Clinical trial NCT02878785
Conditions: Acute Myeloid Leukemia
Keywords: AML
Sponsor: University of Maryland, Baltimore
Start date: 2016-08-01; Completion date: 2020-11-19
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
The purpose of this study is to find the best way to combine a new chemotherapy drug with one that is already in use to treat AML. The new experimental drug is called talazoparib (also known as BMN-673), and it is not approved by the Federal Drug Administration (FDA). The FDA is allowing the use of talazoparib for the purposes of this study.

Decitabine is used to treat bone marrow diseases called myelodysplastic syndromes (MDS), as well as off label for AML.

Lab work suggests that talazoparib will increase the effects of decitabine in leukemia cells.

Investigators hope that treating patients with decitabine and talazoparib together will be more successful that treating patients with decitabine alone.

This study has two parts. The purpose of part one the study is to find out the best doses of decitabine and talazoparib to use when they are given together to treat AML. The purpose of part two is to see how well the drugs work together to treat AML.

All participants in the study will be treated with decitabine and talazoparib.

Part one of the study will include as few as two people and as many as 36 people to find the best dose levels of the study drugs. Part one will begin enrolling first. Part two of the study will not start until the Part one of the study is complete. Participants will be told which part of the study they may be enrolled in. Part two of the study may include as few as 79 people and as many as 135 people. Part two includes three separate arms. Participants enrolled in Part two of the study, will be assigned to one of the three arms below in order to test the success rate of the study drug dose determined by Part one:

* Arm A will enroll adult patients with AML who are thought not to be likely to tolerate or respond to standard chemotherapy;
* Arm B will enroll adult patients with AML that has not responded to previous treatment or has come back after responding to previous treatment;
* Arm C will enroll adult patients previously treated with a DNA methyltransferase inhibitor (decitabine, azacitidine or guadecitabine).

This is a multi-center study. Up to 171 people may take part in this study globally.

Detailed description:
In this clinical trial, investigators combine decitabine and talazoparib in the treatment of patients with AML. Decitabine will be given in the established regimen of IV daily dosing for 5 days every 28 days. Talazoparib will be initiated orally daily on a continuous basis, beginning on Day 1 of Course 1. In this phase 1 trial, decitabine and talazoparib will be tested at 3 and 4 dose levels, respectively, yielding up to 6 combinations. Doses will be escalated based on tolerability using a 'classic' 3+3 design. Once the MTD for decitabine combined with 0.25 mg talazoparib is established, the dose of talazoparib will be escalated with the dose of decitabine kept fixed at the provisional MTD dose. There is no further stepping up or down of the drugs in the combination.

The regimen for phase 2 testing will be chosen based on tolerability, but also based on available pharmacodynamic and efficacy data. In phase 2, the selected combination regimen will be studied for efficacy.

Each patient will be treated until occurrence of either unacceptable toxicity or disease progression. Bone marrow aspirate and biopsy will be performed on approximately day 28 of each treatment course unless circulating blasts persist in the peripheral blood, until documentation of CR or CRi. Bone marrow aspirate and biopsy will then be repeated at time of clinical concern for disease progression.

In Phase 1, the clinical trial will enroll patients with relapsed and refractory AML in order to test the novel combination initially in patients with less favorable outcomes with decitabine alone. This is being done to avoid the possibility of compromising the outcomes of untreated patients, who have up to a 40% response rate to 5-day decitabine as a single agent, in the unlikely possibility that the combination is inferior. The regimen will then also be tested in previously untreated AML patients unfit for chemotherapy in phase 2.

Arms: arm 1: Phase 1:

Decitabine by IV daily for 5 days every 28 days. Talazoparib orally daily days 1-28.

The 'outer layer' of this nested dose escalation trial will escalate the dose of the two drugs by sequentially going through dose levels 1-6 in the table found in the protocol. The standard algorithm of the 3+3 design will be applied. arm 2: Phase 2:

Recommended Phase 2 Dose (RP2D) The MTD of the combination of decitabine with a dose of talazoparib of at least 0.25 mg is defined as the maximal tolerated dose of decitabine studied - and for that dose level, combined with the maximum dose of talazoparib for which the incidence of DLT was less than 33% in 6 participants treated and this will be chosen as the recommended Phase 2 dose (RP2D). Among potential combined dose levels at MTD, available pharmacodynamic data (PARP trapping) will also be considered in the choice of RP2D, as will any significant indications of differences in clinical efficacy arm 3: Adult patients with AML who are thought not to be likely to tolerate or respond to standard chemotherapy arm 4: Adult patients with AML that has not responded to previous treatment or has come back after responding to previous treatment arm 5: Adult patients previously treated with a DNA methyltransferase inhibitor (decitabine, azacitidine or guadecitabine)
Interventions: intervention 1: Decitabine intervention 2: talazoparib
Intervention descriptions: intervention 1: DNA methyltransferase inhibitor intervention 2: poly ADP ribose polymerase (PARP) inhibitor

Protocol documents:
Prot_SAP_000.pdf: 
 
Protocol #: 1565GCC – Phase I/II Trial of Talazoparib + Decitabine in AML 
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University of Maryland Local Protocol #: 1565GCC 
 
ClinicalTrials.gov Identifier: NCT02878785 
 
Title: Multicenter phase 1/2 study of combination therapy with the DNA methyltransferase 
inhibitor decitabine and the poly ADP ribose polymerase (PARP) inhibitor talazoparib (BMN 673) 
for untreated acute myeloid leukemia (AML) in adult patients unfit for cytotoxic chemotherapy or 
relapsed/refractory AML 
 
Coordinating Center: University of Maryland Marlene and Stewart Greenebaum 
Comprehensive Cancer Center, Baltimore, Maryland 
 
Principal Investigator: 
 
Maria Baer, M.D. 
 
University of Maryland Greenebaum Comprehensive Cancer Center  
 
22 S. Greene Street 
 
Baltimore MD, 21201 
 
Phone: 410-328-8708     
 
Fax: 410-328-6896 
 
email: mbaer@umm.edu 
 
Laboratory Co-Investigator: 
 
Feyruz Rassool, Ph.D.  
 
University of Maryland Greenebaum Comprehensive Cancer Center  
 
655 W. Baltimore St, BRB, Room 8–037 
 
Baltimore, MD 21201 
 
Phone: 410-706-5337       
 
Fax: 410-706-6666 
 
email: frassool@som.umaryland.edu 
 
Statistician: 
 
 
Coordinating Center Contact: 
Søren M. Bentzen, Ph.D., D.M.Sc. 
Gary Saum, BA 
Howard Hall 109D       
 
22 S. Greene Street 
Phone: 410-706-8506  
 
Phone: 410-328-7680 
Fax: 410-706-8548         
 
Fax:  410-328-1180 
email: sbentzen@som.umaryland.edu          e-mail: gary.saum@umm.edu 
 
Other Participating Institutions: 
Temple/Fox Chase Cancer Center, 
Philadelphia, Pennsylvania 
 
Patricia Kropf, MD  
Phone: 215-214-3129      
Fax: 215-214-3127 
email: Patricia.Kropf@tuhs.temple.edu 
University of Southern California Norris 
Comprehensive Cancer Center, Los 
Angeles, California 
Casey L. O’Connell, MD  
Phone: 323-226-2622     
Fax: 323-865-0060 
email: OConnell_C@med.usc.edu 
 
Investigational Agent: Talazoparib, Pfizer, Inc. 
IND #s:  131131 
IND Sponsor:  University of Maryland, Baltimore 
 


 
Protocol #: 1565GCC – Phase I/II Trial of Talazoparib + Decitabine in AML 
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Protocol Type / Version # / Version Date: Original / Version #1 / July 14, 2015;  
Version #2 / March 19, 2016; Version #3 / August 3, 2016; Version #4/ January 4th, 2017; Version 
5.0 April 17th, 2018 
 
 


 
Protocol #: 1565GCC – Phase I/II Trial of Talazoparib + Decitabine in AML 
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SCHEMA 
 
Phase 1 
 
Decitabine is administered intravenously (IV) daily for 5 days every 28 days through Cohort 6. 
Decitabine is administered intravenously (IV) daily for 10 days every 28 days in Cohort 7.  
 
Talazoparib is administered orally daily on days 1-28. 
 
 
 
 
 
 
 
 
*NOTE: DECITABINE IS DOSED IN MG/M2, BUT TALAZOPARIB IS DOSED IN MG. 
 
The ‘outer layer’ of this nested dose escalation trial will escalate the dose of the two drugs by 
sequentially going through dose levels 1-6 in the table. The standard algorithm of the 3+3 design 
will be applied as specified below. 
 
If the MTD has not been reached at dose level 6, the RP2D of decitabine will be 20 mg/m2 
combined with a dose of talazoparib of 1.0 mg. If 2 or more participants develop DLT at dose level 
1, the combination of decitabine and talazoparib will be considered too toxic for further clinical 
development. 
 
If the provisional MTD for decitabine in combination with talazoparib is dose level 1 or 2, one or 
the other of the ‘inner layers’ of the trial will be activated. If the provisional MTD corresponds to 
level 2, the dose of decitabine will be fixed at 15 mg/m2 and the dose of talazoparib will be 
escalated through steps 2a-c, again using the algorithm of the 3+3 design below. If the tolerance 
is not exceeded at level 2c, then the RP2D of decitabine is 15 mg/m2 combined with a dose of 
talazoparib of 1.0 mg. 
 
Similarly, if the provisional MTD for the combination of the two agents from the outer layer is level 
1, the dose of decitabine will be fixed at 10 mg/m2 and the dose of talazoparib will be escalated 
through steps 1a-c, again using the algorithm of the 3+3 design below to define the MTD of the 
combination.  
 
If Cohort 6, with 20 mg/m2 decitabine daily for 5 days and talazoparib 1 mg daily, is completed 
without dose-limiting toxicity, Cohort 7, consisting of decitabine, 20 mg/m2 daily for 10 days and 
talazoparib, 1 mg daily, will be added. 
 
Following completion of Cohort 6 or Cohort 7 without dose-limiting toxicity, a minimum of 9 or 
maximum of 17 participants not previously treated with DNMTis (decitabine, azacitidine and/or 
guadecitabine) will be enrolled to assess response in this patient population.  
 
Cohort 7 will consist of a minimum of 3 participants with a maximum of 6 participants. 
 
Phase 2 
 
 
Talazoparib* (mg) 
0.25 
0.50 
0.75 
1.0 
Decitabine* 
(mg/m2) 
10 
1 
1a 
1b 
1c 
15 
2 
2a 
2b 
2c 
20 
3 
4 
5 
6 


 
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Decitabine is administered intravenously (IV) daily for 5 or 10 days every 28 days, depending on 
Phase 1 results. 
 
Talazoparib is administered orally daily days 1-28. 
 
Phase 2 doses and schedule will be determined based on data from Phase 1. 
 
Phase 2, Trial A – a minimum of 25 participants up to a maximum of 63 participants will be enrolled 
in the Trial A portion of Phase 2 
 
Phase 2, Trial B – a minimum of 22 participants to a maximum of 40 participants will be enrolled 
in the Trial B portion of Phase 2 
 
Total Phase 2 enrollment – a total minimum of 47 and a total maximum of 103 participants will be 
enrolled in Phase II of this study 
 
 


 
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TABLE OF CONTENTS 
Page # 
1. OBJECTIVES .......................................................................................................................... 7 
1.1 PrimaryObjectives ................................................................................................................. 7 
1.2 Secondary Objectives ........................................................................................................... 7 
2. BACKGROUND ...................................................................................................................... 8 
2.1 Acute Myeloid Leukemia ....................................................................................................... 8 
2.2 Decitabine ............................................................................................................................. 9 
2.3 Talazoparib ......................................................................................................................... 10 
2.4 Rationale ............................................................................................................................. 11 
2.5 Correlative Studies .............................................................................................................. 13 
3. PARTICIPANT SELECTION ................................................................................................. 14 
3.1 Eligibility Criteria .................................................................................................................. 14 
3.2 Exclusion Criteria ................................................................................................................ 16 
3.3 Inclusion of Women and Minorities ...................................................................................... 17 
4. REGISTRATION PROCEDURES ......................................................................................... 17 
5. TREATMENT PLAN .............................................................................................................. 18 
5.1 Agent Administration ........................................................................................................... 18 
5.2 Phase 1 Dose Escalation .................................................................................................... 19 
5.3 Phase 2 ............................................................................................................................... 21 
5.4 General Concomitant Medication and Supportive Care Guidelines ..................................... 21 
5.5 Duration of Therapy ............................................................................................................. 22 
5.6 Criteria for Removal from Study .......................................................................................... 22 
5.7 Duration of Follow-up .......................................................................................................... 23 
6. DOSING DELAYS/DOSE MODIFICATIONS ......................................................................... 23 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ......................................... 25 
7.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ................................. 25 
7.2 Adverse Event Characteristics ............................................................................................ 29 
7.3 Reporting of Adverse Events Experiences .......................................................................... 30 
8. PHARMACEUTICAL INFORMATION.................................................................................... 33 
8.2 Talazoparib ......................................................................................................................... 34 
9. BIOMARKER aND CORRELATIVE STUDIES ...................................................................... 36 
9.1 Sample Collection ............................................................................................................... 36 
9.2 Sample Processing ............................................................................................................. 37 
9.3 Shipping of Samples ........................................................................................................... 37 
9.4 Storage of Samples/Biobanking .......................................................................................... 37 
9.5 Colony Formation, Immunofluorescence, PARP Trapping, mRNA and Protein Expression, 
and DNA DSB Repair. ............................................................................................................... 38 
9.6 DNA Methylation ................................................................................................................. 45 
9.7 Potential Predictors of Response ........................................................................................ 46 
10. STUDY CALENDAR ............................................................................................................ 47 


 
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10.1 Screening Evaluations ....................................................................................................... 48 
10.2 Study Evaluations .............................................................................................................. 48 
10.3 Post-Study Follow-up ........................................................................................................ 49 
11. MEASUREMENT OF EFFECT ............................................................................................ 50 
11.1 Definitions of Response for Acute Leukemia ..................................................................... 50 
12. DATA REPORTING / REGULATORY REQUIREMENTS .................................................... 51 
12.1 Compliance with Laws and Guidances ............................................................................. 51 
12.2 Multi-institutional Data Management.................................................................................. 53 
13. STATISTICAL CONSIDERATIONS ..................................................................................... 53 
13.1 Dose Escalation and Nesting of Dose Levels .................................................................... 53 
13.2 ‘3+3’ Design ...................................................................................................................... 54 
13.3 Expansion cohort at RP2D ................................................................................................ 55 
13.4 Stratification Factors .......................................................................................................... 56 
13.5 Analysis of Secondary Endpoints ...................................................................................... 56 
13.6 Biomarkers and Pharmacodynamic Markers ................................................................... 576 
13.7 Reporting and Exclusions………………………………………………………………………57 
 
REFERENCES…………………………………………………………………………………………..58 
 
APPENDIX A –PERFORMANCE STATUS CRITERIA……………………………………………...61 
APPENDIX B – AML SAMPLE PROCUREMENT ..................................................................... 62 
APPENDIX C – PARTICIPANT DIARY FOR TALAZOPARIB ................................................... 67 
 
APPENDIX D – LAB ANALYSIS PRIORITY DIAGRAM……………………………………………68 
 
INVESTIGATOR AGREEMENT……………………………………………………………………….69 
 
 


 
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1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1    Phase 1 
 
To determine the recommended Phase 2 doses of combined decitabine intravenously (IV) daily 
for 5 or 10 days and talazoparib orally daily continuously in patient participants with refractory or 
relapsed acute myeloid leukemia (AML). 
 
1.1.2    Phase 2 
 
1.1.2.1  To determine the safety of decitabine and talazoparib combination therapy in newly 
diagnosed AML patient participants unfit for intensive chemotherapy.  
 
1.1.2.2 To determine the efficacy of decitabine and talazoparib combination therapy in newly 
diagnosed AML patient participants unfit for intensive chemotherapy. 
 
1.1.2.3 To determine the safety of decitabine and talazoparib combination therapy in patient 
participants with relapsed and refractory AML. 
 
1.1.2.4 To determine the efficacy of decitabine and talazoparib combination therapy in patient 
participants with relapsed and refractory AML. 
 
1.1.2.5 To explore the safety of decitabine and talazoparib therapy in AML patient participants 
previously treated with a DNA methyltransferase inhibitor (azacitidine, decitabine or 
guadecitabine) for AML or for antecedent MDS. 
 
1.1.2.6 To explore the efficacy of decitabine and talazoparib therapy in AML patient participants 
previously treated with a DNA methyltransferase inhibitor (azacitidine, decitabine or 
guadecitabine) for AML or for antecedent MDS. 
 
1.1.2.7 To determine treatment duration, disease-free survival (DFS) and overall survival (OS) 
for each of the three patient participant cohorts. 
 
 
1.2 
Secondary Objectives 
 
1.2.1  
Phase 1 
 
1.2.1 To observe and record anti-tumor activity while on protocol therapy. Although the clinical 
benefit of this drug combination has not yet been established, the intent of offering this 
treatment is to provide a possible therapeutic benefit, and thus participants will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability. 
 
1.2.2 To explore pharmacodynamic effects of decitabine IV daily for 5 or 10 days every 28 days 
and talazoparib orally daily continuously in patient participants with relapsed or refractory 
AML. 
 
1.2.3 To explore cytogenetic and molecular predictors of response to decitabine and talazoparib 
combination therapy. 


 
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1.2.2 
Phase 2 
 
1.2.2.1 To explore biomarker correlates of response. 
 
1.2.2.2 To explore pharmacodynamic correlates of response. 
 
 
2. 
BACKGROUND 
 
2.1 
Acute Myeloid Leukemia 
 
AML is a malignancy that arises in a hematopoietic stem cell in the bone marrow and is 
characterized by maturation arrest of a malignant clone of myeloid cells (1,2). Immature myeloid 
cells, or blasts, accumulate in the bone marrow, with failure of normal hematopoiesis. AML is fatal 
if not effectively treated. The initial goal of treatment is induction of complete remission (CR), 
defined by normal blood counts and normal bone marrow morphology, or, less preferably, 
complete remission with incomplete count recovery (CRi), defined by normal bone marrow 
morphology but incomplete blood count recovery. Post-remission therapy is then administered 
with the goal of prolonging disease-free survival (DFS) and maximizing the likelihood of cure.  
 
The mainstay of remission induction therapy for AML for the last 40 years has been combination 
chemotherapy including the nucleoside analogue cytarabine and an anthracycline, usually 
daunorubicin or idarubicin (1,2). Other chemotherapy drugs, including etoposide, mitoxantrone, 
topotecan, flavopiridol and the nucleoside analogs cladribine, clofarabine or fludarabine have 
been added or substituted in diverse treatment regimens. Post-remission therapy may consist of 
high-dose cytarabine or hematopoietic stem cell transplantation (HSCT). While the backbone of 
AML therapy has changed little, recognition of subsets of patients who are unlikely to achieve 
long-term DFS has allowed appropriate application of allogeneic HSCT, and enrollment on clinical 
trials when standard therapy is unlikely to be effective. Unfortunately, current 5-year survival for 
AML patients is only 23% (2). Survival has improved over several decades in younger adults, but 
not in those with prognostically unfavorable AML cell karyotypes, or with the prognostically 
unfavorable molecular abnormality fms-like tyrosine kinase 3 internal tandem duplication (FLT3-
ITD). Other subgroups that fare poorly include older adults and those with AML evolved from an 
antecedent marrow disorder such as a MDS or with therapy-related AML (t-AML) (1,2). New 
therapies are needed, especially for patients in groups with poor responses to current cytotoxic 
chemotherapy. Patients with AML resistant to, or relapsing after, cytotoxic chemotherapy also 
need new approaches. 
 
Untreated AML patients may be considered “unfit for chemotherapy” if deemed unlikely to tolerate 
chemotherapy or to respond to chemotherapy, based on patient and/or disease characteristics. 
Patient characteristics may include poor performance status, comorbidities and/or advanced age, 
while disease characteristics may include prognostically unfavorable AML karyotype and/or AML 
evolved from an antecedent marrow disorder such as MDS, or t-AML (1,2). 
 
AML patients considered unfit for chemotherapy and patients with AML resistant to, or relapsing 
after, cytotoxic chemotherapy are currently often treated with DNA methyltransferase inhibitors 
(DNMTis). To improve responses, combinations of DNMTis and novel agents are being studied 
in clinical trials in these patients (1,2). 


 
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2.2 
Decitabine 
 
Decitabine, or 5-aza-2'-deoxycytidine is a cytidine analog that functions as a DNA 
methyltransferase inhibitor (DNMTi) and was found to induce cellular differentiation at low 
concentrations by reversing DNA methylation-induced gene silencing (3).  
 
Clinical testing of decitabine was undertaken in MDS. Following promising data in initial small 
phase 2 trials in MDS (4), Wijermans et al. performed a large multicenter phase II trial of 
decitabine a dose of 15 mg/m2 infused intravenously (IV) over a 4-hour period every 8 hours for 
3 consecutive days, repeated every 6 weeks (5). The overall response rate was 49% for all 
patients, and was 64% in patients with a high-risk International Prognostic Scoring System (IPSS) 
score, and response duration was 36 weeks for patients who achieved CR. In the first phase III 
trial of decitabine (6), 170 patients with MDS, including 70% with higher-risk IPSS scores, were 
randomized to receive either decitabine in the above schedule or best supportive care (BSC). The 
overall improvement rate in the decitabine arm was 30%, compared with 7% in the BSC arm, and 
time to AML or death was significantly prolonged in patients with higher-risk MDS. Decitabine was 
FDA-approved for treatment of MDS with the above schedule on May 2, 2006. 
 
There were subsequent efforts to optimize the decitabine schedule for treatment of MDS. Patients 
with higher-risk MDS and chronic myelomonocytic leukemia (CMML) were randomly assigned to 
one of three treatment schedules: 20 mg/m2 IV daily for five days, 20 mg/m2 subcutaneously (SQ) 
daily for five days, and 10 mg/m2 IV daily for ten days. The five-day IV schedule produced a CR 
rate of 39%, compared with 21% and 24% in the five-day SQ and ten-day IV schedule, 
respectively, and was selected as optimal (7). Steensma et al. (8) studied the 5-day IV schedule, 
repeated every 4 weeks, in 99 MDS patients, demonstrating an overall response rate of 32% (17 
CR and 15 marrow CRs), and an overall improvement rate of 51%, included 18% hematologic 
improvement (HI). The 5-day dosing regimen was approved for treatment of MDS on March 12, 
2010.  
 
