  

NCI Protocol #: 10264 
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Statistician: 
Yu Shyr 
Center for Quantitative Sciences 
571 Preston Building 
Nashville, TN 37232-6848 
615-636-2572 
615-936-2601 (fax) 
yu.shyr@vanderbilt.edu 
Study Coordinator: 
Anne Caldwell, RN, BSN, OCN Clinical 
Research Nurse Yale Cancer Center, 
Clinical Trial Office Yale University 
37 College Street 
New Haven, CT 06510 
Office : 203-785-3465 
Cell: 203-475-7321 
Fax: 203-737-3401 
 
Responsible Research Nurse: 
Anne Caldwell, RN, BSN, OCN 
Clinical Research Nurse, Hematology 
Clinical Trials Office 
Yale University 
37 College Street 
New Haven, CT 06510 
Office: 203-785-3465 
Cell: 203-475-7321 
Anne.caldwell@yale.edu 
Responsible Data Manager: 
Anne Caldwell, RN, BSN, OCN 
Yale Cancer Center, Clinical Trial Office 
Yale University 
37 College Street 
New Haven, CT 06510 
Office: 203-785-3465 
anne.caldwell@yale.edu 
 
 
NCI-Supplied Agent: Olaparib AZD2281 (NSC# 747856 ) 
 
IND #:  
 
IND Sponsor: DCTD, NCI 
 
Protocol Type / Version # / Version Date: 
 
Original / January 11, 2019 
Revision 1 / March 27, 2019 
Revision 2a / June 4, 2019 
Revision 3 / July 3, 2019 
Revision 4a / September 5, 2019 
Revision 4b / September 10, 2019 
Revision 4c / September 12, 2019 
Revision 4d / September 13, 2019 
Revision 4e / October 4, 2019 
Revision 5 / January 16, 2020 
Amendment 1/ Revision 6 / September 8, 2020 
      Amendment 2 / Revision 7 / August 30, 2021 
      Amendment 3/Revision 8/November 22, 2021 
      Amendment 4/Revision 9/November 16, 2022 
      Amendment 5/Revision 10/July 27, 2023 
      Amendment 6/Revision 11/December 11, 2024 
 

NCI Protocol #: 10264 
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SCHEMA 
 
 
 
 
AML = Acute myeloid leukemia; MDS = Myelodysplastic syndrome; IDH = Isocitrate dehydrogenase; ECOG = 
Eastern Cooperative Oncology Group 

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TABLE OF CONTENTS 
SCHEMA ........................................................................................................................................ 3 
1. 
OBJECTIVES ..................................................................................................................... 7 
1.1 
Primary Objective ................................................................................................... 7 
1.2 
Secondary Objectives .............................................................................................. 7 
1.3 
Exploratory Objectives ........................................................................................... 7 
2. 
BACKGROUND ................................................................................................................ 8 
2.1 
Study Diseases ........................................................................................................ 8 
2.2 
Olaparib (AZD2281) ............................................................................................. 16 
2.3 
Rationale ............................................................................................................... 19 
2.4 
Correlative Studies Background ........................................................................... 20 
3. 
PATIENT SELECTION ................................................................................................... 25 
3.1 
Eligibility Criteria ................................................................................................. 25 
3.2 
Exclusion Criteria ................................................................................................. 27 
3.3 
Inclusion of Women and Minorities ..................................................................... 29 
4. 
REGISTRATION PROCEDURES ................................................................................... 30 
4.1 
Investigator and Research Associate Registration with CTEP ............................. 30 
4.2 
Site Registration .................................................................................................... 31 
4.3 
Patient Registration ............................................................................................... 33 
4.4 
General Guidelines ................................................................................................ 35 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................ 36 
5.1 
Summary Table for Specimen Collection ............................................................. 36 
5.2 
Specimen Procurement Kits and Scheduling ........................................................ 38 
5.3 
Specimen Tracking System Instructions ............................................................... 38 
5.4 
Specimen Collection ............................................................................................. 41 
5.5 
Shipping Specimens from the Clinical Site to the EET Biobank  ......................... 42 
5.6 
Shipping Specimens from the Clinical Site to Other Laboratories ....................... 44 
5.7 
Biomarker Plan ..................................................................................................... 46 
5.8 
Integral Correlative Study ..................................................................................... 48 
5.9 
Integrated Correlative Studies ............................................................................... 48 
5.10 
Exploratory/Ancillary Correlative Studies ............................................................ 49 
6. 
TREATMENT PLAN ....................................................................................................... 52 
6.1 
Agent Administration ............................................................................................ 52 
6.2 
General Concomitant Medication and Supportive Care Guidelines ..................... 54 
6.3 
Duration of Therapy .............................................................................................. 58 
6.4 
Duration of Follow-Up .......................................................................................... 58 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 59 

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7.1 
Dose Levels ........................................................................................................... 59 
7.2 
Management of hematological toxicity ................................................................. 59 
7.3 
Management of non-hematological toxicity ......................................................... 60 
7.4 
Interruptions for intercurrent non-toxicity related events ..................................... 61 
7.5 
Renal Impairment .................................................................................................. 61 
7.6 
Dose Reductions when Receiving Strong/Moderate CYP3A4 Inhibitors ............. 62 
8. 
PHARMACEUTICAL INFORMATION ......................................................................... 62 
8.1 
Olaparib (AZD2281) (NSC 747856) .................................................................... 62 
9. 
STATISTICAL CONSIDERATIONS .............................................................................. 66 
9.1 
Study Design/Endpoints ........................................................................................ 66 
9.2 
Sample Size/Accrual Rate ..................................................................................... 68 
9.3 
Stratification Factors ............................................................................................. 68 
9.4 
Analysis of Secondary Endpoints ......................................................................... 68 
9.5 
Exploratory Endpoints .......................................................................................... 69 
9.6 
Reporting and Exclusions ..................................................................................... 70 
10. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ............................. 70 
10.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .................... 73 
10.2 
Adverse Event Characteristics .............................................................................. 73 
10.3 
Expedited Adverse Event Reporting ..................................................................... 73 
10.4 
Routine Adverse Event Reporting ........................................................................ 77 
10.5 
Pregnancy .............................................................................................................. 77 
10.6 
Secondary Malignancy .......................................................................................... 77 
10.7 
Second Malignancy ............................................................................................... 77 
11. 
STUDY CALENDAR ....................................................................................................... 79 
12. 
MEASUREMENT OF EFFECT ....................................................................................... 81 
12.1 
Antitumor Effect – Hematologic Tumors ............................................................. 81 
12.2 
Other Response Parameters................................................................................... 82 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ............................................................................................................ 83 
13.1 
Study Oversight ..................................................................................................... 83 
13.2 
Data Reportin8379 
13.3 
Data Quality Portal ................................................................................................ 85 
13.4 
CTEP Multicenter Guidelines ............................................................................... 86 
13.5 
Collaborative Agreements Language .................................................................... 86 
13.6 
Genomic Data Sharing Plan .................................................................................. 88 
13.7 
Incidental/Secondary Findings Disclosure Procedure ........................................... 88 
14. 
REFERENCES ................................................................................................................. 89 
APPENDIX A 
PERFORMANCE STATUS CRITERIA .................................................. 94 

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APPENDIX B 
PATIENT CLINICAL TRIAL WALLET CARD .................................... 96 
APPENDIX C 
ACTIONS REQUIRED IN CASES OF COMBINED 
INCREASE OF AMINOTRANSFERASE AND TOTAL BILIRUBIN – 
HY’S LAW 
97 
APPENDIX D 
ACCEPTABLE BIRTH CONTROLS METHODS .................................. 101 
APPENDIX E 
PATIENT INFORMATION SHEET ON DIARRHEA 
MANAGEMENT
 
102 
APPENDIX F 
PATIENT MEDICATION DIARY - OLAPARIB ................................... 104 
APPENDIX G 
WORLD HEALTH ORGANIZATION DIAGNOSTIC 
CRITERIA FOR ACUTE MYELOID LEUKEMIA AND 
MYELODYSPLASTIC SYNDROMES......................................................................... 106 

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1. OBJECTIVES 
 
1.1 
Primary Objective 
 
1.1.1 To determine the rate of complete response (CR) to olaparib using a composite CR 
endpoint (CR + CR with incomplete hematologic response [CRi] + CR with partial 
hematologic response [CRh]) in subjects with Isocitrate Dehydrogenase (IDH)1/2 mutant 
myelodysplastic syndrome (MDS) or IDH1/2-mutant Acute Myeloid Leukemia (AML). 
 
1.2 
Secondary Objectives 
 
1.2.1 To determine the overall response rate (ORR) to olaparib using a composite ORR 
endpoint (CR + morphologic leukemia-free state [MLFS] + partial response [PR]) in 
patients with IDH mutant AML or MDS treated with olaparib. 
 
1.2.2 To establish the progression free survival (PFS) of patients with IDH mutant AML or 
MDS treated with olaparib. 
 
1.2.3 To determine the overall survival (OS) of patients with IDH mutant AML or MDS treated 
with olaparib. 
 
1.2.4 To establish the duration of response (DOR) to treatment with olaparib. 
 
1.2.5 To evaluate the safety and tolerability of olaparib in AML or MDS patients. 
 
1.3 
Exploratory Objectives 
 
1.3.1 To establish a relationship between treatment response and correlative studies such as 
plasma and bone marrow 2-Hydroxyglutarate (2HG) levels, and IDH variant allele 
frequency. 
 
1.3.2 To evaluate persistence of double strand breaks in IDH 1/2 mutant AML or MDS. 
 
1.3.3 To evaluate response to therapy in the different IDH mutant genotypes. 
 
1.3.4 To perform molecular profiling assays on malignant and normal tissues, including, but 
not limited to, whole exome sequencing (WES), RNA sequencing (RNAseq) order to: 
 
1.3.4.1 
identify potential predictive and prognostic biomarkers beyond any genomic 
alteration by which treatment may be assigned. 
 
1.3.4.2 
identify resistance mechanisms using genomic DNA- and RNA-based assessment 
platforms. 
 
 
1.3.5 To contribute genetic analysis data from de-identified biospecimens to Genomic Data 

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Commons (GDC), a well annotated cancer molecular and clinical data repository, for 
current and future research; specimens will be annotated with key clinical data, including 
presentation, diagnosis, staging, summary treatment, and if possible, outcome. 
 
1.3.6 To bank blood and bone marrow aspirate obtained from patients at the EET 
Biobank at Nationwide Children's Hospital. 
 
2. 
BACKGROUND 
 
2.1 
Study Diseases 
 
Acute myeloid leukemia (AML) is a heterogenous clonal disorder that is characterized by 
uncontrolled clonal expansion of myeloid progenitor cells (blasts) that leads to bone marrow 
failure. Myelodysplastic syndrome (MDS) is a distinct heterogenous clonal disorder 
characterized by bone marrow dysplasia and ineffective hematopoiesis that leads to peripheral 
cytopenias and a variable clinical course. The pathogeneses of both these disorders includes 
recurrent genomic alterations that help define biologically distinct clinical subtypes (Döhner et 
al., 2017; Papaemmanuil et al., 2016). Despite the significant advancement in our understanding 
of genetic abnormalities that drive AML pathogenesis, the overall therapeutic algorithm has 
remained relatively static for several decades. Improved understanding at the genomic level has 
led to the emergence of some promising targeted therapies in the past year, however, at present 
prognosis of patients with relapsed or refractory disease remains poor. Thirty percent of MDS 
patients will progress to AML, and survival for AML arising from MDS is dismal. 
 
Recurring heterozygous IDH1 mutations were identified as one of the most frequently occurring 
mutations in the AML cancer genome sequencing project (Mardis et al., 2009; Cancer Genome 
Atlas Research 2013). Mutations in IDH2, the mitochondrial homolog of IDH1, are present in 
approximately 10% of patients with AML (Clark et al., 2016). IDH 1/2 mutations are also 
present in 5-12% of patients with MDS (DiNardo et al., 2015a). The normal function of 
isocitrate dehydrogenase (IDH) enzymes is to catalyze the conversion of isocitrate to α- 
ketoglutarate (KG) in the citric acid cycle. In AML there are three recurring pathogenic single 
allele missense IDH mutations (IDH1-R132, IDH2-R140, IDH2-R172) that occur within the 
conserved active site and lead to loss of the expected Krebs Cycle reaction (Ward et al., 2010). 
These mutations confer a neomorphic activity on the encoded enzymes, such that they convert - 
KG to (R)-2-Hydroxyglutarate (2HG) (Dang et al., 2010). Emerging research indicates that (R)- 
2HG is an oncometabolite, with pleiotropic effects on cell biology, including chromatin 
methylation and cellular differentiation, although many questions remain about its impact on 
tumorigenesis and therapy response (Losman and Kaelin, 2013; Molenaar et al., 2014). In AML, 
increased cellular 2HG levels contribute to epigenetic mechanisms of pathogenesis by inhibiting 
αKG-dependent enzymes that are important for normal deoxyribonucleic acid (DNA) 
methylation (Conway O’Brien et al., 2014; Dang et al., 2016). The prognostic significance of 
IDH mutations in AML is controversial due to the influence of co-occurring mutations as well as 
the specific point mutation involved (DiNardo et al., 2015b; Green et al., 2011; Paschka et al., 
2010), however IDH1/2 mutations have a more consistently negative prognostic impact in MDS 
with shorter overall survival and greater risk for leukemic progression (Bejar et al., 2015; Jin et 
al., 2014; Medeiros et al., 2017; Thol et al., 2010). 

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2.1.1 Evidence supporting PARP inhibitor testing in IDH1/2-mutant tumors with a focus on 
IDH 1/2 mutant AML and MDS 
 
Therapies for AML and MDS remain very limited, despite advancement in our understanding of 
disease biology, particularly in the setting of chemotherapy and hypomethylating agent 
refractory disease, respectively. Approximately 20% of AML patients and up to 12% of MDS 
patients harbor IDH1/2 mutations (Papaemmanuil et al., 2016). While a Food and Drug 
Administration (FDA) approved IDH-1 and -2 inhibitors are available for IDH-mutant AML, 
mutant IDH1/2 inhibitors simply block the neomorphic function of the mutant proteins, without 
evidence of impact on the mutant IDH clone. There is no clear biomarker to predict response to 
mutant IDH inhibitors and of the responders, a clear majority will eventually relapse. Recent 
publications have determined that patients who relapse almost uniformly develop either 
resistance mutations that impede IDH inhibitor binding or isoform switch from one IDH enzyme 
to the other (Harding et al., 2018; Intlekofer et al., 2018). In either case, at the time of relapse 
from mutant IDH inhibitors there is an increase in production of the oncometabolite 2HG, that 
was suppressed by the inhibitors. 
 
2HG exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor 
progression via their inhibitory effects on αKG-dependent dioxygenases (Xu et al., 2011). The 
former is an oncometabolite that is induced by the neomorphic activity conferred by IDH1/2 
mutations, while the latter is produced under pathologic process such as hypoxia. Our 
collaborators at Yale University (Drs. Bindra and Halene) made the novel discovery that IDH1/2 
mutations induce a homologous recombination (HR) defect which renders tumor cells 
exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors (Sulkowski et al., 
2017). As 2HG accumulates in IDH1/2-mutant cells, HR disruption causes cells to rely on 
alternate low fidelity DNA repair pathways, thus hastening genomic instability and cell death. 
Remarkably, this “BRCAness” phenotype can be completely reversed by treatment with small 
molecule inhibitors of mutant IDH1, and, conversely, it can be entirely recapitulated by 
treatment with 2HG alone in cells with wild-type (WT) IDH1/2. IDH1-dependent PARP 
inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived 
glioma cells in culture, genetically-matched tumor xenografts in vivo and patient derived AML 
cells. Similar synthetic lethal interaction between IDH1/2 mutations and PARP inhibitors were 
also reported by other laboratories, which further strengthens the validity of this discovery 
(Molenaar et al., 2018). Collectively, these findings directly challenge the current therapeutic 
strategy to block IDH1/2-mutant function, and they instead provide a novel approach to treat 
IDH1/2-mutant tumors with PARP inhibitors. Furthermore, these results uncover an unexpected 
link between oncometabolites, altered DNA repair, and genetic instability. 
 
Thus, PARP inhibitor therapy could potentially eradicate the mutant hematopoietic stem cell by 
exploiting intrinsic cellular defects in IDH mutant cells, which will lead to durable remission. 
For patients previously treated with mutant IDH inhibitors, at the time of progression/treatment 
failure 2HG production is restored, also “restoring” their HR defect and PARP sensitivity. 
 
2.1.1.1 
Overview 

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IDH1/2 mutations induce an HR defect that renders 
tumor cells sensitive to PARP inhibition; the 
mechanism of action for this interaction is 
summarized in Figure 1 (Sulkowski et al., 2017). 
This novel and unexpected phenotype was 
validated across five unique and genetically diverse 
cell line pairs that were engineered to express 
either the WT or the mutant IDH1/2 proteins, and 
the Bindra lab confirmed the observed double 
strand break (DSB) repair defect using multiple 
orthogonal functional assays. This interaction was 
also demonstrated in a number of clinically 
relevant models, including IDH1/2-mutant primary 
patient-derived cell lines and genetically-matched 
tumor xenografts. 
 
2.1.1.2 
Mutant IDH1/2-induced 2HG 
suppresses HR and confers exquisite 
PARP inhibitor sensitivity. 
 
The Bindra Laboratory created a clustered 
regularly interspaced short palindromic repeats- 
associated (CRISPR/Cas)-engineered R132H 
model cell line, and subsequently utilized it in a 
focused, unbiased screen for synthetic lethal 
interactions with a large collection of DNA 
damaging agents and DNA repair inhibitors 
(Sulkowski et al., 2017). This screen revealed an 
unexpected interaction between mutant IDH1 and 
PARP inhibitor sensitivity (Table 1). This novel 
finding was then validated in a comprehensive series of clonogenic survival assays, to quantify 
the magnitude of differential sensitivity. 
The mutant IDH1-dependent PARP 
inhibitor sensitivities were profound and 
approached a 50-fold difference 
compared to IDH1-WT cells, with the 
FDA-approved PARP inhibitor, olaparib 
(Figure 2). This interaction was 
confirmed with a number of PARP 
inhibitors, suggesting a class-effect. In 
addition, a similar phenotype in IDH2- 
mutant cells was confirmed (Sulkowski 
et al., 2017). These results were 
reproducible in several cell lines, 
including a doxycycline (dox)-inducible 
R132H-mutant IDH1 ORF (Turcan et 
Fig. 3. PARP inhibitor 
sensitivity in an 
immortalized astrocyte cell 
line with dox-inducible 
mutant IDH1 ORF. 
Fig. 2. Synthetic lethal 
interaction between the 
IDH1-mutation and PARP 
inhibition in HCT116 cells. 
Fig. 1. Proposed mechanism of action of mutant 
IDH1/2-induced BRCAness and consequent 
PARP inhibitor synthetic lethality. 

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al., 2012) astrocyte cell line, where both transient and long-term induction of mutant IDH1 
protein expression conferred marked levels are BMN-673 sensitivity, as detected by clonogenic 
survival analysis (Figure 3), as well as several additional human glioma cell lines. 
 
In addition, the Bindra lab demonstrated the IDH1/2-induced BRCAness phenotype in a range of 
AML/MDS-related and clinically relevant, primary models in vitro, including patient-derived 
glioma cell lines and primary AML bone marrow cultures (Sulkowski et al., 2017). For 
example, in primary bone marrow cultures derived from AML patients with known IDH1 or 
 
 
IDH2 mutations, increased baseline persistence of DSBs by comet assay, which is a classic 
approach to assess functional DSB repair activity, were detected compared to their WT 
counterparts (Figure 4a,b). Furthermore, this phenotype was completed reversed by treatment 
with small molecule mutant IDH2 inhibitors (Figure 4c). 
Fig. 4. (A) Evidence of a DNA repair defect in IDH1/2-mutant primary bone marrow 
cultures, as detected by comet assays, (B) representative comet assay images, and (C), 
reversal of the observed DNA repair defect using small molecule mutant IDH2 inhibitors. 