Decitabine also has efficacy in AML and is well tolerated, and therefore is also currently in 
widespread use to treat AML in patients who are previously untreated and “unfit” for 
chemotherapy or who have refractory or relapsed AML with low likelihood of response to intensive 
chemotherapy (9-14). Cashen et al. (9) treated 55 older previously untreated AML patients with 
decitabine 20 mg/m2 IV daily for 5 days every 4 weeks. Importantly, decitabine was continued 
until disease progression or an unacceptable adverse event occurred; patients received a median 
of three (range, one to 25) cycles. The overall response rate was 25% (CR rate, 24%). Overall 
median survival was 7.7 months, and 30-day mortality rate 7%. The most common toxicities were 
myelosuppression, neutropenic fever and fatigue. In a phase II, multicenter study of decitabine in 
the same schedule as first-line therapy in 227 older patients with AML (10), 59 patients (26%) 
achieved CR, including 30 with CR and 29 with PR, and 60 (26%) had a lesser antileukemic effect, 
for an overall response rate of 52%. Median overall survival was 5.5 months and one-year survival 
rate, 28%. Toxicities were predominantly hematologic.  
 
In a subsequently reported multicenter, randomized, open-label, phase III trial, 485 older patients 
with newly diagnosed AML were randomly assigned 1:1 to 5-day decitabine or either supportive 
care or low-dose cytarabine (11). The primary end point was OS; the secondary end point was 
rate of CR plus CR without platelet recovery (CRp). The primary analysis with 396 deaths (81.6%) 
showed a non-significant increase in median OS with decitabine, 7.7 months (95% CI, 6.2 to 9.2) 
versus 5.0 months (5% CI, 4.3 to 6.3) with P = .108, hazard ratio [HR], 0.85; 95% CI, 0.69 to 
1.04). An unplanned analysis with 446 deaths (92%) showed a survival benefit for decitabine (HR, 


 
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0.82; 95% CI, 0.68 to 0.99; nominal P = .037). The most common drug-related AEs with decitabine 
were thrombocytopenia (27%) and neutropenia (24%). Decitabine was approved for treatment of 
AML in Europe based on the results of this study. It was not approved for treatment of AML in the 
US, but is in widespread use off-label. As with decitabine treatment of MDS, decitabine treatment 
for AML continues on an ongoing basis, until disease progression. 
 
Decitabine has also been used in a 10-day regimen for AML (12-14). The ten-day decitabine 
regimen produced response rates of 64% (47% CR and 17% CRi), 40.4% (CR) and 42% (31% 
CR and 11% CRi) in untreated AML patients unfit for chemotherapy (10-12). Survival in 
responders was 481 days (approximately 16 months) and 19.4 months in the two series in which 
it was stated (13,14). In contrast, the 10-day decitabine regimen produced a CR rate of only 15.7% 
in patients with refractory or relapsed AML (13). 
 
 
2.3 
Talazoparib 
 
Talazoparib (BMN 673) (15) is an orally bioavailable inhibitor of the nuclear enzyme poly ADP 
ribose polymerase (PARP), with potential antineoplastic activity. Talazoparib selectively binds to 
PARP and prevents PARP-mediated DNA repair of single-strand DNA breaks via the base 
excision repair pathway. This enhances the accumulation of DNA strand breaks, promotes 
genomic instability and eventually leads to apoptosis. PARP catalyzes post-translational ADP-
ribosylation of nuclear proteins that signal and recruit other proteins to repair damaged DNA and 
is activated by single-strand DNA breaks.  
 
Talazoparib is a PARP inhibitor (PARPi) with superior potency (PARP1 IC50 0.57 nmol/L) and 
favorable metabolic stability, oral bioavailability, and pharmacokinetic properties (15,16). In 
addition, talazoparib is able to trap PARP in the low nanomolar range (15). 
 
in vitro metabolism studies of talazoparib in hepatic microsomes from rats, dogs and humans 
demonstrated that talazoparib has >90% stability over 2 hours in all three species. Fecal excretion 
was the major route of elimination.  
 
It is unlikely that talazoparib will demonstrate CYP450 inhibition- or induction-based drug-drug 
interactions when co-administered with corresponding substrates. Treatment with up to 10 μM 
talazoparib in human liver microsomes showed no direct, time- or metabolism-dependent 
inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4 enzymes.  
 
Clinical trials of talazoparib to date in patients with solid tumors have demonstrated good 
tolerability and established a dose of 1 mg orally (PO) daily (17-19). The dose-limiting toxicity was 
thrombocytopenia (18). 
 
A phase 1 clinical trial of talazoparib in advanced hematologic malignancies was initiated in 2011. 
This was a two-arm, open-label study to determine the MTD and assess the safety, 
pharmacokinetics, pharmacodynamics, and preliminary efficacy of talazoparib in patients with 
AML, MDS, chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Arm 1 enrolled 
patients with either AML or MDS. Arm 2 enrolled patients with either CLL or MCL. The study 
enrolled 33 patients and was closed in May 2014. Results were reported at the 2014 European 
Hematology Association (EHA) meeting (20). Oral talazoparib was administered on a continuous 
daily schedule (21-day cycle) at escalating dose levels. Thirty-three patients (Arm 1: 21 AML, 4 
MDS; Arm 2: 4 CLL, 4 MCL), 10F/23M, median age 71 years (range 22-86), ECOG performance 
status 0-1, were enrolled. Median number of previous regimens was 3 (range, 1-7) in Arm 1 and 


 
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6 (range 1-13) in Arm 2. Talazoparib dose levels were: 100, 200, 300, 450, 900, 1350 and 2000 
μg/day. Dose-limiting toxicities (DLTs) included neutropenic fever and neutropenic sepsis in 2/4 
patients at 2000 μg/day in Arm 1 and severe neutropenia in 2/5 patients at 900 μg/day in Arm 2. 
Overall, the most frequent drug-related adverse events were fatigue (all grades=27%), 
neutropenia (27%), nausea (24%), infections (21%), and thrombocytopenia (12%). No alopecia 
was reported. No responses were seen. Stable disease was seen in 13/25 patients in Arm 1 and 
5/8 patients in Arm 2. One MDS patient received 24 cycles of talazoparib (484 days) and became 
red blood cell (RBC) transfusion-independent. It was concluded that the MTD of talazoparib 
appeared to be different in patients with AML, MDS, CLL and MCL, and that talazoparib had 
limited activity as a single agent in a combined group of patients with advanced hematological 
malignancies. 
 
In the novel combination regimen to be tested in this clinical trial, talazoparib will be studied at 
doses of 0.25, 0.5, 0.75 and 1 mg. 
 
 
2.4 
Rationale 
 
2.4.1 DNA Methyltransferase Inhibitors 
 
In addition to causing gene promoter hypomethylation and consequent gene re-expression, 
DNMTis also have additional mechanisms of action in MDS and AML. In particular, decitabine 
has been found to cause formation of DNA double-strand breaks (DSBs), with repair of this 
damage following drug removal (21). Decitabine also induces reactive oxygen species (ROS) in 
myeloid leukemia cells (22).  
 
2.4.2 PARP-dependent Aberrant DNA Repair in AML 
 
The Rassool laboratory has demonstrated upregulation of a highly error-prone alternative non-
homologous end-joining (alt NHEJ) pathway for repair of DNA DSBs in myeloid leukemias, with 
increased expression of its component proteins, including PARP (23-25). PARP was initially 
characterized as a key component of base excision repair of DNA single-strand breaks, but was 
subsequently found to also be a key part of the alt NHEJ DNA DSB repair pathway, which 
functions as backup to the classical NHEJ pathway. The alt NHEJ DNA DSB repair pathway is 
sensitive to PARPis, which inhibit poly (ADP-ribose) synthesis by PARP-1 (26). Myeloid leukemia 
cells were shown to be sensitive to PARPis, suggesting their dependence on PARP for survival 
(27).  
 
2.4.3 PARP Inhibitors  
 
PARPis are in clinical trials in patients with homologous recombination-deficient tumors, primarily 
breast and ovarian cancers in patients with BRCA mutation. They are also being tested as 
radiosensitizers and chemosensitizers in sporadic cancers (28). 
 
The PARPis most extensively studied to date include olaparib (AZD-2281) and veliparib (ABT-
888) (28). Other PARPis include niraparib (MK-4827), CEP-9722, E7016/GPI-21016, rucaparib 
(AG-014699/PF-01367338) and talazoparib (28). It was recently shown that PARPis differ 
markedly in their ability to trap PARP-1-DNA complexes, with the extent of trapping correlating 
with cytotoxicity: niraparib (MK-4827)> olaparib (AZD-2281)>>veliparib (ABT888) (29). 
Talazoparib is able to trap PARP in the low nanomolar range (15) and has superior potency 
(PARP1 IC50 0.57 nmol/L) (15).  


 
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There are relatively few data on PARPis in AML. The PARPi ABT-888 was found to sensitize 
myeloid leukemia cell lines to temozolamide (30), and the PARPi olaparib was recently found to 
disrupt base excision repair of lesions induced by decitabine (31). There is also little clinical 
experience in AML. Several clinical trials have been undertaken, with results not yet reported. 
 
The PARPi to be studied in this clinical trial is the novel potent PARPi talazoparib (15). 
 
2.4.4 Combined DNA Methyltransferase and PARP Inhibitors in AML 
 
The Baylin laboratory demonstrated that transient exposure to DNMTis at low nM concentrations 
reprograms cancer cells, altering gene expression patterns in key cellular pathways, including 
DNA repair pathways (32). They and others have also demonstrated that DNMTs interact with 
PARP in complexes (33). Since DNMTis trap DNMT on DNA and chromatin, it was hypothesized 
that co-treatment of leukemia cells with DNMTis would further trap PARP in chromatin and at 
DSBs, sensitizing cells to PARPis. Testing this hypothesis has been a focus of the Rassool 
laboratory. 
 
The Rassool laboratory has demonstrated that pre-treatment of myeloid leukemia cell lines and 
AML patient samples with decitabine at low nanomolar (20 nM) concentrations sensitizes them to 
PARPis, including ABT-888 and talazoparib (34). These combinations induce a significant 
decrease in methylcellulose colony formation, compared to treatment with DNMTi or PARPi alone. 
This was particularly evident in cell lines (2 of 4) and primary patient samples (3 of 6) with 
FLT3/ITD mutations, which are present in AML cells in approximately a third of patients and are 
associated with unfavorable prognosis. Moreover, decitabine and PARPis appear to cooperate to 
enhance the basic mechanism underlying the activity of PARPis, increasing the cytotoxic DNA-
PARP complexes on chromatin, resulting in retention of PARP1 and DNMT1 at DSBs and 
decreased DNA DSB repair. Additionally, we have found that DNMTis decrease expression of 
homologous recombination (HR) DSB repair genes, suggesting that HR activity is also impaired 
through this mechanism. These data support combined DNMTi and PARPi as a novel treatment 
regimen for myeloid malignancies. This concept has now also been validated in vivo in 
immunodeficient mice engrafted with MV4-11 or MOLM14 cells, human leukemia cell lines with 
FLT3-ITD, treated simultaneously with the DNMTi azacitidine and the PARPi talazoparib. In this 
scenario, concurrent administration of azacitidine 0.5 mg/kg + talazoparib 0.1 mg/kg markedly 
suppresses tumor growth for at least 30 days, in relation to treatment with either drug alone (34).  
 
Patients with MDS and AML respond to DNMTis, but response rates and response duration need 
to be improved, and combinations with other agents are being studied. DNMTis may sensitize 
cells to other therapeutic agents, and this sensitization may serve as a basis for novel combination 
regimens. Based on our preclinical data, we propose a novel regimen combining DNMTis and 
PARPis.  
 
2.4.5 Clinical Trial Strategy 
 
In this clinical trial, we combine decitabine and talazoparib in the treatment of patient participants 
with AML. Decitabine will be given in the established regimen of IV daily dosing for 5 or 10 days 
every 28 days. Talazoparib will be initiated orally daily on a continuous basis, beginning on Day 
1 of Cycle 1. In this phase 1 trial, decitabine and talazoparib will be tested at 3 and 4 dose levels, 
respectively, yielding up to 6 combinations. Doses will be escalated based on tolerability using a 
‘classic’ 3+3 design. Once the MTD for decitabine combined with 0.25 mg talazoparib is 
established, the dose of talazoparib will be escalated with the dose of decitabine kept fixed at the 


 
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provisional MTD dose. There is no further stepping up or down of the drugs in the combination. 
 
The regimen for phase 2 testing will be chosen based on tolerability, but also based on available 
pharmacodynamic and efficacy data. In phase 2, the selected combination regimen will be studied 
for efficacy.  
 
Each participant will be treated until occurrence of either unacceptable toxicity or disease 
progression. Bone marrow aspirate and biopsy will be performed on approximately day 28 of each 
treatment cycle unless circulating blasts persist in the peripheral blood, until documentation of CR 
or CRi. Bone marrow aspirate and biopsy will then be repeated at time of clinical concern for 
disease progression. 
 
In Phase 1, the clinical trial will enroll patient participants with relapsed and refractory AML in 
order to test the novel combination initially in patients with less favorable outcomes with decitabine 
alone. This is being done to avoid the possibility of compromising the outcomes of untreated 
patients, who have up to a 40% response rate to 5-day decitabine as a single agent, in the unlikely 
possibility that the combination is inferior. The regimen will then also be tested in previously 
untreated AML patient participants unfit for chemotherapy in phase 2. 
 
2.5 
Correlative Studies 
 
2.5.1 Pharmacodynamic Studies 
 
Pharmacodynamic studies will be performed in cycle 1 on blood samples obtained pre-treatment 
on Day 1, and on Day 5 one hour after the decitabine injection, and on Day 8 anytime. These 
studies will be conducted on all participants. For participants receiving 10-day decitabine, 
sampling will be on Days 1, 5, 8 and 10, one hour after the decitabine injection.  
 
As detailed in 2.4.4, our mechanistic hypothesis is that decitabine and talazoparib will cooperate 
to increase the cytotoxic DNA-PARP complexes on chromatin, resulting in decreased DNA DSB 
repair and decreased cell survival. The assays in 2.5.1.1 and 2.5.1.2 will test components of this 
mechanism. 
 
2.5.1.1 Colony Formation, Immunofluorescence, PARP Trapping, mRNA and Protein 
Expression, and DNA DSB Repair.  
 
1) Colony-forming assays 
2) Immunostaining for H2AX (a marker for DNA DSBs), RAD51 and other DSB repair, epigenetic 
and DNA replication markers.  
3) PARP trapping 
4) PAR assay    
5) Protein expression of DSB repair genes, including PARP1, PAR, RAD51, KU70/80 and DNA 
ligase 3, and epigenetic markers, including EZH2 and DNMT1, by Western blot analysis  
6) Levels of mRNA expression of DSB repair genes, including PARP1, RAD51, KU70/80 and 
DNA ligase 3, by quantitative polymerase chain reaction (Q-PCR) 
7) Levels of DSB repair, measured using in vitro plasmid-based assays 
 
These studies will be performed in the laboratory of Dr. Rassool at UMGCCC. 
 
 


 
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2.5.1.2 DNA methylation 
 
Changes in DNA methylation will also be studied, as follows: 
 
1) Whole genome methylation analyses using the Infinium 450K array platform. 
2) Bisulfite-Pyrosequencing of Line 1 and 10 tumor suppressor genes. 
 
Samples will be shipped to the Van Andel Research Institute (VARI), where they will be processed 
and distributed for the above studies. The studies will be performed in core laboratories of VARI-
Stand Up to Cancer (SU2C) Epigenetics Dream Team members or collaborators. 
 
 
2.5.1.3 Immune response endpoints 
 
These studies will be performed in the future if funding allows.  T-cell response pre- and post-
treatment and cytokine release will be assessed. 
 
2.5.2 Potential Predictors of Response 
 
Potential predictors of response will be explored, including karyotype, FLT3 and NPM1 mutations, 
mutations in genes regulating methylation, including DNMT3A, TET2, IDH1, IDH2 and EZH2, as 
well as PARP expression levels.  
 
These studies will be performed on pre-treatment bone marrow, or on blood if marrow is 
inaspirable. Karyotype will be determined by standard cytogenetic analysis at each institution. 
Mutations will be studied as part a myeloid gene mutation panel. PARP expression levels and 
PAR activity will be measured in Dr. Rassool’s laboratory as part of the studies detailed above. 
Low baseline levels of homologous recombination DSB repair activity may also predict response 
to the drug combination and will also be explored.  
 
 
3. 
PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
1) Diagnosis of AML based on 2008 WHO criteria (35). AML may be de novo, following a prior 
hematologic 
disorder, 
including 
MDS 
or 
Philadelphia 
chromosome-negative 
myeloproliferative neoplasm, and/or therapy-related. 
 
2) PHASES 1 AND 2: Patient participants with AML that has relapsed after, or is refractory to, 
first-line therapy, with or without subsequent additional therapy, and are currently considered 
unfit for, or unlikely to respond to, cytotoxic chemotherapy. 
 
3) PHASE 2 ONLY: Patient participants previously untreated for AML who are considered unfit 
for cytotoxic chemotherapy by virtue of performance status, comorbidities, advanced age 
and/or low likelihood of response based on disease characteristics, or who decline cytotoxic 
induction chemotherapy. 
 
4) Patient participants who have undergone autologous stem cell transplantation (autoSCT) are 
eligible provided that they are  4 weeks from stem cell infusion. 
 


 
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5) Patient participants who have undergone allogeneic SCT (alloSCT) are eligible if they are  
60 days from stem cell infusion, have no evidence of graft versus host disease (GVHD) > 
Grade 1, and are  2 weeks off all immunosuppressive therapy. 
 
6) 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 adverse events 
(excluding alopecia) due to agents administered more than 4 weeks earlier should have 
recovered to < Grade 1. Participants 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 (AE) and do not need to 
resolve to < Grade 1. 
 
7) Prior DNA methyl transferase inhibitor administration (azacitidine, decitabine or 
guadecitabine) for AML or for antecedent MDS is allowed if this clinical trial is considered the 
best treatment option, but azacitidine, decitabine or guadecitabine must have been stopped 
at least 3 weeks prior to Day 1 of treatment on the study.  
 
8) Participants are required to stop receiving myeloid growth factors at least 1 week (Neupogen) 
or 2 weeks (Neulasta) before starting treatment on the study. 
 
9) Age ≥18 years.   
Because no dosing or adverse event data are currently available on the use of decitabine or 
talazoparib in participants <18 years of age, children are excluded from this study, but will be 
eligible for future pediatric trials. 
 
10) ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
11) Life expectancy of greater than 2 months. 
 
12) Participants must have normal organ function as defined below: 
 
• 
Total bilirubin within normal institutional limits unless thought due to hemolysis or to 
Gilbert’s syndrome; 
• 
AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal; 
• 
Creatinine within normal institutional limits; 
 
OR 
• 
Creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above 
institutional normal. 
 
13) Female participants of childbearing potential must have a negative pregnancy test, and female 
participants of childbearing potential and male participants must agree to use adequate 
contraception. 
 
Decitabine has been assigned to pregnancy category D by the FDA. Pregnant women must 
not take decitabine and female participants must immediately stop taking decitabine and 
inform their doctor if they become pregnant during treatment. Decitabine is expected to result 
in adverse reproductive effects and can cause fetal harm when administered to a pregnant 
woman. In preclinical studies in mice and rats, decitabine was teratogenic, fetotoxic, and 
embryotoxic.  


 
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Studies in pregnant animals to evaluate the effect of talazoparib on pregnancy have not been 
performed. 
 
Because decitabine is known to be teratogenic and the effects of talazoparib on the 
developing human fetus are unknown, women of child-bearing potential and men must agree 
to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior 
to study entry and for the duration of study participation. Should a woman become pregnant 
or suspect that she is pregnant while she or her partner is participating in this study, she 
should inform the treating physician immediately. Men treated or enrolled on this protocol must 
also agree to use adequate contraception prior to the study, for the duration of study 
participation, and 4 months after completion of decitabine and talazoparib administration. 
 
It is not known whether decitabine is excreted in human milk. Similarly, studies in lactating 
animals to evaluate the effect of talazoparib have not been performed, and thus, it is not 
known whether talazoparib is excreted in human milk. Therefore, breast-feeding should be 
stopped during decitabine and talazoparib treatment. 
 
14) Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
Exclusion Criteria 
 
1) Patients with acute promyelocytic leukemia. 
 
2) Patients with active central nervous system leukemia or requiring maintenance intrathecal 
chemotherapy. 
 
3) Patients receiving concurrent chemotherapy, radiation therapy, or immunotherapy for AML. 
 
4) Patients receiving any other investigational agents. 
 
5) Hyperleukocytosis with >50,000 blasts/μl. Hydroxyurea for blast count control is permitted 
before starting treatment, but must be stopped at least 24 hours prior to starting treatment on 
the study. Patients will be withdrawn from the study if > 50,000 blasts/μl occur or recur > 14 
days after starting treatment on the study. 
 
6) Active, uncontrolled infection. Patients with infection controlled with antibiotics are eligible. 
 
7) Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart 
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations 
that per investigator’s judgment would limit compliance with study requirements. 
 
8) Patients who are pregnant or nursing. 
 
9) Patients who have had chemotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin 
C) or radiotherapy within 2 weeks for antecedent malignancies prior to entering the study, or 
those who have not recovered from adverse events due to agents administered more than 4 
weeks earlier. 
 
10) History of allergic reactions attributed to compounds of similar chemical or biologic 


 
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composition to decitabine or talazoparib. 
 
11) Known HIV infection. 
 
HIV-positive patients are at increased risk of lethal infections when treated with marrow-
suppressive therapy. Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
 
12) Previous treatment with talazoparib.  
 
 
3.3 
Inclusion of Women and Minorities 
 
Men and women of all races and ethnic groups are eligible for this trial.  
 