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2.1.1.3 
Mechanism of action studies and effects of small molecule mutant IDH1 inhibitors 
 
Functional DSB repair assays confirmed a profound HR defect in 
IDH1/2-mutant cells (Sulkowski et al., 2017). Remarkably, our 
collaborators in the Bindra lab found that 2HG alone was 
sufficient to down-regulate HR repair activity in cells with WT 
IDH1/2 genes. Suppression of HR by 2HG was significant and 
was observed after the attenuation of two key HR genes, BRCA2 
and Rad51, using the well-established DR-GFP assay to measure 
the activity of this pathway (Figure 5). Mechanistically, this 
phenotype can be entirely recapitulated by exposure to either 
2HG enantiomers, and it cannot be explained by the alterations 
in nicotinamide adenine dinucleotide (NAD)+ levels that have 
been seen in IDH1/2-mutant cancers (Tateishi et al., 2015). 
These data suggest that 2HG-induced HR suppression is 
mediated via direct inhibition of KG-dependent dioxygenases, 
in particular KDM4A. We can recapitulate the IDH1/2- 
associated HR-defective phenotype by treatment of WT cells 
with small molecule KDM4A inhibitors, and can reverse the 
effect in mutant cells by overexpression of KDM4A. 
Importantly, it was noted that treatment with a mutant IDH1- 
specific small molecule inhibitor known to potently suppress 
2HG production (and similar to drugs that are currently in 
clinical trials) reversed the observed HR defect and eliminated 
the associated PARP inhibitor sensitivity. This reversal was 
demonstrated in both mutant IDH1/2 cell lines, and also in a cell 
line harboring an endogenous IDH1 mutation. Reversal of the mutant IDH1-associated DSB 
repair defect was confirmed using three unique small molecule inhibitors of the mutant protein, 
and also with siRNAs targeting the IDH1 gene, thus ruling out potential off-target effects of the 
inhibitors. These data strongly suggest that inhibition of mutant IDH1 activity with small 
molecule inhibitors, as is currently being pursued in multiple clinical studies, is not the most 
efficacious approach to treat these tumors. This is also the rationale for inclusion of IDH 
inhibitor naive patients despite the availability of IDH2 inhibitors as part of standard of care 
(further described in Section 2.3). Representative data from our group that supports these 
findings is presented in Figure 6, and extensive data supporting these findings is provided in our 
manuscript. In addition, this work showed that 2HG exposure induced elevated rates of DSBs in 
a range of cell lines with diverse genetic backgrounds, including immortalized astrocytes, 
primary melanoma cultures, breast cancer cell lines, and U2OS cells, suggesting that this is a 
fundamental effect of this metabolite. Of note, treatment of plasmid DNA with 2HG in vitro for 
8 hours did not induce any DNA cleavage, which ruled out any possible direct effect of this 
molecule on DNA. Representative data supporting these findings is presented in Figure 7 (from 
Fig. 6. Reversal of the IDH- 
associated DSB repair defect 
with a small molecule inhibitor of 
mutant IDH1, which can me 
recapitulated in IDH WT cells by 
treatment with 2HG alone. 
Fig. 5. (A) DR-GFP HR 
assay schematic. (B) (R)- 
2HG suppresses HR at 
levels similar to 
siRad51/siBRCA2 in IDH1- 
WT (U2OS) cells. 

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our group) for reference. 
 
 
 
 
2.1.1.4 
In vivo synthetic lethal interaction between mutant IDH1 tumors and PARP inhibition 
 
IDH1-mutant mouse xenografts treated with PARP inhibitors showed a statistically significant 
growth delay when compared to vehicle control. In contrast, no statistically significant 
differences between PARP inhibitors and vehicle in IDH1-WT tumor xenografts were detected. 
This effect was confirmed with two isogenic pairs of IDH1-mutant versus –WT cell lines grown 
as xenografts (HCT116 and HeLa), as well as cell lines with endogenous IDH1 mutations (e.g., 
HT1080 fibrosarcoma cell lines, which harbor an R132C IDH1 mutation). Representative data 
from out group for HCT116 tumor xenografts is shown in Figure 8 for reference. 
 
 
2.1.1.5 
Mutant IDH1/2 synthetic lethality correlates with PARP trapping activity of PARP 
Fig. 7. 2HG exposure induces a DSB repair defect in cell lines with diverse genetic backgrounds. 
IDH1 Mutants 
Fig. 8. (A) PARP inhibitors selectively kill HCT116 IDH1-mutant tumor xenografts with (B) 
minimal effects on IDH1-WT cells; (C) BLI monitoring of treatment responses. 

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inhibitors. 
 
Recent studies from the Bindra group indicate that PARP inhibitors which specifically “trap” 
PARP protein at sites of DNA damage, are most effective against IDH1/2-mutant cells. 
Examples of PARP-trapping PARP inhibitors include: BMN-673, niriparib, ruciparib BGB-290, 
and olaparib (Murai et al., 2012). In contrast, veliparib, while very effective as a catalytic 
inhibitor of PARP function, is an extremely poor PARP-trapper (Murai et al., 2012). These 
PARP inhibitors were profiled for synthetic lethality with IDH1-mutant vs. WT cells, which 
confirmed activity with these PARP-trapping PARP inhibitors, and also that veliparib was not 
effective under these conditions. Representative data for BGB-290 is presented below in Figure 
9, and data for olaparib and BMN-673 was presented above. 
 
2.1.2 Clinical efficacy of Synthetic Lethal Targeting of HR defects 
with PARP inhibitors 
 
Olaparib is an orally bioavailable PARP inhibitor that has been 
approved by the FDA as the first monotherapy to treat BRCA-mutant 
advanced ovarian cancer (Kim et al., 2015). PARP is involved in 
surveillance and maintenance of genome integrity and functions as a 
key molecule in the repair of DNA single-stranded breaks (SSBs) 
(Pommier et al., 2016). PARP-inhibited cells accumulate unrepaired 
SSBs leading to double strand breaks when encountered by the 
replication machinery. 
 
Based on the principle of synthetic lethality, treatment with single- 
agent PARP inhibitor has a dramatic therapeutic impact in a 
proportion of patients with germ-line or tumor-based (somatic) 
mutations in BRCA1 or BRCA2. Favorable response data have also been observed in a subset of 
patients without evidence of BRCA1/2 mutations, and there is emerging consensus that other 
molecular alterations in DNA repair pathways, including HR deficiency, can increase the 
likelihood of response to PARP inhibitors (Bryant et al., 2005; Farmer et al., 2005). There are 
now three FDA-approved PARP inhibitors for the treatment of HR-deficient ovarian cancer, and 
it is likely that several more will be approved in the next 2-3 years. Robust response rates have 
been observed with these agents, often with PFS improvements in the range of 2-5 fold 
compared to control groups (Curtin and Szabo, 2013). 
 
The use of DNA repair inhibitors in IDH1/2-mutant malignancies is analogous to the rationale 
used for treating BRCA-deficient cells with a PARP inhibitor. As 2HG accumulates in IDH1- 
mutant cells, HR is disrupted which causes cells to rely on alternative low fidelity DNA repair 
pathways, thus hastening genomic instability and cell death. This creates a “BRCAness” 
phenotype which renders them increasingly susceptible to agents that impair the DNA damage 
response. 
 
2.1.3 Targeted therapy for IDH mutant Acute Myeloid Leukemia/Myelodysplastic Syndrome 
Clinical trials and use of PARP inhibitors 
Fig. 9. Confirmation of 
PARP-trapping PARP 
inhibitor sensitivity with BGB- 
290 in IDH1-mutant versus – 
WT cells. 

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Ongoing trials of targeted therapy for IDH1/2-mutant AML and MDS thus far have primarily 
focused on the impact of new allosteric inhibitors of mutant IDH. The first in class IDH 
inhibitor is the IDH2 inhibitor AG-221, or enasidenib, and was approved by the FDA for 
relapsed or refractory AML demonstrated clinical efficacy in AML as a single agent with 
responses in approximately 40% of patients with IDH2 mutations (Stein et al., 2017). However, 
response was relatively short lived, with median DOR of less than 6 months, with persistence of 
mutant IDH2 clones. More recently, ivosidenib, an IDH1 inhibitor was also approved by the 
FDA based on similar response rates (DiNardo et al., 2018) in the IDH1 mutant population. 
Several other IDH1, IDH2, and dual IDH1/2 inhibitors are currently investigated in early phase 
trials as single agent therapies, as well as in combination with hypomethylating agents or 
intensive chemotherapy. At the present time there are no approved targeted therapies for IDH1 
mutant leukemia and IDH 1/2 mutant MDS. 
 
There is very limited data assessing the PARP inhibitor therapy in AML or MDS. Molecular and 
pre-clinical data previously demonstrated PARP inhibitor sensitivity in leukemic cells driven by 
AML1 protein-eight Twenty One (AML1-ETO) and promyelocytic leukemia protein-retinoic 
acid receptor-alpha (PML-RARα), which suppress DNA damage repair (Esposito et al., 2015), 
and anti-leukemic activity when combining PARP inhibitors with DNA damaging agents. 
Applying this concept, a recent Phase 1 trial assessed the safety of the combination of 
temozolomide, a DNA damaging agent with veliparib, a PARP inhibitor (Gojo et al., 2017). 
This combination was well tolerated. In addition, there is one ongoing Phase 1 trial of the PARP 
inhibitor talazoparib in an unselected population combining several hematologic malignancies 
(NCT01399840) that has completed accrual (results are not yet available). This is encouraging 
with regard to tolerability for our proposed olaparib monotherapy Phase 2 trial. 
 
A Phase 1/2 clinical trial in an unselected relapsed/ refractory AML population combining PARP 
inhibitors with decitabine, a hypomethylating agent, (NCT02878785) is currently underway. 
The additive benefit of a PARP inhibitor in an unselected population of patients may be limited, 
with an underwhelming response rate overall, but with robust response in the IDH mutant 
population. Given the frequency of IDH mutations in an unselected AML population, this may 
lead to a negative trial, despite efficacy in a selected population. By limiting our trial to patient’s 
with IDH mutations that are known to intrinsic cellular defects sensitizing them to PARP 
inhibitor therapy, we will maximize our chance of success. 
 
Phase 1/2 trials combining other DNA damaging agents, such as topotecan/ carboplatin, with 
veliparib (a PARP inhibitor with poor PARP trapping function) in an unselected population of 
hematologic malignancies are also currently underway (NCT00588991, NCT03289910), 
however we postulate that combination therapy may prove be too toxic for many patients with 
relapsed or refractory acute leukemia, particularly due to hematologic toxicity in an already 
vulnerable population. Additionally, the benefits of PARP inhibition may not be as robust given 
the use of veliparib in these trials. Finally, we are cognizant of the fact that PARP inhibitors 
have been implicated in the development of MDS/AMLwhich raised some concern and warrants 
judicious use of the therapy (development of MDS/AML was noted in less than 1.5% of patients, 
or 21/1680 patients, with olaparib monotherapy in clinical trials, including long term follow up 
per FDA review) (Highlights of Prescribing Information: Lynparza, 2018). Rationale for the use 
of olaparib in this setting would include the fact that all the patients who developed these 

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secondary hematologic malignancies were heavily pre-treated with DNA damaging agents such 
as platinum agents and ionizing radiation, which are not part of the treatment algorithm for 
management of MDS or AML, and more importantly, we strongly believe that in this select 
subset of AML and MDS patients the benefit of olaparib will greatly outweigh any potential risk. 
Similar to anthracyclines, which are known to cause secondary hematologic malignancies, but 
remain part of the backbone of induction therapy, we believe PARP inhibitor therapy will 
become a key component of management of IDH mutant hematologic malignancies in the near 
future. 
 
By targeting the IDH mutant leukemia/ MDS population with olaparib, a PARP-trapping PARP 
inhibitor, we expect a robust response; synthetic lethality without the additive toxicity of 
chemotherapy. Our proposed trial is the first study that will test the efficacy of a PARP 
inhibitor-based therapeutic regimen specifically targeting IDH1/2-mutant relapsed or refractory 
AML and MDS. 
 
2.2 
Olaparib (AZD2281) 
 
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP 
ribose)] polymerisation (PARP) inhibitor (PARP-1, -2 and -3) that is being developed as an oral 
therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy 
and other anti-cancer agents. 
 
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair 
mechanisms. PARP enzymes are essential for repairing DNA SSBs. Inhibiting PARPs leads to 
the persistence of SSBs, which are then converted to the more serious DNA DSBs during the 
process of DNA replication. During the process of cell division, DSBs can be efficiently 
repaired in normal cells by HR. Tumors with HR deficiencies (HRD), such as ovarian cancers in 
patients with BRCA1/2 mutations, cannot accurately repair the DNA damage, which may 
become lethal to cells as it accumulates. In such tumor types, olaparib may offer a potentially 
efficacious and less toxic cancer treatment compared with currently available chemotherapy 
regimens. 
 
BRCA1 and BRCA2 defective tumors are intrinsically sensitive to PARP inhibitors, both in 
tumor models in vivo (Rottenberg et al., 2008, Hay et al., 2009) and in the clinic (Fong et al., 
2009). The mechanism of action for olaparib results from the trapping of inactive PARP onto 
the single-strand breaks preventing their repair (Helleday 2011; Murai et al., 2012). Persistence 
of SSBs during DNA replication results in their conversion into the more serious DNA DSBs 
that would normally be repaired by HR repair. Olaparib has been shown to inhibit selected 
tumor cell lines in vitro and in xenograft and primary explant models as well as in genetic BRCA 
knock-out models, either as a stand-alone treatment or in combination with established 
chemotherapies. 
 
2.2.1 Mechanism of Action 
 
The mechanism of action for olaparib activity as a single agent has been proposed to involve the 
trapping of inactivated PARP onto the single-strand breaks preventing their repair and generating 

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a potential block for cellular DNA replication (Helleday, 2011; Murai et al., 2012).  An 
important consequence of this is that processing of trapped PARP-DNA complexes and/or the 
stalling of replication forks, or collapsing of replication forks, is predicted to lead to the 
generation of the more serious DNA DSBs. These DSBs would normally be repaired by a 
process that involves Ataxia Telangiectasia Mutated (ATM) (a major DNA DSB signaling 
kinase, the ‘MRN’ nuclease protein complex; made up of Meiotic Recombination 11 Homolog A 
[MRE11A], human RAD50 homolog [RAD50] and Nijmegen breakage syndrome1 [NBS1]) and 
additional homologous recombination DNA repair (HRR) proteins such as E. coli DNA repair 
protein RAD51 homolog (RAD51), BRCA1, and BRCA2. 
 
In some instances where DNA repair defects may not result in the same level of sensitivity as 
BRCA mutations, and therefore single agent olaparib treatment may not be sufficient to induce 
cell kill through synthetic lethality, it may still be possible to induce tumor cell death through 
combinations with ionizing radiation or chemotherapies that either increase DNA damage 
accumulation or mitotic stress. The latter is relevant since it is often during mitosis that 
unrepaired DNA damage leads to cell death through a process known as mitotic catastrophe 
(Castedo et al., 2004). 
 
2.2.2 Clinical Pharmacokinetics and Metabolism 
 
As of December 15, 2017, there is pharmacokinetic (PK) data from 11 clinical studies. Olaparib 
is orally available and the tablet formulation is rapidly absorbed, reaching peak plasma 
concentration (tmax) in 1.5 hours (Investigator’s Brochure, 2018). The plasma concentrations 
decline in a biphasic manner with an average terminal elimination half-life (t1/2) of 14.9 hours 
(standard deviation [Sd] 8.2 hours). The mean apparent oral clearance rate was approximately 
7.4 L/hour (Sd 3.9 L/hour). The mean volume of distribution (Vd) of olaparib following a single 
administration of 300 mg oral tablet dose was 158 L (Sd 136 L) indicating olaparib is distributed 
into the tissues. 
 
The metabolism of olaparib was assessed in a study of six female patients ranging in age from 
34-72 years (Investigator’s Brochure, 2018). Upon the administration of a single 100 mg dose of 
olaparib containing 1x50 mg capsule of radiolabeled [14C]-olaparib and 1x50 mg capsule of 
unlabeled olaparib, 70% of the radioactivity in the blood was olaparib. Three metabolites each 
comprised around 10% of the material: M12 (9.3%, ring-open piperazin-3-ol), M15 (10.3%, 4- 
fluorophenol (hydroxy)methyl), and M18 (13.7%, piperazin 3-ol). 
 
Olaparib is eliminated in both the urine (44% of the dose) and feces (42% of the dose) 
(Investigator’s Brochure, 2018). In the urine, olaparib was the most abundant component, 
accounting for between 10% and 19% of the dosed material. Up to 37 further drug-related 
components were observed, 18 of which were quantifiable by high performance liquid 
chromatography with mass spectrometric detection (HPLC/MS) with radioactivity detection. At 
least 20 components were observed in the pooled fecal samples with 6 components accounting 
for >1% of the dose and the remaining metabolites detectable only by HPLC/MS. The major 
components present were unchanged olaparib (0.6 to 14% of the dose) and M15 (0.9 to 8% of 
the dose). Four further metabolites (M9, M12, M23 and M25) were also prominent each 
accounting for ≤6% of the dose. 

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The PK parameters for multiple dosing of olaparib are well predicted from the single dose 
studies. There is not extensive accumulation with multiple dosing. At 300 mg oral dose bis in 
die (BID), the temporal change parameter (area under the curve [AUC] at steady state/AUC 
following a single dose) was approximately 1.5 (Sd 0.6) (Investigator’s Brochure, 2018). 
 
At capsule doses ≥40 mg, the inhibition of PARP-1 measured in peripheral blood mononuclear 
cells (PBMC) reached its maximum of 50% to 60% of the baseline, and this level of inhibition 
was achieved by 6 hours after the first dose of olaparib and was maintained with repeated dosing 
(Investigator’s Brochure, 2018). In tumor biopsies from 60 breast cancer patients who received 
doses of olaparib between 10 mg BID and 400 mg BID, PARP inhibition ranged from 20% to 
80% and did not relate to the dose. 
 
2.2.3 Clinical Safety Summary 
 
Olaparib monotherapy has been associated with adverse reactions generally of mild or moderate 
severity (Common Terminology Criteria for Adverse Events v.5.0 [CTCAE] Grade 1 or 2) and 
generally not requiring treatment discontinuation (Investigator’s Brochure, 2018). In a pool of 
1248 patients, the most frequently observed adverse reactions across clinical trials in patients 
receiving olaparib monotherapy (≥10%) were nausea, vomiting, diarrhea, dyspepsia, fatigue, 
headache, dysgeusia, decreased appetite, dizziness, and anemia. Anemia and other hematologic 
toxicities were generally low grade (Grade 1 or 2). However, anemia was the most commonly 
reported Grade ≥3 adverse event (AE) reported in clinical trials. The median time to first report 
of anemia was approximately 4 weeks (approximately 7 weeks for Grade ≥3). Anemia can be 
managed with dose interruptions, dose reductions, and blood transfusions where appropriate. In 
one Phase 3 trial in ovarian cancer patients, the incidence of anemia was 43.6% of patients, with 
Grade ≥3 in 19.5% of patients, leading to dose interruptions (16.9%), dose reductions (8.2%), 
discontinuation of treatment (3.1%). In addition, 17.9% of patients treated with olaparib 
required one or more blood transfusions during treatment. 
 
In clinical studies with olaparib the incidence of Grade ≥2 shifts (elevations) from baseline in 
blood creatinine was approximately 15% (Investigator’s Brochure, 2018). Data from a double- 
blind placebo-controlled study showed median increase up to 23% from baseline remaining 
consistent over time and returning to baseline after treatment discontinuation, with no apparent 
clinical sequelae; 90% of patients had creatinine values of Grade 0 at baseline and 10% were 
Grade 1 at baseline. 
 
Nausea was generally reported very early, with first onset within the first month of olaparib 
treatment in the majority of patients (Investigator’s Brochure, 2018). Vomiting was reported 
early, with first onset within the first 2 months of olaparib treatment in the majority of patients. 
Both nausea and vomiting were reported to be intermittent for the majority of patients and can be 
managed by dose interruption, dose reduction and/or antiemetic therapy. Antiemetic prophylaxis 
was not required. 
 
Studies of olaparib in combination with various chemotherapy agents indicate an increase in 
bone marrow toxicity (anemia, neutropenia, thrombocytopenia) greater than expected if the 

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agents had been administered alone (Investigator’s Brochure, 2018). The effects are generally 
transient, but treatment delays are common and alternative administration schedules/toxicity 
management processes have been evaluated within some of these studies. When this type of 
toxicity has occurred, it has been managed by routine clinical practice including dose delays, 
dose reductions, intermittent dosing, and/or the use of supportive care measures, including 
granulocyte colony stimulating factor (G-CSF). 
 
The incidence of developing MDS/AML in patients treated in clinical trials with olaparib 
monotherapy, including long-term survival follow-up, was <1.5% and the majority of events had 
a fatal outcome (Investigator’s Brochure, 2018). 
 
Pneumonitis has been reported in <1.0% patients treated with olaparib monotherapy in clinical 
studies (Investigator’s Brochure, 2018). When olaparib was used in clinical studies in 
combination with other therapies there have been events with a fatal outcome. If patients present 
with new or worsening respiratory symptoms such as dyspnea, cough and fever, or an abnormal 
chest radiologic finding is observed, olaparib treatment should be interrupted and prompt 
investigation initiated. If pneumonitis is confirmed, olaparib treatment should be discontinued 
and the patient treated appropriately. 
 
2.3 
Rationale 
 
As shown in the study schema the proposed study is a 4-arm Phase 2, open-label study of PARP 
inhibition (olaparib) in advanced relapsed or refractory IDH1/2-mutant AML and MDS. At 
present, an IDH2 and IDH1 inhibitor, enasidinib and ivosidenib respectively, are FDA approved 
for the management of patients with IDH2 mutant leukemia (Stein et al., 2015; DiNardo et al., 
2018). Based on the scientific rationale described (synthetic lethality of the mutant clone due to 
accumulation of toxic metabolites), we hypothesize that inhibition of mutant IDH1/2 with small 
molecule inhibitors is not the most efficacious approach to treat IDH mutant leukemia. Indeed, 
the synthetic lethality of olaparib is likely most robust in the setting of IDH mutant activity (due 
to oncometabolite accumulation), and possibly blunted to some degree with the use of an IDH 
inhibitor. Therefore, we propose a separate arm for evaluation of patients pretreated with IDH 
inhibitor therapy. In addition, we propose the inclusion of IDH inhibitor -naïve AML patients 
who present within a “window of opportunity” in this trial (IDH inhibitors are yet to be approved 
in the MDS setting. AML and MDS have been separated as they are distinct diagnoses, and 
within each disease group patients have been separated by their exposure to IDH inhibitors; IDH 
inhibitor naïve and IDH inhibitor exposed. Recognizing that other FDA approved therapeutic 
options are available, but also that these patients may have a dramatic response to olaparib 
monotherapy, IDH inhibitor naïve patients will be monitored very closely, including frequent 
bloodwork and bone marrow evaluation 4 week (or earlier as needed) to safeguard against 
progression and allow for transition to standard of care therapy within the 12-week period prior 
to response assessment in the case of progression. 
 
Relapsed/ refractory patients may also have co-occurring targetable mutations, such as FLT3 
ITD. At the present time there is no consensus in the AML community on the ideal sequencing 
of targeted therapies when multiple options are applicable. This is reflected in the current NCCN 
AML recommendations. In these situations, we will need to rely on the judgement of the local 

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investigator/ provider to choose the optimal therapeutic option. 
 
In this study, we propose to directly translate our laboratory findings into a proof of concept, 
biomarker-driven Phase 2 clinical trial. Our study will specifically target IDH1/2-mutant AML 
and MDS. Phase 1 data combining other PARP inhibitors (e.g., veliparib) and DNA damaging 
agents have demonstrated that this therapeutic strategy is well tolerated, with activity in an 
unselected advanced AML population. These results are likely to be amplified in a mutant 
IDH1/2- selected population, and with the use of a more potent PARP inhibitor, olaparib. There 
is concern regarding the risk of development of MDS and AML associated with PARP 
inhibitors. We believe that by selecting IDH mutated patients, we will significantly increase the 
therapeutic index and the benefit will greatly outweigh the risk. We will determine the safety of 
olaparib in IDH mutant relapsed or refractory AML and MDS, and subsequently evaluate the 
overall response rate of this population. In addition, we will employ several unique biomarkers, 
including 2HG detection in both plasma and bone marrow biopsy samples to refine our 
understanding of disease response. This Phase 2 trial that will utilize a Simon 2-stage design. 
This study will be open at all ETCTN sites, which supports our ability to accrue patients for this 
study in a reasonable time-frame. 
 
This study has the potential to establish a completely novel treatment approach for IDH1/2- 
mutant tumors, and they will lay the groundwork for future studies aimed at exploiting, rather 
than suppressing, 2HG-induced BRCAness in AML and MDS. 
 
2.4 
Correlative Studies Background 
 
The molecular landscape of cancer is just beginning to be defined. However, we do not know 
enough about the genomic and molecular landscape of tumors from patients who enter early 
phase clinical trials. With this study, we will attempt to learn more about specific molecular 
features of cancers from this patient subgroup. It is particularly important to learn, as early as 
possible, if there are molecular features within a particular malignant histology or across 
malignant histologies that can inform about potential response or resistance to treatments in early 
phase clinical trials. Such knowledge will be used to design more efficient later stage clinical 
trials for more efficient and more effective drug development. 
 
2.4.1 Integral Biomarker 
 
2.4.1.1 
IDH1 or IDH2 mutation 
 
This approach to select patients is commonly used in several recent and ongoing clinical trials 
focused on IDH1/2-mutant tumors (e.g., NCT02454634, NCT02771301, NCT02381886, 
NCT02826642, NCT02074839, NCT02746081, NCT01915498, NCT02481154). 
 
2.4.2 Integrated Biomarkers 
 
2.4.2.1 
Peripheral blood and bone marrow 2HG levels 

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The main objectives of this assay are to: 1) correlate the chances of response to olaparib with 
baseline 2HG levels and 2) evaluate the longitudinal variations of 2HG levels as a marker of 
response to treatment and progression. 
 
Based on our experience, as detailed in the background section, the “BRCAness” of IDH 
mutated patients is related to the exposure of the cell to 2HG. We hypothesize that patients with 
elevated levels of 2HG may have a better response to olaparib. We also want to confirm that 
olaparib is able to reduce the levels 2HG and maintain low levels of 2HG in treated patients. 
 
 
2.4.3 Exploratory Biomarkers 
2.4.3.1 
Genomic profiling 
Objectives: 
• The molecular landscape of IDH1/2-mutant AML and MDS predictably determines 2HG 
level. 
• The features on this molecular landscape serve as candidate predictive biomarkers of 
treatment response. 
• To evaluate the impact of olaparib on clonal architecture and clonal evolution. 
 
We hypothesize that 1) the molecular landscape of IDH1/2-mutant AML and MDS predictably 
determines 2HG level, and 2) the features on this molecular landscape serve as candidate 
predictive biomarkers of treatment response. We will test these hypotheses by comprehensive 
genomic profiling to elucidate co-occurring mutations, DNA methylation patterns, and gene 
expression profiles, in all patients enrolled on this study. We will study baseline and on- 
treatment bone marrow aspirate samples, and also at progression when possible, which also will 
allow us to assess changes in mutant IDH1/2 variant allele fractions, and also to probe for the 
emergence of molecular resistance markers over time. 

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For the WES studies, we will search for tumor-specific mutations in known oncogenes and 
tumor suppressors, as well as additional gene mutations. We are particularly interested in 
mutations known to co-occur with IDH1/2 mutations: NPM1, FLT3, SRSF2, DNMT3A, NRAS, 
KRAS, RUNX1, KMT2A, PTEN, PHF6, TP53, BCOR, STAG2, etc. (see Figure 10 where 79% of 
375 AML cases show genetic alterations from this list). For single cell DNA Seq studies we will 
base the sequencing panel on mutations identified by the clinical targeted exome and the 
research WES. We will perform single cell DNA seq on baseline, best response and progression 
samples. For the RNAseq studies, we will use previously published and publicly available data 
sets to test whether our cases can be categorized  within gene expression clusters found in 
IDH1/2-mutant cancers, using a k-nearest neighbor classification procedure. In addition, we will 
use RNAseq data to identify recurrent translocations. For the methylation studies, we will use 
previously published and publicly available data sets (Huang et al., 2018; Benetatos and 
Vartholomatos, 2018; Wang et al., 2018) to test whether our cases fall within unique 
methylation clusters found in IDH1/2-mutant cancers. 
 
2.4.3.2 
Phamacometabolomic profiling 
Objective: 
• Olaparib may induce a specific metabolic signature that may correlate with clinical 
response. 
 
Novel metabolomics technologies allow high-throughput assessment of a large number of 
endogenous metabolites, which provide powerful tools for mapping biochemical pathways 
implicated in disease and in response to drug treatment. Pharmacometabolomics is an emerging 
field that applies metabolomics to define metabolic signature of drug exposure, thereby enabling 
identification of biochemical pathways implicated in drug efficacy and adverse drug reactions. 
 
We hypothesize that by defining metabolite profiles both at baseline (prior to) and post drug 
exposure, pharmacometabolomics profile modifications will provide early insights into 
Figure 10: Oncoprint analysis of selected oncogenes and tumor suppressor genes and other reported co- 
occurring genes in 375 AML cases from TCGA, NEJM 2013 and AML TCGA Provisional). 

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mechanism of drug action and molecular basis for variation in drug response. 

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We will also explore the feasibility of comparing this signature with similar signatures from 
patients treated with olaparib in the context of solid tumor with or without IDH mutations. 
 
We will identify the circulating metabolites that are significantly altered by olaparib exposure, 
which may provide insights into the mechanism of drug action. In addition, if the sample size 
allows, we will examine the associations between the metabolite changes and PK parameters, 
pharmacodynamic response, toxicity, or clinical response. This may help identify potential 
circulating biomarkers for the early prediction of clinical outcome. 
2.4.3.3 
Avatar studies 
Objectives: 
• Test the extent to which Avatar models can recapitulate treatment responses (or failures) 
in parallel to patients on study 
• Test other DNA repair inhibitors for improved efficacy 
• Determine if combinations strategies (i.e., DNA damaging agents, DNA repair inhibitors, 
epigenetic targeted agents [hypomethylating agents, HDAC inhibitors], 
immunotherapies) will enhance treatment response. 
 
In subsets of patients where baseline bone marrow aspirates yield sufficient cells (>1x107), we 
will create patient-derived xenograft (PDX) models. We will use these to test the efficacy of 
olaparib and other DNA repair inhibitors, either alone or in combination, with or without DNA 
damaging agents, against IDH1/2-mutant AML/MDS. Such studies will be informative for 
future AML/MDS trials that seek to maximally exploit the observed mutant IDH1/2-induced 
DNA repair defect. 
 
We will utilize a cutting-edge mouse model for human AML/MDS xenotransplantation recently 
developed by the Halene laboratory in collaboration with the laboratory of Dr. Richard Flavell 
using cytokine-humanized immunodeficient M-CSFh/h IL-3/GM-CSFh/h SIRPAh/m TPOh/h 
Rag2−/− Il2rg−/− (MISTRG) mice (Rongvaux et al., 2014; Rathinam et al., 2011; Strowig et al., 
2011). While Nod Scid γ-/- (NSG) mice have become the gold standard for transplantation of 
human hematopoietic cells, engraftment remains low, with predominance of CD3+ human T- 
cells or CD19+ B-cells with only minimal myeloid engraftment (Martin et al., 2010), or limited 
to the injected tibial bone, when aided by co-injection of human mesenchymal stem cells 
(Muguruma et al., 2011). To circumvent the limitations of current xenotransplant models, 
MISTRG were engineered via knock-in technology to express human cytokines in place of their 
murine counterparts (Rongvaux et al., 2011). The MISTRG mice carry humanized alleles for M- 
CSFh/h, IL-3/GM-CSFh/h, hSIRPαh/m, and hTPOh/h on the RAG2-/- γc-/- background, and are 
viable, healthy and fertile. Each of these gene-humanizations significantly improves the 
engraftment, differentiation and maintenance of human hematopoietic stem and progenitor cells 
(published characterization of multiple strains of knock-in mice on the RAG2−/−γc−/− 
background [Rathinam et al., 2011; Rongvaux et al., 2011]). Importantly, MISTRG mice lack 
the DNA repair defect inherent to the severe combined immunodeficiency (scid) genotype of 
NSG mice that is due to loss of DNA protein kinase (DNA-PK) (Biederman et al., 1991; Fulop 
and Phillips, 1990; Komatsu et al., 1995; Jeggo et al., 1995). DNA-PK is a critical mediator of 
non-homologous end joining (NHEJ), which is the other main DSB repair pathway that competes 

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with HR. As such, the use of MISTRG mice is critical for our proposed studies, since we will be 
testing combinations of DNA repair (e.g. PARP) inhibitors and DNA damaging agents for 
activity against AML cells transplanted in mice. 
 
MISTRG mice support improved engraftment of both normal CD34+ cells as well as CD34+ 
cells from all subtypes of MDS and of AML that otherwise do not engraft in NSG. MISTRG 
mice engraft hematopoietic stem cells and support multi-lineage development (Rongvaux et al., 
2014). Importantly, MISTRG show improved support of secondary engraftment, essential for 
the successful propagation of the PDX xenografts. Secondary MDS/AML MISTRG recipients 
successfully allow engraftment of primary MDS/AML from NSG or MISTRG mice, while NSG 
mice as secondary recipients support engraftment only for a subset of AML (data not shown). 
Secondary engraftment serves two purposes: 1) only true leukemia stem cells will give rise to 
secondary engraftment and leukemia stem cells are at the origin of disease relapse; 2) while 
primary engrafted mice can show considerable heterogeneity, secondary engrafted mice tend to 
exhibit more homogeneous engraftment levels; 3) secondary engrafted mice tend to represent 
uniform clonal distribution. 
 
 
3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 Age ≥18 years. Because no dosing or AE data are currently available on the use of 
olaparib in patients <18 years of age, children are excluded from this study, but will be 
eligible for future pediatric trials. 
 
3.1.2 Diagnosis of MDS or AML per World Health Organization 2016 classification. AML 
may be de novo, or following a prior hematologic disorder, including MDS or 
Philadelphia chromosome-negative myeloproliferative neoplasm, and/or therapy-related. 
Please refer to Appendix G. 
 
3.1.3 Patients must have a documented IDH1 or IDH2 mutation within 30 days of inclusion 
based on mutational testing. Only specific mutations that lead to a neomorphic 
phenotype will be eligible for enrollment, and include those listed below (Mondesir et al., 
2016) 
IDH1: R132V, R132G, R132S, R132L, R132C and R132H 
IDH2: R140W, R140L, R140Q, R172W, R172G, R172S, R172M, R172K 
 
3.1.4 Patients with AML or MDS should have disease that has relapsed after, or is refractory 
to, first-line therapy, with or without subsequent additional therapy. 
 
3.1.5 Patients with MDS should have at least a MDS-EB1 at the inclusion and have a revised 
International Prognostic Symptom Score risk stratification of intermediate, high, or very 
high risk. 
 
3.1.6 For patients with a known history of human immunodeficiency virus (HIV)-infected patients on 
effective anti-retroviral 

NCI Protocol #: 10264 
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27 
 
 
therapy with undetectable viral load within 6 months are eligible for this trial. 
 
3.1.7 For patients with a known history of chronic  hepatitis B virus (HBV) infection, the 
HBV viral  load must be undetectable on suppressive therapy, if indicated. 
 
3.1.8 Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured. For patients with HCV infection who are currently on treatment, they are eligible 
if they have an undetectable HCV viral load. 
 
3.1.9 Patients may or may not have been previously treated with IDH targeted therapies. 
 
3.1.10 Patients who have undergone allogeneic stem cell transplant (alloSCT) are eligible if they 
are ≥180 days from stem cell infusion, have no evidence of graft versus host disease 
(GVHD) > Grade 1, and are ≥2 weeks off all immunosuppressive therapy. 
 
3.1.11 Previous cytotoxic chemotherapy must have been completed at least 3 weeks and 
radiotherapy at least 2 weeks prior to Day 1 of treatment on the study, and all AEs 
(excluding alopecia) due to agents administered more than 4 weeks earlier should have 
recovered to < Grade 1. Patients with hematologic malignancies are expected to have 
hematologic abnormalities at study entry. Hematologic abnormalities that are thought to 
be primarily related to leukemia are not considered to be toxicities (AEs) and do not need 
to resolve to < Grade 1. 
 
3.1.12 ECOG performance status 0-2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.13 Patient must have recovered from toxicities of any prior treatment regimen (no CTCAE 
grading over 1 for non-hematological toxicities, return to baseline for hematological 
values). 
 
3.1.14 Ability to understand and the willingness to sign a written informed consent document. 
Patients with impaired decision-making capacity may have a close relative, guardian, 
caregiver, or Legally Authorized Representative consent on their behalf 
 
3.1.15 Patients must have adequate organ function measured within 28 days prior to 
administration of study treatment as defined below: 
− 
Total bilirubin ≤ 1.5x institutional upper limit of normal (ULN) unless considered 
due to Gilbert’s syndrome 
 
− 
Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase 
[SGOT]) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate 
Transaminase [SGPT]) ≤ 2.5 x institutional upper limit of normal unless 
considered due to organ leukemic involvement. If liver metastases are present in 
which case they must be ≤ 5x ULN 
 
− 
Creatinine clearance of > 30 ml/min 

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28 
 
 
− 
Patients are eligible for this study if low blood count and transfusion support are 
due to the MDS/AML. 
 
3.1.16 Patients must have, in the best estimate of the treating physician, a life expectance of at 
least 12-16 weeks. 
 
3.1.17 Postmenopausal or evidence of non-childbearing status for women of childbearing 
potential: negative urine or serum pregnancy test within 28 days of study treatment and 
confirmed prior to treatment on Day 1. 
 
Postmenopausal is defined as: 
 
− 
Amenorrheic for 1 year or more following cessation of exogenous hormonal 
treatments 
 
− 
Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the 
post menopausal range for women under 50 
 
− 
radiation-induced oophorectomy with last menses >1 year ago 
− 
chemotherapy-induced menopause with >1 year interval since last menses 
− 
surgical sterilisation (bilateral oophorectomy or hysterectomy) 
Male patients must use a condom during treatment and for 3 months after the last dose 
of olaparib when having sexual intercourse with a pregnant woman or with a woman 
of childbearing potential. Female partners of male patients should also use a highly 
effective form of contraception (see appendix D for acceptable methods) if they are of 
childbearing potential. 
3.2 
Exclusion Criteria 
 
3.2.1 Patients with acute promyelocytic leukemia. 
 
3.2.2 Patients with active central nervous system (CNS) leukemia or requiring maintenance 
intrathecal chemotherapy. 
 
3.2.3 Patients receiving concurrent chemotherapy, radiation therapy, or immunotherapy for 
AML/MDS. 
 
3.2.4 Patients actively receiving any other investigational agents. 
 
3.2.5 Management of treatment for patients with co-occurring mutations, like FLT3, will be 
prioritized by the treating physician after discussion of treatment options with the patient 
 
3.2.6 Hyperleukocytosis with >50,000 WBC/mcl. Hydroxyurea for WBC count control is 
permitted before starting treatment and may be continued until Day 28 of Cycle 1. The 

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29 
 
 
maximum dose of hydrea will be 6 grams per day. Patients will be withdrawn from the 
study if >50,000 WBC/mcl occur or recur >14 days after starting treatment on the study. 
 
3.2.7 Active, uncontrolled infection. Patients with infection controlled with antibiotics are 
eligible. 
 
3.2.8 Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, 
non-malignant systemic disease or active, uncontrolled infection. Examples include, but 
are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) 
myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord 
compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on 
High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that 
prohibits obtaining informed consent. 
 
3.2.9 Patients who are pregnant or nursing. Pregnant women are excluded from this study 
because olaparib is a PARP inhibitor with the potential for teratogenic or abortifacient 
effects. Because there is an unknown but potential risk for AEs in nursing infants 
secondary to treatment of the mother with olaparib, breastfeeding should be discontinued 
if the mother is treated with olaparib. These potential risks may also apply to other 
agents used in this study. 
 
3.2.10 Resting electrocardiogram indicating uncontrolled, potentially reversible cardiac 
conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled 
symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, 
electrolyte disturbances, etc.), or patients with congenital long QT syndrome. 
 
3.2.11 Patients with symptomatic uncontrolled CNS disease. Imaging to confirm the absence of 
brain metastases is not required. Patients with spinal cord compression unless considered 
to have received definitive treatment for this and evidence of clinically stable disease for 
28 days. 
 
3.2.12 The patient can receive a stable dose of corticosteroids, up to 20 mg by mouth (PO) 
prednisone daily, before and during the study as long as these were started at least 4 
weeks prior to treatment. 
 
3.2.13 Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication. 
 
 
3.2.14 Any previous treatment with PARP inhibitor, including olaparib. 
 
3.2.15 Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or 
moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout 
period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks 

NCI Protocol #: 10264 
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30 
 
 
for other agents. 
 
3.2.16 Major surgery within 2 weeks of starting study treatment and patients must have 
recovered from any effects of any major surgery. 
 
3.2.17 Patients with a known hypersensitivity to olaparib or any of the excipients of the product. 
 
3.2.18 Patient with active malignancies requiring active treatment that interferes with protocol 
therapy and/or with significant risk of clinical relapse within 12 months that would 
require treatment interfering with protocol therapy are excluded. 
 
3.2.19 Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 
2) caused by previous cancer therapy, excluding alopecia. 
 
3.2.20 Patients receiving any systemic chemotherapy or radiotherapy (except for palliative 
reasons) within 3 weeks prior to study treatment 
 
3.2.21 Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. 
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout 
period prior to starting olaparib is 2 weeks. Patients without reasonable alternative may 
be included in the trial after discussion with the medical monitor. 
 
3.2.22 Previous double umbilical cord blood transplantation (dUCBT). 
 
3.2.23 Breast feeding women. 
 
 
3.3 
Inclusion of Women and Minorities 
 
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. 
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
The epidemiology of AML and MDS shows a relatively even gender distribution with a slight 
male predominance. In therapy related myeloid neoplasms, there is an over-representation of 
women related to the high number of breast cancer survivors. There is no difference of 
incidence of AML, MDS, or presence of IDH mutation based on ethnicity or race. 

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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 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to Oncology Patient Enrollment Network (OPEN), Rave, or acting as a 
primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr. 
 
RCR utilizes five person registration types. 
• IVR: MD, DO, or international equivalent, 
• NPIVR: advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD), 
• AP: clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
(e.g., Roster Update Management System [RUMS], OPEN, Rave,), 
• Associate (A): other clinical site staff involved in the conduct of NCI-sponsored trials, 
and 
• Associate Basic (AB): individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, 
and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 

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32 
 
 
 
• Addition to a site roster, 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN, 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval, 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, or as 
the CI on the DTL must be rostered at the enrolling site with a participating organization (i.e., 
Alliance). 
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval 
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRB Manager to indicate 
their intent to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network. Site preferences can be set at the network 
or protocol level. Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol. 
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 

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• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and 
• Compliance with all protocol-specific requirements (PSRs). 
 
4.2.1 Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted based on person and site roster assignment. To participate, the 
institution and its associated investigators and staff must be associated with the LPO or a 
Participating Organization on the protocol. 
 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
• Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO CT018, 
and protocol number 10264, 
• Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB initiative, IRB data will load automatically 
to the CTSU as described above.) 
4.2.2 Protocol Specific Requirements For NCI Protocol #10264 Site Registration 
Upon site registration approval in RSS, the enrolling site may access OPEN to complete 
enrollments. The enrolling site will select their credentialed provider treating the subject in the 
OPEN credentialing screen, and may need to answer additional questions related to treatment in 
the eligibility checklist. 
 