 
4. 
REGISTRATION PROCEDURES 
Informed consent and HIPAA authorization will be obtained prior to screening of potentially eligible 
patients. Patients will sign a statement of informed consent that meets the requirements of the 
Code of Federal Regulations Title 21, International Conference on Harmonization (ICH) E6 Good 
Clinical Practices, and the local Institutional Review Board (IRB). Prior to pre-study procedures, 
a unique ID number will be assigned to the participant. 
Once the signed informed consent has been obtained, pre-study evaluation studies will be 
performed. After the pre-study evaluation studies are completed, eligibility of the participant will 
be reviewed. Eligible participants will be enrolled on the study. Decitabine and talazoparib dose 
levels will be assigned. 
Participants should begin protocol treatment within 14 days of signing consent.  
To register a participant, the following information should be completed/compiled by the research 
coordinator/data manager and faxed to 410-328-1180 or e-mailed to the Coordinating Center 
Contact, Gary Saum, at gary.saum@umm.edu: 
• 
Signed informed consent form; 
• 
HIPAA authorization form (if not part of consent); 
• 
Institution name; 
• 
Treating physician; 
• 
Copy of required laboratory tests (source documentation for eligibility and pre-study 
procedures) including pathology report (if pathology report not immediately available, the 
investigator must sign the eligibility worksheet confirming diagnosis and submit the 
pathology report when available); 
• 
Eligibility screening worksheet; and 
• 
Registration form. 
 
The research coordinator or data manager at the participating site will then call 410-328-7680 or 
e-mail Gary Saum (gary.saum@umm.edu), the Coordinating Center Contact, to verify eligibility.   
 
To complete the registration process, the Study Coordinator or Coordinating Center Contact at 
the Coordinating Center will: 


 
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• 
Assign a participant study ID number; 
• 
Register the participant on the study; 
• 
Assign decitabine and talazoparib dose levels; 
• 
Fax or e-mail the participant study number and dose levels to the participating site; and 
• 
Call the research coordinator or data manager at the participating site and verbally confirm 
registration. 
 
A participant may not start treatment on the study until registration is confirmed by the 
Coordinating Center. 
 
 
5. 
TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment may be administered on an outpatient or inpatient basis.  
 
Table 1. 
Regimen description 
 
Regimen Description 
Agent 
Premedications; Precautions Dose 
Route 
Schedule 
Cycle 
Length 
Decitabine 
Premedicate with antiemetic 
daily prior to decitabine 
** 
IV 
Days 1-5  
28 days  
(4 weeks ± 
3 days) 
 
 
Talazoparib  
Can be administered 
regardless of food intake. 
** 
PO 
Days 1-28  
**Doses as appropriate for assigned dose level. 
 
• 
Talazoparib orally Days 1-28 (± 3 days) at the same time each morning. 
• 
Decitabine should be administered at a consistent time, after talazoparib. 
 
NOTE: Participants will be requested to maintain a medication diary (Appendix C) of each dose 
of talazoparib. The medication diary will be returned to study staff at the end of each cycle.  
 
Reported adverse events and potential risks are described in Section 7.   
 
Dose modifications are described in Section 6.   
 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's AML. 
 
5.1.1 Decitabine 
 
Decitabine is administered intravenously (IV) daily for 5 or 10 days every 28 days (± 3 days). An 
antiemetic should be taken prior to each decitabine dose and, if needed, following administration 
of decitabine. 
 
 


 
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5.1.2 Talazoparib 
 
Talazoparib is taken orally (PO) daily Days 1-28 (± 3 days) at the same time each day, before 
decitabine administration. It can be taken regardless of food intake. 
 
Participants will be requested to maintain a medication diary of each dose of talazoparib. The 
medication diary will be returned to study staff at the end of each 28-day cycle. 
5.1.3 Other Modalities or Procedures 
 
None 
 
 
 
5.2 
Phase 1 Dose Escalation  
 
5.2.1 Dose Escalation Schedule 
 
Table 2. Dose escalation schedule 
 
  
Talazoparib (mg)* 
0.25 
0.50 
0.75 
1.0 
1.0 
Decitabine* 
(mg/m2) 
10 
1 
1a 
1b 
1c 
- 
15 
2 
2a 
2b 
2c 
- 
20 
3 
4 
5 
6 
7** 
*NOTE: DECITABINE IS DOSED IN MG/M2, BUT TALAZOPARIB IS DOSED IN MG. 
** Cohort 7 will receive 20 mg/m2 of decitabine for 10 days and 1 mg of Talazoparib continuously.  
  
The ‘outer layer’ of this nested dose escalation trial will escalate the dose of the two drugs by 
sequentially going through dose levels 1-6 in the table. The standard algorithm of the 3+3 design 
will be applied as specified below. 
 
If the MTD has not been reached at dose level 6, the RP2D of decitabine will be 20 mg/m2 
combined with a dose of talazoparib of 1.0 mg. If 2 or more participants develop DLT at dose level 
1, the combination of decitabine and talazoparib will be considered too toxic for further clinical 
development. 
 
If the provisional MTD for decitabine in combination with talazoparib is dose level 1 or 2, one or 
the other of the ‘inner layers’ of the trial will be activated. If the provisional MTD corresponds to 
level 2, the dose of decitabine will be fixed at 15 mg/m2 and the dose of talazoparib will be 
escalated through steps 2a-c, again using the algorithm of the 3+3 design below. If the tolerance 
is not exceeded at level 2c, then the RP2D of decitabine is 15 mg/m2 combined with a dose of 
talazoparib of 1.0 mg. 
 
Similarly, if the provisional MTD for the combination of the two agents from the outer layer is level 
1, the dose of decitabine will be fixed at 10 mg/m2 and the dose of talazoparib will be escalated 
through steps 1a-c, again using the algorithm of the 3+3 design below to define the MTD of the 
combination.  
 
Phase 1 was originally planned through Cohort 6 above. In Cohorts 1 through 5, the study has 
enrolled almost exclusively patients previously treated with decitabine and/or azacitidine. The 
combination regimen has been very well tolerated, but response rates have been low. Given 


 
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excellent tolerability and low response rate, and given favorable results of 10-day decitabine in 
several series (12-14), we have opted to expand the Phase 1 component of the study with a 10-
day decitabine cohort, Cohort 7, and, following completion of dose escalation, to enroll an 
expansion cohort of DNMTi-naïve patients at the RP2D. The statistical design has been 
updated as follows: 
 
If Cohort 6, with 20 mg/m2 decitabine daily for 5 days and talazoparib 1 mg daily, is completed 
without dose-limiting toxicity, Cohort 7, consisting of decitabine, 20 mg/m2 daily for 10 days and 
talazoparib, 1 mg daily, will be added. 
 
Following completion of Cohort 6 or Cohort 7 without dose-limiting toxicity, a minimum of 9 and a 
maximum of 17 patients not previously treated with DNMTis (decitabine, azacitidine and/or 
guadecitabine) will be enrolled to assess response in this patient population at the RP2D.  
 
The aim of the expansion cohort will be to expand the safety data and to look for signs of activity 
in the DNMTi-naïve population. 
  
Let P be the response rate of the combination at the RP2D. If we define a ‘poor’ response rate 
as P0=5% and a ‘good’ response rate as P1=25%, then we can test the null hypothesis that 
P≤P0 versus H1: P≥P1 with =0.05 and power (1-) of 80%  using Simon’s two-stage design. If 
we enroll 9 patients and see no responses, we can stop early for futility. If we see at least one 
response, we would then enroll an additional 8 patients in the second stage for a total of 17 
patients. If we see 3 or more responses among the 17 patients, we can reject that the response 
rate is 5% or less with an error rate of 0.043. If we see 2 or fewer responses, we can reject the 
hypothesis that P≥25% with an actual (type II) error rate of 19.7%. 
 
 
5.2.2 Definition of Dose-Limiting Toxicity 
 
Dose-limiting toxicities will be evaluated in Cycle 1.  
 
Toxicity will be evaluated according to Version 4.0 of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE). Dose-limiting toxicity will consist of any of the following adverse events 
with an attribution of possible, probable, or definitely related to the study therapy: 
• 
Any grade 4 treatment-related non-hematologic toxicity (except for infection, 
fever, neutropenic fever or bleeding, which are expected in this patient 
population). 
• 
Any grade 3 treatment-related non-hematologic toxicity (except for infection, 
fever, neutropenic fever or bleeding, which are expected in this patient 
population) that does not resolve to ≤ grade 2 within 48 hours.  
• 
Myelosuppression will be considered a dose-limiting toxicity if ANC <0.5 x 109/L 
and platelets <20 x 109/L (untransfused) persist on day 43, with bone marrow 
cellularity of  5% and no evidence of leukemia in the bone marrow. 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
5.2.3 Dose Escalation 
 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-limiting 


 
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toxicity (DLT) is defined above.   
Table 3. Dose escalation decision rules 
 
Number of Participants with DLT at a 
Given Dose Combination Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 participants at the next dose combination. 
≥2 
Dose escalation will be stopped.  This dose combination will 
be declared the maximally administered dose (highest dose 
administered).  Three (3) additional participants will be 
entered at the next lowest dose combination if only 3 
participants were treated previously at that dose. 
1 out of 3 
Enter at least 3 more participants at this dose combination. 
• 
If 0 of these 3 participants experience DLT, proceed to 
the next dose combination. 
• 
If 1 or more of this group experience DLT, then dose 
escalation is stopped, and this dose combination is 
declared the maximally administered dose combination.  
Three (3) additional participants will be entered at the 
next lowest dose combination if only 3 participants were 
treated previously at that dose combination. 
≤1 out of 6 at highest dose combination 
level below the maximally administered 
dose combination 
This is generally the recommended phase 2 dose 
combination. At least 6 participants must be entered at the 
recommended phase 2 dose combination. 
 
 
5.3 
Phase 2 
 
Decitabine is administered intravenously (IV) daily for 5 or 10 days every 28 days (± 3 days). An 
antiemetic should be taken prior to each decitabine dose. 
 
Talazoparib is administered orally daily Days 1-28 (± 3 days) at the same time each morning, 
before decitabine administration. 
 
Phase 2 doses will be determined based on data from Phase 1, as detailed in the statistical 
section. 
 
 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
5.4.1 Antiemetic Therapy 
 
Antiemetic therapy should be administered prior to decitabine, and, if needed, following 
administration of decitabine. The following antiemetics are recommended prior to each dose of 
decitabine and on an as needed basis: ondansetron (4-16 mg PO/IV) or equivalent 5HT3 
antagonist. However, at the discretion of the treating physician, other anti-emetics may be 
administered, such as prochlorperazine 5-10 mg PO/IV every 6-8 hours, promethazine 12.5-25 
mg PO/IV every 6 hours, or lorazepam 0.5-1 mg every 6 hours. 
 
5.4.2 Tumor Lysis Prophylaxis and Management 
 
To prevent the occurrence and complications of tumor lysis-induced hyperuricemia, all 


 
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participants without known allergy may receive allopurinol (zyloprim) 300 mg orally once a day 
starting on or before Day 1 and continuing until tumor lysis has abated. If a participant cannot 
take allopurinol, febuxostat (Uloric) 40 mg orally once a day can be prescribed. Rasburicase can 
be administered at the discretion of the treating physician to acutely lower uric acid levels, in 
conjunction with initiation of allopurinol or febuxostat to block uric acid formation. G6PD levels 
should be checked in appropriate participants, such as Black men, before rasburicase 
administration. 
 
For individuals at risk for tumor lysis-induced hyperphosphatemia, phosphate binders (such as 
PhosLo, Amphojel, Renagel) can be administered every 4-6 hours starting on or before Day 1 
and should continue as needed until tumor lysis has abated. 
 
5.4.3 Infection Prophylaxis 
 
Participants may receive prophylaxis directed against bacterial, viral and/or fungal infections, 
according to institutional practices, at the discretion of the principal investigator at the treating 
institution and the treating physician.  
 
5.4.4 Hematopoietic Growth Factors 
 
Participants are required to stop receiving myeloid growth factors at least 1 week (Neupogen) or 
2 weeks (Neulasta) before starting treatment on the study. During the cycle of treatment, use of 
myeloid growth factors is permitted according to American Society of Clinical Oncology (ASCO) 
guidelines for participants with prognostic factors predictive of clinical deterioration and at the 
discretion of the treating physician. The use of growth factors must be recorded as concomitant 
medications. 
 
 
5.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment should continue on an 
ongoing basis until one of the following criteria applies: 
• 
Disease progression; 
• 
Intercurrent illness that prevents further administration of treatment; 
• 
Unacceptable adverse event(s); 
• 
Participant decides to withdraw from the study; or 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the investigator. 
 
There is no maximum number of treatment cycles. 
 
 
5.6 
Criteria for Removal from Study 
 
Participants will be removed from study when any of the criteria listed in Section 5.5 applies. The 
reason for study removal and the date the participant was removed must be documented in the 
Case Report Form. 
 
 


 
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5.7 
Duration of Follow-up 
 
Participants will be followed for 4 weeks after removal from study, then they will be followed every 
6 months until death. Participants removed from study for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. 
 
 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
Timing of cycle initiation and dose levels of decitabine and talazoparib starting with Cycle 2 will 
be guided by neutrophil/platelet counts after the prior cycle and peripheral blood (PB) and/or bone 
marrow (BM) blast percentage, as shown in Table 4, which describes dose modification and delay 
based on Day 28 or later PB counts starting with Cycle 2.  
 
The treating physician may delay study drug treatment (decitabine and talazoparib) on Day 29 of 
any cycle regardless of neutrophil/platelet counts and/or leukemic blasts if the treating physician 
deems it in the patient’s best interest to delay treatment. Treatment should be resumed at such 
time that it is deemed in the patient’s best interest to do so. Reasons for delaying and for restarting 
should be documented in the medical record.  
 
Bone marrow aspirate and biopsy will be performed on day 25-29 of cycle 1, and on day 25-29 of 
each subsequent treatment cycle unless circulating blasts persist in the peripheral blood, until 
documentation of CR or CRi. Bone marrow aspirate and biopsy will also be performed as needed 
to evaluate lack of count recovery (neutrophils <1000/μL and/or platelets <50,000/μ) by day 43) 
in the absence of blood blasts 
 
Missed Doses 
IV administration of the first 5 doses of Decitabine must be given within the first 7 days of the 
28-day cycle. IV administration of the 10 doses of Decitabine must be given within the first 12 
days of the 28-day cycle.  
 
Talazoparib is taken orally on Days 1-28 of each cycle at the same time each morning. Missed 
morning doses may be taken later in the day. If a full day is missed, do not double up the next 
day. 
 


 
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Table 4.      Decitabine and talazoparib dosing adjustment guidelines based on end of cycle 
≥1 (C≥1, Day 29 or later) peripheral blood blasts and counts and bone marrow leukemic 
blasts (C≥1, Day 43)** 
 
Day 29 (+/- 4 days) 
Day >43 
Leukemic 
blasts in blood 
No leukemic 
blasts in 
blood, but 
leukemic 
blasts in bone 
marrow  
No leukemic 
blasts in blood or 
marrow  
Leukemic blasts 
in blood or 
marrow on Day 
43 
No leukemic blasts 
in blood or marrow 
and counts 
<thresholds 
Neutrophils 
<1000/μL 
or 
Platelets  
<50,000/μL 
Administer both 
decitabine and 
talazoparib full 
doses, on 
schedule. 
Administer 
both decitabine 
and 
talazoparib full 
doses, on 
schedule. 
Delay decitabine 
and talazoparib 
until counts 
>threshold*, then 
administer 
decitabine and 
talazoparib full 
doses if <Day 43. 
Administer both 
decitabine and 
talazoparib full 
doses. 
Hold decitabine and 
talazoparib until 
counts >threshold*, 
then decrease both 
decitabine and 
talazoparib by one 
dose level. 
Neutrophils 
≥1000/μL 
and 
Platelets  
≥50,000/μL 
Administer both 
decitabine and 
talazoparib full 
doses, on 
schedule. 
Administer 
both decitabine 
and 
talazoparib full 
doses, on 
schedule. 
Administer both 
decitabine and 
talazoparib full 
doses, on 
schedule. 
Administer both 
decitabine and 
talazoparib full 
doses. 
Administer both 
decitabine and 
talazoparib full 
doses. 
*Threshold = Neutrophils ≥1000/μL and Platelets ≥50,000/μL 
** The treating physician may delay study drug treatment (decitabine and talazoparib) on Day 29 
of any cycle regardless of neutrophil/platelet counts and/or leukemic blasts if the treating 
physician deems it in the patient’s best interest to delay treatment. Treatment should be resumed 
at such time that it is deemed in the patient’s best interest to do so. Reasons for delaying and for 
restarting should be documented in the medical record.  
 
Decitabine dose levels are shown in Table 5. 
 
Talazoparib dose levels are shown in Table 6. 
 
Table 5.      Decitabine dose levels 
 
Decitabine (mg/m2) 
10* 
15 
20 
*Minimum dose allowed 
 
Table 6.      Talazoparib dose levels 
 
Talazoparib (mg) 
0.25* 
0.5 
0.75 
1 
*Minimum dose allowed 


 
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7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
7.1.1 CAEPRs for Decitabine 
 
In a single-arm MDS study (N=99) DECITABINE was dosed at 20 mg/m2 intravenous, infused 
over one hour daily for 5 consecutive days of a 4 week cycle. Table 7 presents all adverse events 
regardless of causality occurring in at least 5% of participants. 
 
 
Table 7. Adverse Events Reported in ≥5% of Participants in a Single-arm Study* 
 
                                                                             DECITABINE  
                                                         N=99 (%)              
Blood and lymphatic system disorders 
Anemia 
31 (31%) 
Febrile neutropenia 
20 (20%) 
Leukopenia 
6 (6%) 
Neutropenia 
38 (38%) 
Pancytopenia 
5 (5%) 
Thrombocythemia 
5 (5%) 
Thrombocytopenia 
27 (27%)  
Cardiac disorders 
Cardiac failure congestive 
5 (5%) 
Tachycardia 
8 (8%)  
Ear and labyrinth disorders 
Ear pain 
6 (6%)  
Gastrointestinal disorders 
Abdominal pain 
14 (14%) 
Abdominal pain upper 
6 (6%) 
Constipation 
30 (30%) 
Diarrhea 
28 (28%) 
Dyspepsia 
10 (10%) 
Dysphagia 
5 (5%) 
Gastro-esophageal reflux 
disease 
5 (5%) 
Nausea 
40 (40%) 
Oral pain 
5 (5%) 
Stomatitis 
11 (11%) 
Toothache 
6 (6%) 
Vomiting 
16 (16%)  


 
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General disorders and administration site conditions 
Asthenia 
15 (15%) 
Chest pain 
6 (6%) 
Chills 
16 (16%) 
Fatigue 
46 (46%) 
Mucosal inflammation 
9 (9%) 
Edema 
5 (5%) 
Edema peripheral 
27 (27%) 
Pain 
5 (5%) 
Pyrexia 
36 (36%)  
Infections and infestations 
Cellulitis 
9 (9%) 
Oral candidiasis 
6 (6%) 
Pneumonia 
20 (20%) 
Sinusitis 
6 (6%) 
Staphylococcal bacteremia 
8 (8%) 
Tooth abscess 
5 (5%) 
Upper respiratory tract infection 
10 (10%) 
Urinary tract infection 
7 (7%)  
Injury, poisoning and procedural complications 
Contusion 
9 (9%)  
Investigations 
Blood bilirubin increased 
6 (6%) 
Breath sounds abnormal 
5 (5%) 
Metabolism and nutrition disorders 
Anorexia 
23 (23%) 
Decreased appetite 
8 (8%) 
Dehydration 
8 (8%) 
Hyperglycemia 
6 (6%) 
Hypokalemia 
12 (12%) 
Hypomagnesemia 
5 (5%)  
Musculoskeletal and connective tissue 
disorders 
Arthralgia 
17 (17%) 
Back pain 
18 (18%) 
Bone pain 
6 (6%) 
Muscle spasms 
7 (7%) 
Muscular weakness 
5 (5%) 
Musculoskeletal pain 
5 (5%) 
Myalgia 
9 (9%) 
Pain in extremity 
18 (18%)  


 
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Nervous system disorders 
Dizziness 
21 (21%) 
Headache 
23 (23%)  
Psychiatric disorders 
Anxiety 
9 (9%) 
Confusional state 
8 (8%) 
Depression 
9 (9%) 
Insomnia 
14 (14%)  
Respiratory, thoracic and mediastinal disorders 
Cough 
27 (27%) 
Dyspnea 
29 (29%) 
Epistaxis 
13 (13%) 
Pharyngolaryngeal pain 
8 (8%) 
Pleural effusion 
5 (5%) 
Sinus congestion 
5 (5%)  
Skin and subcutaneous tissue disorders 
Dry skin 
8 (8%) 
Ecchymosis 
9 (9%) 
Erythema 
5 (5%) 
Night sweats 
5 (5%) 
Petechiae 
12 (12%) 
Pruritus 
9 (9%) 
Rash 
11 (11%) 
Skin lesion 
5 (5%)  
Vascular disorders 
Hypertension 
6 (6%) 
Hypotension 
11 (11%) 
* In this single arm study, investigators reported adverse events based on clinical signs and 
symptoms rather than predefined laboratory abnormalities. Thus not all laboratory abnormalities 
were recorded as adverse events. 
 
Discussion of Clinically Important Adverse Reactions 
In the single-arm study (N=99) when DECITABINE was dosed at 20 mg/m2 intravenous, infused 
over one hour daily for 5 consecutive days, the highest incidence of Grade 3 or Grade 4 adverse 
events were neutropenia (37%), thrombocytopenia (24%) and anemia (22%). Seventy-eight 
percent of participants had dose delays, the median duration of this delay was 7 days and the 
largest percentage of delays was due to hematologic toxicities. Hematologic toxicities and 
infections were the most frequent causes of dose delays and discontinuation. Eight participants 
had fatal events due to infection and/or bleeding (seven of which occurred in the clinical setting 
of myelosuppression) that were considered at least possibly related to drug treatment. Nineteen 
of 99 participants permanently discontinued therapy for adverse events. 
No overall difference in safety was detected between participants >65 years of age and younger 
participants in these myelodysplasia trials. No significant gender differences in safety or efficacy 


 
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were detected. Participants with renal or hepatic dysfunction were not studied. Insufficient 
numbers of non-white participants were available to draw conclusions in these clinical trials.  
Serious Adverse Events that occurred in participants receiving DECITABINE regardless of 
causality, not previously reported in Table 7 include: 
• 
Blood and Lymphatic System Disorders: myelosuppression, splenomegaly. 
• 
Cardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial 
fibrillation, supraventricular tachycardia.  
• 
Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage. 
• 
General Disorders and Administrative Site Conditions: chest pain, catheter site 
hemorrhage.  
• 
Hepatobiliary Disorders: cholecystitis. 
• 
Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, 
peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, 
Mycobacterium avium complex infection. 
• 
Injury, Poisoning and Procedural Complications: post procedural pain, post procedural 
hemorrhage. 
• 
Nervous System Disorders: intracranial hemorrhage. 
• 
Psychiatric Disorders: mental status changes. 
• 
Renal and Urinary Disorders: renal failure, urethral hemorrhage. 
• 
Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary 
embolism, respiratory arrest, pulmonary mass. 
• 
Allergic Reaction: Hypersensitivity (anaphylactic reaction) to DECITABINE has been 
reported in a Phase 2 trial. 
 
The following adverse reactions have been identified during post-approval use of DECITABINE. 
Because these reactions are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug 
exposure. 
 
Cases of Sweet’s Syndrome (acute febrile neutrophilic dermatosis) have been reported. 
 
7.1.2 CAEPRs for Talazoparib 
 
Two clinical studies were completed and three studies were ongoing at the time of protocol 
authorship. In the completed food effect study (673-203), single-dose talazoparib (500 μg) was 
safe and well tolerated in healthy male volunteers.  
 
In the completed Study PRP-002 in advanced hematological malignancies and ongoing Study 
PRP-001 in advanced tumors, dose-limiting toxicities were observed at 900 μg/day and at 900 
and 1100 μg/day, respectively, at the time of protocol authorship. Grade 3-4 events of anemia, 
neutropenia, and thrombocytopenia occurred in both studies and are being monitored closely 
throughout the clinical program.  
 
The Phase 1 study (enrollment closed September 2014), PRP-001, initiated 03 January 2011, is 
an open-label, single-arm study evaluating talazoparib in adults with advanced tumors. The most 
commonly reported AEs were anemia, fatigue, and nausea. There were eight deaths assessed 
unrelated to study treatment.  
 
The Phase 2 study, 673-201, initiated 08 May 2014, is an open-label, two-stage, two-cohort study 
evaluating talazoparib in adult females with locally advanced or metastatic breast cancer. Anemia, 


 
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neutropenia, and fatigue have each been reported for two of the four participants enrolled as of 
30 November 2014. No SAEs or withdrawals from treatment have occurred.  
 
The Phase 3 study, 673-301, initiated 30 October 2013, is an open-label, randomized, parallel-
group, two-arm study of talazoparib versus protocol-specific physician’s choice therapy in 
participants with germline BRCA mutation locally advanced and/or metastatic breast cancer. Of 
the 54 participants enrolled as of 30 November 2014, it is presumed about 36 were receiving 
talazoparib and about 18 were receiving another single-agent chemotherapy, based upon the 2:1 
randomization scheme, but which participants were receiving which treatment is unknown. A 
Grade 3 pleural effusion requiring hospitalization resolved after 5 days. Two participants died due 
to disease progression and one participant died of neutropenic sepsis related to treatment, an 
identified risk for talazoparib (and for most comparator chemotherapies). Anemia, fatigue, nausea, 
headache, and thrombocytopenia have been the most commonly reported AEs. Three 
participants experienced SAEs that resolved without sequelae and resulted in no withdrawals 
from study treatment: leukopenia, anemia, and neutropenia (one participant), decreased 
neutrophil count (one participant), and atrial flutter (one participant). 
 
7.2 
Adverse Event Characteristics 
 
 
Adverse Events 
According to the ICH definition, an adverse event (AE) is any untoward medical occurrence in a 
participant or clinical investigation subject administered a pharmaceutical product, and that does 
not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries that represent an exacerbation (increase 
in frequency, severity, or specificity) of pre-existing conditions.  Whenever possible, it is preferable 
to record a diagnosis as the AE term rather than a series of terms relating to a diagnosis.  
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
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. 
 
Serious Adverse Event (SAE) is defined as any of the following: 
• 
Any death that occurs while the participant is enrolled in the study including the 
follow-up period or within 30 days of completing the study 
• 
Immediately life-threatening adverse event 
• 
Requires inpatient hospitalization 


 
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• 
Prolongation of an existing hospitalization 
• 
Congenital anomaly/birth defect 
• 
Medically important event 
• 
Disability/incapacity (persistent or significant) 
 
7.3 
Reporting of Adverse Events Experiences 
 
Adverse event information will be collected in an ongoing fashion through participant reporting 
AEs to their physician or health care provider.  Seriousness and relatedness will be assessed by 
the treating physician, with appropriate reporting. Investigators are responsible for monitoring the 
safety of participants who have entered this study and for alerting the UMGCCC Data and Safety 
Monitoring and Quality Assurance Committee (DSM/QAC) to any event that seems unusual, even 
if this event may be considered an unanticipated benefit to the participant.  Adverse events should 
be recorded in source documents and captured on case report forms.   
A designated primary contact person based at the treatment center will be responsible for the 
collection and reporting of AEs for participants participating in the program. 
 
7.3.1 Expedited/Serious Adverse Event Reporting 
 
A serious adverse event (SAE) is defined as any AE that: 
• 
Results in death 
• 
Is life threatening, that is, places the participant at immediate risk of death from the event 
as it occurred. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death 
• 
Requires in-patient hospitalization or prolongation of an existing in-patient 
hospitalization. Admission of a participant to the hospital as an in-patient as a result of 
an AE, even if the participant is released on the same day, qualifies as hospitalization 
• 
Results in persistent or significant disability or incapacity. An event qualifies as resulting 
in a persistent or significant disability or incapacity if it involves a substantial disruption of 
the participant’s ability to carry out usual life functions.  This definition is not intended to 
include experiences of relatively minor or temporary medical significance. 
• 
Is a congenital anomaly or birth defect, an AE that occurs in the child or fetus of a 
participant exposed to the product prior to conception or during pregnancy 
• 
Important medical event that does not meet any of the above criteria, but may jeopardize 
the participant or require medical or surgical intervention to prevent one of the outcomes 
listed above. 
More than one of the above criteria may apply to any specific event. 
 
All events that meet the definition of a serious adverse experience (SAE) or a drug safety and 
surveillance event (i.e pregnancy) which occur at any time during the clinical study or within 30 
days of receiving the last dose of study drug(s), whether or not related to the study drug(s), must 
be reported by the Principal Investigator or designee to the Sponsor. FDA Form 3500A 
(MedWatch form) should be used to report the SAE to the Sponsor within 24 hours of site event 
notification using both of the Sponsor contacts below:   
 
Attn:  Maria Baer, MD 
Attn: Gary Saum, BA 
 
Fax:  410-328-6896 
Fax: 410-328-6896 
 
Email: mbaer@umm.edu 
Email: gary.saum@umm.edu 
 
 


 
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The MedWatch form should also be used to report new or corrected event information.  In addition, 
sites should report the event to their local Institutional Review Board per institutional policy.   
 
Serious, related, unexpected adverse events will be reported to the FDA by the Sponsor within 7 
days of unexpected and fatal/life threatening events, and within 15 days for unexpected and 
serious events as required by 21CFR312.32. If the serious adverse event or event of clinical 
interest (i.e. pregnancy) meets the threshold for FDA or drug safety and surveillance reporting, 
the Sponsor will forward the event information to FDA and Pfizer, Inc. 
 
Pregnancy  
Pregnancy in a participant being treated with the product should be reported immediately (within 
24 hours of becoming aware of the pregnancy) to the sponsor by using the FDA 3500A 
(MedWatch Form). Every effort should be made to follow the participant through resolution of the 
pregnancy (termination or delivery) and report the resolution of the FDA 3500A (MedWatch Form) 
to the sponsor. The sponsor will forward the event information to FDA and Pfizer, Inc. 
 
The Investigator/Sponsor will provide Pfizer, Inc., with a copy of this report. 
 
Note:  A death on study requires both routine and expedited reporting regardless of causality, 
unless as noted below.  Attribution to treatment or other cause must be provided. 
 
The Site Principal Investigator is responsible for appropriate medical care of study participants 
during the study in connection with protocol procedures.  After a study participant’s completion of 
or discontinuation from the study, the investigator remains responsible to follow, through an 
appropriate health care option, adverse events that are serious or that caused the study 
participant to discontinue before completing the study. 
 
Reporting to Pfizer, Inc. 
 
Serious Adverse Event Reporting: 
  
Within 24 hours of awareness of a serious adverse event, whether or not related to the study 
drug, the Site Investigator will complete and submit a Medwatch 3500A Form to the Sponsor 
containing all required information (reference 21 CFR 312.32).  The Sponsor will then submit a 
copy of this MedWatch 3500A form to the Pfizer, Inc. Safety Evaluation & Reporting fax, within 
the same timeframe.  
  
The contact information for Sponsor submission of SAEs and 24-hour reports for events of 
overdose and specified liver test abnormalities is as follows:  
 
Name: Safety Evaluation & Reporting.  
Fax:     1-866-997-8322  
Phone: 1-800-752-9737  
  
The initial report should include, at minimum, the following:  
∙             Study number (673-301)  
∙             Site name and number  
∙             Investigator name  
∙             Participant number, sex, and age  
∙             Details of study drug administration  
∙             The date of the report  


 
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∙             A description of the SAE (event term, seriousness of the event)  
∙             Causal relationship to the study drug 
 
Follow-up information for the event should be sent to the Sponsor promptly (within 7 days) as 
necessary. 
 
All serious adverse events (SAEs) and pregnancy reports whether or not considered drug-related 
should be reported to Pfizer, Inc.(via Safety Evaluation and Reporting contact information below) 
within 24 hours of receipt by the Sponsor, using the FDA 3500A (MedWatch Form) provided by 
the site. 
 
The period during which all non-serious AEs and SAEs will be reported begins after informed 
consent is obtained and will continue through 30 days after of the last study visit or 30 days after 
the last dose of study medication, whichever comes first. 
All non-serious adverse events whether or not considered drug-related should be reported to 
Pfizer, Inc.on a monthly basis by the Sponsor via a line listing which includes the following 
information: Participant ID number, Date of Birth/Age, Gender, adverse event, onset date, 
outcome, resolution date (if applicable), severity, seriousness, action taken with study drug and 
causality. Therefore, all Site Investigators are responsible for submitting all non-serious adverse 
events whether or not considered drug-related via a line listing, to the sponsor, inclusive of the 
same information listed above. 
 
Site clinicians should not wait to collect additional information that fully documents the event 
before notifying the Sponsor of an SAE or pregnancy. The Sponsor may be required to report 
certain SAEs to regulatory authorities within 7 calendar days of being notified about the event; 
therefore it is important that site clinicians submit additional information to the sponsor as soon 
as it becomes available.   
 
Product Complaints Reporting 
 
A product complaint (“Complaint”) is any direct, written, electronic, or oral communication of 
dissatisfaction that alleges deficiencies related to the identity, quality, durability, labeling, purity, 
stability, appearance, effectiveness, safety, and/or design of a drug  product after it is released 
for distribution.  
 
Complaints that simultaneously fall under Adverse Event definitions under this Protocol need only 
be reported via the Adverse Event reporting procedure set forth in this Protocol.   
 
Investigator or designee (Reporter) shall capture the following Complaint information as relates 
to talazoparib used under this Protocol: 
 
• 
Date complaint received 
• 
Product Name and Lot Number 
• 
Indicate if the product is available for return to Pfizer, Inc. for investigation  
• 
Quantity Affected 
• 
Detailed Description of complaint 
• 
Study Protocol Number 
• 
Investigator Name 


 
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• 
Site Contact 
• 
Site Number 
• 
Participant Number  
• 
Name and contact information of the person who is reporting the complaint as well as 
name and contact information of the complainant.  The reporter may be contacted by 
Pfizer, Inc..  
 
The Investigator or designee (Reporter) will use his or her best efforts to report Complaints to 
Pfizer, Inc. within five days of learning of the Complaint.  
 
Investigator or designee will submit the complaint information to Pfizer, Inc., as follows: 
 
Name: Safety Evaluation & Reporting.  
Fax:     1-866-997-8322  
Phone: 1-800-752-9737  
 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Sections 7.1 and 7.2. 
 
8.1 
Decitabine  
 
8.1.1 Drug Substance (Active Pharmaceutical Ingredient) 
 
DECITABINE (decitabine) for Injection contains decitabine (5-aza-2’-deoxycitidine), an analogue 
of the natural nucleoside 2’-deoxycytidine.  
 
Chemical Name (IUPAC):  
4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-
2(1H)-one 
Chemical Formula:  
 
C8H12N4O4 
Molecular Weight:  
 
228.21 Da 
 
 
Decitabine is a fine, white to almost white powder. Decitabine is slightly soluble in ethanol/water 
(50/50), methanol/water (50/50) and methanol; sparingly soluble in water and soluble in 
dimethylsulfoxide (DMSO). 
 
8.1.2 Drug Product and Formulation 
 
DECITABINE (decitabine) for Injection is a white to almost white sterile lyophilized powder 
supplied in a clear colorless glass vial. Each 20 mL, single dose, glass vial contains 50 mg 
decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate) and 11.6 
mg sodium hydroxide. 
 
8.1.3 Packaging, Storage, and Handling 
 
Decitabine, 50 mg single-dose vial individually packaged in a carton. 
 


 
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Store vials at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). 
  
Occupational Safety and Health Administration (OSHA) Guidelines for handling cytotoxic drugs 
outlined in the American Journal of Hospital Pharmacy should be followed (36). As with other 
potentially toxic anti-cancer agents, care should be exercised in the handling and preparation of 
decitabine. The use of gloves and protective garments is recommended. Preparation should occur 
in a vertical laminar flow biological hood using proper aseptic technique. For skin contact or 
spillage, refer to the material safety data sheet (MSDS) for treatment options. 
 
8.1.4 Formulation, Dosage, and Administration 
 
DECITABINE is administered at a dose of 20 mg/m2 by continuous intravenous infusion over 1 
hour repeated daily for 5 or 10 days. This cycle should be repeated every 4 weeks. Participants 
may be premedicated with standard anti-emetic therapy. 
If myelosuppression is present, subsequent treatment cycles of DECITABINE should be delayed 
until there is hematologic recovery (ANC ≥1,000/μL platelets ≥50,000/μL). 
 
It is recommended that participants be treated for a minimum of 4 cycles; however, a complete or 
partial response may take longer than 4 cycles. 
 
DECITABINE is a cytotoxic drug and caution should be exercised when handling and preparing 
DECITABINE. Procedures for proper handling and disposal of antineoplastic drugs should be 
applied. Several guidances on this subject have been published (36). 
 
DECITABINE should be aseptically reconstituted with 10 mL of Sterile Water for Injection (USP); 
upon reconstitution, each mL contains approximately 5.0 mg of decitabine at pH 6.7-7.3. 
Immediately after reconstitution, the solution should be further diluted with 0.9% Sodium Chloride 
Injection or 5% Dextrose Injection to a final drug concentration of 0.1-1.0 mg/mL. Unless used 
within 15 minutes of reconstitution, the diluted solution must be prepared using cold (2˚C - 8˚C) 
infusion fluids and stored at 2˚C - 8˚C (36˚F - 46˚F) for up to a maximum of 4 hours until 
administration. 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior 
to administration, whenever solution and container permit. Do not use if there is evidence of 
particulate matter or discoloration. 
 
DECITABINE (decitabine) for Injection is supplied as a sterile, lyophilized white to almost white 
powder, in a single-dose vial, packaged in cartons of 1 vial. Each vial contains 50 mg of 
decitabine. 
 
8.1.5 Drug Supply 
 
Decitabine will be purchased commercially and billed to insurance. 
 
 
8.2 
Talazoparib 
 
8.2.1 Names  
 
Code Name:  
BMN 673ts  


 
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Generic Name:  
Talazoparib tosylate  
USAN Name:  
Talazoparib tosylate  
INN Name:  
Talazoparib  
Trade Name:  
None  
 
8.2.2 Active Ingredient  
 
The active ingredient is talazoparib tosylate, the tosylate salt of the active moiety, Talazoparib; 
the chemical name (8S ,9R) 5-fluoro-8-(4-fluorophenyl-2,7,8,9-tetrahydro-9-(1- methyl-1H-1,2,4-
triazol-5-yl)- 3H-pyrido[4,3,2 de]phthalazin-3-one, 4 methylbenzenesulfonate (1:1). (Chemical 
Abstracts Service Nomenclature).  
 
8.2.3 Pharmacological Class  
 
Talazoparib is a PARP inhibitor.  
 
8.2.4 Structural Formula 
  
Talazoparib tosylate (salt):  
Molecular Formula: C26H22F2N6O4S (C19H14F2N6O • C7H8O3S)  
Molecular Weight: 552.5624  
Talazoparib free base:  
Molecular Formula: C26H22F2N6O4S  
Molecular Weight: 552.5624  
1.453 mg talazoparib tosylate is equivalent to 1.00 mg talazoparib free base.  
 
8.2.5 Route of Administration  
 
Oral administration. 
 
8.2.6 Method of Manufacture  
 
Talazoparib tosylate is manufactured by chemical synthesis in accordance with current Good 
Manufacturing Practices.  
 
8.2.7 Formulation of the Study Drug  
 
The drug product is a capsule formulation comprised of a blend of talazoparib tosylate drug 
substance and silicified microcrystalline cellulose filled into a hypromellose capsule. The capsules 
are presented in three strengths (0.10 mg, 0.25 mg, and 1.0 mg free base equivalent) 
distinguished by capsule color or size and described in milligrams (mg) per capsule. Capsules 
used for initial clinical studies were presented in four strengths (25 μg, 50 μg, 250 μg, and 1.0 
mg) and described in micrograms (μg) per capsule.  
 
8.2.8 Storage, Labeling, and Destruction  
 
The drug product is stored at room temperature (15º-30º C; 59º-86º F). The sponsor should be 
notified of any temperature excursions immediately. Capsules used for initial clinical studies were 
packaged in perforated unit-dose blister cards composed of cold- form aluminum foil and push-
through aluminum lidding. Capsules used for subsequent clinical studies (0.10 mg, opaque ivory, 
size 4; 0.25 mg, opaque white, size 4; 1.0 mg, opaque flesh, size 4) are supplied in high-density 


 
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polyethylene bottles, with induction-sealed closures, containing 30 drug product capsules. The 
label on the packaging has instructions in English (or other language, as required) and may 
contain any or all of the following information: sponsor’s name, study number, name of the 
investigational product, contents, recommended storage condition, a precautionary statement, 
product retest or expiration date, lot number, and participant ID. 
 
Any returned, expired, or unused drug should be destroyed at the site, using the site’s drug 
destruction SOP. Evidence of destruction must be sent to the Sponsor. Sites are to send SOP for 
drug destruction to the sponsor.    
 
8.2.9 Agent Ordering 
 
All sites will request their own site’s supply of Talazoparib directly from Pfizer and Pfizer will 
arrange the supply via the Pfizer supply chain.  
 
 
9. 
BIOMARKER AND CORRELATIVE STUDIES 
 
9.1 
Sample Collection 
See Protocol Appendix B and the site laboratory manual for sample collection guidelines. 
 
9.1.1 Peripheral blood 
 
Up to 20 ml of peripheral blood for pharmacodynamics will be collected from participants on: 
• 
Cycle 1, Day 1, before any treatment; 
• 
Cycle 1, Day 5, one hour after administration of decitabine is completed, and 
• 
Cycle 1, Day 8, anytime 
• 
For participants receiving 10-day decitabine, sampling will be on Days 1, 5, 8 and 10, one 
hour after the decitabine injection.  
 
Up to 10 mL of peripheral blood for epigenetic studies will be collected from participants on:  
• 
Cycle 1, Day 1, before any treatment;  
• 
Cycle 1, Day 5, one hour after administration of decitabine;  
• 
Cycle 1, Day 8, anytime; 
• 
For participants receiving 10-day decitabine, sampling will be on Days 1, 5, 8 and 10, one 
hour after the decitabine injection.  
• 
Cycle 1, Day 29, (± 3 days) before any treatment; and 
• 
Day 29 (± 3 days) of every cycle, before any treatment. 
 
 
9.1.2 Bone Marrow (Epigenetic) 
 
Up to 10mL of bone marrow collected on: 
• 
Screening; 
• 
Cycle 1, Day 29 (± 3 days) , before any treatment.  
• 
Days 25-29 (± 3 days) of every cycle, before any treatment (unless circulating blasts 
persist in the peripheral blood), until documentation of CR or CRi. 
 
 


 
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9.1.3 Buccal Swab 
 
Two buccal swabs will be collected at screening 
 
 
9.1.4 Coding of Samples  
 
The clinical study team will record the participant's unique study ID and the sample number in the 
in the participant research record. 
 
Samples leaving the clinical sites will not be labeled with PHI.  
 
 
9.2 
Sample Processing 
 
Samples will be processed as described below and according to the lab manual for specific 
assays. Sample collection prioritization is noted in Protocol Appendix D. 
 
Unused portions of the samples will be aliquoted and stored according to VARI Biorepository 
standards for future, unplanned research. 
 
 
9.3 
Shipping of Samples 
 
Samples will be sent from the clinical sites to the Rassool laboratory and to VARI. Please see the 
lab manual for shipping instructions. Secondary shipment may be necessary at the discretion of 
the PI for either unused portions of samples from the Rassool laboratory to VARI for banking, or 
from VARI to collaborating institutions for completion of the prescribed correlative assays below.  
 
All shipping of specimens will be in compliance with Federal, state and local regulations and IATA 
standards. 
 
 
9.4 
Storage of Samples/Biobanking 
 
Bone marrow, peripheral blood, and buccal swab samples collected for correlative studies 
performed in this protocol, and components from the processed cells, may be stored indefinitely 
to answer research scientific questions related to AML, study drugs, epigenetics, immune 
response and/or cancer. The Participant retains the right to have the sample material destroyed 
at any time by contacting the Principal Investigator and making the request in writing. If a 
participant withdraws from the study, their research samples will be kept and used as described 
elsewhere in the protocol unless the participant specifically requests their destruction in writing. 
 
Samples will be stored at the clinical sites for no more than 2 weeks until shipped to the Rassool 
Laboratory or to VARI. The Rassool laboratory will send unused portions of the samples to VARI 
at completion of the study. The VARI Biorepository will serve as long-term, biobanking storage 
for the samples and unused sample derivatives.  
 
 


 
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9.5 
Colony Formation, Immunofluorescence, PARP Trapping, mRNA and Protein 
Expression, and DNA DSB Repair.  
 
The following processes will be conducted in the event that there is sufficient blood sample left 
over from the study. See Appendix D for sample analysis priorities. 
 