• ETCTN Specimen Tracking Training 
o 
All data entry users (Clinical Research Associate Role) at each participating site 
will need to complete the Theradex-led training. 
o 
Theradex will provide a certificate of completion, which will need to be 
submitted to the CTSU through the Regulatory Submission Portal. 
o 
The training is a one-time only requirement per individual. If an individual has 
previously completed the training for another ETCTN study, the training does 
not need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU. However, new versions of the Specimen Tracking 
System may require new training. 
o 
This training will need to be completed before first/further patient enrollment at a 
given site. 
o 
Peter Clark and Diana Vulih are the main points of contact at Theradex for the 
training (PClark@theradex.com and Dvulih@theradex.com, Theradex phone: 
609-799-7580). 

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34 
 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website. 
To access the Regulatory Submission Portal, log on to the CTSU members’ website ➔ 
Regulatory ➔ Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific DTL using the DTL application in the Delegation 
Log section on the CTSU members’ website. The Clinical Investigator (CI) is required to review 
and electronically sign the DTL prior to the site receiving an Approved site registration status 
and enrolling patients to the study. To maintain an approved site registration status the CI must 
re-sign the DTL at least annually and when a new version of the DTL is released; and activate 
new task assignments requiring CI sign-off. Any individual at the enrolling site on a 
participating roster may initiate the site DTL. Once the DTL is submitted for CI approval, only 
the designated DTL Administrators or the CI may update the DTL. Instructions on completing 
the DTL are available in the Help Topics button in the DTL application and include a Master 
Task List, which describes DTL task assignments, CI signature, and CTEP registration 
requirements. 
 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site’s registration status on the members’ side of the CTSU website. 
 
• Log on to the CTSU members’ website 
• Click on Regulatory at the top of your screen 
• Click on Site Registration 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status shown only reflects institutional compliance with site 
registration requirements as outlined above. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the 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 

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35 
 
 
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. 
• If a DTL is required for the study, the registrar(s) must hold the OPEN Registrar 
task on the DTL for the site. 
• 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. 
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
 
 
4.3.2 Special Instructions for Patient Enrollment 
 
For the ETCTN Biobanking and Molecular Characterization Initiative, 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 

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36 
 
 
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 ETCTN Biobanking and Molecular Characterization 
portion of this protocol. 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) and the IWRS-assigned UPID for 
this trial. Important: Remove any personally identifying information, including, but 
not limited to, the patient’s name, initials, and patient ID# for this treatment trial, 
from the institutional pathology report prior to submission. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org. For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 28 days. For AML 
patients, treatment should be started as rapidly as possible. Issues 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 
Study Coordinator should be notified of cancellations as soon as possible. 

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37 
 
 
 
5. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
5.1 
Summary Table for Specimen Collection 
 
Time Point 
Specimen 
Send Specimens To: 
Enrollment/Baseline 
• 
Bone marrow (2-3 mL, EDTA tube) 
Local CLIA Laboratory 
• 
Peripheral blood (25 mL, EDTA) 
• 
Bone marrow (2-3 mL, EDTA tube) 
Pharmacology Core, Karmanos Cancer 
Institute, Wayne State University School 
of Medicine 
• 
Buccal Swab 
• 
Peripheral blood (25 mL, EDTA, fresh) 
• 
Bone marrow (4-6 mL, EDTA tube, fresh) 
EET Biobank 
• 
Bone marrow (4-6 mL, EDTA tube, fresh) 
Halene Lab, Yale School of Medicine 
End of Cycle 1 
• 
Peripheral blood (25 mL, EDTA) 
• 
Bone marrow (2-3 mL, EDTA tube)* 
Pharmacology Core, Karmanos Cancer 
Institute, Wayne State University School 
of Medicine 
IDHi-naïve cohort only: 
• 
Peripheral blood (25 mL, EDTA, fresh) 
• 
Bone marrow (4-6 mL, EDTA tube, fresh) 
EET Biobank  
End of Cycle 3 
• 
Peripheral blood (25 mL, EDTA) 
• 
Bone marrow (2-3 mL, EDTA tube)* 
Pharmacology Core, Karmanos Cancer 
Institute, Wayne State University School 
of Medicine 
• 
Peripheral blood (25 mL, EDTA, fresh) 
• 
Bone marrow (4-6 mL, EDTA tube, fresh) 
EET Biobank 
End of Cycle 6 
• 
Peripheral blood (25 mL, EDTA) 
• 
Bone marrow (2-3 mL, EDTA tube)* 
Pharmacology Core, Karmanos Cancer 
Institute, Wayne State University School 
of Medicine 
• 
Bone marrow (4-6 mL, EDTA tube, fresh) 
EET Biobank 
End of Cycle 9 
• 
Peripheral blood (25 mL, EDTA) 
• 
Bone marrow (2-3 mL, EDTA tube)* 
Pharmacology Core, Karmanos Cancer 
Institute, Wayne State University School 
of Medicine 
• 
Bone marrow (4-6 mL, EDTA tube, fresh) 
EET Biobank 
End of Cycle 12 
• 
Peripheral blood (25 mL, EDTA) 
• 
Bone marrow (2-3 mL, EDTA tube)* 
Pharmacology Core, Karmanos Cancer 
Institute, Wayne State University School 
of Medicine 
• 
Bone marrow (4-6 mL, EDTA tube, fresh) 
EET Biobank 
End of Treatment 
• 
Peripheral blood (25 mL, EDTA) 
• 
Bone marrow (2-3 mL, EDTA tube)* 
Pharmacology Core, Karmanos Cancer 
Institute, Wayne State University School 
of Medicine 
• 
Peripheral blood (25 mL, EDTA, fresh)* 
• 
Bone marrow (4-6 mL, EDTA tube, fresh)* 
EET Biobank 

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38 
 
 
• 
Bone marrow (4-6 mL, EDTA tube, fresh) 
Halene Lab, Yale School of Medicine 

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39 
 
 
*Optional collection 
 
 
5.2 
Specimen Procurement Kits and Scheduling 
 
5.2.1 Specimen Shipping Kits 
Kits are not provided for this study. Sites must use institutional supplies for the collection and 
shipment of specimens. 
 
5.2.2 Scheduling of Specimen Collections 
Fresh blood and bone marrow shipped to the EET Biobank can be collected Monday through 
Friday, and shipped overnight for receipt Tuesday through Saturday. 
Specimens submitted frozen (e.g., bone marrow aspirate and plasma) can be collected on any day 
but must be stored frozen and shipped to Karmanos Cancer Institute on Monday through 
Thursday. In the event that frozen specimens cannot be shipped immediately, they must be 
maintained at -80°C. 
 
Specimens shipped to the EET Biobank and shipped to Yale University for single cell 
sequencing studies (Section 2.4.3.1) and for avatar studies (Section 2.4.3.3) must be fresh 
and shipped same day of procedure to arrive the following day. All other samples may be 
frozen. 
 
5.3 
Specimen Tracking System Instructions 
 
All biospecimens collected for this trial must be submitted using the ETCTN Rave Specimen 
Tracking System (STS) unless otherwise noted. The system is accessed through special Rave 
user roles: “CRA Specimen Tracking” for data entry at the treating institutions and 
“Biorepository” for users receiving the specimens for processing and storage at reference labs 
and the Biorepository. Please refer to the Medidata Account Activation and Study Invitation 
Acceptance link on the CTSU website under the Rave/DQP tab. 
 
Important: Failure to complete required fields in STS may result in a delay in sample 
processing. Any case reimbursements associated with sample submissions will not be credited 
if samples requiring STS submission are not logged into STS. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software. 
 
For questions regarding the Specimen Tracking System, please contact the Theradex Help Desk 
at CTMSSupport@theradex.com. 
 
A shipping manifest must be included with all sample submissions. 
 
5.3.1 Specimen Labeling 

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5.3.1.1 Blood and Bone Marrow Aspirate Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma) and bone marrow specimens: 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood, serum) 
• Collection date and time (to be added by hand) 
 
5.3.1.2 Example of Specimen Label 
 
The following image is an example of a tissue specimen label printed on a standard Avery label 
that is 1” high and 2.625” wide. 
 
 
 
The QR code in the above example is for the Specimen ID shown on the second line. 
NOTE: The QR code label is currently under development at Theradex as of 31-Aug-2018; 
therefore, labels generated by the STS for this study may not include a QR code. 
 
The second line item from the end includes four data points joined together: 
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. 
 
5.3.2 Overview of Process at Treating Site 
 
5.3.2.1 OPEN Registration 
 
All registrations will be performed using the OPEN system. OPEN communicates 
automatically with the IWRS which handles identifier assignments, any study 

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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. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.3.2.2 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 (if applicable), Tissue type, Surgical Path ID, 
number of labels needed (include extra labels to apply to reports to be uploaded). 
CRF generates unique Specimen ID. 
Step 2: Print labels using report in EDC and collect specimen. 
• Label specimen containers and write collection date and time on each label. 
• After collection, store labeled specimens as described in Section 5.4. 
• Apply an extra specimen label to each report before scanning. Return to the 
Histology and Disease form to upload any initial Pathology, Bone Marrow, 
and/or Molecular Reports (up to 4), Surgical reports and Pathology Verification 
form (when applicable). Return to Specimen Tracking Enrollment CRF to 
upload any molecular report (one per specimen) and/or specimen specific 
pathology or related report (one per specimen). Uploaded reports should have 
protected health information (PHI) data, like name, mailing address, medical 
record number or social security number (SSN) redacted. Do not redact the 
surgical pathology ID (SPID), block number or relevant dates (such as collection 
date), and include the UPID and patient ID on each document. 
 
Step 3: Complete specimen data entry. 
• Specimen Transmittal Form: Enter Collection date and time and other required 
specimen details. 
 
Step 4: When ready to ship, enter shipment information. 
• Shipping Status CRF: Enter tracking number, your contact information, 
recipient, number of containers and ship date once for the 1st specimen in a 
shipment. 
• Copy Shipping CRF: Select additional specimens to add to an existing shipment 

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referenced by the tracking number. 
 
Step 5: Print shipping list report and prepare to ship. 
• Print two copies of the shipping list, one to provide in the box, the other for your 
own records. 
• Print pathology or other required reports to include in the box. Be sure the printed 
copy includes the specimen label. 
 
Step 6: Send email notification. 
• For only one of the specimens in the shipment, click “Send Email Alert” 
checkbox on the Shipping Status CRF to email recipient. 
 
Step 7: Ship the specimen(s). 
 
5.4 
Specimen Collection 
 
5.4.1 Collection of Blood in EDTA Tubes for Plasma Processing (shipped to Karmanos Cancer 
Institute) 
 
1. Label EDTA tubes according to the instructions in Section 5.3.1. 
2. Collect 25 mL blood in EDTA tube(s) and gently invert tube to mix. 
3. Within 1 h after blood collection, plasma will be separated from the blood sample by 
centrifugation (1500 x g, 10 minutes, at 4°C) 
4. Using a clean transfer pipette, disperse plasma into labeled vials (using the label 
printed from the ETCTN Specimen Tracking System or following the instructions in 
Section 5.3.1) creating 4 aliquots of approximately equal volume. Avoid picking up 
the blood cells when aliquoting by keeping the pipet above the cell layers and leaving 
a small amount of plasma in the tube. 
5. Tightly secure the cap of the vials before storage. Aliquoting and freezing of plasma 
specimens should be completed within 1 hour of centrifugation. 
Store plasma vials upright in a specimen box or rack in a -80°C freezer prior to shipping to the 
Karmanos Cancer Institute. Do not allow specimens to thaw after freezing. 
5.4.2 Collection of Bone Marrow Aspirate for Frozen Samples (shipped to Karmanos Cancer 
Institute) 
 
1. Label EDTA tubes according to the instructions in Section 5.3.1. 
2. Collect 2-3 mL bone marrow aspirate in each EDTA tube and gently invert tube to 
mix. Bone marrow aspirates will be processed within 1 hour of collection: bone 
marrow will be layered on Ficoll without dilution, spun at 450g for 20 min with 
breaks off, and 4 aliquots will be made and frozen in chilled FBS 90%/DMSO 
10% at -80°C prior to delivering to laboratory. Do not allow specimens to thaw 
after freezing. 
3. Bone marrow collections for each assay should be collected in separate tubes, with 
slight adjustment of the aspirate needle for each pull (and visual confirmation of 
spicules to confirm quality of aspirate). 
 
5.4.3 Collection of Peripheral Blood or Bone Marrow Aspirate for Fresh Samples (shipped to 

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the EET Biobank or Yale University) 
 
1. Label EDTA tubes according to the instructions in Section 5.3.1. 
2. Collect peripheral blood or bone marrow aspirate in each EDTA tube (refer to Section 
5.1 for volumes), and gently invert to mix. 
3. Samples may be sent in the EDTA tubes at ambient temperature if received within 24 
hours (must ship same day). 
4. Ship on day of collection (whenever possible) according to instructions in section 5.6. 
5. If bone marrow cannot be shipped on the day of collection, they need to be 
ficolled and viably cryopreserved within 24 hours of procedure (FBS 90%/ 
DMSO 10% or other freezing medium) on site and shipped at a later time on 
dry ice. 
 
5.5 
Shipping Specimens from the Clinical Site to the EET Biobank 
 
5.5.1 Specimen Shipping Instructions 
 
 
5.5.1.1 
Shipping Fresh Blood or Bone Marrow 
 
The following supplies are needed to ship whole blood or bone marrow: (1) a sturdy 
shipping container (e.g., a cardboard or styrofoam box), (2) a leak proof biohazard 
envelope with absorbent material*, (3) a puncture and pressure resistant envelope (e.g. 
Tyvek envelope), (4) an Exempt Human Specimen sticker, and (5) a pre-paid FedEx air 
bill. 
 
1. 
Before packaging specimens, verify that each specimen is labeled according to 
the instructions above and that lids of all primary receptacles containing liquid 
are tightly sealed. 
2. 
Place the specimens in zip-lock bags. Use a separate zip-lock bag for each 
specimen type and time point. 
3. 
Place the zip-lock bags in the biohazard envelope containing absorbent material. 
Expel as much air as possible and seal securely. 
4. 
Wrap the biohazard envelope with bubble wrap or other padded material. 
5. 
Put the padded specimens into a Tyvek envelope. Expel as much air as possible 
and seal securely. 
6. 
Place the Tyvek envelop in a sturdy shipping container (e.g., cardboard FedEx 
box). 
7. 
Insert a copy of the required forms into a plastic bag and place in the box. 
8. 
Close the outer lid of the shipping box and tape it shut with durable sealing tape. 
9. 
Complete a FedEx air bill and attach to top of shipping container. 
10. Attach an Exempt Human Specimen sticker to the side of the shipping container. 
11. Ship specimens via overnight courier to the address below. FedEx Priority 
Overnight is strongly recommended to prevent delays in package receipt. 
 
5.5.2 Shipping Address for the EET Biobank 
 

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Ship to the address below. Ship fresh blood and bone marrow specimens the same day of 
specimen collection. Do not ship specimens the day before a holiday or weekend. 
 
EET Biobank 
2200 International Street 
Columbus, OH  43228 
PH: (614) 722-3270 
FAX: (614) 722-2856 
Email: BPCMGLab@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred. 
 
NOTE: The ETCTN Biorepository FedEx Account will not be provided to submitting 
institutions. 
 
5.5.3 Contact Information for Assistance 
For all queries, please use the contact information below: 
EET Biobank  
Phone: (614) 722-3270 
E-mail: BPCMGLab@nationwidechildrens.org 
 
 
5.6 
Shipping Specimens from the Clinical Site to Other Laboratories 
 
5.6.1 Shipping of Specimens to Karmanos Cancer Institute 
 
5.6.1.1 
Specimen Shipping Instructions 
 
All frozen plasma, blood, and tumor samples should be placed in cardboard tray/box, 
so  samples remain upright. This tray/box is to be placed in a Styrofoam carton with 10-
15 lbs of dry ice (block with or without pellets) to keep samples frozen during shipping. 
A  copy of PK sheets should be in the shipping box, reflecting the samples that are 
being sent. Samples should be shipped via FedEx Priority Overnight service. Please 
notify Jing Li via email (LiJing@wayne.edu) when samples are shipped and include 
the shipment tracking number. 
 
Samples can be batched and shipped. 
5.6.1.2 
Shipping Address 
Jing Li 
Pharmacology Core 
Karmanos Cancer Institute 
4100 John R, HWCRC – room 523 
Detroit, MI 48201 

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5.6.1.3 
Contact Information for Assistance 
 
Dr. Jing Li 
Phone: (313) 576-8258 
Email: LiJing@wayne.edu 
 
5.6.2 Shipping of Specimens to Yale University 
 
5.6.2.1 
Shipping Address 
 
Yale School of Medicine/ Section of Hematology 
300 George Street 
Room 787A 
New Haven, CT 06511 
5.6.2.2 
Contact Information for Assistance 
Dr. Stephanie Halene 
Phone: (203)-812-9731 
Email: stephanie.halene@yale.edu 

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46 
 
 
 
5.7 
Biomarker Plan 
 
List of Biomarker Assays in Order of Priority 
Priority 
Biomarker 
Name 
Biomarker 
Assay 
Biomarker Type and 
Purpose 
M/O 
Specimen(s) and Time Point(s) 
Laboratory Performing 
Assay 
1 
IDH1/2 
Mutation 
DNA sequencing 
or PCR 
• Integral 
• Eligibility criteria 
M 
• Bone marrow aspirate 
• Enrollment 
Local CLIA-certified laboratory 
2 
2HG Levels 
LC-MS/MS 
• Integrated 
• Potential biomarker of 
response 
M 
• Plasma 
• Enrollment, after Cycles 1, 3, 6, 9, 12, 
and end of treatment 
Jing Li, Karmanos Cancer 
Institute 
LiJing@wayne.edu 
3 
2HG Levels 
LC-MS/MS 
• Exploratory 
• Potential biomarker of 
response 
M/O 
• Bone marrow aspirate 
• Mandatory: enrollment 
• Optional: after Cycles 1, 3, 6, 9, 12, and 
end of treatment 
Jing Li, Karmanos Cancer 
Institute 
LiJing@wayne.edu 
4 
Genomic 
Profiling 
Whole exome 
sequencing 
• Exploratory 
• To evaluate clonal evolution 
and clonal architecture 
M/O 
• DNA from buccal swab (enrollment 
only) 
• DNA from bone marrow aspirate* 
• DNA from blood 
• Mandatory: enrollment, after Cycles 1, 3, 
6, 9, and 12 
• Optional: end of treatment 
• End of Cycle 1: IDHi-naïve cohorts only 
Chris Karlovich – MoCha, 
National Cancer Institute 
chris.karlovich@nih.gov 
5 
Genomic 
Profiling 
RNA sequencing 
• Exploratory 
• To evaluate clonal evolution 
and clonal architecture 
M/O 
(Will be assessed using RNA from bone 
marrow aspirate and blood obtained from 
WES biomarker.) 
• Mandatory: enrollment, after Cycles 1, 3, 
6, 9, and 12 
• Optional: end of treatment 
• End of Cycle 1: IDHi-naïve cohorts only 
Chris Karlovich – MoCha, 
National Cancer Institute 
chris.karlovich@nih.gov 
 
 
6 
 
Genomic 
Profiling 
 
Single Cell DNA 
Sequencing 
• 
Exploratory 
• 
Evaluation of the clonal 
heterogeneity/evolution by 
single cell DNA sequencing 
 
M/O 
Samples from the biorepository will be used 
• 
bone marrow sample at enrollment, 
after Cycles  1  (optional), 3 , 6, 12 
and end of treatment 
Stephanie Halene, Yale 
University 
Stephanie.halene@yale.edu 
Ranjit Bindra, Yale University 
Ranjit.bindra@yale.edu 
7 
Avatar 
Studies 
PDX model 
• Exploratory 
• To evaluate disease 
response 
M 
• Bone marrow aspirate 
• Enrollment 
Stephanie Halene, Yale 
University 
Stephanie.halene@yale.edu 
Ranjit Bindra, Yale University 
Ranjit.bindra@yale.edu 

 December 11, 2024 
47 
 
 
 
Priority 
Biomarker 
Name 
Biomarker 
Assay 
Biomarker Type and 
Purpose 
M/O 
Specimen(s) and Time Point(s) 
Laboratory Performing 
Assay 
8 
Genomic 
Profiling 
Infinium 
methylation 
array 
• Exploratory 
• To evaluate clonal evolution 
and clonal architecture 
M/O 
(Will be assessed using DNA from bone 
marrow aspirate and blood obtained from 
WES biomarker.) 
• Mandatory: enrollment, after Cycles 1, 3, 
6, 9, and 12 
• Optional: end of treatment 
• End of Cycle 1: IDHi-naïve cohorts only 
Michael Berens, Translational 
Genomics Research Institute 
mberens@tgen.org 
9 
Pharmacom- 
etabolomic 
Profiling 
LC-MS/MS 
• Exploratory 
• To evaluate metabolic 
signatures 
O 
(Will be assessed using plasma and bone 
marrow aspirate collected for 2HG levels.) 
• Enrollment, after Cycles 1, 3, 6, 9, 12, 
and end of treatment 
Jing Li, Karmanos Cancer 
Institute 
LiJing@wayne.edu 
*Availability of bone marrow sample: If a bone marrow procedure is not available for any reason, we can consider using a peripheral blood sample (30 mL per 
time point) for the different studies, provided that a minimum of 1g/L of circulating blasts are present on the differential of the CBC. 