As detailed in section 2.4.4, our mechanistic hypothesis is that decitabine and talazoparib will 
cooperate to increase the cytotoxic DNA-PARP complexes on chromatin, resulting in decreased 
DNA DSB repair. The following assays will test components of this mechanism: 
 
1) Colony forming assays in methyl cellulose.  
2) Immunostaining for H2AX (a marker for DNA DSBs), DSB repair, including RAD51 (a major 
component of the homologous recombination pathway), epigenetic and DNA replication markers. 
3) PARP trapping. 
4) PAR activity    
5) Protein and mRNA expression of DSB repair genes, including PARP1, PAR, RAD51, KU70/80, 
DNA ligase 3, and epigenetic factors, including EZH2 and DNMT1, by Western blot analysis  
6) Levels of mRNA expression of DSB repair genes, including PARP1, RAD51, KU70/80 and 
DNA ligase 3, by quantitative polymerase chain reaction (Q-PCR) 
7) Levels of DSB repair, measured using in vitro plasmid-based assays.  
 
 
9.5.1 Collection of Samples  
 
Please see lab manual for sample collection procedures. 
 
 
9.5.2 Processing of Samples  
 
Please see lab manual for sample processing procedures. 
 
Peripheral blood mononuclear cells (MNC) will be isolated from AML samples by density 
centrifugation using Ficoll Hypaque (Sigma), according to the manufacturer’s instructions. 
Differential cell counts will be performed after Wright-Giemsa staining, and recorded. MNCs will 
be sent to the Rassool laboratory as flash frozen pellets and as viably frozen cells. For flash frozen 
cells, MNCs will be centrifuged at 1500 rpm for x 5 mins and cell pellets will be flash frozen in 
liquid nitrogen for RT-PCR, western blotting, and PARP trapping analyses. For viably frozen cells, 
MNCs will be viably frozen in IMDM (Invitrogen) with 10% FBS and 5% DMSO for colony formation 
and immunofluorescence assays.  
 
Details of assays are below. Note that these assays are subject to change based on experience 
with samples. 
 
9.5.3 Colony-Forming Assays  
 
a) Hypothesis and Rationale: 
 
Colony numbers decrease in AML cells treated with talazoparib and decitabine. 
 
b) Mechanistic Rationale:  
 


 
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Our recently published data show that AML cells treated with decitabine and/or the PARP inhibitor 
Talazoparib demonstrate decreased colony forming ability in methylcellulose (34). The 
mechanistic rationale is that the combination of decitabine and talazoparib will lead to increased 
cytotoxicity or anti-proliferative effects, resulting in decreased colony formation.  
 
c) Intended Use Within this Study:  
 
This study will determine whether colony formation is decreased in treated samples from 
participants, relative to pre-treatment samples. 
 
d) Detailed Protocol:  
 
Viably frozen MNCs will be, thawed, counted, and suspended in 0.4 mL HPGM (Lonza) so that a 
density of 100 thousand cells per 1.1 mL is obtained when the 0.4 mL cells suspension is mixed 
with 4 mL MethoCult (StemCell Technologies). Each sample will be plated in technical triplicates 
(100 thousand cells per well in 1.1 mL Methocult) on a non-tissue culture treated 6-well plate 
(Greiner Bio) and incubated for 10-14 days at 370C + 5% CO2. At the end of the incubation period, 
colonies will be stained with 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenlytetrazolium chloride (1 
mg/mL) overnight at 370C and counted using a colony counter (Synbiosis, Frederick, MD).  
 
e) Quantification of Colony Numbers and Statistical Analysis:  
 
Number of colonies from triplicates will be determined in samples taken during treatment relative 
to pre-treatment samples. Colony numbers for treatment samples will divided by colony numbers 
from respective pre-treatment samples, and expressed as a percentage of the pretreatment value. 
Result reporting: Results will be represented as average percentage colony formation relative to 
pre-treatment ± SEM. All statistical analyses will be performed using the Student t-test, with p-
values ≤ 0.05 considered significant. We expect that colony numbers will be significantly 
decreased in Day 5 post-treatment AML samples, compared with Day 1 pre-treatment samples.  
 
 
9.5.4 
H2Ax foci and DSB repair, including RAD51 (a major component of the homologous 
recombination pathway), and co-localization of EZH2, DNMT1, DNA replication factors and 
other proteins (Immunofluorescence). 
 
a) Hypothesis and Rationale 
 
Levels of H2Ax foci will increase and RAD51 foci will decrease in AML cells treated with 
decitabine and talazoparib. Co-localization of epigenetic and/or DNA replication factors 
is expected with γH2Ax. 
 
b) Mechanistic Rationale: Published reports demonstrate that γH2Ax is a marker for DNA 
damage and in particular, lethal DSBs (34) Unpublished data from our laboratory demonstrate 
that AML cells treated with decitabine at low, non-cytotoxic, concentrations show no change in 
levels of γH2AX, compared with untreated controls. In contrast, AML cells treated with talazoparib 
at low nanomolar concentrations or ABT888 at 500 nM demonstrate increased levels of γH2AX, 
compared with controls, and AML cells treated with combinations of decitabine and talazoparib 
or ABT888 have increased levels of γH2AX, compared with talazoparib or ABT888 alone. 
Furthermore, our preliminary data in AML cell lines suggest that homologous recombination (HR) 
is downregulated by DNMTis.  RAD51 is a marker for homologous recombination that should 


 
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decrease with treatment.  Thus, the mechanistic rationale for the combination of decitabine and 
talazoparib is that the decitabine is reprogramming the epitranscriptome to down-regulate HR, 
including RAD51, leading to increased AML cell death.  
 
c) Intended Use Within this Study: This study will determine whether levels of cytotoxic DSBs 
increase in treated samples from AML participants (relative to pretreatment samples), as 
measured by formation of γH2AX foci and decrease of  RAD51 foci (i.e. decreased HR), and 
whether these changes will correlate with clinical responses.    
 
c) Intended Use Within this Study: This study will determine whether levels of cytotoxic DSBs 
increase in treated samples from AML participants (relative to pretreatment samples), as 
measured by H2AX foci, whether RAD51 foci decrease (i.e. decreased HR), whether other 
epigenetic and DSB repair proteins co-localize with these foci, and whether these changes will 
correlate with clinical responses.    
 
d) Assay Methods  
 
i. Detailed Protocol: Viably frozen AML MNCs will be thawed and cytospun onto glass slides 
(0.2 X 106 cells/slide) for 5 minutes at 200 rpm in 1X PBS on a Shandon Cytospin 4. Cells will 
then be fixed for 30 minutes in 4% paraformaldehyde, washed 3 times in DPBS (+Cacl2 and 
MgCl2, DPBS++), permeabilized for 10 minutes in permeabilization solution (50mM NaCl, 
3mM MgCl2, 10mM HEPES, 200mM Sucrose and 0.5% Triton X-100 in PBS 1X), washed 3 
times in DPBS (+Cacl2, +MgCl2) supplemented with BSA 1% (DPBS-BSA) and then blocked 
overnight in DPBS++ supplemented with 10% serum. After incubation with mouse monoclonal 
anti-H2A.x (1:100, Upstate) and rabbit polyclonal anti-RAD51 (1:100, Santa Cruz 
Biotechnologies, Dallas, TX) or isotype controls for one hour at 370C in DPBS-BSA, cells will 
be washed and then incubated with Dylight 594-anti-mouse and Dylight 488-anti rabbit (1:200, 
KPL, Gaithersburg, MD) for one hour at 370C prior to counterstaining with 4’,6 diamidino-2-
phenylindole, dihydrochloride (DAPI, 0.3 µg/ml, Promega, Madison, WI) in mounting medium 
(Vectashield, Vector Laboratories, Burlingame, CA). Slides will be examined using a Nikon 
fluorescent microscope Eclipse 80i (100X/1.4 oil, Melville, NY).  
 
ii. Foci Quantitation: Images of cells with from at least 50 cells/slide will be captured using a 
CCD (charge-coupled device) camera and the imaging software NIS Elements (BR 3.00, 
Nikon). H2AX and RAD51 foci contained within these imaged cells will be counted and the 
data will be expressed as numbers of foci per cell. 
 
iii. Statistical Analysis and Result Reporting: Immunostaining for H2AX and other proteins 
including RAD51 foci will be performed on MNCs from AML PB samples obtained on Day 1 
pre-treatment and on Day 5 following treatment. H2AX and other proteins including RAD51 
foci will be quantitated as described in the foci quantitation section below and results will be 
compared with those of pretreated controls. We expect that H2AX foci/cell will increase and 
other proteins including RAD51 foci will decrease in AML samples taken post-treatment on 
Day 5, compared with pre-treatment on Day 1. Results will be reported as the average number 
of foci/cell in each sample within an individual participant. The Student’s t-test will be used to 
determine significant difference between pre-treatment and post-treatment samples, p ≤ 0.05 
considered significant.  
 
iv. Correlation with Clinical Responses: H2AX and other proteins including RAD51 and 
epigenetic factors in AML participant samples will be correlated with clinical responses, in 


 
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collaboration with Dr Søren Bentzen. 
 
 
9.5.5 PARP Trapping 
 
a) Hypothesis and Rationale 
 
Levels of PARP trapping will increase in AML participant samples following treatment with 
talazoparib and decitabine, and increases in PARP trapping will correlate with clinical responses. 
 
b) Mechanistic Rationale: PARP inhibitors trap PARP1 in chromatin as one of their mechanisms 
of action, and PARP trapping correlates with the cytotoxic effects of PARP inhibitors (16,29). The 
laboratory of Dr. Rassool has demonstrated that decitabine treatment also leads to trapping of 
PARP in chromatin in AML cells, and that combinations of decitabine and PARPis enhance PARP 
trapping, in relation to the effect of either drug alone (34). Thus the mechanistic rationale for the 
combination of decitabine and talazoparib is that it will increase PARP trapping in chromatin, 
leading to increased AML cell death.  
 
c) Intended Use Within this Study: This study will determine whether PARP trapping is 
increased in chromatin fractions of AML blasts after 5 or 10 days of combined decitabine and 
talazoparib treatment, compared with pre-treatment samples. These results will also be correlated 
with participant responses.  
 
d)  Assay Methods  
 
i. Detailed Protocol:  
Method 1: Chromatin quantification: Flash frozen [2 vials] MNCs will be used to isolate 
chromatin fractions using the Subcellular Protein Fractionation kit (Thermo Fisher Scientific, 
Waltham, MA), following manufacturer instructions. Immunoblotting will then be performed 
following standard procedures using 5 ug of chromatin lysate. Proteins will be loaded onto 4-
20% SDS-PAGE gel (Bio-Rad laboratories, Hercules, CA), transferred on PVDF membrane 
(GE Healthcare Life Sciences, Pittsburgh, PA) and blots will be washed in Tris Buffered 
Saline-0.1% Tween 20 (TBST) three times, blocked in TBST-5% bovine serum albumin 
(TBST-BSA) for an hour at least and first antibodies in TBST-BSA are applied overnight at 
4oC on a shaker. Blots will be washed again 3 times and secondary antibodies, anti-Mouse-
horse radish peroxidase (HRP; Cell signaling, Danvers, MA) or anti-Rabbit-HRP (BioLegend, 
San Diego, CA) or alkaline phosphate (AP; Bio-Rad) in TBST are applied for one hour followed 
by 3 washes and detection of HRP using enhanced chemiluminescence or alkaline 
phosphatase using 5-bromo-4-chloro-3-indolyl-phosphate/nitro blue tetrazolium (BCIP/NBT; 
Promega). Blots will be probed for PARP1, using PARP1 mouse monoclonal (1:3000, C2-10, 
BD Biosciences) and DNMT1 using mouse monoclonal (1:5000, Imgenex, San Diego, CA). 
Histone H3 rabbit polyclonal (1:30000, Sigma-Aldrich) will be used as the loading control.  
Method 2: Proximity ligation assay (PLA): The procedure will be performed using the Duolink 
In Situ assay kit (Sigma) according to manufacturer’s instructions (sigma.com/duolink). Briefly, 
viably frozen AML MNCs will be processed as described in section 9.5.4 for 
immunofluorescence. Primary antibodies mouse anti-PARP1 (Sigma) and rabbit anti-H2Ax 
(Cell Signaling Technologies) will be used at 1:400 and incubated overnight at 4oC, followed 
by 3 washes in PBS. Secondary antibodies conjugated to PLA plus and minus probes will be 
diluted 1:5 in antibody dilution buffer (included in kit) and slides incubated for 1hr at 37oC 
followed by three washes in PBS. Ligation, amplification, and counterstaining are performed 
according to kit instructions. Slides will be examined using a Nikon fluorescent microscope 


 
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Eclipse 80i (100X/1.4 oil, Melville, NY). 
 
ii. Densitometry, Image analysis, Statistical Analysis and Result Reporting: Protein 
levels on immunoblots will be quantitated by densitometry using Quantity-one software 
(v.4.6, Bio-Rad) after scanning nonsaturated luminograms. PLA fluorescent spots from at 
least 50 cells/slide will be captured using a CCD (charge-coupled device) camera and the 
imaging software NIS Elements (BR 3.00, Nikon). Result reporting: C1D1 Samples (pre-
treatment) are set at 1 for PARP1 band density (determined using ImageJ Software [NIH]), 
and PARP trapping in treatment samples (C1D5 and C1D8) will be assessed relative to 
pre-treatment samples as fold change. For PLA, results will be reported as the average 
number of fluorescent spots per cell in each sample from an individual participant. 
Treatment samples will be compared to pre-treatment samples in three technical 
replicates (each sample will be analyzed three times) using the average of the logarithm 
of the fold change ± SEM. All statistical analyses will be performed using the Student’s t-
test on the log-transformed values, with p-values ≤ 0.05 considered significant.  
 
iii. Correlation with Clinical Responses: PARP trapping results in AML participant samples 
will be correlated with clinical responses, in collaboration with Dr Søren Bentzen, Director 
of Biostatistics at the University of Maryland and of the Biostatistics Shared Service, 
UMGCCC. 
 
 
9.5.6 DNA repair and epigenetic factors - Protein and mRNA Expression  
 
a) Hypothesis and Rationale 
 
Protein and mRNA levels of DNA repair and epigenetic factors decrease in soluble fractions from 
AML cells treated with talazoparib and decitabine. 
 
b) Mechanistic Rationale: Cells treated with decitabine or azacitidine have decreased levels of 
DNMT1, 2 and 3a in soluble (non-chromatin) fractions (37). Our unpublished data show that 
soluble cellular lysates from AML cells treated with decitabine and/or the PARP inhibitor ABT888 
demonstrate decreased levels of both DNA repair and epigenetic factors..  In addition, increased 
caspase cleavage is observed with the drug combination. In contrast, chromatin fractions 
demonstrate increased levels of PARP1.  
 
The mechanistic rationale is that the combination of decitabine and the PARP inhibitor talazoparib 
will lead to decreased levels of these above factors in soluble (non-chromatin) cellular fractions, 
and, in contrast, increased levels of PARP1 in chromatin.  
 
c) Intended Use Within this Study: This study will determine whether levels of these factors 
decrease in soluble cellular fractions, in contrast to increased PARP trapping in chromatin, in 
treated samples from AML participants, relative to pre-treatment samples. 
 
 
d) Detailed Protocol 
 
i. 
Immunoblotting: AML MNCs (flash frozen) will be used to isolate whole cell lysates, 
following standard procedures described previously (38,39). Immunoblotting will then be 
performed following standard procedures using 5 ug of whole cell lysate. Proteins will be 
loaded onto 4-20% SDS-PAGE gel (Bio-Rad laboratories, Hercules, CA), transferred onto 


 
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PVDF membrane (GE Healthcare Life Sciences, Pittsburgh, PA) and blots will be washed 
in Tris Buffered Saline-0.1% Tween 20 (TBST) three times, blocked in TBST-5% bovine 
serum albumin (TBST-BSA) for an hour at least and first antibodies in TBST-BSA are 
applied overnight at 4oC on a shaker. Blots will be washed again 3 times and secondary 
antibodies, anti-Mouse-horse radish peroxidase (HRP; Cell signaling, Danvers, MA) or 
anti-Rabbit-HRP (BioLegend, San Diego, CA) or alkaline phosphate (AP; Bio-Rad) in 
TBST will be applied for one hour, followed by 3 washes and detection of HRP using 
enhanced chemiluminescence or alkaline phosphatase using 5-bromo-4-chloro-3-indolyl-
phosphate/nitro blue tetrazolium (BCIP/NBT; Promega). Blots will be probed for PARP1, 
using PARP1 mouse monoclonal antibody (1:3000, C2-10, BD Biosciences) and DNMT1 
and DNMT3a using mouse monoclonal antibodies (1:5000, Imgenex, San Diego, CA). 
Actin rabbit polyclonal (1:30000, Sigma-Aldrich) will be used as the loading control.  
 
ii. 
Q-Real-time-RT PCR: mRNA will be isolated from AML MNCs (flash frozen) using the 
Machery-Nagel NucleoSpin RNA kit according to manufacturer's instructions. mRNA is 
then quatified on Nanodrop and diluted to 100-200ng/ul. cDNA is generated using the 
Applied Biosystems High Capacity cDNA RT kit. Preparation of the mastermix is 
performed according to manufacturer’s instructions and mastermix and mRNA are added 
to a PCR tube or plate. Reverse transcription is performed in a BIORAD PCR machine 
with temperature and time settings according to instructions in the cDNA RT kit. cDNA is 
then diluted to 5ng per PCR reaction and reaction is set up in a 96- or 384-well plate using 
RT2 SYBR Green mastermix.. The plate is sealed and centrifuged. PCR is performed with 
a hot start of 90oC for 10 min, and then 40 cycles of 95oC for 15 seconds followed by 60oC 
for 1 min in a BIORAD PCR machine.  
 
 
iii. 
Densitometry and Statistical Analysis: Protein levels on immunoblots will be quantified 
by densitometry using the Quantity-one software (v.4.6, Bio-Rad) after scanning non-
saturated luminograms. Band densities from treatment samples will be compared with 
band densities from pre-treatment samples and expressed as fold change. Result 
reporting: The log of the fold change relative to pre-treatment densities in three 
independent experiments will be reported as a mean value ± SEM. All statistical analyses 
will be performed using the Student t-test, with p-values ≤ 0.05 considered significant. We 
expect that protein levels of PARP1 and DNMTs will be significantly decreased in Day 5 
post-treatment AML samples, compared with Day 1 pre-treatment samples. These results 
will be correlated with PARP trapping data in chromatin, using the Spearman’s rank 
correlation. 
 
9.5.7    Poly ADP Ribose (PAR) Polymerase Activity Assay 
 
a) 
Hypothesis and Rationale: PAR activity should be decreased as a marker of talazoparib 
acitiviy.  
b) 
Intended Use Within this Study:  Decreased activity may correlate with the potential 
effects of the PARP inhibitor  talazoparib 
c) 
Detailed Protocol: The assay will be performed using the Trevigen HT PARP in vivo 
Pharmacodynamic 
Assay 
according 
to 
manufacturer’s 
instructions 
(https://trevigen.com/docs/protocol/protocol_4520-096-K.pdf). In short, immobilized PAR 
monoclonal antibody in the wells of a 96-well plate capture cellular PAR and PAR 
attached to proteins. Incubation with a polyclonal PAR-detecting antibody, followed by 
addition of a goat anti-rabbit IgG-HRP secondary and a chemiluminescent HRP substrate 
yields relative light units (RLU) that directly correlate with the amount of cellular PAR. 


 
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9.5.8 DSB Repair  
 
a) Hypothesis and Rationale: The combination of decitabine and talazoparib will lead to 
increased PARP trapping and decreased RAD51 foci formation that will decrease the HR 
DSB repair response, leading to increased cytotoxic DSBs. We will perform exploratory 
assays in AML participant samples to determine whether DSB NHEJ repair activity is 
altered in response to decitabine and talazoparib treatment.  
 
b) Intended Use Within this Study: This study will determine whether levels of HR are 
decreased and whether levels of NHEJ are altered in response to treatment, in treated 
samples from AML participants (relative to pretreatment samples), as measured by HR 
and NHEJ assays, respectively, and whether these alterations will correlate with clinical 
responses.    
 
c) Detailed Protocol: HR assay: in vitro HR assay will be performed using the HR assay kit 
(Norgen Biotek) according to kit protocol, with exceptions. Instead of transfecting AML 
MNCs, nuclear lysates from MNCs and HR plasmids (dl-1 and dl-2) will be incubated with 
nuclear lysates as described above. Following overnight incubation, plasmids repaired by 
HR will be assayed by RT-PCR (Bio-Rad) using the kit’s assay and universal primers. 
NHEJ assay: Nuclear extracts will be isolated from AML MNCs (viably frozen), following 
standard procedures described previously (38,39). To measure efficiency of NHEJ, we will 
use a modified in vitro protocol of the EJ5-Isce1 reporter assay as described in (40). The 
pimEJ5GFP reporter (Addgene, Cambridge MA) will be linearized with I-Sce1 (New 
England Biolabs, Ipswich, MA) at 370C overnight, dephosphorylated using Shrimp Alkaline 
phosphatase (New England Biolabs) for one hour at 370C before column purification 
(Qiagen, Gaithersburg, MD). For the NHEJ reaction, 500ng of linearized EJ5-Isce1 will be 
incubated with 5ug of E-buffer (20 mM Tris–HCl pH 8.0, 20% glycerol, 0.1 mM K(OAc), 
0.5 mM EDTA, 1 mM DTT; 2 x 1hr) dialyzed nuclear extracts diluted in ligation buffer (10X 
T4 Ligase Buffer, 2 mM ATP, 50 μM deoxynucleotide triphosphates). After an overnight 
incubation at 160C, EJ5 will be purified through column purification and subjected to PCR 
for 
amplification 
of 
GFP 
genes 
using 
the 
primers 
P1 
(Fwd) 
5’-
CTGCTAACCATGTTCATGCC-3’, p2 (Rev) 5’-AAGTCGTGCTGCTTCATGTG-3’, as 
described by (40). The PCR products is then run onto 2% Agarose gel and product will be 
visualized with the GelStar™ Nucleic Acid Stain (Lonza).  
 
d) Analysis and Result Reporting: HR activity will be assessed using ΔΔCt method. Result 
reporting: The fold change in PCR product band density of treatment samples (C1D5 and 
C1D8) is estimated relative to that of C1D1 samples (pretreatment) using Bio-Rad’s 
Quantity One Software. Log transformed fold changes will be compared between groups 
whenever relevant, as described above. For HR assay, samples will be normalized to 
C1D1 (set at 1) and expressed as fold change in HR activity. For NHEJ, ligated plasmid 
(PCR product) is calculated relative to total DNA loaded and expressed as relative 
efficiency of NHEJ repair (fold change compared to control). H3 expression is used as a 
loading control for the amount of protein in each reaction.  
 
 
9.5.9 
Immune Response Endpoint 
 
Viably frozen cells and serum will be sent to VARI and these studies will be performed in the 


 
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future if funding allows.  T-cell response pre- and post-treatment and cytokine release will be 
assessed. 
 