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Prioritization of analyses for pauci-cellular samples with low cell yield: 
• Metabolomic studies can be done on blood only (DiNardo et al., 2013). We will so prioritize 
the use of bone marrow for the other exploratory objectives. For bone marrow studies, at 
enrollment and EOT, the priority will be the WES/RNAseq study followed by single-cell 
DNA sequencing, avatar studies and the methylation studies. During treatment, the priority 
will be the WES/RNAseq, single-cell DNA sequencing and the avatar study, which take 
precedent over the methylation studies. 
• The viably cryopreserved bone marrow cells can be used as a back-up for the WES, or 
the methylation analyses. 
• Considering time points: For exploratory objectives, if a prioritization needs to be discussed 
on serial samples, we will keep as a high priority the baseline, end of Cycle 1, and end-of - 
treatment (EOT) samples. Samples for end of Cycle 3, 6, 9, and 12 are low priority. 
 
5.8 
Integral Correlative Study 
 
5.8.1 Detection of IDH1/2 Mutations 
 
5.8.1.1 Site Performing Correlative Study 
 
Mutation-detection for eligibility will be conducted by CLIA-certified laboratories. The 
WES performed by the Molecular Characterization (MoCha) Laboratory (see Section 
5.10.1 for details) will be used as a confirmation method, but will not be used for 
eligibility. 
 
5.9 
Integrated Correlative Studies 
 
5.9.1 Determination of 2HG Levels in Plasma 
 
5.9.1.1 Site Performing Correlative Study 
 
The determination of 2HG levels will be performed in the laboratory of Dr. Jing Li at the 
Karmanos Cancer Institute. 
 
5.9.1.2 Specimen(s) Receipt and Processing 
 
The levels of 2HG in plasma samples will be determined using a validated LC-MS/MS 
method in Karmanos Cancer Institute (KCI) Pharmacology Core. Samples will be 
shipped to the KCI Pharmacology Core for analysis. The LC-MS/MS analysis will be 
performed on an AB Sciex QTRAP 6500 LC-MS/MS system, which consists of an 
enhanced high-performance hybrid triple quadrupole and linear ion trap mass 
spectrometer, interfaced with a SHIMADZU Nexera ultra-high-performance liquid 
chromatography system. 
 
The method has been developed and fully validated for the selectivity, sensitivity, 
linearity, intra- and inter- accuracy and precision, recovery, and stability, based on the US 
FDA Guidance to Bioanalytical Method Validation. In brief, the chromatographic 
separation will be achieved on a Phenomenex SynergiTM Polar-RP column (150 × 2 mm, 

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4 mcm) using a gradient elution consisting of mobile phase A (0.03% formic acid in 
water) and mobile phase B (0.03% formic acid in acetonitrile), at the flow rate of 0.25 
mL/min. 2HG and its stable isotope-labeled internal standard will be monitored under 
negative electrospray ionization mode at the mass transitions m/z, 147.0 > 128.9 and 
150.0 > 131.9, respectively. 
 
2HG levels in plasma will be compared to treatment responses. In addition, we will 
compare 2HG levels with genomic profiling studies proposed below in order to assess 
whether correlations can be made with (a) co-occurring mutations, (b) gene expression 
patterns, and (c) methylation profiles. 
 
 
5.10 Exploratory/Ancillary Correlative Studies 
 
5.10.1 Determination of 2HG Levels in Bone Marrow Aspirate 
 
5.10.1.1 Site Performing Correlative Study 
 
The determination of 2HG levels will be performed in the laboratory of Dr. Jing Li at the 
Karmanos Cancer Institute. 
 
5.10.1.2 Specimen Receipt and Processing 
 
The levels of 2HG in bone marrow biopsy samples will be determined using a validated 
LC-MS/MS method in Karmanos Cancer Institute (KCI) Pharmacology Core. Samples 
will be shipped to the KCI Pharmacology Core for analysis. The LC-MS/MS analysis 
will be performed on an AB Sciex QTRAP 6500 LC-MS/MS system, which consists of 
an enhanced high-performance hybrid triple quadrupole and linear ion trap mass 
spectrometer, interfaced with a SHIMADZU Nexera ultra-high-performance liquid 
chromatography system. 
 
The method has been developed and fully validated for the selectivity, sensitivity, 
linearity, intra- and inter- accuracy and precision, recovery, and stability, based on the US 
FDA Guidance to Bioanalytical Method Validation. In brief, the chromatographic 
separation will be achieved on a Phenomenex SynergiTM Polar-RP column (150 × 2 mm, 
4 mcm) using a gradient elution consisting of mobile phase A (0.03% formic acid in 
water) and mobile phase B (0.03% formic acid in acetonitrile), at the flow rate of 0.25 
mL/min. 2HG and its stable isotope-labeled internal standard will be monitored under 
negative electrospray ionization mode at the mass transitions m/z, 147.0 > 128.9 and 
150.0 > 131.9, respectively. 
 
2HG levels in bone marrow will be compared to treatment responses. In addition, we 
will compare 2HG levels with genomic profiling studies proposed below in order to 
assess whether correlations can be made with (a) co-occurring mutations, (b) gene 
expression patterns, and (c) methylation profiles. 

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5.10.2 Genomic Profiling (WES, RNAseq, and Infinium Methylation Array) 
 
5.10.2.1 
Specimen Receipt and Processing at the EET Biobank 
 
Upon receipt at the EET Biobank, the bone marrow and blood will be processed for 
mononuclear cells using a ficoll-hypaque gradient (baseline and relapse time points) or 
processed for white blood cells by lysing red blood cells (all other time points). Bone 
marrow and blood will undergo pathology review to assess the number of blasts. 
Mononuclear cells and white blood cells will be frozen in a freezing media and stored in 
a liquid nitrogen vapor phase freezer until distribution for testing. At each time point, 
DNA and RNA will be co-extracted from bone marrow and blood. Nucleic acids will be 
stored in a -80°C freezer until distribution for testing. 
 
All samples will be co-extracted for DNA and RNA at each time point. 
 
5.10.2.2 Sites Performing Correlative Study 
 
WES and RNAseq will be performed by the MoCha Laboratory, and Infinium 
Methylation assays will be performed by the laboratory of Michael Berens at the 
Translational Genomics Research Institute (TGen). 
 
Genomic profiling will be performed systematically on a separate sample of the bone 
marrow aspirate, or a “second pull” obtained specifically for biomarker studies. WES 
study, RNAseq, and methylome will require relatively low amount of nucleic acids with 
100 ng of DNA for WES or methylome and 100 ng of RNA for the RNAseq. 
 
5.10.3 Pharmacometabolomic Profiling 
 
5.10.3.1 Specimen(s) Receipt and Processing at the Karmanos Cancer Institute 
Pharmacology Core 
 
Samples will be processed according to institutional SOPs. 
 
5.10.3.2 Site Performing Correlative Study 
 
Pharmacometabolomic profiling will be performed in the laboratory of Dr. Jing Li at the 
Karmanos Cancer Institute. 
 
5.10.3.3 Specimen Receipt and Processing 
 
We will apply a LC-MS/MS based targeted metabolomics platform to define the plasma 
metabolic signature of olaparib exposure in AML patients. Metabolic profiling will be 
performed in the pre- and post- olaparib treatment plasma samples using a targeted 
metabolomics platform, which has been established in the KCI Pharmacology Core. This 
platform can quantitatively measure about 300 metabolites that are involved in major 
human metabolic pathways (Table 2). All LC-MS/MS analyses were performed on an 

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AB SCIEX QTRAP 6500 LC-MS/MS system. Analyst 1.6 software was used for system 
control and data acquisition and MultiQuant 3.0 software was used for data processing 
and quantitation. 
 
Table 2 Typical endogenous metabolites measured by the LC-MS/MS based targeted metabolomics 
platform. 
Classes or Pathways 
Number of Metabolites 
Glycolytic, TCA cycle, and pentose phosphate pathway 
25 
Nucleosides, nucleotides and NAD-related metabolites 
40 
Amino acid and related metabolites 
60 
Acyl CoAs 
10 
Acyl Carnitines 
20 
Bile acids 
15 
Ceramides 
10 
Steroids 
10 
Short chain fatty acids 
8 
Phospholipids 
15 
Gut microbial related metabolites 
15 
Miscellaneous Metabolites 
65 
Total 
293 
 
 
5.10.4 Creation of Patient-Derived Xenograft (PDX) Models from Baseline Bone Marrow 
Biopsies. 
 
5.10.4.1 Specimen Receipt and Processing at Yale University 
Specimens will be processed according to institutional SOPs. 
5.10.4.2 Sites Performing Correlative Study 
 
PDX modeling will be performed in the laboratories of Dr. Stephanie Halene and Dr. 
Ranjit Bindra at Yale University. 
 
We will stratify MDS/AML PDX mice to treatment arms via pre-treatment determination 
of engraftment levels in peripheral blood and bone marrow via aspiration. We will 
determine 2HG levels in plasma before and after treatment. At conclusion of the 
treatment we will euthanize animals and determine treatment efficacy via comprehensive 
analysis that includes complete blood count (CBC), flow cytometric analysis for human 
cell percentage and differentiation, histology, hematopoietic and non-hematopoietic 
organ infiltration, and spleen size. In addition, to determine the efficiency of the 
treatment to eliminate the leukemia stem cell we will perform single cell RNAseq and 
serial transplantation into tertiary recipients to phenotypically and functionally assess 
possible persistence of leukemic stem cells. 
 
       5.10.5   Evaluation of the clonal heterogeneity evolution by single cell DNA sequencing 
 
        5.10.5.1  Specimens will be processed according to institutional SOPs 

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5.10.5.2  Sites performing correlative study 
 
Single cell DNA sequencing will be performed in the laboratories of Dr. Stephanie 
Halene and Dr. Ranjit Bindra at Yale University 
 
We will use patient’s bone marrow samples collected at enrollment and after Cycles 1 [optional], 3, 
6, 12 and at end of treatment. Mononuclear cells will be separated using a Ficoll Hypaque 
purification method and viably cryopreserved in FBS 90%/DMSO10% or other appropriate freezing 
medium. At time of sequencing batches of 4 samples will be processed at the same time and 
evaluated using the Mission Bio Tapestri single cell DNA sequencing platform. A minimum of 10^4 
living cells are required to proceed for each sample and we will be using the commercially available 
45-gene panel. We will compare the evolution of the subclones at the different stages of the 
treatment, evaluate the proportion of IDH mutated clones persisting after treatment, evaluate the co-
mutations as well as the most common mechanisms of resistance (e.g. IDH mutation switch, 
development of a RAS or FLT3 mutant clone). A subset of the samples (e.g. patients with 
concomitant IDH and SRSF2 mutations) will be evaluated with a customized panel and another 
subset of patients will be evaluated using a multi-omic approach using in parallel a barcoded 
cytometry antibody panel.  
 
 
 
6. 
TREATMENT PLAN 
6.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Reported AEs and potential risks are 
described in Section 10. Appropriate dose modifications are described in Section 7. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Regimen Description 
Agent 
Premedications / 
Precautions 
Dose 
Route Schedule 
Cycle 
Length 
Olaparib 
• Do not consume 
grapefruit juice. 
• Olaparib tablets 
can be taken with 
or without food. 
If CrCl = 30 - 50 mL/min: 
200 mg (2 x 100 mg tablets) 
Tablet 
PO 
q12h 
Daily 
28 days 
(4 weeks) 
If CrCl > 50 mL/min: 
300 mg (2 x 150 mg tablets) 
PO = oral administration, q12h = every 12 hours 
 
• For patients with CrCl between 30 and 50 mL/min, the starting dose will be 200 mg bid. 
• For patients with CrCl > 50 mL/min, the starting dose will be 300 mg bid. 
 

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6.1.1 Olaparib 
 
Patients will be administered olaparib every 12 hours (q12h). Olaparib tablets should be taken at 
the same time each day, approximately 12 hours apart with one glass of water. The olaparib 
tablets should be swallowed whole and not chewed, crushed, dissolved, or divided. Olaparib 
tablets can be taken with or without food. It is prohibited to consume grapefruit, grapefruit juice, 
or Seville oranges while on olaparib therapy. 
 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted. Should any patient enrolled on the 
study miss a scheduled dose for whatever reason (e.g., as a result of forgetting to take the tablets 
or vomiting), the patient will be allowed to take the scheduled dose up to a maximum of 2 hours 
after that scheduled dose time. If greater than 2 hours after the scheduled dose time, the missed 
dose is not to be taken and the patient should take their allotted dose at the next scheduled time. 
 
The patient will be requested to maintain a medication diary (see Appendix F) of each dose of 
medication. The medication diary will be returned to clinic staff at the end of each course. 
 
6.1.2 Overdose 
 
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established. 

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Olaparib must only be used in accordance with the dosing recommendations in this protocol. 
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol 
should be reported as an overdose. Per the Olaparib Investigator’s Brochure (2019), the 
Maximum Tolerated Dose is 300 mg twice daily (tablet). 
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately. 
 
6.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of olaparib with other concomitantly administered 
drugs, the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, vitamins, nutritional supplements, or alternative therapies at the time of enrollment 
and throughout the study. The case report form should capture the dates of administration 
(including start/end dates if known), dosage (including dosing frequency/schedule), and reason 
for use. The PI should be alerted if the patient is taking any agent known to affect or with the 
potential for drug interactions. The study team should check a frequently-updated medical 
reference for a list of drugs to avoid or minimize use of. Appendix B (Patient Drug Information 
Handout and Wallet Card) should be provided to patients if available. 
 
6.2.1 Anti-Emetics/Anti-Diarrheal 
 
From screening part 2 onwards, should a patient develop nausea, vomiting and /or diarrhea, then 
these symptoms should be reported as AEs and appropriate treatment of the event given. An 
information sheet for patients regarding management and reporting of diarrhea can be found in 
Appendix E. 

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6.2.2 Medications that may NOT be administered: 
 
Prohibited medications 
 
Prohibited medication/class of drug: 
Anticancer therapy: 
Chemotherapy 
Immunotherapy 
Hormonal therapy* 
Radiotherapy (except palliative) 
Biological therapy including growth factors 
Other novel agents 
 
 
 
 
 
 
Live virus vaccines 
Live bacterial vaccines 
 
 
 
*Hormone Replacement Therapy (HRT) is acceptable 
 
6.2.3 Restricted concomitant medications 
Not permitted while the patient is receiving study 
medication. 
 
Hydroxyurea up to 6 g/day in the context of the 
management of proliferative AML is allowed during 
screening and until the end of cycle 1. It should be 
discontinued as soon as possible based on 
investigator clinical judgement. Note the risk or 
severity of adverse effects can be increased when 
hydroxyurea is combined with olaparib. 
 
Intrathecal chemotherapy for maintenance (but not 
active treatment of CNS disease) of a controlled CNS 
disease is allowed. 
Not permitted while the patient is receiving study 
medication and during the 30 day follow up period. 
An increased risk of infection by the administration 
of live virus and bacterial vaccines has been observed 
with conventional chemotherapy drugs and the effects 
with olaparib are unknown. 

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Restricted concomitant medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
Strong CYP3A inhibitors: 
itraconazole, telithromycin, clarithromycin, 
boosted protease inhibitors, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir 
Moderate CYP3A inhibitors: 
ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil 
Strong or moderate CYP3A inhibitors should be 
avoided with olaparib. If there is no suitable 
alternative concomitant medication then the dose of 
olaparib should be reduced for the period of 
concomitant administration. The dose reduction of 
olaparib should be recorded in the CRF with the 
reason documented as concomitant CYP3A inhibitor 
use. 
• 
Strong CYP3A inhibitors – reduce the dose 
of olaparib to 100 mg twice daily for the 
duration of concomitant therapy with the 
strong inhibitor and for 5 half lives 
afterwards. 
• 
Moderate CYP3A inhibitors - reduce the dose 
of olaparib to 150 mg twice daily for the 
duration of concomitant therapy with the 
moderate inhibitor and for 3 half lives 
afterwards. 
• 
After the washout of the inhibitor is 
complete, the olaparib dose can be re- 
escalated. 
Strong inducers: 
phenobarbital, phenytoin, rifampicin, rifabutin, 
rifapentine, carbamazepine, nevirapine, 
enzalutamide and St John’s Wort 
Moderate CYP3A inducers: 
bosentan, efavirenz and modafinil 
Strong or moderate CYP3A inducers should not be 
taken with olaparib. If the use of any strong or 
moderate CYP3A inducers are considered necessary 
for the patient’s safety and welfare this could 
diminish the clinical efficacy of olaparib. If a patient 
requires use of a strong or moderate CYP3A inducer 
then they must be monitored carefully for any change 
in efficacy of olaparib. 

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Restricted concomitant medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
• 
CYP3A4 substrates: hormonal 
contraceptive, simvastatin, cisapride, 
cyclosporine, ergot alkaloids, fentanyl, 
pimozide, sirolimus, tacrolimus and 
quetiapine 
• 
CYP2B6 substrates: bupropion, 
efavirenz 
• 
OATP1B1substrates: bosentan, 
glibenclamide, repaglinide, statins and 
valsartan 
• 
OCT1, MATE1 and MATE2K 
substrates: metformin 
• 
OCT2 substrates: serum creatinine 
• 
OAT3 substrates: furosemide, 
methotrexate 
Effect of olaparib on other drugs: 
• 
Based on limited in vitro data, olaparib may 
increase the exposure to substrates of CYP3A4, 
OATP1B1, OCT1, OCT2, OAT3, MATE1 and 
MATE2K. 
• 
Based on limited in vitro data, olaparib may 
reduce the exposure to substrates of 2B6. 
• 
Caution should be observed if substrates of these 
isoenzymes or transporter proteins are co- 
administered. 
Anticoagulant therapy 
Patients who are taking warfarin may participate in 
this trial; however, it is recommended that 
international normalized ratio (INR) be monitored 
carefully at least once per week for the first month, 
then monthly if the INR is stable. Subcutaneous 
heparin and low molecular weight heparin are 
permitted. 
Palliative radiotherapy 
Palliative radiotherapy may be used for the treatment 
of pain at the site of bony metastases that were 
present at baseline only after completion of the Cycle 
6 response assessment, provided the investigator does 
not feel that these are indicative of clinical disease 
progression during the study period. Study treatment 
should be discontinued for a minimum of 3 days 
before a patient undergoes therapeutic palliative 
radiation treatment. Study treatment should be 
restarted within 4 weeks as long as any bone marrow 
toxicity has recovered. 

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Restricted concomitant medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
Administration of other anti-cancer agents 
Patients must not receive any other concurrent anti- 
cancer therapy, including investigational agents, 
while on study treatment. Patients may use 
hydroxyurea, as outlined in the inclusion criteria, for 
leukocytosis. While not standard therapy for patients 
with AML or MDS, Patients may continue the use of 
bisphosphonates if they are already on these 
therapies. Low dose corticosteroids may also be used 
for any chronic condition provided the dose is stable 
during the study and they were started at least 4 
  
weeks prior to beginning study treatment. 
 
 
6.3 
Duration of Therapy 
 
In the absence of treatment delays due to AE(s), treatment may continue until one of the 
following criteria applies: 
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable AE(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
• 
Clinical progression 
• 
In patients without prior exposure to IDH inhibitors: the absence of CR/CRh/mCR 
• 
Patient non-compliance 
• 
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. 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent 
 
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). 
 
6.4 
Duration of Follow-Up 
 
Patients will be seen 90 days after the last dose of the study drug for a follow-up visit and then 
followed for survival q3 months (+/- 4 weeks) thereafter  until death. Patients removed from 
study for unacceptable AE(s) will be 

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followed until resolution or stabilization of the AE. Survival data will be followed until death 
from any cause. 
 
 
7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
7.1 
Dose Levels 
 
Any toxicity observed during the course of the study could be managed by interruption of the 
dose of study treatment or dose reductions. Repeat dose interruptions are allowed as required, 
for a maximum of 2 weeks of treatment interruption total. If the interruption is any longer, the 
study team must be informed. Study treatment can be dose reduced to 250 mg twice daily as a 
first step and to 200 mg twice daily as a second step. If the reduced dose of 200 mg twice daily 
is not tolerable, no further dose reduction is allowed and study treatment should be discontinued. 
When dose reduction is necessary patients will take one 150 mg tablet and one 100 mg tablet 
twice daily or two x 100 mg tablet twice daily, or one 150 mg tablet twice daily or one 100 mg 
tablet twice daily. 
 
Once dose is reduced, escalation is not permitted (except following concomitant treatment with 
CYP3A4 inhibitors – see Section 6.2.3). 
 
Olaparib dose reductions to manage adverse events 
Initial Dose 
Following re-challenge post 
interruption: Dose reduction 1 
Dose reduction 2 
300 mg twice daily 
(2 x 150 mg tablets) 
250 mg twice daily 
(1 x 100 mg + 1 x 150 mg tablets) 
200 mg twice daily 
(2 x 100 mg tablets) 
 
7.2 
Management of hematological toxicity 
 
Hematologic toxicity will be defined using specific AML/MDS criteria: For patients with 
documenting response, any CTCAE grade 4 ANC or platelet toxicity lasting >42 days from the 
initiation of the cycle will be considered a DLT. 
 
In the absence of active disease, study drug should be interrupted until recovery of the 
hematologic toxicity to ≤ Grade 3 for all subjects regardless of baseline cytopenia. The 
treatment will then be re-started at the lower dose level as indicated on section 7.1 of the 
protocol. 
 