 
9.6 
DNA Methylation 
 
 
Samples will be shipped to the VARI, where they will be processed and distributed for the studies, 
which will be performed in core laboratories of VARI-Stand Up to Cancer (SU2C) Epigenetics 
Dream Team members or collaborators. 
 
Changes in DNA methylation will be studied, as follows: 
 
a) Whole Genome Methylation Analyses Using Available DNA Methylation Array Platform, 
Such as the Illumnia Infinium Methylation Assay Platform (41). 
 
The HumanMethylation450 BeadChip is a powerful tool in epigenetics research. The 
Illumina Infinium Methylation Assay uses only 1 µg of DNA and interrogates more than 485,000 
methylation sites per sample at the single-nucleotide resolution. The array covers 99% of RefSeq 
genes, with an average of 17 CpG sites per gene region distributed across the promoter, 5'UTR, 
first exon, gene body, and 3'UTR. It covers 96% of CpG islands, with additional coverage in island 
shores and the regions flanking them.  
Additional categories includes: 
• 
CpG sites outside of CpG islands 
• 
Non-CpG methylated sites identified in human stem cells 
• 
Differentially methylated sites identified in tumor versus normal (multiple forms 
of cancer) and across several tissue types 
• 
CpG islands outside of coding regions 
• 
miRNA promoter regions 
 
One 6.0 ml EDTA tube of bone marrow will be collected in a de-identified manner and shipped to 
VARI where the sample will be processed to remove WBC/Blast cell population for isolation of 
DNA that will be used in the 450K methylation array assays.  VARI will ship a bone marrow (BM) 
specimen collection kit to the clinical study team. The BM specimen kit will have labels with a de-
identified number set. The clinical study team will use the BM kit de-identified number to record 
for their participant records so that future 450K Infinium array research results can be correlated 
to the participants in the study.  
 
The VARI Genomic Core Laboratory or VARI-SU2C collaborator will perform the methylation 
array according to standard operating procedures for sample processing, DNA isolation, and the 
methylation assay.  
 
b)  Bisulfite-Pyrosequencing of Line 1 + 10 Tumor Suppressor Genes (42). 
DNA will be extracted and treated with bisulfite. Genomic DNA (2 μg) will be denatured by 0.2 M 
NaOH at 37°C for 10 minutes followed by incubation with freshly prepared 30 μL of 10 mM 
hydroquinone and 520 μL of 3 M sodium bisulfite (pH 5.0) at 50°C for 16 hours. DNA will be 
purified with a Wizard Miniprep Column (Promega, Madison, WI), desulfonated with 0.3 M NaOH 
at 25°C for 5 minutes, precipitated with ammonium acetate and ethanol, and dissolved in 50 μL 
of TE buffer (Tris-HCl 10 mM, EDTA 1 mM, pH 8.0). Bisulfite-treated DNA (40-80 ng) will be 
amplified with gene-specific primers in a 2-step polymerase chain reaction (PCR). The second 


 
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step of PCR will be used to label single DNA strand with biotin using a universal primer tag or 
gene-specific primers biotinylated at the 5′ end. Each PCR step will be performed in a total volume 
of 20 μL of 67 mM Tris-HCl (pH = 8.8), 16 mM ammonium sulfate, 2 mM MgCl2, 0.125 mM dNTPs, 
1 U Taq polymerase, and 100 nM PCR primers. TQ30 oligonucleotide (50 nM) will be used as a 
reversible inhibitor of Taq polymerase in the first step of the PCR. 
DNA methylation will be measured as the percentage of bisulfite-resistant cytosines at CpG sites 
by pyrosequencing with the PSQ HS 96 Pyrosequencing System (Biotage, Charlottesville, VA) 
and Pyro Gold CDT Reagents (Biotage). Mean values from all pyrosequenced CpG sites will be 
used as a measure of methylation of a given gene. We will also measure DNA methylation at the 
5′ end of the LINE-1 repeat (GenBank accession number X58075) to assess global methylation 
levels. 
 
9.7 
Potential Predictors of Response 
 
Potential predictors of response will be explored (see section 13.6), including karyotype, FLT3 
and NPM1 mutations, mutations in genes regulating methylation including DNMT3A, TET2, IDH1, 
IDH2 and EZH2, as well as PARP expression levels. These studies will be performed on pre-
treatment bone marrow, or on blood if marrow is inaspirable. Karyotype will be determined by 
standard cytogenetic analysis at each institution. Mutations will be studied as part a myeloid gene 
mutation panel at VARI. PARP expression levels will be measured as detailed above. 
 
 


 
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10. 
STUDY CALENDAR 
Table 8. Study Calendar 
 
 
Pre- 
Study 
Wk 
1h 
Wk 
2 h 
Day 
10 i 
W
k 
3 
h 
Wk 
4 h 
Wk 
5 h 
Wk 
6 h 
Wk 
7 h 
Wk 
8 h 
Wk 
9 h 
Wk 
10 h 
Wk 
11 h 
Wk 
12 h 
… h Off 
Stu
dy 
Post-
Study 
Follow-
Up 
Decitabine 
 
A 
 
 
 
 
A 
 
 
 
A 
 
 
 
A 
 
 
Talazoparib 
 
B 
B 
 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
X 
 
X 
X 
X 
(X) 
X 
(X) 
X 
(X) 
(X) 
(X) 
 
X 
 
Concurrent medsf 
X 
 
X-------------------------------------------------------------------------------- 
X 
 
 
Physical exam 
X 
X 
X 
 
X 
X 
X 
(X) 
X 
(X) 
X 
(X) 
(X) 
(X) 
X 
X 
 
Vital signs 
X 
X 
X 
 
X 
X 
X 
(X) 
X 
(X) 
X 
(X) 
(X) 
(X) 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
X 
X 
(X) 
X 
(X) 
X 
(X) 
(X) 
(X) 
X 
X 
 
Performance status 
X 
X 
X 
 
X 
X 
X 
(X) 
X 
(X) 
X 
(X) 
(X) 
(X) 
X 
X 
 
CBC w/diff, plts 
X 
X 
X 
 
X 
X 
X 
(X) 
X 
(X) 
X 
(X) 
(X) 
(X) 
X 
X 
 
Serum chemistrya 
X 
X 
X 
 
X 
X 
X 
(X) 
X 
(X) 
X 
(X) 
(X) 
(X) 
X 
X 
 
Coagulation studies 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG and/or 
Echocardogram 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
 
X-------------------------------------------------------------------------------X 
X 
X 
X 
Survival Status 
 
 
 
 
 
X 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate, biopsyc 
X 
 
 
 
 
 
(X) 
 
 
 
(X) 
 
 
 
(X) 
 
 
Bone Marrow 
Cytogenetics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Myeloid Mutation 
Panelg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Buccal swab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood correlative 
studies 
 
Xd 
 
 
X  i 
 
 
Xe 
 
 
 
Xe 
 
 
 
Xe  
 
 
A 
Decitabine IV daily, Days 1 through 5 or 10, at a consistent time, after talazoparib. 
B 
Talazoparib orally daily continuously, taken at a consistent time in the morning. 
a 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, 
potassium, magnesium, total protein, SGOT [AST], SGPT [ALT], sodium, uric acid. 
b 
Serum pregnancy test (women of childbearing potential). 
c     Bone marrow aspirate and biopsy will be performed on day 25-29 of cycle 1, as well as 
       on day 25-29 of each treatment cycle (unless circulating blasts persist in the peripheral blood), until documentation of CR or 
CRi. Bone marrow aspirate and biopsy will also be performed as needed to evaluate lack of count recovery (neutrophils 
<1000/μL and/or platelets <50,000/μ) at week 7 in the absence of blood blasts, and at time of clinical concern for disease 
progression after CR or CRi.  
d      Blood pharmacodynamic samples (green and lavender tubes) in Cycle 1 on Day 1 pre-treatment, on Day 5 1-hour post 
decitabine treatment, and on Day 8.  For participants receiving 10-day decitabine, sampling will be on Days 1, 5, 8 and 10, one 
hour after the decitabine injection.  
e     Blood pharmacodynamic samples (lavender tubes only) in subsequent Cycles on Day 29.  
f     Any medications, including supplements and herbs 
g    At the discretion of the treating Physician 
h    (± 3 days) i for Cohort 7 and/or the expanded cohort only 
( )   As clinically indicated, if needed, throughout the study.   


 
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10.1 
Screening Evaluations 
 
Baseline evaluations are to be conducted after patients sign informed consent and within 14 days 
prior to start of protocol therapy.  In the event that the participant’s condition is deteriorating, 
laboratory evaluations should be repeated within 48 hours prior to initiation of therapy.  
 
Screening evaluations include: 
• 
Medical history and physical examination, including measurements of height and weight, 
performance status, vital signs (blood pressure, pulse rate, respiration rate and 
temperature); concurrent medication assessment 
• 
Complete blood count (CBC) (hemoglobin, WBC, and platelet count) and manual 
differential white blood cell count; 
• 
Coagulation studies: aPTT, PT, INR, fibrinogen, with D-dimer as clinically indicated; 
• 
Blood chemistries:  electrolytes (sodium, potassium, bicarbonate and chloride), glucose, 
BUN, creatinine, ALT, AST, total bilirubin, alkaline phosphatase, calcium, phosphorus, 
magnesium, albumin, total protein, LDH and uric acid;  
• 
Blood pregnancy test for women of childbearing potential; 
• 
Bone marrow aspirate and biopsy 
• 
Bone marrow cytogenetics  
• 
Bone marrow myeloid mutation panel (at discretion of treating Physician)  
• 
Two Buccal swabs for mutation studies 
• 
Electrocardiogram (EKG) and/or echocardiogram (ECHO) will be performed only as 
clinically indicated.  
 
10.2 
Study Evaluations 
 
10.2.1 Cycle 1 
• 
During treatment cycle 1 on study, history and physical examination with vital 
signs, weight and performance status should be performed at least weekly and 
can be performed on any day of the week.  
• 
CBC/manual differential and comprehensive chemistry tests should be performed 
at least weekly.  
• 
Blood must be drawn for pharmacodynamics and research testing on day 1 before 
treatment, on day 5 one hour after decitabine injection and on day 8 at any time.  
• 
For participants receiving 10-day decitabine, sampling will be on Days 1, 5, 8 and 
10, one hour after the decitabine injection.  
• 
The Cycle 1 Day 10 visit will coincide with an infusion visit and will consist 
of a correlative blood draw only and can be handled as a nurse visit.  
• 
Coagulation studies should be performed as clinically indicated. 
• 
Bone marrow aspirate and biopsy should be performed on day 25-29 of the first 
treatment cycle. 
• 
Toxicity rating using the NCI Common Terminology Criteria for Adverse Events 
version 4.0 will be performed as needed. 
 


 
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10.2.2 Cycle 2 
• 
During treatment cycle 2, physical examination with vital signs, medical history, 
weight and performance status should be performed at least every two weeks and 
can be performed on any day of the week.  
• 
CBC/manual differential and comprehensive chemistry tests should be performed 
at least every two weeks.  
• 
Coagulation studies should be performed as clinically indicated. 
• 
Bone marrow aspirate and biopsy should be performed pre-dose, approximately 
on day 25-29 unless circulating blasts persist in the peripheral blood. 
• 
Toxicity rating using the NCI Common Terminology Criteria for Adverse Events 
version 4.0 will be performed as needed. 
 
10.2.3 Subsequent Cycles  
• 
During cycle 3 and subsequent cycles, physical examination with vital signs, 
weight, and performance status should be performed at least on day 1 of each 
treatment cycle.  
• 
CBC/manual differential and comprehensive chemistry tests should be performed 
at least on day 1 of each treatment cycle.  
• 
Coagulation studies should be performed as clinically indicated. 
• 
Bone marrow aspirate and biopsy should be performed pre-dose, approximately 
on day 25-29 of each treatment cycle unless circulating blasts persist in the 
peripheral blood, until documentation of CR or CRi. Bone marrow aspirate and 
biopsy will also be performed pre-dose, as needed to evaluate lack of count 
recovery (neutrophils <1000/μL and/or platelets <50,000/μL) by day 43 in the 
absence of blood blasts, and at time of clinical concern for disease progression 
after CR or CRi. 
• 
EKG and/or ECHO will be performed only as clinically indicated.  
• 
Toxicity rating using the NCI Common Terminology Criteria for Adverse Events 
version 4.0 will be performed as needed. 
 
10.2.4 Off Study Assessments 
 
Once a participant discontinues participation in the study, the participant will be asked to return 
within 30 days for the following assessments. This return visit will depend upon the status of the 
participant and while recommended, is not required: 
• 
Performance status evaluation  
• 
Limited medical history and physical examination 
• 
Vital signs, weight 
• 
CBC with manual  
• 
Differential, platelet count 
• Blood chemistries 
• 
Adverse event evaluation 
 
 
10.3 
Post-Study Follow-up 
 
Participants will be followed for survival and possible long-term toxicity from treatment. Follow-up 
will continue at least every 6 months until death. If not seen at hospital visits, participants will be 


 
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contacted by telephone or by email.  Further therapy will be at the discretion of the treating 
physician. 
 
 
 
 
 
11. 
MEASUREMENT OF EFFECT 
 
Response definitions will be according to the revised International Working Group (IWG) response 
criteria for AML as published by Cheson et al. (43). 
 
11.1 
Definitions of Response for Acute Leukemia   
 
11.1.1 Complete Remission (CR):  
 
Bone marrow with < 5% blasts and with maturation of all cell lineages, no Auer rods, an absolute 
neutrophil count  1,000/l and a platelet count  100,000/l, transfusion independence, absence 
of blasts in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance 
of any extramedullary disease (soft tissue involvement).  Clearance of cytogenetic abnormalities 
will not be required for CR, but will be noted and described separately.  
 
11.1.2 Complete Remission with Incomplete Blood Count Recovery (CRi):  
 
CRi satisfies all CR criteria except for residual neutropenia ANC < 1,000/l and/or platelets < 
100,000/l, but platelet transfusions are not necessary. 
 
11.1.3 Partial Remission (PR):   
 
Must meet all criteria of a CR except that the bone marrow may contain 5-25% blasts, and at least 
50% decrease in bone marrow blast percentage from baseline must be present. 
 
11.1.4 Hematologic Improvement (HI):  
 
At least 50% decrease in marrow blasts or extramedullary disease, including peripheral blood 
blasts; ANC 500-1000/l; platelets 20,000-100,000/l or improved transfusion needs.   
 
11.1.5 No Response (NR):    
 
No criteria for CR, CRi, PR or HI are met. 
 
 
11.1.6 Relapse:   
 
Any of the following, occurring after either CR, CRi, or PR:  
• 
The reappearance of circulating blasts not attributable to “overshoot” following 
recovery from myelosuppressive chemotherapy (at least 2 measurements). 
• 
≥ 5% blasts in the bone marrow, not attributable to another cause (e.g. bone 
marrow regeneration), or in case of PR > 50% increase in bone marrow blast % 
from best assessment. 
• 
The reappearance or development of cytologicaly proven extramedullary disease. 


 
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• 
Molecular and/or genetic relapse is characterized by reappearance of a 
cytogenetic or molecular abnormality. 
 
11.1.7 Duration of Response 
 
The duration of response is measured from the time measurement criteria for CR or CRi are met 
until the first date that recurrent or progressive disease is objectively documented. The duration 
of CR is measured from the time measurement criteria are first met for CR until the first date that 
recurrent disease is objectively documented  
 
11.1.8 Progression-Free Survival 
 
All participants will be assessed for PFS, defined as the time between study entry and the first 
date that recurrent or progressive disease is objectively documented, or death from any cause 
occurs.  
 
11.1.9 Overall Survival 
 
Overall survival will be measured from time of enrollment onto this study to the time of death. 
 
 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Compliance with Laws and Guidances 
 
This study will be conducted in accordance with current U.S. Food and Drug Administration 
(FDA) Regulations, Good Clinical Practices (GCPs) and International Counsel on 
Harmonization (ICH) E6 Guidelines. 
 
12.1.1 Institutional Review Board (IRB) 
 
This protocol must be submitted to a local IRB in accordance with the Code of Federal 
Regulations (CFR), and FDA and International Counsel on Harmonization (ICH) E6 Guidelines. 
Study procedures will begin once local IRB approval is secured. All amendments, instances 
of reportable new information (i.e. unanticipated problems, data breaches, etc.) and continuing 
review reports must be submitted to the local IRB of record. 
 
12.1.2 Clinical Trial Monitoring 
 
Data safety and verification monitoring will be conducted in accordance with the Greenebaum 
C o m p r e h e n s i v e  
Cancer 
Center 
Sponsor-Investigator 
Monitoring 
Standard 
Operating Procedure (SOP), the Code of Federal Regulations (CFR), and FDA and 
International Counsel on Harmonization (ICH) E6 Guidelines. 
 
12.1.3 Data and Safety Monitoring Board (DSMB) 
 


 
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DSMB oversight will be conducted in accordance with the Greenebaum Comprehensive 
Cancer Center DSMB standard operating procedures. 
 
It is the responsibility of the Principal Investigator to oversee the safety of the study. This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above.  
 
This study will be monitored by the UMGCCC Data and Safety Monitoring and Quality Assurance 
Committee and will follow the Data Safety and Monitoring Plan as outlined in the Clinical 
Investigator Handbook of the UMGCCC Clinical Research Office. Monitoring will be conducted 
as per the plan on file with the University of Maryland IRB (also available in the UMGCCC Clinical 
Investigator Handbook found at http://www.umgcc.org/research/clinical_research.htm). 
 
12.1.4 FDA Reporting 
 
The FDA Annual Report will be submitted to the Agency within +/- 60 days of the date on the 
IND approval letter. Major amendments will be submitted to FDA at the time of IRB submission. 
Minor amendments will be reported to FDA at the time of the next major amendment or at the 
next FDA Annual Report (whichever comes first). 
 
12.1.5 Records Retention 
 
Essential documents should be retained until at least 2 years after the last approval of a   
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation 
of clinical development of the investigational product. Records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records will be maintained in secure offsite 
storage after completion of study follow-up and data analysis. 
 
12.1.6 Compliance with Trial Registration and Results Posting Requirements 
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted 
will allow participants to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information. 
 
12.1.7 University of Maryland Data Management 
 
Clinical data will be entered into the OnCore® database by the designated data manager at 
the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer 
Center (UMGCCC). Oncore® is used for data entry in a way that is compliant with 21CFR11.10 
(electronic medical records) and is equipped for HIPAA-compliant internet-based entry of 
protocol tracking and review information. 
 
All study data will be collected by the research team at each and every study visit and recorded 


 
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in the research record. This data will then be entered in to the OnCore® study database. 
 
All source documents will be obtained and retained along with any study forms, and placed into 
the participant’s research folder. 
 
12.2 
Multi-institutional Data Management 
 
Remote VPN access will be provided for each participating site along with Oncore® training. This 
access and training will occur prior to enrollment of the first participant at the site, in order to 
ensure that staff are adequately trained and able to enter data within 5 days of the visit occurring. 
All study data will be collected by the research team at each and every study visit and recorded 
in the research record. This data will then be entered in to the OnCore® study database. 
 
All source documents will be obtained and retained along with any study forms, and placed into 
the participant’s research folder according to the policies around record retention in place at each 
site. 
 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Dose Escalation and Nesting of Dose Levels 
 
The statistical design of this Phase 1 trial is a ‘traditional’ 3+3 design. Only participants with 
relapsed or refractory AML will be enrolled in the trial. Participants who withdraw from the trial for 
any other reason than toxicity and who have not already developed a dose-limiting toxicity (DLT) 
at that point, will be replaced by recruiting another participant at the same dose level. Due to the 
clinical setting and the putative mechanistic action of talazoparib as a sensitizer of the effect of 
decitabine, escalation of the two agents will use a nested Phase I design giving priority to the 
dose of decitabine: the design will estimate the maximum tolerable dose of decitabine in 
combination with a dose of talazoparib of 0.25 mg or higher. The nested design is defined by 
Table 9 below: 
 
Table 9 
Dose Escalation and Nesting of Dose Levels 
 
 
Talazoparib (mg) 
0.25 
0.50 
0.75 
1.0 
1.0 
Decitabine 
(mg/m2) 
10 
1 
1a 
1b 
1c 
- 
15 
2 
2a 
2b 
2c 
- 
20 
3 
4 
5 
6 
7* 
 
* Cohort 7 will receive 20 mg/m2 of decitabine for 10 days and 1 mg of Talazoparib continuously.  
 
The ‘outer layer’ of this nested dose escalation trial will escalate the dose of the two drugs by 
sequentially going through dose levels 1-6 in the table. The standard algorithm of the 3+3 design 
will be applied as specified below. 
 
If Cohort 6, with 20 mg/m2 decitabine daily for 5 days and talazoparib 1 mg daily, is completed 
without dose-limiting toxicity, Cohort 7, consisting of decitabine, 20 mg/m2 daily for 10 days and 
talazoparib, 1 mg daily, will be added. 
 


 
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Following completion of Cohort 6 or Cohort 7 without dose-limiting toxicity, a maximum of 17 
participants not previously treated with DNMTis (decitabine, azacitidine and/or guadecitabine) will 
be enrolled to assess response in this patient population.  
 
If the MTD has not been reached at dose level 7, the RP2D of decitabine will be 20 mg/m2 for 10 
days combined with a dose of talazoparib of 1.0 mg. 
 
At the time of revising the protocol, the toxicity data demonstrated that the MTD has not been 
reached at dose level 5. The following decision rules were not activated but are preserved in this 
version of the protocol for completeness. 
 
If 2 or more participants develop DLT at dose level 1, the combination of decitabine and 
talazoparib will be considered too toxic for further clinical development. 
 
If the provisional MTD for decitabine in combination with talazoparib is dose level 1 or 2, one or 
the other of the ‘inner layers’ of the trial will be activated. If the provisional MTD corresponds to 
level 2, the dose of decitabine will be fixed at 15 mg/m2 and the dose of talazoparib will be 
escalated through steps 2a-c, again using the algorithm of the 3+3 design below. If the tolerance 
is not exceeded at level 2c, then the RP2D of decitabine is 15 mg/m2 combined with a dose of 
talazoparib of 1.0 mg. 
 
Similarly, if the provisional MTD for the combination of the two agents from the outer layer is level 
1, the dose of decitabine will be fixed at 10 mg/m2 and the dose of talazoparib will be escalated 
through steps 1a-c, again using the algorithm of the 3+3 design below to define the MTD of the 
combination.  
 