The definition and management of hematologic toxicities is complex and we strongly encourage 
the local investigator to contact the study team to discuss the next steps of management if a 
hematologic toxicity is suspected. 
 
Note that a complete response with inadequate platelet recovery will not considered a 
hematologic toxicity. 

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Olaparib dose reductions to manage hematological toxicities 
Initial Dose 
Dose reduction 1 
Dose reduction 2 
300 mg twice daily 
(2 x 150 mg tablets) 
250 mg twice daily 
(1 x 100 mg + 1 x 150 mg tablets) 
200 mg twice daily 
(2 x 100 mg tablets) 
 
 
7.3 
Management of non-hematological toxicity 
 
Repeat dose interruptions are allowed as required, for a maximum of 2 weeks of treatment 
interruption total. If the interruption is any longer than this the study monitor must be informed. 
Where toxicity reoccurs following re-challenge with study treatment, and where further dose 
interruptions are considered inadequate for management of toxicity, then the patient should be 
considered for dose reduction or must permanently discontinue study treatment. 
 
Study treatment can be dose reduced to 250 mg twice daily as a first step and to 200 mg twice 
daily as a second step. Treatment must be interrupted if any NCI-CTCAE Grade 3 or 4 AE 
occurs which the investigator considers to be at least possibly related to administration of study 
treatment, excluding febrile neutropenias and neutropenic infections. 
 
7.3.1 Management of new or worsening pulmonary symptom 
 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities occur in 
the absence of a clear diagnosis, notably consideration for lung infection, an interruption in study 
treatment dosing is recommended and further diagnostic workup (including a high resolution 
computed tomography [CT scan]) should be performed to exclude pneumonitis. 
 
Following investigation, if no evidence of abnormality is observed on CT imaging and symptoms 
resolve, then study treatment can be restarted, if deemed appropriate by the investigator. If 
significant pulmonary abnormalities are identified, these need to be discussed with the Study 
Physician. 
 
7.3.2 Management of nausea and vomiting 
 
Events of nausea and vomiting are known to be associated with olaparib treatment. These events 
are generally mild to moderate (CTCAE Grade 1 or 2) severity, intermittent and manageable on 
continued treatment. The first onset generally occurs in the first month of treatment for nausea 
and within the first 6 months of treatment for vomiting. For nausea, the incidence generally 
plateaus at around 9 months, and for vomiting at around 6 to 7 months. 
 
No routine prophylactic anti-emetic treatment is required at the start of study treatment, however, 
patients should receive appropriate anti-emetic treatment at the first onset of nausea or vomiting 
and as required thereafter, in accordance with local treatment practice guidelines. Alternatively, 
olaparib tablets can be taken with a light meal/snack (i.e., 2 pieces of toast or a couple of 
biscuits). 

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As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), generally a 
single agent anti-emetic should be considered e.g., dopamine receptor antagonist, antihistamines. 
 
7.4 
Interruptions for intercurrent non-toxicity related events 
 
Study treatment dose interruption for conditions other than toxicity resolution should be kept as 
short as possible. If a patient cannot restart study treatment within 4 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be discussed 
with the study physician. 
 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF. 
 
Study treatment should be stopped at least 3 days prior to planned surgery. After surgery study 
treatment can be restarted when the wound has healed. No stoppage of study treatment is 
required for any needle biopsy procedure. 
 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered. 
 
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, patients should 
be advised to use caution while driving or using machinery if these symptoms occur. 
 
Olaparib dose reductions for non-toxicity related events 
Initial Dose 
Following re-challenge post 
interruption: Dose reduction 1 
Dose reduction 2 
300 mg twice daily 
(2 x 150 mg tablets) 
250 mg twice daily 
(1 x 100 mg + 1 x 150 mg tablets) 
200 mg twice daily 
(2 x 100 mg tablets) 
 
7.5 
Renal Impairment 
 
If after study entry and while still on study therapy, a patient’s estimated CrCl falls below the 
threshold for study inclusion (>30 ml/min), retesting should be performed promptly. 
A dose reduction is recommended for patients who develop moderate renal impairment 
(calculated creatinine clearance by Cockcroft-Gault equation or based on a 24-hour urine test of 
between 30 and 50 ml/min) for any reason during the course of the study: the dose of olaparib 
should be reduced to 200 mg twice daily. 
 
Because the CrCl determination is only an estimate of renal function, in instances where the CrCl 
falls to between 31 and 50 mL/min, the investigator should use his or her discretion in 
determining whether a dose change, or discontinuation of therapy is warranted. 
 
Olaparib has not been studied in patients with severe renal impairment (CrCl ≤ 30 mL/min) or 
end-stage renal disease; if patients develop severe impairment or end stage disease it is 
recommended that olaparib be discontinued. 

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7.6 
Dose Reductions when Receiving Strong/Moderate CYP3A4 Inhibitors 
 
As noted in Section 6.2.3, patients should avoid taking strong or moderate CYP3A4 inhibitors 
while receiving olaparib. The use of any such agent must be discussed with the study monitor. 
If there is no suitable alternative concomitant medication, the dose of olaparib should be reduced 
for the period of concomitant administration. The dose reduction of olaparib should be recorded 
in the case report form (CRF) with the reason documented as concomitant CYP3A inhibitor use. 
 
Olaparib dose reductions if patient must take a strong or moderate CYP3A inhibitor 
Initial Dose 
Dose if Receiving a Strong 
CYP3A inhibitor 
Dose if Receiving a Moderate 
CYP3A inhibitor 
300 mg twice daily 
(2 x 150 mg tablets) 
100 mg twice daily 
(1 x 100 mg tablets) 
150 mg twice daily 
(1 x 150 mg tablets) 
 
 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the AEs and potential risks associated with the investigational agent administered in this 
study can be found in Section 10.1. 
 
8.1 
Olaparib (AZD2281) (NSC 747856) 
 
Chemical Name: 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4- 
fluorophenyl)methyl]phthalazin-1(2H)-one 
 
Other Names: AZD2281; KU-0059436; CO-CE 42 
 
Classification: PARP inhibitor 
 
CAS Registry Number: 763113-22-0 
 
Molecular Formula: C24H23FN4O3 
M.W.: 434.46 
 
Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range 
 
Mode of Action: Olaparib is an inhibitor of subclasses 1, 2, and 3 of polyadenosine 5′ 
diphosphoribose polymerase (PARP-1, PARP-2, and PARP-3). In tumors that are deficient 
in the homologous recombination DNA repair pathway (example, BRCA mutants), 
inhibition of PARP by olaparib causes accumulation of DNA double-strand breaks and 
genomic instability. Olaparib may also enhance the effects of DNA damage caused by 
ionizing radiation and chemotherapy. 
 
Description: crystalline solid 

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How Supplied: AstraZeneca supplies and the Pharmaceutical Management Branch (PMB), CTEP, 
Division of Cancer Treatment and Diagnosis (DCTD) distributes olaparib as green, film- 
coated tablets in 100 mg and 150 mg strengths. 
 
• 
100 mg tablets are 14.5 mm x 7.25 mmoval-shaped 
• 
150 mg are 14.5 mm x 7.25 mmoval-shaped 
 
Tablets are packaged in induction-sealed high-density polyethylene (HDPE) bottles with 
child-resistant closures. Each bottle contains 32 tablets with desiccant. 
 
Tablet core components include active drug substance, copovidone, colloidal silicon 
dioxide, mannitol and sodium stearyl fumarate. Film coating contains hydroxypropyl 
methylcellulose (hypromellose), macrogol 400 (polyethylene glycol 400), titanium dioxide, 
iron oxide yellow and iron oxide black. 
 
Storage: Store in a secure location below 30° C (86° F). 
 
If a storage temperature excursion is identified, promptly return olaparib (AZD2281) to 
room temperature and quarantine the supplies. Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Shelf-life studies are ongoing. Sites are not permitted to re-package tablets. Once the 
bottle is opened, olaparib tablets must be used within 3 months of the opening date; 
unused tablets should be discarded. Instruct patients not to open a bottle until they are 
ready to use it. 
 
Route and Method of Administration: Oral. Take tablets without regard to meals. 
 
Potential Drug Interactions: In vivo data indicate that CYP3A4/5 is important for olaparib 
metabolism and clearance in humans. For this reason, avoid concomitant administration of 
strong and moderate CYP 3A4/5 inducers and inhibitors. Consult the protocol document 
or study investigator prior to making any dose adjustments related to potential drug-drug 
interactions. 
 
In vitro data shows olaparib is a substrate for P-glycoprotein (P-gp), but not for organic 
anion-transporting polypeptides (OATP1B1 and OATP1B3), organic cation transporter 1 
(OCT1), multi-drug resistance protein 2 (MRP-2) efflux transporter or breast cancer 
resistance protein (BCRP). Administration of strong P-gp inhibitors and inducers should be 
avoided with concurrent olaparib. 
 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and 
induces CYP 1A2, 2B6, and 3A4. Therefore, avoid concomitant administration of sensitive 
substrates, particularly those with narrow therapeutic ranges. 

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Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug and toxin 
extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, but not an 
inhibitor of OATP1B3 or MRP-2. In vitro studies suggest that olaparib may increase 
exposure of substrates of these transport systems, although the clinical relevance is not clear. 
The manufacturer recommends that statins, in particular, should be administered with 
caution when given concomitantly with olaparib. 
 
Patient Care Implications: Pre-clinical data indicate that olaparib adversely affects embryofetal 
survival and development. Therefore, women of child-bearing potential and their partners 
should agree to use two (2) highly effective forms of contraception starting at signing of the 
informed consent, throughout study participation and for at least one (1) month after the last 
dose of olaparib. It is not known whether olaparib is found in seminal fluid, so as a 
precaution, male study participants must use a condom during treatment and for three (3) 
months after the last dose and should avoid fathering a child or donating sperm during this 
same time period. The study investigator should discuss the most appropriate forms of 
highly effective contraceptive methods for each patient. 
 
Lactation is a protocol exclusion criterion and not advised since there is potential for serious 
adverse reactions in breastfed infants. Advise lactating women to not breastfeed during 
study treatment and for one (1) month after receiving the last dose of olaparib. 
 
Because the adverse events related to olaparib may include asthenia, fatigue and 
dizziness, patients should be advised to use caution while driving or using machinery. 
 
There are no data on the effect of olaparib on wound healing, therefore as a precaution, 
olaparib treatment should be stopped at least 3 days prior to planned surgery. After 
surgery olaparib can be restarted when the wound has healed. No stoppage of olaparib is 
required for any needle biopsy procedure. 
 
Study treatment should be discontinued for a minimum of 3 days before a patient 
undergoes therapeutic or palliative radiation treatment. Study treatment should be 
restarted within 4 weeks as long as any bone marrow toxicity has recovered. 
 
Availability 
 
Olaparib (AZD2281) is an investigational agent supplied to investigators by the DCTD, NCI. 
 
Olaparib (AZD2281) is provided to NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and DCTD, NCI (see Section 13.5). 
 
• Agent Ordering and Agent Accountability 
 
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 

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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. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. 
Access to OAOP requires the establishment of a CTEP Identity and Access Management (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. 
 
Starter supplies will not be provided. Patients must be registered prior to agent ordering. Sites 
may request expedited orders Monday-Thursday when they provide courier information. 
 
• 
Agent Inventory Records 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
 
• 
Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB 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. Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
• 
Useful Links and Contacts 
 
.1 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
.2 
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
.3 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
.4 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP 
.5 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
.6 
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
.7 
IB Coordinator: IBCoordinator@mail.nih.gov 
.8 
PMB email: PMBAfterHours@mail.nih.gov 
.9 
PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 

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9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
9.1.1 Study Design 
 
This is an open-label study of olaparib in advanced relapsed or refractory IDH1/2-mutant AML 
and MDS. The study will have 4 arms. Arm 1 will include patients with relapsed or refractory 
AML with no prior exposure to IDH inhibitors (inhibitor naïve). Arm 2 will be composed of 
patients with relapsed or refractory AML with prior exposure to IDH inhibitors. Arm 3 will 
include patients with relapsed or refractory MDS with no prior exposure to IDH inhibitors 
(inhibitor naïve). Arm 4 will be composed of patients relapsed or refractory MDS with prior 
exposure to IDH inhibitors. 
 
The effect of PARP inhibitors is dependent on 2-HG levels, and 2-HG levels are high in both 
IDH inhibitor naïve patients, as well as in patients who relapse after IDH inhibitors. While 2-HG 
levels are suppressed in patients actively on IDH inhibitors (independent of response, which 
discourages concomitant administration), in patients who relapse after IDH inhibitors 2-HG 
levels are seen to increase despite continued IDH inhibitor therapy. This has been seen in 
numerous studies (e.g., Intlekofer et al., 2018). Therefore, we expect a rather similar efficacy of 
PARP inhibitors in both IDH inhibitor naïve and IDH inhibitor pre-treated patients. 
 
For the null hypothesis, the CR rate is 30% in IDH inhibitor naïve AML patient, not for patients 
with previous IDHi exposure. For the MDS, population, the data for IDHi naïve patients are still 
limited and we will have a conservative estimate that the rate of response will be similar to 
AML. The null hypothesis for patients already treated with at least 1 line of therapy and an IDH 
inhibitor will be set at 5% given the absence of available options for either MDS or AML. 
Sample sizes and futility rules: 
 
 
Cohort 
H0 
H1 
Alpha 1 
sided 
beta 
Sample 
size 
stage 1 
Futilit 
y 
Sample 
size 
total* 
Efficacy 
AML 
IDHi 
naive 
30 
50 
5 
20 
19 
6 or 
less 
39 
17 or more 
AML 
IDHi 
exposed 
5 
35 
5 
10 
8 
0 
14 
3 or more 
MDS 
IDH I 
naive 
30 
50 
5 
20 
19 
6 or 
less 
39 
17 or more 
MDS 
IDHi 
5 
35 
5 
20 
6 
0 
12 
3 or more 

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exposed 
The calculations are based on a Simon 2 Stage Minimax design. 
* without the drop-out rate of 15% 
 
The safety and efficacy will be evaluated by an independent data review committee at each 
critical step of the protocol. Given the patient population, we considered a potential drop-out rate 
of 15%. Expected monthly accrual is 3-4 patients per month, with a proposed total sample size 
of 94 patients, over 2 years. 
 
Demographic information such as age and race will be tabulated. Descriptive statistics, 
including means, standard deviations, and ranges for continuous parameters, as well as 
percentages and frequencies for categorical parameters, will be presented. Adverse medical 
events will be tabulated. CTCAE Grade 3 and Grade 4 laboratory abnormalities will be listed. 
 
9.1.2 Primary Endpoints 
 
The primary objective of this stratified Phase 2 study is to determine the CR using a modified 
CR endpoint (CR+CRi+CRh). 
 
The safety and efficacy will be evaluated by an independent data review committee at each 
critical step of the protocol. 
 
9.1.2.1 
Efficacy Evaluation 
 
Clinical efficacy will be evaluated by MDS International Working Group (IWG) 2006 criteria 
(Cheson et al., 2006) and AML IWG 2003 criteria (Cheson et al., 2003) after 6 cycles of 
treatment. The primary endpoint will be cumulative composite CR (CR, CRi, CRh) and we will 
also record the cumulative ORR will include complete remission (CR), complete remission with 
incomplete blood count recovery (CRi), partial response (PR), and bone marrow complete 
remission (marrow CR/MLFS) achieved at least at one point during these 6 cycles. 
 
9.1.3 Stopping Rule for Toxicity 
 
Treatment and study participation may be stopped for excessive toxicity, defined as “any non- 
hematologic SAE at least possibly related to the drug leading to a treatment interruption of more 
than 2 weeks or any grade 4 ANC or PLT toxicity for which treatment can’t be restarted within 
42 days of the initiation of the cycle and in the absence of active disease. Febrile 
neutropenias/neutropenic infections are excluded from this definition.” 
 
The maximum toxicity rate allowed in the protocol will be 20% globally and 20% in each 
individual arm. We will have monthly evaluations of the toxicity rate during the study as well as 
for study milestones (end of stage 1 of the Simon design for each individual arm). Data will be 
reviewed by the coordinating team and the local PI. Based on the number of treated patient and 
the number of patients qualifying for an excessive toxicity, we will have a go/no-go decision for 
the continuation of the study and/or arm: 

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Number of patients 
Hold inclusions if DLT are seen in 
0-10 
2 pts or more 
11-15 
3 pts or more 
16-20 
4 pts or more 
21-25 
5 pts or more 
26-30 
6 pts or more 
31-35 
7 pts or more 
 
 
9.2 
Sample Size/Accrual Rate 
 
Expected monthly accrual is 3-4 patients per month, with a proposed total sample size of 94 
patients, over 2 years. 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska 
Native 
1 
1 
1 
1 
4 
Asian 
2 
2 
0 
0 
4 
Native Hawaiian or 
Other Pacific Islander 
1 
1 
0 
0 
2 
Black or African 
American 
6 
6 
4 
4 
20 
White 
20 
20 
10 
10 
60 
More Than One Race 
2 
0 
2 
0 
4 
Total 
32 
30 
17 
15 
94 
 
9.3 
Stratification Factors 
 
Patients will be stratified based on prior exposure to IDH inhibitors. Both untreated and pre- 
treated cohorts will be evaluated independently from the statistical perspective. AML and MDS 
patients will also be analyzed separately. 
 
9.4 
Analysis of Secondary Endpoints 

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9.4.1 Toxicity Evaluation and Reporting 
All patients will be evaluated for toxicity. 
• Non-hematologic toxicity will be evaluated by CTCAE v5 criteria. 
• Hematologic toxicity will be defined using specific AML criteria: a hematologic 
dose limiting toxicity will be defined by the absence of the recovery of a cytopenia 
(ANC, PLT, Hgb) to baseline levels (Day 1 of the cycle) within 6 weeks of Day 1, in 
the absence of signs of active disease in blood and bone marrow. 
9.4.2 Evaluation of Objective Response Rate 
 
The effectiveness of the drug in patients for each cohort will be independently assessed by 
composite CR rate (CR+CRi+CRh). Objective Response Rate (ORR) will be included as a 
secondary endpoint, calculated as a composite CR+MLFS+PR. The exact two-sided 95% 
confidence intervals for the ORR will be reported. For lifetime data analyses, e.g., overall and 
progression free survival, the study survival will be estimated using the Kaplan-Meier method 
with the 95% confidence intervals (CIs). The CI based on the Greenwoods variance will be 
reported. In addition, the possible risk factors will be compared for survival with log-rank test. 
For multivariate analysis, the proportional hazards Cox model will be applied to investigate 
potential prognostic factors, such as age and stage of disease on the survival data. The adjusted 
p-values of the odds ratios and the adjusted 95% confidence interval will be reported. 
 
9.4.3 Survival Definitions 
• OS will be defined by the time interval between the first day of therapy to the time of 
death or last follow-up, whichever comes first. 
• PFS will be defined by the time interval between the first day of therapy to the time 
of documentation of progression, death of any cause, or last follow-up, whichever 
comes first. 
• DOR will be defined by the time interval between the first documentation of 
response to the time of documentation of progression, death of any cause, or last 
follow-up, whichever comes first. 
• 
9.5 
Exploratory Endpoints 
 
We expect to have all patients evaluated for correlatives at least at baseline, and it is reasonable 
to expect at least 10 patient samples per timepoint/technique to interpret potential trends. In the 
event that insufficient bone marrow is collected, blood samples may be used (30 mL per 
collection), provided that a minimum of 1g/L of circulating blasts are present on the differential 
of the CBC. 
 
9.5.1 Changes in 2HG Levels 

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The Mann-Whitney U test will be used to test for differences in post-treatment plasma 2HG 
concentrations between patients with a response to treatment and those without. We will also 
test for differences in Δ2HG (defined as pre-treatment minus post-treatment plasma 
concentration) between patients with a response to treatment and those without. Differences with 
p≤0.05 will be considered significant. The area under the receiver operating characteristic curve 
(ROC AUC) will be calculated to determine the cutoff value of the Δ2HG difference. The 
optimal cutoff value will be determined at the point on the ROC curve at (sensitivity + specificity 
− 1) is maximized (Youden index). 
 
 
9.6 
Reporting and Exclusions 
 
9.6.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with olaparib. 
 
9.6.2 Evaluation of Response 
 
All patients that finish at least 1 cycle of therapy will be considered evaluable for clinical 
response. Clinical efficacy (Cumulative Overall Response Rate, ORR) will be evaluated by 
MDS IWG 2006 criteria (Cheson et al., 2006) and AML IWG 2003 criteria (Cheson et al., 2003) 
after 6 cycles of treatment. Cumulative ORR will include CR, Cri, PR, marrow CR achieved at 
least at one point during these 6 cycles. 
 
 
10. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
AE monitoring and reporting is a routine part of every clinical trial. The following list of AEs 
(Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 10.3) will determine 
whether the event requires expedited reporting via the Medidata Rave in addition to routine 
reporting. 
 
10.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Olaparib (AZD2281, NSC 747856) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. 
In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting 
(SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs 
(SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted 
below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification. Frequency is provided based on 3449 patients. Below is the CAEPR for Olaparib (AZD2281). 