 
13.2 
 ‘3+3’ Design 
 
There are several variations to the 3+3 design, 
and it may therefore be helpful to describe the 
current design in detail. Three participants will 
be accrued at each dose level until a DLT is 
seen, see flow diagram. The first dose level at 
which one DLT is seen will be expanded to six 
participants. If only one DLT is seen, dose 
escalation will continue in three-participant 
cohorts. If one DLT is seen among the three 
participants accrued at one of the subsequent 
dose levels, the cohort treated at that dose 
level will be expanded to six participants. If two 
or more of the six participants experience DLT, 
then the maximum tolerated dose (MTD) is 
considered to be exceeded, and the next lower dose level is considered the MTD provided that 6 
participants were treated at this dose level. If not, this level is considered a candidate MTD and 
expanded to 6 participants. The algorithm will stop when there is <2 of 6 participants with DLTs 
at the candidate MTD level and this will be defined as the MTD.  
 
The minimum number of participants in the trial is 2 – this would be the number enrolled if the two 
first participants at level 1 both were to experience a DLT. The maximum number of dose 
combinations tested is 7 This yields a – hypothetical – upper limit on the number of participants 


 
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enrolled of 59, arising if exactly 1 DLT is observed at each of the 7 dose levels plus an additional 
17 patients for the post Cohort 6 / 7 DNMTi-naïve expansion cohort. 
 
If Cohort 6, with 20 mg/m2 decitabine daily for 5 days and talazoparib 1 mg daily, is completed 
without dose-limiting toxicity, Cohort 7, consisting of decitabine, 20 mg/m2 daily for 10 days and 
talazoparib, 1 mg daily, will be added. 
 
Following completion of Cohort 6 or Cohort 7 without dose-limiting toxicity, a maximum of 17 
participants not previously treated with DNMTis (decitabine, azacitidine and/or guadecitabine) will 
be enrolled to assess response in this patient population.  
 
The aim of the expansion cohort will be to expand the safety data and to look for signs of activity 
in the DNMTi-naïve population. 
  
 
13.2.1 
Recommended Phase 2 Dose (RP2D) 
 
The MTD of the combination of decitabine with a dose of talazoparib of at least 0.25 mg is defined 
as the maximal tolerated dose of decitabine studied – and for that dose level, combined with the 
maximum dose of talazoparib for which the incidence of DLT was less than 33% in 6 participants 
treated and this will be chosen as the recommended Phase 2 dose (RP2D).  
 
Among potential combined dose levels at MTD, available pharmacodynamic data (PARP 
trapping) will also be considered in the choice of RP2D, as will any significant indications of 
differences in clinical efficacy. 
 
 
13.3 
Expansion cohort at RP2D 
 
Testing of decitabine combined with talazoparib at the RP2D will be conducted with Overall 
Complete Remission (OCR) as the primary endpoint in an expansion cohort with the aims of 
expanding the safety data and looking for signs of activity in the DNMTi-naïve population. If at 
least three of 17 DNMTi-naïve patients respond to treatment, we will proceed with the Phase 2 
trial. 
 
13.4 
Phase 2  
 
Trial A will enroll adult participants with AML who are deemed unfit for standard cytotoxic 
chemotherapy;  
 
Trial B will enroll adult participants with relapsed or refractory AML;  
 
The phase II component of the trial will use Simon’s optimal two-stage design (44) with a 1-sided 
=0.05 and power (1-) of 80%. This design specifies two target response probabilities: p0 is the 
OCR corresponding to the null hypothesis that the combination of the two drugs is not more active 
than decitabine alone; p1 is the OCR considered “promising” for further development of the 
combination in a future trial.  
 
Staggered entry of participants will be allowed due to the relatively long delay between enrolling 
a participant and verification of an OCR and the expected relatively high accrual rate from the 


 
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multi-centric collaborative network. A maximum of 12 participants will be allowed to be enrolled in 
each trial in addition to the number required in the first stage of the trial before making the call 
regarding possible closure of the trial due to futility. Staggered entry is considered acceptable as 
decitabine is an active standard therapy in the studied indications and there is no mechanistic 
reason to expect an antagonistic interaction from adding talazoparib. 
 
13.3.1 
Trial A (unfit for chemotherapy, azacitidine-, decitabine- and guadecitabine-
naïve) 
 
We select a p0=25% response rate as the null hypothesis for the OCR after treatment with the 
combination of decitabine and talazoparib. For p1 we choose 40%. 
 
The null hypothesis, that the true OCR is 25%, will be tested against the 1-sided alternative 
hypothesis. In the first of the two stages of the trial, 25 participants will be enrolled. If 6 or fewer 
responses are achieved in these 25 participants, the study will be stopped early for futility. 
Otherwise, an additional 38 participants will be enrolled. The null hypothesis will be rejected if 22 
participants or more achieve a response out of the total 63 participants enrolled. This design yields 
a type I error rate () of 0.047 and a power of 80.0% when the true response probability is 40%. 
 
13.3.2 
Trial B (relapsed or refractory, azacitidine-, decitabine- and guadecitabine-naïve) 
 
The null hypothesis, that the true response probability is p0=10%, will be tested against the 1-
sided alternative hypothesis, p1=25%. In the first stage of the phase II trial, 22 participants will be 
enrolled. If 2 or fewer responses are achieved in these 22 participants, the study will be stopped 
early for futility. Otherwise, an additional 18 participants will be enrolled. The null hypothesis will 
be rejected if 8 or more participants achieve a response out of the total 40 participants enrolled. 
This design yields a type I error rate () of 0.040 and a power of 80.03% when the true response 
probability is 25%.  
 
A minimum of 25 participants and a maximum of 63 participants will be enrolled in Trial A 
of Phase II. A minimum of 22 participants and a maximum of 40 participants will be enrolled 
in Trial B of Phase II.  
 
In Phase II of this study a total minimum of 44 participants and a total maximum of 103 
participants will be enrolled.  
 
 
13.4 
Stratification Factors 
 
There is no stratification in phase I of this trial. Stratification in phase II is based on disease 
status and prior treatment and is effectuated by allocation to one of trials A or B that will be run 
in parallel and each will be analyzed and reported separately. 
 
 
13.5 
Analysis of Secondary Endpoints 
 
In Phase I, we will tabulate the incidence of OCR as a function of dose level. These data will be 
subject to a binary logistic regression model to test for a trend in OCR as a function of the dose 
of each of the two agents.  
 
A more detailed characterization of the safety profile of the drug combination delivered at the 


 
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RP2D will be reported from the phase II population. The distribution of the grade of toxicity 
according to the CTCAE ver. 4.0 as well as the incidence of high grade toxicities with exact 95% 
CIs will be reported. In case of transient toxicities, the Kaplan-Meier estimate of the time to 
resolution will be presented. 
 
 
13.6 
Biomarkers and Pharmacodynamic Markers 
 
An exploratory, hypothesis-generating analysis of heterogeneity of treatment effects in will be 
conducted using binary logistic regression with OCR as the dependent variable. Participant-
related factors as well as pharmacodynamic and biomarker data will be tested as explanatory 
variables. The results of this analysis will be reported in addition to the main trial outcomes. 
Potential covariates to be tested include karyotype, FLT3 and NPM1 mutations, mutations in 
genes regulating methylation including DNMT3A, TET2, IDH1, IDH2 and EZH2, as well as PARP 
expression levels and participant and treatment characteristics. In addition, ordinal logistic 
regression will be conducted with the actual response level as the dependent variable and 
pharmacodynamic and biomarker data as explanatory variables, as above. 
 
 
13.7 
Reporting and Exclusions 
 
All participants who received at least one treatment cycle will be included in the intention-to-treat 
(ITT) population and this population will be the basis for the primary analysis and reporting of 
efficacy and toxicity outcomes in the three parallel phase II trials. For each trial, the proportion of 
participants who achieved OCR with exact 95% CIs will be reported as will the distributions of 
relapse-free survival, overall survival, and 100 day mortality using Kaplan-Meier estimates.  
 
 


 
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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 – AML SAMPLE PROCUREMENT 
 
PURPOSE 
 
This procurement procedure describes the processes for collecting and shipping samples for the 
Van Andel Research Institute-Stand Up 2 Cancer (VARI-SU2C) Epigenetics Dream Team Project 
entitled, Multicenter Phase 1/2 Study of Combination Therapy with the DNA Methyltransferase 
Inhibitor Decitabine and the Poly ADP Ribose Polymerase (PARP) Inhibitor Talazoparib (BMN 
673) for Acute Myeloid Leukemia (AML) in Adult Patients with Relapsed/Refractory Disease 
(Short name: AML Project).This includes collection supplies and kits, collection forms, consent, 
collection guidelines and shipping instructions. 
 
 
SAFETY 
All study personnel involved in this procedure are required to follow their institutional safety 
procedures, including, but not limited to, appropriate personal protective equipment such as 
gloves, lab coats and protective glasses. Treat all tissue and blood products as potentially 
infectious and dispose of them according to site institutional procedures and protocols. 
SUPPLIES 
• 
EDTA Tubes (Preferred: BD Vacutainer® 6.0 mL lavender-top EDTA Blood Collection 
tubes, supplied by clinical site) 
• 
Sodium Heparin collection tubes (Preferred: BD vacutainer ® 6.0 mL green-top tubes, 
supplied by clinical site) 
• 
Buccal swab kit (supplied by VARI) 
• 
Specimen shipping kit (supplied by VARI) 
 
 
PROCEDURE 
1. 
Collection Supplies 
1.1. 
VARI will supply each collection site with a stock of buccal swab kits and blank sample 
labels to be affixed to each sample.  
1.2. 
The clinical site will supply EDTA (lavender-top) and Sodium Heparin (green-top) 
collection tubes. 
1.3. 
VARI will provide each site with kits to return the samples to VARI.  These kits will 
contain, at minimum, the following: 
1.3.1. Insulated shipper 
1.3.2. 2 cold packs 
a. Remove both cold packs and freeze at -20C for at least 2 hours.  Cold packs should 
remain frozen until shipment. 
 
1.3.3. Pre-printed return label (Fed-Ex) 
 


 
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2. 
Data Collection Form 
2.1. 
All tissue collected must be accompanied by a completed VARI-SU2C Data Collection 
Form. The Data Collection Form must be completed prior to shipment of samples.  
2.2. 
The Data Collection Form is specific to a Participant collection event.  The following 
fields should be completed: 
2.2.1. De-Identified Study Participant ID: This is a de-identified study participant identifier 
maintained only by the clinical site performing the collection. This identifier must be 
linked to the medical record number of the study participant. 
a. This number must be assigned with each collection and must be compared to the 
master list to ensure all participants only receive one de-identified participant ID. 
 
2.2.2. Collection Date: The date the tissue was collected and prepared. 
2.2.3. Collection Time: The time of both blood and bone marrow collection. 
2.2.4. Timepoint: The collection event timepoint. This will be protocol specific, such as Pre-
treatment, cycle 1, Day 8, etc. 
2.2.5. Form Completed By: The person filling out the data collection form. 
2.2.6. Age: The age of the participant at time of tissue/blood collection 
2.2.7. Sex: The sex of the participant. 
2.2.8. Race/Ethnicity: The race and/or ethnicity of the participant recorded in collection 
(clinical) site’s electronic medical record. 
2.2.9. Number of EDTA (blood) tubes submitted. 
2.2.10. Number of Sodium Heparin (bone marrow) tubes submitted. 
2.2.11. Check whether the bone marrow is in good condition and not clotted. 
2.2.12. Circle the aspirate number of the bone marrow submitted. 
2.2.13. Circle yes or no to indicate whether the bone marrow was collected in a heparin 
containing syringe. 
2.2.14. Person responsible for sample shipment. 
2.2.15. Person completing the form. 
2.2.16. Any additional comments or notes important to the collection/shipping event. 
 
 


 
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3. 
Participant Consent 
3.1. 
All participants must consent for any donation prior to any specimen collection.  Please 
refer to the collection site’s Trial Study consent protocols for all consent procedures.  
 
4. 
Blood/Bone Marrow/Saliva Procurement Guidelines 
4.1. 
Peripheral Blood Collection 
4.1.1. See Section 9 of this protocol for blood collection timepoints. 
4.1.2. Collect 10mL of blood in two 6mL lavender-top, K2-EDTA vacutainers. If 6mL lavender 
K2-EDTA tubes are not available, collect 10mL of peripheral blood in available size 
lavender-top, K2-EDTA tubes. 
a. Draw peripheral blood according to collection site’s institutional venipuncture 
protocols. 
4.1.3. Collect 20mL of blood in four 6mL green-top, sodium heparin (NaHep) vacutainers. If 
6mL NaHep tubes are not available, collect 20mL of peripheral blood in available size green-top 
(NaHep) tubes. 
4.1.4. Invert each vacutainer (green and lavender) 8-10 times to ensure sufficient mixing. 
4.1.5. Label each tube with the De-identified Participant Study ID, participant initials, date (of 
collection), timepoint (cycle/day) and sample type (PB). 
4.1.6. Keep samples at room temperature. 
4.1.7. Process samples within one hour of collection. 
 
4.2. 
Bone Marrow Collection 
4.2.1. See Biomarker and Correlative Studies protocol section for bone marrow collection 
timepoints. 
4.2.2. Collect 10mL of bone marrow in two 6mL green-top, Sodium Heparin (NaHep) 
vacutainers. If 6mL NaHep tubes are not available, collect 10mL of bone marrow in 
available green-top, NaHep tubes. 
a. Draw bone marrow according to collection site’s institutional bone marrow aspiration 
protocols. 
4.2.3. Invert each vacutainer 8-10 times to ensure sufficient mixing. 
4.2.4. Label each tube with the De-Identified Study Participant ID, participant initials, date (of 
collection), timepoint (cycle/day) and sample type (BM). 


 
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4.2.5. Keep samples at room temperature. 
4.2.6. Process samples within one hour of collection. 
 
4.3. 
Saliva Collection 
4.3.1. Utilizing the Isohelix Buccal Swab kit, open the package from one end. 
4.3.2. Remove the swab from the tube. 
4.3.3. Insert the swab into the Participant’s mouth and rub firmly against the inside of the cheek 
or underneath the lower or upper lip. Rub for 1 minute. Use reasonable, firm and solid 
pressure. 
4.3.4. Place the swab back into the tube. Do not touch the brush with your fingers. 
4.3.5. Place thumbnail in the small groove set in the handle, then snap the handle in two by 
bending to one side. Let the swab head fall into the tube. 
4.3.6. Seal the tube securely with one of the caps.  
4.3.7.   Label each tube with the De-identified Participant Study ID, participant initials, date (of 
collection), timepoint (cycle/day) and sample type (swab). 
 
5. Blood/Bone Marrow/Saliva Shipment 
5.1. 
Ship all samples on the same day as collection. 
 
5.2. 
Confirm Data Collection Form is completed. 
 
5.3. 
Make a copy of the Data Collection Form and retain for your institution’s study records. 
 
5.4. 
Pack the shipping container: 
 
5.4.1. Place all collection vacutainer tubes in the small, inner box. Remove and dismantle the 
styrofoam insert for tube placement. Each side of the styrofoam compartment in the 
smaller inner box holds 4 tubes. 
 
a. Place the peripheral blood vacutainers in the 4 grooves in one side (ensure that the 
blood tubes have been properly mixed, 5-10 times, top to bottom, prior to shipment). 
 
b. Place the bone marrow vacutainers in 2 grooves in the opposite side(ensure that the 
bone marrow tubes have been properly mixed, 5-10 times, top to bottom, prior to 
shipment). 
 
c. Place the buccal swab tube into a groove on the same side and the bone marrow 
vacucatiners. 


 
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5.4.2. Place the fully assembled styrofoam insert into the provided Biohazard Ziploc bag with 
absorbent paper and seal the Ziploc bag. 
 
5.4.3. Place the Ziploc bag with the Styrofoam insert inside the small cardboard box and close 
the box. 
 
5.4.4. Place the small box inside the larger plastic ziplock bag then place it in the large, outer 
insulated shipper. 
 
5.4.5. Retrieve the 2 frozen cold packs, ensure they are completely frozen, and place them on 
either side of the small, inner box. 
 
5.4.6. Place the Styrofoam lid on the insulated shipper and place the completed Data 
Collection Form on top of the lid. 
 
5.4.7. Close the cardboard flaps and seal the package. Be sure to remove the pre-printed 
FedEx air bill from the outer insulated shipper prior to sealing the package. 
 
5.5. 
Peel off the yellow removable label covering the UN3373 sticker on the outside of the 
insulated shipper. 
 
5.6. 
Once shipments are scheduled, send an email to pbs.lab@vai.org to notify VARI of 
incoming shipment. Please include the following information: 
 
5.6.1. Subject line: “VARI-SU2C AML Project shipment from (collection site)” 
 
5.6.2. Email body: 
Ship date 
FedEx tracking number (found on pre-printed air bill) 
Collection site name and De-Identified Study Participant ID 
 
5.6.3. Schedule each shipment with FedEx (1-800-463-3339) using local pick-up/drop-off 
locations. 
 
a. If FedEx is unable to pick up the sample due to a late collection, refrigerate the 
samples until the next available FedEx pickup time. 
 
For any additional questions or to request collection kits, contact VARI at 616-234-5122 or 
pbs.lab@vai.org. 
 
 


 
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APPENDIX C – PARTICIPANT DIARY FOR TALAZOPARIB 
 
Note: Talazoparib should be taken at a consistent time every day. Please complete this 
diary each day after you take your dose of Talazoparib. 
 
Day of Study 
Date 
Dose taken 
Time taken 
If not taken, reason 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
Please remember to return this form and any unused Talazoparib to the study staff. Thanks! 
 
To be Completed by Staff: 
Received on ___________  by ______________________________ 


 
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APPENDIX D – LAB ANALYSIS PRIORITY DIAGRAM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20mL PBL drawn 
Isolate MNCs 
Viably freeze 
one vial of 5 
million for 
colony 
formation 
Flash freeze two 
microfuge tubes of 15 
million each for PARP-
trapping (30 million 
total) 
Flash freeze two 
microfuge tubes of 5 
million each for 
Western blotting (10 
million total) 
Flash freeze two vials of 
5 million each for RT-
PCR (10 million) 
Flash freeze two 
vials of 15 million 
each for DSB repair 
assay (30 million 
total) 
Viably 
freeze 
remaining 
cells (if any) 
Prioritization  
Highest  
Lowest 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
Viably freeze 1 vial of 5 
million for 
immunofluorescence 
(7) 


 
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INVESTIGATOR AGREEMENT 
 
University of Maryland Local Protocol #: 1565GCC 
 
ClinicalTrials.gov Identifier: NCT02878785 
 
Title: Multicenter phase 1/2 study of combination therapy with the DNA methyltransferase 
inhibitor decitabine and the poly ADP ribose polymerase (PARP) inhibitor talazoparib (BMN 673) 
for untreated acute myeloid leukemia (AML) in adult patients unfit for cytotoxic chemotherapy or 
relapsed/refractory AML 
 
 
 
 
I have read this protocol in its entirety and agree that it contains all necessary details for 
carrying out the study. I will conduct this study as outlined and within the time periods 
designated. I understand that the study may be terminated or enrollment suspended at any time 
by the sponsor, with or without cause, or by me if it becomes necessary to protect the best 
interests of the study participants. I confirm that I will conduct this study in accordance with the 
protocol as written, and in accordance with ICH GCP guidelines, the ethical principles of the 
Declaration of Helsinki, and applicable local regulations.  
 
I will provide copies of the protocol and all study related information to all responsible individuals 
who assist me in the conduct of this study. I will discuss this material with them to ensure they 
are fully informed of the conduct of the study, the study drug, and the obligations of 
confidentiality.  
 
 
 
 
Principal (Site) Investigator:  
 
Name (printed or typed): ________________________________________________________ 
 
Institution and Address: 
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________ 
 
Telephone Number: ____________________________________________________________ 
 
 
Signature: ______________________________________________    Date: _______________ 
 
 

ICF_001.pdf: 
1 
 
 
 
 
 
 
RESEARCH CONSENT FORM 
 
Protocol Title: 1565GCC: Multicenter phase 1/2 study of combination therapy with the 
DNA methyltransferase inhibitor decitabine and the poly ADP ribose polymerase 
(PARP) inhibitor talazoparib (BMN 673) for untreated acute myeloid leukemia (AML) in 
adult patients unfit for cytotoxic chemotherapy or relapsed/refractory AML                           
 
Study No.: HP-00066370                                    Version: 3.1, Protocol v. 5; 17Apr2018 
 
Principal Investigator: Maria Baer, M.D.                           Phone #: (410) 328-8708  
 
Sponsor: Dr. Maria Baer, University of Maryland, Baltimore 
 
Participant Name: ____________________________       MR#___________________ 
 
 
You are being invited to take part in this research study (or “study”, for short) because 
you have acute myeloid leukemia (AML) that:  
• did not respond to treatment (“refractory”), or  
• responded to treatment but needs treatment again now (“relapsed”), or  
• has not been treated yet, and your doctor thinks that you cannot be safely treated 
with standard chemotherapy or that your leukemia is not likely to respond to 
standard chemotherapy. 
 
Please take your time to make your decision. It is important that you read and 
understand several general facts about research studies: 
 
(a) 
Taking part in a research study is voluntary.    
 
(b) 
You may or may not be helped by taking part in a research study, but knowledge 
gained from your taking part in the research study may help others;  
 
(c) 
You may decide not to take part in a research study or, if you take part in a research 
study, you may decide to stop taking part at any time. If you decide not to take part in a 
research study or to stop taking part, this will not affect your medical care by your 
doctor and your healthcare team.   
 
The purpose and nature of the study, possible benefits, risks and discomforts, other 
options, your rights as a participant, and other information about the study are 
discussed below. You are urged to discuss any questions that you have about this study 
with members of the study team. Take as much time as you need to discuss the study 
with your health care providers and with your family and friends. The decision to take 
part or not is yours.  
 


2 
 
 
If you decide to join the study, you will sign and date where indicated at the end of this 
form.   
 
If you choose not to take part in this study, your healthcare at the University of 
Maryland, Baltimore will not be affected. 
 
This research study is being funded by the Van Andel Research Institute-Stand Up To 
Cancer (VARI-SU2C) Epigenetics Dream Team. The study drug for this study is being 
provided by a pharmaceutical company called Pfizer, Inc.  
 