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NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
Version 2.6, June 5, 2023 
 

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 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 3449] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 4) 
 
 
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
  
Abdominal pain 
 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
INFECTIONS AND INFESTATIONS 
  
 
Upper respiratory infection 
 
  
 
Urinary tract infection 
 
  
INVESTIGATIONS 
  
 
Creatinine increased 
 
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 
4) 
 
 
Platelet count decreased 
  
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Muscle cramp 
 
  
 
Myalgia 
 
  
 
Pain in extremity 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) 
  
 
 
Leukemia secondary to oncology 
chemotherapy 
  
 
 
Myelodysplastic syndrome 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
  
 
 
Skin and subcutaneous tissue 
disorders - Other (angioedema) 
  
 
 
Skin and subcutaneous tissue 
disorders - Other (erythema 
  

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NOTE: New Primary Malignancies other than MDS/AML 
New primary malignancies have been reported in <1% of patients. There were other contributing factors/potential alternative explanations 
for the development of the new primary malignancy in all cases, including documented BRCA mutation, treatment with radiotherapy and 
extensive previous chemotherapy including carboplatin, taxanes, anthracyclines and other alkylating and DNA damaging agents. Most are 
not attributed to olaparib. 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time 
of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the 
protocol and the agent should be included in the e-mail. 
 
Adverse events reported on Olaparib (AZD2281) trials, but for which there is insufficient evidence to suggest that there was a 
reasonable possibility that Olaparib (AZD2281) caused the adverse event: 
 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (nodal rhythm); Chest pain - cardiac; Sinus bradycardia; Sinus 
tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Hypothyroidism 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Colonic obstruction; Dry mouth; Dysphagia; Enterocolitis; Esophageal 
stenosis; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (gastrointestinal hemorrhage); Gastrointestinal 
disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other (intestinal perforation); Ileus; Jejunal perforation; Obstruction 
gastric; Pancreatitis; Periodontal disease; Rectal hemorrhage; Small intestinal obstruction; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Fever; Malaise; Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (systemic inflammatory response syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Dermatitis radiation; Fracture; Gastrointestinal anastomotic leak; 
Injury, poisoning and procedural complications - Other (vena cava injury); Wound dehiscence 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood bilirubin increased; GGT 
increased; Hemoglobin increased; Lipase increased; Lymphocyte count decreased; Serum amylase increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hypermagnesemia; Hypocalcemia; Hypokalemia; 
Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Avascular necrosis; Bone pain; Generalized muscle weakness; 
Muscle weakness lower limb; Muscle weakness upper limb; Neck pain; Rotator cuff injury; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment related secondary 
malignancy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Concentration impairment; Encephalopathy; Intracranial 
hemorrhage; Peripheral sensory neuropathy; Reversible posterior leukoencephalopathy syndrome; Stroke; Syncope; Transient ischemic 
attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Hallucinations; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other (decreased glomerular filtration rate); 
Renal and urinary disorders - Other (hydronephrosis); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; Hypoxia; Oropharyngeal pain; 
Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Pruritus 
VASCULAR DISORDERS - Arterial thromboembolism; Flushing; Hot flashes; Hypertension; Hypotension; Peripheral ischemia; 
Thromboembolic event 
 
 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 3449] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
nodosum) 
VASCULAR DISORDERS 
  
 
 
Vascular disorders - Other (venous 
thromboembolism) 
  

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Note: Olaparib (AZD2281) 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.5 
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 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only: 
- 
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 Medidata Rave only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
Section 10.3.5. 
 
• Attribution of the AE: 
 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
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 

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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 
website: 
 
• Study specific documents: Protocols > Documents > Education and Promotion, 
and 
• Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU 
Operations Information > User Guides. 
 
NCI requirements for SAE reporting are available on the CTEP website: 
 
• NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid 
elines.pdf. 
 
 
10.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals: Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter. CTEP-AERS provides a copy feature for 
other e-mail recipients. 

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10.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note: A death on study requires both routine and expedited reporting, regardless of 
causality. Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” 
in the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious AEs, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An AE is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening AE 
3) 
An AE that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS AEs that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
NOTE: Protocol specific exceptions to expedited reporting of serious AEs are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious AEs that occur more than 30 days after the last administration of investigational agent/intervention and 
have an attribution of possible, probable, or definite require reporting as follows: 

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10.3.4 Olaparib Adverse Events of Special Interest 
 
AEs of special interest (AESI) are events of scientific and medical interest specific to the further 
understanding of olaparib’s safety profile and require close monitoring and rapid communication 
by the investigators to CTEP. An AESI may be serious or non-serious. The AESI for olaparib 
are the following Important Potential Risks: 
1. MDS/AML 
2. New primary malignancy (other than MDS/AML) 
3. Pneumonitis 
4. Cases of potential drug-induced liver injury (DILI) that include an elevated ALT 
or AST in combination with either an elevated bilirubin or clinical jaundice, as 
defined by Hy’s Law and based on the following observations: 
o Treatment-emergent ALT or AST >3×ULN (or >3× baseline value in 
disease states where LFTs may be elevated at baseline) in combination 
with total bilirubin >2×ULN (of which ≥35% is direct bilirubin). 
o Treatment-emergent ALT or AST >3×ULN (or >3× baseline value in 
disease states where LFTs may be elevated at baseline) in combination 
with clinical jaundice. 
 
Any event of MDS/AML, new primary malignancy, pneumonitis, or potential DILI should be 
reported in an expedited manner to CTEP via Medidata Rave regardless of whether it is 
considered a non-serious AE (e.g., non-melanoma skin cancer) or SAE, and regardless of the 
investigator’s assessment of causality or knowledge of the treatment arm. For cases of potential 
DILI, report all relevant laboratory abnormalities and related AEs using the appropriate CTCAE 
terms. 
 
Events of MDS, AML, or new primary malignancy occurring more than 30 days after the last 
study treatment must be reported via Medidata Rave regardless of seriousness or causality. 
Investigators will be asked during the regular follow-up for OS if the patient has developed 
MDS/AML or a new primary malignancy and prompted to report any such cases. 
 
10.3.5 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
Medidata Rave. However, they still must be reported through the routine reporting 
mechanism (Section 10.4): 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 

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CTCAE SOC 
Adverse Event 
Grade 
≥24h 
Hospitalizationa 
Investigations 
Neutrophil Count Decreased 
4 
Regardless 
Investigations 
Platelet Count Decreased 
4 
Regardless 
Blood & Lymphatic System 
Disorders 
Anemia 
4 
Regardless 
a Indicates that an AE required hospitalization for ≥24 hours or prolongation of hospitalization by ≥24 
hours of a patient. 
 
10.4 
Routine Adverse Event Reporting 
 
All AEs must be reported in routine study data submissions. AEs reported expeditiously 
through Medidata Rave must also be reported in routine study data submissions. 
 
AE data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents. AEs are reported in a routine manner at scheduled times during the 
trial using Medidata Rave. For this trial the AE CRF is used for routine AE reporting in Rave. 
 
10.5 
Pregnancy 
 
Although not an AE in and of itself, pregnancy as well as its outcome must be documented via 
Medidata Rave. In addition, the Pregnancy Information Form included within the NCI 
Guidelines for Adverse Event Reporting Requirements must be completed and submitted to 
CTEP. Any pregnancy occurring in a patient or patient’s partner from the time of consent to 90 
days after the last dose of study drug must be reported and then followed for outcome. Newborn 
infants should be followed until 30 days old. Please see the “NCI Guidelines for Investigators: 
Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” 
(at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on how to 
report pregnancy and its outcome to CTEP. 
 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via Medidata Rave. Three options are available to 
describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., AML) 
o MDS 
o Treatment-related secondary malignancy 

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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 
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11. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy. Scans 
and x-rays must 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 hours prior to 
initiation of the next cycle of therapy. 
 
Pre- 
Study 
Cycle 
1 
+/-1 
Cycle 
2 
+/-1 
Cycle 
3 
+/-1 
 
Cycle 
4 
+/-3 
Cycle 
5 
+/-3 
Cycle 
6 
+/-3 
Cycle 
7 
+/-3 
Cycle 
8 
+/-3 
Cycle 
9 
+/-3 
Cycle 
10 
+/-3 
Cycle 
11 
+/-3 
Cycle 
12+ 
+/-3 
EOT 
+/-7 
90 
day f/u 
a 
+/-
14 
Olaparib 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Concurrent meds 
X 
X 
X 
Physical examb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
evaluation g 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry c, f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine testing f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG (as indicated) 
X 
Adverse event 
evaluation 
X 
X 
X 
Pregnancy test d 
X 
Response assessment e 
without prior IDH 
inhibitor exposure 
X 
X 
X 
X 
X 
Response assessment e 
with prior IDH 
inhibitor exposure 
X 
X 
X 
X 
Bone marrow 
aspiration 
X 
X 
X 
X 
X 
X 
X 
Blood collection for 
biomarker assays h 
X 
X 
X 
X 
X 
X 
X 
Buccal swab 
X 

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A:  Olaparib: Dose as assigned; 200 or 300 mg q12h daily PO. 
a: 
90 day f/u evaluation. 
b: 
Note: Physical exams and Performance status evaluations are based on a 4-week cycle. At minimum, performance status should be 
evaluated at the beginning of  every cycle. 
c: 
CBC with differential and platelets assessment to occur twice weekly during Week 1 of Cycle 1, once weekly during Weeks 2-4 of Cycle 1, 
and then once per cycle thereafter. Assessment to include albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, uric acid. 
d: 
Pregnancy test for women of childbearing potential. 
e: 
Response Assessment includes bones marrow biopsy, and marrow and plasma 2HG levels. Response per AML IWG (IWG) 2003 criteria and 
MDS IWG 2006 (modification) criteria. 

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EOT= end of treatment, q12h = every 12 hours, PO = by mouth, BUN=blood urea nitrogen; LDH=lactic dehydrogenase; 
SGOT[AST]=serum glutamic oxaloacetic transaminase [aspartate transaminase]; SGPT[ALT]=serum glutamic pyruvic 
transaminase [alanine transaminase]. CRF = Case Report Form. 
 
12. MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Hematologic Tumors 
 
For patients not previously exposed to IDH inhibitors, response is assessed after cycles 1, 3, 6, 9, 
and 12 for the first year. For patients with prior IDH inhibitor exposure, response is assessed 
after cycles 3, 6, 9, and 12 for the first year on treatment. 
 
Category 
Definition 
Comment 
Complete Response 
(CR) 
Bone marrow blasts <5%; absence of 
circulating blasts and blasts with Auer rods; 
absence of extramedullary disease; ANC ≥1.0 
× 109/L (1,000/mcL); platelet count ≥100 × 
109/L (100,000/mcL)* 
CR with incomplete 
hematologic recovery 
(CRi)/CRh 
All CR criteria except for residual neutropenia 
(<1.0 × 109/L [1,000/mcL]) or 
thrombocytopenia (<100 × 109/L 
[100,000/mcL])* 
CRh: complete remission with partial 
hematological recovery (platelets > 50,000 
mcL and ANC > 500/mcL) 
Morphologic leukemia- 
free state (“marrow 
CR”, MLFS) 
Bone marrow blasts <5%; absence of blasts 
with Auer rods; absence of extramedullary 
disease; no hematologic recovery required 
Marrow should not merely 
be aplastic—at least 200 
cells should be 
enumerated, or cellularity 
should be at least 10% 
Partial response (PR) 
All hematologic criteria of CR; decrease of 
bone marrow blast percentage to between 5% 
and 25%; and decrease of pretreatment bone 
marrow blast percentage by at least 50% 
Especially important in the 
context of phase 1-2 
clinical trials 
Stable disease (SD) 
Absence of CR, CRi, PR, MLFS; and criteria 
for PD not met 
The period of stable 
disease should last at least 
3 months 
f: 
 Clinical Safety Laboratory Assessments to occur twice weekly during Week 1 of Cycle 1, once weekly during Weeks 2-4 of Cycle 1, and 
then once per cycle. Assessment to include: Haematology/Haemostasis (whole blood), B-Haemoglobin (Hb), B-Leukocyte count, B-Absolute 
neutrophil count, B-Absolute lymphocyte count, B-Platelet count, B-Mean cell volume (MCV), Urinalysis (dipstick), U- 
Hb/Erythrocytes/Blood, U-Protein, U-Glucose, and Clinical Chemistry (serum or plasma): S/P-Creatinine, S/P-Bilirubin, total, S/P- Alkaline 
phosphatise (ALP), S/P-Aspartate transaminase (AST), S/P-Alanine transaminase (ALT), S/P-Albumin, S/P-Potassium, S/P- 
Calcium, total, S/P-Sodium, S/P-Urea or Blood Urea Nitrogen (BUN), S/P-Total Protein, S/P lactate dehydrogeneases (LDH), S/P uric acid, 
& phosphorus 
 g 
Coagulation evaluation to occur twice weekly during Week 1 of Cycle 1, once weekly during Weeks 2-4 of Cycle 1, and then once per cycle  
          thereafter. Assessment to include activated partial thromboplastin time (APTT), Prothrombin Time/international normalized ratio 
(PT/INR), 
and Fibrinogen as indicated in the calendar, or as clinically indicated (i.e., upon suspicion of DIC). Each coagulation test result will be 
recorded in CRF. Coagulation evaluation to be conducted pre-study, Cycle 1 Day 1, Cycle 1 Day 15, and Day 1 of Cycles 2, 4, 6, 9, 12,  
every third cycle after cycle 12, and at End of Treatment. 
H    Blood and bone marrow collections to occur after the cycle. 
Note: Each Cycle is 28 days.; Visit Windows:  Cycle 1 – 3 (+/-1 day); Cycle 4 – 12+ (+/-3 days);  EOT +/- 7 days; 90 f/u +/-14 days  
 

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Category 
Definition 
Comment 
Progressive disease 
(PD) 
Evidence for an increase in bone marrow blast 
percentage and/or increase of absolute blast 
counts in the blood: 
• 
>50% increase in marrow blasts over 
baseline (a minimum 15% point 
increase is required in cases with 
<30% blasts at baseline; or persistent 
marrow blast percentage of >70% over 
at least 3 months; without at least a 
100% improvement in ANC to an 
absolute level (>0.5 × 109/L 
[500/mcL], and/or platelet count to 
>50 × 109/L [50,000/mcL] 
nontransfused) 
• 
>50% increase in peripheral blasts 
(WBC × % blasts) to >25 × 109/L 
(>25,000/mcL) (in the absence of 
differentiation syndrome**) 
• 
New extramedullary disease 
In general, at least two 
cycles should be 
administered prior to PD 
assessment. 
Patients with PD may 
remain on study, after 
discussion with the PI, if it 
is judged that they are 
deriving clinical benefit 
from doing so. 
Primary refractory 
disease 
No CR or CRi after two courses of intensive 
induction treatment; excluding patients with 
death in aplasia or death due to indeterminate 
cause 
Death in aplasia 
Death occurring ≥7 days following completion 
of initial treatment while cytopenic; with 
aplastic or hypoplastic bone marrow obtained 
within 7 days of death, without evidence of 
persistence leukemia 
Death due to 
indeterminate cause 
Deaths occurring before completion of therapy, 
or <7 days following its completion; or deaths 
occurring ≥7 days following completion of 
initial therapy with no blasts in the blood, but 
no bone marrow examination available 
Hematologic relapse 
(after CR, CRi) 
Bone marrow blasts ≥5%; or reappearance of 
blasts in the blood; or development of 
extramedullary disease 
* CBC values for up to 14 days after bone marrow assessment may be used to determine response. 
** Certain targeted therapies, e.g., those inhibiting mutant IDH proteins, may cause a differentiation syndrome, 
i.e., a transient increase in the percentage of bone marrow blasts and an absolute increase in blood blasts. In the 
setting of therapy with such compounds, an increase in blasts may not necessarily indicate PD. 
ANC=absolute neutrophil count, IDH=isocitrate dehydrogenase, MFC=multiparameter flow cytometry, RT- 
qPCR=real-time quantitative polymerase chain reaction, WBC=white blood count. (Döhner et al., 2017) 
 
12.2 
Other Response Parameters 
 
Other endpoints can be found in Section 9.4. 

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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 PI 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 serious AEs; 
reporting of expedited AEs; and accumulation of reported AEs from other trials testing the same 
drug(s). The Protocol PI and statistician have access to the data at all times through the CTMS 
web-based reporting portal. 
 
During the Phase 2 portion of the study, the Protocol PI will have, at a minimum, quarterly 
conference calls with the Study Investigators and the CTEP Medical Officer(s) to review accrual, 
progress, and pharmacovigilance. Decisions to proceed to the second stage of a Phase 2 trial will 
require sign-off by the Protocol PI and the Protocol Statistician. 
 
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 AEs 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. To access Rave via iMedidata: 
 
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account, and 
• 
Assigned one of the following Rave roles on the relevant Lead Protocol Organization 
(LPO) or Participating Organization roster at the enrolling site: Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type, 
o To hold Rave Investigator role, the individual must be registered as an NPIVR or 
IVR, and 

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o To hold Rave Read Only role, site staff must hold an Associates (A) registration 
type. 
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
 
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 
(https://login.imedidata.com/selectlogin) using 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 
accessed by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name. 
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website in the Rave section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
 
13.2.1 Method 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS). Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP). Information on CTMS reporting is available at: 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. On-site 
audits will be conducted on an 18-36 month basis as part of routine cancer center site visits. 
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission. For CTMS monitored studies, after users have activated their 
accounts, please contact the Theradex Help Desk at (609) 799-7580 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave. 

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Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks. The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS. Metrics for timeliness will be followed and assessed on a quarterly basis. 
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received. Queries will be issued by CTMS directly within Rave. The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve. Monthly web- 
based reports are posted for review by the Drug Monitors in the IDB, CTEP. Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) and 
CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended 
phase 2 dose (RP2D) and a description of any dose-limiting toxicities (DLTs). CTMS will 
utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) 
compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and- 
semantics/metadata-and-models). Customized eCRFs will be included when appropriate to meet 
unique study requirements. The PI is encouraged to review the eCRFs, working closely with 
CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs 
prior to study activation. CTMS will prepare the eCRFs with built-in edit checks to the extent 
possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex. CDUS submissions are performed by Theradex on a monthly 
basis. The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
13.3 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics. 
 
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 

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Total Queries. DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports. Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality. 
 
 
13.4 
CTEP Multicenter Guidelines 
 
Not Applicable 
 
13.5 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 

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a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non- 
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication. Collaborator(s) will have 30 days from the 
date of receipt for review. Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected. 
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release. 
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov 

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89 
 
 
 
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. 
 
13.6 
Genomic Data Sharing Plan 
 
The investigators and statistician and/or bioinformaticians for a study will have access to all data 
on mutations and variants stored in the Theradex Data Base and the GDC. This information will 
be sequestered from access throughout the study until it is analyzed for purposes of reporting and 
publishing of the study results. As specified in the CRADA for the agents used in the clinical 
study, the pharmaceutical collaborator will have at least 6 months, longer if needed for a 
regulatory filing, to review the data and or receive copies of the data once the study is completed 
and analyzed, or sooner, if specified for purposes of generating Intellectual Property. Once these 
timeframes have been exceeded, the data will be available through a Data Access Committee 
(DAC) in the GDC following NCI and Collaborator review of the proposals. 
 
13.7 
Incidental/Secondary Findings Disclosure Procedure 
 
Given the potential clinical implications conferred by detecting a germline and/or somatic 
mutation in one of the proven cancer susceptibility genes, this protocol will use the following 
disclosure procedure, consistent with the recommendations of the American College of Medical 
and Genomics (ACMG) (Green et al., 2013 and Kalia et al., 2016): 
 
The NCI Molecular Characterization Laboratory will review the mutations/variants once at the 
time of initial specimen evaluation according to the most recent version of the ACMG guidance 
on variants. The NCI Molecular Characterization Laboratory will not re-review all specimens 
received if a new version of the ACMG guidance is published after the initial review. 
 
For each participant with a pathogenic or likely pathogenic germline and/or somatic variant 
detected in the WES of blood (as defined in the ACMG guidance), the NCI Molecular 
Characterization Laboratory will report to the Program Director or Scientific Officer the UPID 
and variant(s) identified. The Program Director or Scientific Officer will contact Theradex to 
obtain the name of the protocol, investigator treating the patient, and the Principal Investigator of 
the grant. The treating physician will be contacted by phone and in writing to ask the patient 
whether he or she is interested in learning more about the finding. 
 
If the patient wants to know more, the physician should contact the Program Director for more 
information about the mutation/variant. The treating physician and a medical genetics counselor 
should meet with the patient to discuss the importance and meaning of the finding, but not the 
finding itself, and notify the patient that this research finding must be confirmed by Sanger 
sequencing at the patient’s/patient insurer’s expense in a CLIA-approved laboratory. The 
treating physician and genetic counselor should inform the patient of the confirmed result and its 
meaning and significance to the patient. If desired, the patient may elect to undergo genetic 
counseling and confirmatory CLIA-approved clinical testing on his or her own. Neither the 
research laboratory nor the National Cancer Institute will be responsible for the costs incurred for 
any confirmatory genetic testing or counseling. 

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Curtin, N.J., and C. Szabo. (2013). Therapeutic applications of PARP inhibitors: anticancer 
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Dang, L., D.W. White, S. Gross, et al. (2010). Cancer-associated IDH1 mutations produce 2- 
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DiNardo, C.D., E. Jabbour, F. Ravandi, et al. (2015a). IDH1 and IDH2 mutations in 
myelodysplastic syndromes and role in disease progression. Leukemia. 30:980-984. 
 
DiNardo, C.D., K.J. Propert, A.W. Loren, et al. (2013). Serum 2-hydroxyglutarate levels 
predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid 
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DiNardo, C.D., F. Ravandi, S. Agresta, et al. (2015b). Characteristics, clinical outcome, and 
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DiNardo, C.D., E.M. Stein, S. de Botton, et al. (2018). Durable remissions with ivosidenib in 
IDH1-mutated relapsed or refractory AML. New Eng J Med. 378(25):2386-2398. 
 
Döhner, H., E. Estey, D. Grimwade, et al. (2017). Diagnosis and management of AML in 
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Esposito, M.T., L. Zhao, T.K. Fung, et al. (2015). Synthetic lethal targeting of oncogenic 
transcription factors in acute leukemia by PARP inhibitors. Nat Med. 21(12):1481- 
1490. 
 
Farmer, H., N. McCabe, C.J. Lord, et al. (2005). Targeting the DNA repair defect in BRCA 
mutant cells as a therapeutic strategy. Nature. 434(7035):917-921. 
 
Fong, P.C., D.S. Boss, T.A. Yap, et al. (2009). Inhibition of poly(ADP-ribose) polymerase in 
tumors from BRCA mutation carriers. N Engl J Med. 361(2):123-134. 
 
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DNA repair. Nature. 347(6292):479-482. 
 
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veliparib in combination with temozolomide in acute myeloid leukemia. Clin Cancer 
Res. 23(3):697-706. 
 
Green, C.L., C.M. Evans, L. Zhao, et al. (2011). The prognostic significance of IDH2 mutations 
in AML depends on the location of the mutation. Blood. 118(2):409-412. 
 
Green, R.C., J.S. Berg, W.W. Grody, et al. (2013). ACMG recommendations for reporting of 
incidental findings in clinical exome and genome sequencing. Genet Med. 15:565- 
564. 
 
Harding, J.J., M.A. Lowery, A.H. Shih, et al. (2018). Isoform switching as a mechanism of 
acquired resistance to mutant isocitrate dehydrogenase inhibition. Cancer Discov. 
8(12):1540-1547. 
 
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Helleday, T. (2011). The underlying mechanism for the PARP and BRCA synthetic lethality: 
clearing up the misunderstandings. Mol Oncol. 5(4):387-393. 
 
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Huang, J., Z. Liu, Y. Sun, et al. (2018). Use of methylation profiling to identify significant 
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through trans or cis dimer-interface mutations. Nature. 559:125-129. 
 
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repair, V(D)J recombination and DNA-PK. Bioessays. 17(11):949-957. 
 
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myelodysplastic syndromes: a retrospective cohort study and meta-analysis. PLOS 
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human myelodysplastic syndromes. Haematologica, 96(4):543-551. 
 
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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 hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self- 
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 

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APPENDIX B 
PATIENT CLINICAL TRIAL WALLET CARD 
 
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of your 
healthcare providers and keep 
it with you in case you go to 
the emergency room. 
Patient Name: 
Diagnosis: 
Study Doctor: 
Study Doctor Phone #: 
NCI Trial #: 10264 
Study Drug(S): Olaparib 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 

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APPENDIX C 
ACTIONS REQUIRED IN CASES OF COMBINED INCREASE OF 
AMINOTRANSFERASE AND TOTAL BILIRUBIN – HY’S LAW 
 
Briefly, Hy’s Law cases have the following three components: 
 
The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug or 
placebo 
 
Among trial subjects showing such AT elevations, often with ATs much greater than 
3xULN, one or more also show elevation of serum TBL to >2xULN, without initial findings 
of cholestasis (elevated serum ALP) 
 
No other reason can be found to explain the combination of increased AT and TBL, such as 
viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury 
 
Finding one Hy’s Law case in the clinical trial database is worrisome; finding two is considered 
highly predictive that the drug has the potential to cause severe drug induced liver injury (DILI) 
when given to a larger population. 
 
The following actions are required in cases of combined increase of aminotransferase and total 
bilirubin: 
 
1. Confirmation 
 
In general, an increase of serum AST/A:T to >3xULN should be followed by repeat testing 
within 48 to 72 hours of all four of the usual serum measures (ALT, AST, ALP, and TBL) to 
confirm the abnormalities and to determine if they are increasing or decreasing. There also 
should be inquiry made about symptoms. Serum AT may rise and fall quite rapidly, and waiting 
a week or two before obtaining confirmation of elevations may lead to a false conclusion that the 
initially observed abnormality was spurious. Of greater concern, delay in retesting may allow 
progression to severe worsening if the initial abnormality was the herald of a severe reaction to 
follow. The need for prompt repeat testing is especially great if AST/ALT is much greater than 
3xULN and/or TBL is greater than 2xULN. For outpatient trials, or trials in which subjects are 
far away from the trial site, it may be difficult for the subjects to return to the trial site promptly. 
In this case, the subjects should be retested locally, but normal laboratory ranges should be 
recorded, results should be made available to trial investigators immediately, and the data should 
be included in the case reports. If symptoms persist or repeat testing shows AST/ALT >3xULN 
for subjects with normal baseline measures or 2-fold increases above baseline values for subjects 
with elevated values before drug exposure, it is appropriate to initiate close observation to 
determine whether the abnormalities are improving or worsening. If close monitoring is not 
possible, the drug should be discontinued. 

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2. Close Observation 
 
It is critical to initiate close observation immediately upon detection and confirmation of early 
signals of possible DILI, and not to wait until the next scheduled visit or monitoring interval. A 
threshold of aminotransferase levels greater than 3xULN seems reasonable, as lesser elevations 
are common and nonspecific. If additional testing, beyond that specified in the trial protocol, is 
carried out, it is important that the subject’s information be added to the case report forms and 
database. Close observation includes: 
 
Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the trial drug has been 
discontinued and the subject is asymptomatic. 
Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
Obtaining a history of concomitant drug use (including nonprescription medications and herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets. 
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
NASH; hypoxic/ischemic hepatopathy; and biliary tract disease. 
Obtaining a history of exposure to environmental chemical agents. 
Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct bilirubin). 
Considering gastroenterology or hepatology consultations. 
 
3. Decision to Stop Drug Administration 
 
It has been observed that de-challenge (stopping drug administration) does not always result in 
immediate improvement in abnormal lab values. Abnormal test values and symptoms may 
progress for several days or even weeks after discontinuation of the drug that caused the 
abnormality. For example, rising TBL usually follows serum AT increases by a few days to 
weeks. The primary goal of close observation is to determine as quickly as possible whether 
observed abnormal findings are transient and will resolve spontaneously or will progress. For 
most DILI, no specific antidotes are available (except N-acetylcysteine for acute acetaminophen 
overdose if given promptly, and, possibly, intravenous carnitine for valproic acid hepatotoxicity). 
 
Promptly stopping the offending drug usually is the only potentially effective therapy. 
 
Because transient fluctuations of ALT or AST are common, and progression to severe DILI or 
acute liver failure is uncommon, automatic discontinuation of trial drug upon finding a greater 
than 3xULN elevation of ALT or AST may be unnecessary. For most people, the liver appears 
capable of adapting to injury by foreign chemical substances, which may render a person tolerant 
to the drug despite continued exposure. Stopping a drug at the first hint of mild injury does not 
permit learning whether adaptation will occur, as it does for drugs such as tacrine, which cause 
liver injury but do not cause severe DILI. On the other hand, continuing drug appears 
unacceptably dangerous if there is marked serum aminotransferase elevation or evidence of 
functional impairment, as indicated by rising bilirubin or INR, which represent substantial liver 
injury. Although there is no published consensus on exactly when to stop a drug in the face of 
laboratory abnormalities and the decision will be affected by information on related drugs, the 
accumulating clinical experience, the clinical status of the patient, and many other factors, the 

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following can be considered a basic guide. Discontinuation of treatment should be considered if: 
 
ALT or AST >8xULN 
ALT or AST >5xULN for more than 2 weeks 
ALT or AST >3xULN and (TBL >2xULN or INR >1.5) 
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
 
It should be noted that although these guidelines have not been evaluated systematically in a 
prospective fashion, they represent an approach that is similar to current practice. 
 
4. Evaluating Data for Alternative Causes 
 
An important purpose of close observation is to gather additional clinical information to seek 
other possible causes of the observed liver test abnormalities, such as one of the following 
common causes: 
 
Acute viral hepatitis. The usual onset of hepatocellular DILI is indistinguishable from acute viral 
hepatitis A or B. Hepatitis C is much less often acute in its onset and tends to be insidious, but it 
sometimes can resemble acute DILI. The presence of acute viral hepatitis A, B, and C should be 
evaluated by serological markers. Viral hepatitis D (requires concomitant hepatitis B infection) 
and E are relatively rare in the United States. Hepatitis E is more common in developing 
countries, including Southeast Asia, and should be considered in recent travelers to those 
countries and in patients in trials conducted in those countries. Also rare are hepatocellular liver 
injuries caused by Epstein-Barr virus, cytomegalovirus, herpes simplex virus, toxoplasmosis, 
varicella, and parvovirus, although these infections are seen more typically in immuno- 
suppressed individuals. Adolescent and young adult patients with possible DILI should be tested 
for Epstein-Barr virus. Hepatitis is common among transplant patients with cytomegalovirus 
disease. 
 
Alcoholic and autoimmune hepatitis. Acute alcoholic hepatitis usually is recurrent, with a history 
of binging exposure to alcohol preceding episodes, and it has some characteristic features, such 
as associated fever, leukocytosis, right upper quadrant pain and tenderness, hepatomegaly, and 
AST >ALT, that may help distinguish it from other causes of liver injury. Other features of the 
physical examination may include the presence of stigmata of cirrhosis, such as spider nevi, 
palmar erythema, estrogenic changes in males, and Dupuytren’s contractures. Alcoholic and 
autoimmune hepatitis should be assessed by history, physical examination, and laboratory 
testing, including serologic testing (e.g., antinuclear or other antibodies). 
 
Hepatobiliary disorders. Biliary tract disease, such as migration of gallstones or intrahepatic 
lesions, more often causes cholestatic injury initially and should be investigated with gall bladder 
and ductal imaging studies, especially if ALP is increased. Malignant interruption of the biliary 
tract also should be considered. 
 
NASH. NASH may be seen in obese, hyperlipoproteinemic, and/or diabetic patients and may be 
associated with fluctuating aminotransferase levels, and hepatic and sometimes splenic 

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enlargement. It is sometimes associated with cirrhosis and portal hypertension. 
 
Cardiovascular causes. Cardiovascular disease, especially right heart failure and hypotension or 
any cause of impaired oxygenation of the liver, may cause acute centrilobular hypoxic cell 
necrosis (ischemic hepatitis) with rapid and sometimes spectacular increases of serum AT (e.g., 
AT >10,000 U/L). Cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure, should be assessed by physical examination and history. 
 
Concomitant treatments. It is critical to discover concomitant treatments, including exposure to 
nonprescription and dietary supplement products that might be responsible for injury. Many 
people take multiple drugs, perhaps less often in controlled clinical trials because of exclusion 
criteria, but subjects may not report taking disallowed drugs or other agents. The possible 
exposure to potentially toxic herbal or dietary supplement mixtures (sometimes of unknown 
composition), nonprescription medications such as acetaminophen, or to occupational chemical 
agents may not be volunteered unless subjects are specifically questioned. 
 
5. Follow-Up to Resolution 
 
All trial subjects showing possible DILI should be followed until all abnormalities return to 
normal or to the baseline state. DILI may develop or progress even after the causative drug has 
been stopped. Results should be recorded on the case report form and in the database. Note that 
longer follow-up can sometimes reveal an off-drug repetition of what had appeared to be DILI, 
indicating that liver injury was related to underlying liver disease. 
 
6. Re-challenge 
 
Whether or not to re-challenge a subject who showed mild DILI is a difficult decision. Re- 
exposure may initiate a sometimes explosive and more severe reaction, as was observed with 
halothane several decades ago. Some cases of DILI show indicators of immunological reaction 
such as eosinophilia, rash, fever, or other symptoms or findings, and it is possible that such cases 
are more prone to recur with re-exposure. Re-challenge may not be considered negative unless 
the subject is exposed to and tolerates the same dose and treatment duration that preceded the 
original reaction. A negative re-challenge does not necessarily allow a conclusion that the drug 
did not cause the injury. Most people can adapt to xenobiotic substances, including new drugs, 
and develop tolerance for them. This has been observed even for drugs that can cause severe 
injury, such as isoniazid. The large majority of people showing hepatocellular injury while 
taking isoniazid recover fully or recover while continuing to take the drug, and some, but not all, 
can resume or continue taking the drug without further adverse consequence. If such tolerance 
has developed, the use of re-challenge to verify drug causation would give a false negative result. 
 
Generally, re-challenge of subjects with significant AT elevations (>5xULN) should not be 
attempted. If such subjects are re-challenged, they should be followed closely. Re-challenge can 
be considered if the subject has shown important benefit from the drug and other options are not 
available or if substantial accumulated data with the test drug do not show a potential for severe 
injury. The subject should be made aware of the potential risk, and consent to the re-challenge, 
and the PI consulted. 

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APPENDIX D 
ACCEPTABLE BIRTH CONTROLS METHODS 
 
Olaparib is regarded as a compound with medium/high foetal risk. 
Women of childbearing potential and their partners, who are sexually active, must agree to the 
use of TWO highly effective forms of contraception in combination [as listed below]. This 
should be started from the signing of the informed consent and continue throughout the period of 
taking study treatment and for at least 1 month after last dose of study drug(s), or they must 
totally/truly abstain from any form of sexual intercourse (see below). 
Male patients must use a condom during treatment and for 3 months after the last dose of 
olaparib when having sexual intercourse with a pregnant woman or with a woman of 
childbearing potential. Female partners of male patients should also use a highly effective form 
of contraception if they are of childbearing potential (as listed below). Male patients should not 
donate sperm throughout the period of taking olaparib and for 3 months following the last dose 
of olaparib. 
Acceptable Non-hormonal birth control methods include: 
• Total/True abstinence: When the patient refrains from any form of sexual intercourse and this 
is in line with their usual and/or preferred lifestyle; this must continue for the total duration 
of the trial and for at least 1 month after the last dose of study drug <<for 3 months after last 
dose for male patients>>. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
post-ovulation methods, or declaration of abstinence solely for the duration of a trial] and 
withdrawal are not acceptable methods of contraception). 
• Vasectomised sexual partner PLUS male condom. With participant assurance that partner 
received post-vasectomy confirmation of azoospermia. 
• Tubal occlusion PLUS male condom 
• IUD PLUS male condom. Provided coils are copper-banded 
 
Acceptable hormonal methods: 
• Normal and low dose combined oral pills PLUS male condom 
• Cerazette (desogestrel) PLUS male condom. Cerazette is currently the only highly 
efficacious progesterone based pill. 
• Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom 
• Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom 
• Norelgestromin / EE transdermal system PLUS male condom 
• Intrauterine system (IUS) device (e.g., levonorgestrel releasing IUS -Mirena®) PLUS male 
condom 
• Intravaginal device (e.g., EE and etonogestrel) PLUS male condom 

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APPENDIX E 
PATIENT INFORMATION SHEET ON DIARRHEA 
MANAGEMENT 
 
Diarrhea is a common problem experienced by many patients and is a risk with olaparib. If it is 
not controlled quickly, it can lead to dehydration. 
 
WHEN TO CALL YOUR DOCTOR TO REPORT DIARRHEA 
• Fever 100.5° F or higher with diarrhea. 
• If you are experiencing diarrhea for the first time after starting therapy. Based on questions 
answered during that phone call, we will advise starting with 2 milligrams (mg) of loperamide 
(Imodium) if it seems the symptoms are related to the treatment. 
• If you still have diarrhea 24 hours or more than 6 loose bowel movements after starting 
loperamide (Imodium) (your doctor may advise additional medications or want to 
evaluate you in person if there is a concern that you are becoming dehydrated). 
 
OVER THE COUNTER MEDICATION MANAGEMENT OF DIARRHEA 
• For diarrhea that occurs more than 2 episodes a day, use loperamide (Imodium). We 
recommend that you have loperamide (Imodium) on hand at home before starting 
therapy. 
o 1st episode of diarrhea: Take 2 caplets (4 mg). 
o During the day: Take 1 caplet (2 mg) after each episode of diarrhea. 
o During the night: Take 2 caplets (4 mg) at bedtime if you are still having diarrhea. 
o Do not take more than 8 tablets (16 mg) of loperamide in 24 hours. 
DRINK PLENTY OF FLUIDS 
• 
Drink 8 to 10 large glasses of liquids a day to replace those lost by diarrhea. Drink small 
quantities at a time slowly. 
• 
AVOID caffeinated, very hot, or very cold fluids. 
Examples of acceptable fluids: 
o Water (should only be part of the 8 to 10 glasses a day) 
o Jello/gelatin 
o Gatorade 
o Clear soup or broth 
o Other non-caffeinated fluids 
 
EAT SMALL MEALS OFTEN 
• 
A good choice of foods for diarrhea is the BRAT diet: 
o B - bananas 
o R - rice 
o A - applesauce 
o T - toast 
• 
When these foods are being well tolerated, then you can add other bland low fiber foods 
such as: 
o Chicken (white meat without the skin), steamed rice, crackers, white bread, pasta 
noodles without sauce, and canned or cooked fruits without skins. 
o Foods high in potassium: bananas, apricots without skin, peach nectar, potatoes 

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without skin, broccoli, halibut, mushrooms, asparagus, non-fat milk. 
• 
Foods that can make diarrhea and cramping worse: 
o Fatty, fried, greasy, or spicy foods can cause more problems and discomfort. 
o High-fiber foods: Bran, whole grain cereals, dried fruit, fruit skins, popcorn, nuts, 
and vegetables. 
o Foods that cause gas: Beer, beans, cabbage, carbonated drinks. 

NCI Protocol #: 10264 
Version Date:  December 11, 2024 
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APPENDIX F 
PATIENT MEDICATION DIARY - OLAPARIB 
 
PATIENT’S MEDICATION DIARY 
Today’s date 
 
Agent 
Olaparib 
 
Patient Name 
(initials acceptable) Patient Study ID  
 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form every four weeks. 
2. 
You will take 2 tablets twice each day (supplied as either 100mg or 150mg tables), 
in the morning and 
in the 
evening. 
• 
You should take the tablets with 8 oz. water, with or without any moderate fat or low-fat food. 
• 
Do not consume grapefruit, grapefruit juice, or Seville oranges while on olaparib therapy. 
• 
Do not chew, dissolve, or crush olaparib tablets. 
• 
If you miss a dose, you have up to 2 hours to make this dose up. Otherwise, write “missed” where you would 
normally write the time of your dose. Do not double-up on the next dose. 
• 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be replaced if all of the 
intact tablets can be seen and counted. 
3. 
Record the date, the number of tablets you took, and when you took them. 
4. 
If you have any comments or notice any side effects, please record them in the Comments column. 
5. 
Please return the forms to your physician when you go for your next appointment. 
Day 
Date 
Time of 
morning dose 
# of tablets 
taken 
Time of 
evening dose 
# of tablets 
taken 
Comments 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
CTEP-assigned Protocol # 10264 
Local Protocol #   
 

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22 
23 
24 
25 
26 
27 
28 
 
Patient’s Signature  
 
 
Physician’s Office will complete this section: 
Date patient started protocol treatment  
 
 
 
Patient’s planned total daily dose  
 
  
 
Physician/Nurse/Data Manager’s Signature 

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APPENDIX G 
WORLD HEALTH ORGANIZATION DIAGNOSTIC CRITERIA 
FOR ACUTE MYELOID LEUKEMIA AND MYELODYSPLASTIC 
SYNDROMES 
 
Arber D.A., A. Orazi, R. Hasserjian, et al., (2016). The 2016 revision to the World Health 
Organization classification of myeloid neoplasms and acute leukemia. Blood. 127(2391-2405). 
Acute myeloid leukemia (AML) and related neoplasms 
 
AML with recurrent genetic abnormalities 
 
AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1 
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11 APL with PML-RARA 
AML with t(9;11)(p21.3;q23.3);MLLT3-KMT2A 
AML with t(6;9)(p23;q34.1);DEK-NUP214 
AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM AML 
(megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1 Provisional entity: AML with BCR- 
ABL1 
AML with mutated NPM1 
AML with biallelic mutations of CEBPA 
Provisional entity: AML with mutated RUNX1 
 
AML with myelodysplasia-related changes 
Therapy-related myeloid neoplasms 
AML, NOS 
 
AML with minimal differentiation 
 
AML without maturation 
AML with maturation 
Acute myelomonocytic leukemia 
 
Acute monoblastic/monocytic leukemia 
 
Pure erythroid leukemia 
 
Acute megakaryoblastic leukemia 
 
Acute basophilic leukemia 
 
A 
cute panmyelosis with myelofibrosis 
 
Myeloid sarcoma 
 
Myeloid proliferations related to Down syndrome 

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Transient abnormal myelopoiesis (TAM) 
 
Myeloid leukemia associated with Down syndrome 
 
 
 
Myelodysplastic syndromes (MDS) 
 
MDS with single lineage dysplasia 
 
MDS with ring sideroblasts (MDS-RS) 
MDS-RS and single lineage dysplasia 
MDS-RS and multilineage dysplasia 
MDS with multilineage dysplasia 
MDS with excess blasts 
MDS with isolated del(5q) 
MDS, unclassifiable