PURPOSE OF STUDY 
The purpose of this study is to find the best way to combine a new chemotherapy drug 
with one that is already in use to treat AML. The new experimental drug is called 
talazoparib (also known as BMN-673), and it is not approved by the Federal Drug 
Administration (FDA). The FDA is allowing the use of talazoparib for the purposes of 
this study.  
Decitabine (also known as Dacogen), is being used off-label in this study. Off-label 
means that it has not been approved for AML by the FDA, but a doctor may still 
prescribe it if they believe it might help you. Decitabine is approved for older patients 
with AML in Europe. We want to find out the best dose of each drug to use when we 
treat patients with both drugs together. 
Decitabine is given by injection into an intravenous (IV) line over one hour every day for 
five days. This treatment is repeated every 28 days. 
Decitabine is a member of a class of drugs called DNA methyltransferase inhibitors. 
They are also sometimes called demethylating agents or hypomethylating agents. DNA 
methyltransferase inhibitors change expression of genes inside leukemia cells. 
Changing expression of the genes inside leukemia cells stops growth of leukemia cells. 
Decitabine is used to treat bone marrow diseases called myelodysplastic syndromes 
(MDS), as well as off label for AML.   
Talazoparib is a pill that will be taken every day.  
Talazoparib is a member of a class of drugs called poly ADP ribose polymerase 
inhibitors, or PARP inhibitors. PARP inhibitors stop cells from repairing damage to DNA 
caused by chemotherapy drugs, including DNA methyltransferase inhibitors. Lab work  
suggests that talazoparib will increase the effects of decitabine in leukemia cells.  
We hope that treating patients with decitabine and talazoparib together will be more 
successful that treating patients with decitabine alone.  
This study has two parts. The purpose of Part 1 is to find out the best doses of 
decitabine and talazoparib to use when they are given together to treat AML. Part 1 has 
7 cohorts (groups). You will be told which cohort you will be assigned to if you join the 
study in Part 1. Also, in Part 1 we will study the effects of the drugs on leukemia cells 
obtained from blood samples before dosing and on Days 5 and 8. The purpose of part 
two is to see how well the drugs work together to treat AML. In Part 2 will study the 
effects of the drugs on leukemia cells obtained from blood samples before dosing and 
on Days 1, 5, 8, and 10 (Day 10 only if it is decided for Part 2).  
Everyone in the study will be treated with decitabine and talazoparib.  


3 
 
 
Part one of the study will include as few as two people and as many as 36 people to find 
the best dose levels of the study drugs. Part One will begin enrolling first. Part Two of 
the study will not start until the Part One of the study is complete. You will be told which 
part of the study you may be enrolled in. Part Two of the study may include as few as 
79 people and as many as 135 people. Part Two includes two separate arms. If you are 
enrolled in Part Two of the study, you will be assigned to one of the two arms below in 
order to test the success rate of the study drug dose and frequency found in Part One: 
 
• Arm A will enroll adult patients with AML who are thought not to be likely to 
tolerate or respond to standard chemotherapy;  
• Arm B will enroll adult patients with AML that has not responded to previous 
treatment or has come back after responding to previous treatment;  
 
This is a multi-center study. Up to 171 people may take part in this study globally. As 
many as 36 people may take part in Part One locally. As many as 60 people may take 
part in this study in Part Two locally. 
 
PROCEDURES 
 
Screening  
In order to make sure that you are eligible to take part in this study, the following 
procedures and tests will be done: 
• Review of your medical history 
• Physical exam, including vital signs, height and weight  
• Bloodwork, including blood counts, chemistries and clotting tests (about 2 
teaspoons) 
• Electrocardiogram (EKG) and/or echocardiogram to measure the electrical 
activity of your heart (only if your doctor thinks it is needed for safety) 
• A blood test to check for pregnancy, if you are a woman who can become 
pregnant (less than 1 teaspoon) 
• Bone marrow aspirate and biopsy, including testing for chromosome changes 
and for gene changes frequently found in AML 
• A swab of the inside your cheek to obtain cells to compare with your bone 
marrow cells  
Treatment 
If you are found to be able to enroll on the study after completing your screening tests, 
you will start taking the study drugs within one week. You will be assigned to a dose 
level of decitabine and of talazoparib. You will then begin dosing as described below.  
 
This study is done in repeated cycles that are 28 days long. You will be given decitabine 
as an injection in a vein (IV) over one hour every day for five days, repeated every cycle 
if you are in cohorts 1-6 of Part 1. You will be given decitabine as an injection in a vein 
(IV) over one hour every day for ten days, repeated every cycle, if you are in cohort 7 of 
Part 1. You will be given decitabine as an injection in a vein (IV) over one hour every 
day for five or ten days (depending on the results of Part 1), repeated every cycle, if you 
are in Part 2. You will take talazoparib as a pill by mouth at the same time on every day 


4 
 
 
of every cycle. Missed morning doses may be taken later in the day. If a full day is 
missed, do not double up the next day. 
 
The first cycle will start when you take your first doses of study drugs (Cycle 1 Day 1). 
Cycles may need to be delayed in order to allow your blood counts to recover or to 
allow side effects to get better. If you have low blood counts or other side effects, your 
doses of decitabine and talazoparib may be lowered in the next cycles. 
In order to monitor your safety during dosing and your response to the drugs, the 
procedures listed below will be done: 
 
Time Point 
What will be Done 
Cycle 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• You will receive IV decitabine every day for five days (or 
10 days if you are assigned to cohort 7 Part 1 or if it is 
decided for Part 2).  
• You will swallow a talazoparib pill every day at the same 
time for 28 days. 
• A study drug diary will be given to you on Day 1. You 
will use this to record when you take talazoparib.  
• Weekly medical history review 
• Weekly physical exam, including weight and vital signs 
• Weekly blood draws to check your health (about 2 
teaspoons) 
• Two tablespoons of blood will be drawn at the following 
time points to answer study questions:  
o Day 1 before dosing,  
o Day 5, one hour after IV decitabine, and  
o Day 8 
o Day 10 (for participants on the 10-day decitabine 
regimen only) 
• Two teaspoons of blood will be drawn at the following 
time point to answer study questions:  
o Day 29  
• 
Bone marrow aspirate and biopsy may be done around 
Day 29 if needed to assess your disease  
Cycle 2 
• You will receive IV decitabine every day for five days (or 10 
days if you are assigned to cohort 7 Part 1 or if it is decided 
for Part 2). 
• You will swallow a talazoparib pill every day at the same 
time for 28 days. 
• A new study drug diary will be given to you on Day 1 to 
record when you take talazoparib.  
• Medical history review at least every two weeks 
• Physical exam, including weight and vital signs, at least 
every two weeks. 
• Blood draw to check your health (about 2 teaspoons) at 
least every two weeks. 


5 
 
 
• Two teaspoons of blood will be drawn at the following time 
point to answer study questions:  
o Day 29 
• Bone marrow aspirate and biopsy may be done around Day 
29 if needed to assess your disease. 
Subsequent Cycles 
• You will receive IV decitabine every day for five days (or 10 
days if you are assigned to cohort 7 Part 1 or if it is decided 
for Part 2).  
• You will swallow a talazoparib pill every day at the same 
time for 28 days. 
• A new study drug diary will be given to you on Day 1.  
• Medical history review on Day 1. 
• Physical exam, including weight and vital signs on Day 1. 
• Blood draw to check your health (about 2 teaspoons) on 
Day 1. 
• Two teaspoons of blood will be drawn for research at the 
following time point  to answer study questions:  
o Day 29 
• Bone marrow aspirate and biopsy may be done around Day 
29 if needed to assess your disease 
End of Study 
• Medical history review 
• Physical exam 
• Blood draw to check your health (about 2 teaspoons)  
• You will return any unused study drug and empty bottles.  
• Your study drug diary will be collected.  
Follow up 
• You will be seen or contacted by phone or email at least 
every 6 months after you are off study for the rest of your 
life. Remember taking part in this study is research and you 
may withdraw at any time should you choose. Details about 
withdrawing from the study are listed later on in this 
document.  
 
About 3 cups of blood may be taken from you in total during your first year on the study. Talk 
to your study doctor if you have any questions or concerns about the amount of blood being 
drawn in this study. 
Tell the study doctor or staff about any medicines you are taking.  This includes any over-
the-counter drugs or herbal supplements which you bought from a store.  
You may keep taking the study drugs until your study doctor determines that you should 
stop, due to side effects, progression of disease, or if you decide to stop taking part in the 
study. 
 
Future Lab Studies 
A portion of your bone marrow and blood samples will be stored frozen in a tissue bank. 
These samples will be used by the VARI-SU2C Epigenetics Dream Team for future 
leukemia research. Your samples will be stored for an unlimited time.  


6 
 
 
The use of your samples for future research will be based on whether your sample and 
data meet the scientific needs of the project. Future research may look at your genes, 
which are the units of inheritance that are passed down from generation to generation. 
Genes are responsible for many things about you such as eye color, hair color, blood 
type and hundreds of other traits.  Future genetic testing may possibly include finding 
out the details of how your DNA is put together, or association studies that look at 
genes other than those connected to a specific disease. The gene materials may 
someday be injected into animals for research. We may share your samples and data 
with scientists at other institutions or research organizations.  
Your samples may be used to make cell lines. Making cell lines is the process of using 
a single cell to make a lot of cells that all contain the same genes. It is possible that your 
tissue sample may be used to make a cell line that could be patented and licensed, or 
lead to new commercial products. If this happens, there is no plan to share any financial 
gain with you.  
Using your samples for research is unlikely to help you. The research results may help 
people in the future. We hope that what we learn in future research studies will increase 
our knowledge of human health and that this information may lead to better prevention, 
diagnoses and treatments in the future. 
You will not receive any payments for donating your samples and data into the research 
data bank.   
Your samples will be stored in the data bank without any identifiers, but can be linked to 
your clinical data on the clinical trial.  
Your research results will not be shared with you or with your health care provider.  
You will not be contacted after the research study is over.  
You can decide to change your mind later and withdraw your consent. To do so, please 
call Dr. Maria Baer at (410)-328-8708, or send your decision to withdraw in writing to:  
Dr. Maria Baer  
UMGCCC 
 22 South Greene Street S9D  
Baltimore, Maryland 21201 
 
If you would like your samples to be destroyed as well, you will need to specify as such 
in writing using the address listed above. Any data obtained before you withdraw your 
consent will still be used.  
 
These procedures are being done for the research and will be paid for by the sponsor: 
·        Pregnancy testing 
 
WHAT ARE MY RESPONSIBILITIES IF I TAKE PART IN THIS RESEARCH? 
If you take part in this study, you must be responsible to: 
• Make sure that you understand all information contained in this informed consent 
document.   
• Make sure that your questions and concerns are answered by the study doctor 
and/or the study staff 


7 
 
 
• Come to your doctor’s office or to the Infusion Center for all required study visits, 
and other visits requested by the study staff.  
• Follow all instructions provided by the study doctor and study staff. 
• Tell the study staff right away if you have any new side effects or your side 
effects get worse. 
• Not start taking any new medications, including non-prescribed medicines, 
unless you have permission from your study doctor.  
• Tell the study doctor and/or the study staff about any other medicines or 
supplements that you have taken (including vitamins, herbal or alternative 
remedies, or medicines that you buy over the counter).  
 
POTENTIAL RISKS/DISCOMFORTS 
Possible side effects of decitabine and of talazoparib in previous research studies are 
listed below.  
 
Possible side effects of decitabine in previous research studies: 
The following adverse events (side effects) were seen in earlier studies of decitabine 
and are categorized as Very Common (seen in 10% of patients or more) or Common 
(seen in between 1% and 10% of patients). Some of these affects may not have been 
due to decitabine: 
 
Blood and lymphatic system 
Very Common  
• Low blood iron (anemia)  
• Fever due to blood issues (febrile neutropenia) 
• Low counts of white blood cells called neutrophils (neutropenia)  
• Low blood platelets which can cause bleeding, bruising, and slow blood clotting 
(thrombocytopenia)  
 
Common  
• Low white blood cells (leukopenia) 
• Low blood components (pancytopenia)  
• Over production of blood platelets (thrombocythemia)  
• Blood bilirubin increase  
 
Heart 
Common 
• Chronic issues with pumping blood (congestive heart failure)  
• Abnormally fast heart rate (tachycardia)  
 
Ear  
Common  
• Ear pain 
 
Digestive tract (Gastrointestinal) 
Very Common 
• Abdominal pain   
• Constipation   


8 
 
 
• Diarrhea   
• Nausea   
• Indigestion (dyspepsia)   
• Swelling and sores in the mouth (stomatitis)   
• Vomiting   
 
Common 
• Upper abdominal pain   
• Difficulty swallowing (dysphagia)   
• Acid reflux (gastro-esophageal reflux disease)   
• Oral pain   
• Toothache   
 
General and injection site 
Very Common 
• Physical weakness and low energy (asthenia)   
• Chills   
• Tiredness (fatigue)   
• Fluid buildup and swelling in limbs (peripheral edema)   
• Fever (pyrexia)   
 
Common 
• Chest pain   
• Pain   
• Swelling and inflammation of the mucus membranes (mucosal inflammation)   
• Fluid buildup and swelling (edema)   
 
Infections and infestations 
Very Common 
• Pneumonia   
• Upper respiratory tract infection   
 
Common 
• Bacterial skin infection (cellulitis)  
• Fungal infection in the mouth (oral candidiasis)   
• Sinus infection (sinusitis)   
• Staph infection in the blood (staphylococcal bacteremia)   
• Tooth abscess   
• Urinary tract infection   
 
Injury, poisoning and procedural complications 
Common 
• Bruising (contusion)  
 
Metabolism and nutrition 
Very Common 
• Low weight eating disorder (anorexia)   


9 
 
 
• Low blood potassium (hypokalemia)   
 
Common 
• Decreased appetite   
• Dehydration   
• High blood sugar (hyperglycemia)   
• Low blood magnesium (hypomagnesemia)   
 
Musculoskeletal and connective tissue 
Very Common 
• Joint pain (arthralgia)   
• Back pain   
• Pain in extremity   
 
Common 
• Bone pain   
• Muscle spasms   
• Muscular weakness   
• Musculoskeletal pain   
• Muscle pain (myalgia)   
 
Nervous system  
Very Common 
• Dizziness   
• Headache   
 
Psychiatric 
Very Common 
• Difficulty sleeping (insomnia)   
 
Common 
• Anxiety   
• Confused state   
• Depression   
 
Respiratory and chest area  
Very Common 
• Cough  
• Difficulty breathing (dyspnea)   
• Nose bleed (epistaxis)   
 
Common 
• Pain in the throat area (pharyngolaryngeal pain)   
• Fluid buildup in chest tissues (pleural effusion)   
• Sinus congestion   
• Abnormal breathing sounds 
 


10 
 
 
Skin  
Very Common 
• Blood spots on the skin (petechiae)   
• Rash   
 
Common 
• Dry skin   
• Skin discoloration (ecchymosis)   
• Red rash (erythema)  
• Night sweats   
• Itchy skin (pruritus)   
• Skin lesion   
 
Vascular 
Very Common 
• Low blood pressure (hypotension)   
 
Common 
• High blood pressure (hypertension)  
 
The most common severe adverse events seen in previous studies were low blood 
neutrophils (neutropenia), low blood platelets (thrombocytopenia) and low blood iron 
(anemia). Blood toxicities and infections frequently caused drug dosing to be delayed 
and stopped. Eight patients died due to infection and/or bleeding that were considered 
at least possibly related to the drug. You will be watched very closely for blood based 
toxicities and infections so that you may be treated appropriately. 
 
Possible side effects of talazoparib (commonly seen in previous studies): 
• 
Low blood counts, including low platelet count (thrombocytopenia), low red blood 
cell count, low neutrophil counts (neutropenia), and low white blood cell count 
• 
Anemia (low red blood cells) 
• 
Fatigue (tiredness)  
• 
Vomiting and nausea 
• 
Low white blood cell count and infection 
• 
Headache 
• 
Hair loss (alopecia) 
• 
Decreased appetite 
• 
Diarrhea 
• 
Abnormal/fast heart rhythm 
• 
Blood lab abnormalities (low blood components such as hemoglobin, platelets, 
neutrophils, lymphocytes, leukocytes, and calcium, and /or increase in blood 
components such as glucose, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and alkaline phosphatase. Please talk to the study 
doctor for more information regarding what these abnormalities could mean for 
you. You will be monitored throughout the study for safety. 
 
If you are a woman who is able to become pregnant or a man who is able to father 
a child, there is a risk to your unborn children if you take part in this study. 


11 
 
 
 
For Women: 
If you are a woman who is able to become pregnant, you will have a pregnancy test 
before beginning any study drug. You should use at least one effective birth control 
method (two are preferable when possible) if you are having sexual intercourse. 
If you are pregnant, you cannot join this study because there may be risks to you and 
your unborn baby. Breastfeeding (nursing) mothers cannot join this study since it is not 
known whether the drugs in this study will be passed on to the baby in the mother’s 
milk. 
Tell one of the study doctors right away if: 
• You are pregnant; 
• You get pregnant; or 
• You are breastfeeding. 
 
For Men: 
If your partner becomes pregnant, there could be harm to the unborn baby. You and 
your partner should use at least one effective birth control method (two are preferable 
when possible) if you are having sexual intercourse with a woman of childbearing 
potential. 
If you become pregnant or think that you are pregnant or if your partner becomes 
pregnant or thinks that she is pregnant during the study, you must tell the study doctor 
right away.  If you become pregnant, you will be taken off the study and will undergo the 
end of study procedures. If your partner becomes pregnant, you will remain on the 
study.  If either you or your partner becomes pregnant during the study, you and/or your 
partner will be followed until the end of the pregnancy. 
There may also be side effects, other than listed above that we cannot predict. Other drugs 
will be given to make side effects that occur less serious and less uncomfortable. Many side 
effects go away shortly after the drug or procedure is stopped, but in some cases, side 
effects can be serious, long-lasting, or permanent. 
 
Biopsies:  The removal of tumor tissue for research biopsies can cause pain, bruising 
and possibly infection at the biopsy site. Bleeding may also occur and in rare cases 
transfusions are needed to replace the blood lost. In very rare instances, such bleeding 
could require surgery or could even be fatal. The consent form provided by your study 
doctor for your biopsy will fully explain the risks of the procedure. 
 
Privacy Risks 
Since your personal health information will be used or disclosed to the sponsor, their 
representatives, and other authorized persons and entities, there is the risk of loss of 
confidentiality. Loss of confidentiality will be minimized by storing data in a secure 
location such as a locked office and locked cabinet. Electronic data will be password-
protected. Every effort will be made to protect your privacy.  
 
There may be risks in this study which are not yet known. 
 


12 
 
 
POTENTIAL BENEFITS 
You may or may not personally benefit by taking part in this study. There is no 
guarantee that you will receive direct benefit from your part in this study. We hope the 
information learned from this research study will benefit other patients with relapsed or 
refractory AML in the future. 
 
ALTERNATIVES TO PARTICIPATION 
The following other procedures or treatments are available if you choose not to take part 
in this study:  
• Getting treatment or care for your leukemia without being in a study. 
• Taking part in a different research study.  
• Getting supportive care, but no active treatment for your leukemia. Supportive care 
may include transfusions, antibiotics and medicine to lower your white blood cell 
count. Supportive care does not treat your leukemia, but tries to make you feel 
better; or  
• Getting no treatment for your leukemia. 
If you choose not to take part in this research study, your healthcare at the University of 
Maryland, Baltimore will not be affected. 
 
COSTS TO PARTICIPANTS 
In this study, there are tests and procedures you will have that are standard of care 
(SOC) for treating your disease. SOC tests and procedures would be done whether or 
not you take part in the study. These SOC tests and procedures will be billed to you 
and/or your insurance company. Certain tests and procedures (e.g., infusions, physical 
exams, imaging, some lab tests) that are routine costs for clinical trials will also be billed 
to your insurance.  
 
Your insurance company or government health care program may not want to pay for 
study related treatments and any problems that may come from the study. Before you 
decide to take part in this study, you may want to contact your insurance company so 
that you will know what is covered. Tests and procedures that are done only for the 
research study (not SOC or routine costs in clinical trials) will be paid for by the study 
sponsor. 
 
Once received, your study coordinator will provide you with a copy of your completed 
insurance pre-authorization form.  This document provides authorization details given to 
the University of Maryland Medical Center staff from your insurance carrier as to which 
study procedures your insurance carrier has agreed to cover 
 
PAYMENT TO PARTICIPANTS 
You will be given a parking voucher after completion of your research visits. You will not 
be paid to participate in the study 
 
CONFIDENTIALITY AND ACCESS TO RECORDS 
Efforts will be made to protect your medical records and other personal information to the 
extent allowed by law. However, we cannot guarantee absolute confidentiality. It is a 


13 
 
 
requirement that your involvement in this research study is noted in your medical records. 
Medical records of research study participants are stored and kept according to legal 
requirements. You will not be identified personally in any reports or publications resulting 
from this research study. Your personal information may be disclosed if required by law. 
Organizations that may request to inspect and/or copy your research or medical records for 
quality assurance and data analysis include groups such as: 
• Representatives of University of Maryland, Baltimore (UMB)  
• The Institutional Review Board (IRB) 
• The Office of Human Research Protection (OHRP) 
• Department of Health and Human Services and National Institutes of Health 
• The Food and Drug Administration (FDA) and/or their representatives  
• Pfizer, Inc and/or their representative(s).   
• VARI-SU2C Epigenetics Dream Team and/or their partner(s). 
• Any other individuals/organizations that analyze your health information in connection 
with this study as defined in the study protocol. 
By signing this consent form, you authorize access to this confidential information. You 
also authorize the release of your medical records to UMB by any other hospitals or 
institutions where you might receive medical care of any kind while you are participating 
in this research study.   
The confidentiality of your medical records will be maintained to the extent permitted by 
the applicable laws. If the results of the trial are published, your identity will remain 
confidential. 
If information about your part in this research study is stored in a computer, we will take 
precautions to protect it from unauthorized disclosure, tampering, or damage by 
requiring a unique ID and password to log into the database. In addition, only personnel 
who are associated with the research study will have access to the study-specific 
records in the database.   
Monitors, auditors, the IRB and the Food and Drug Administration will be granted direct 
access to your medical records for verification of the research procedures and date. By 
signing this document, you are authorizing this access. 
Data from this study will be shared with other scientists on the VARI-SU2C Epigenetics 
Dream team who are partnering in conducting this research. The data from the study 
may be published. However, you will not be identified by name. People designated from 
the institutions where the study is being conducted and people from the sponsor will be 
allowed to inspect sections of your medical and research records related to the study. 
Everyone using study information will work to keep your personal information 
confidential. Your personal information will not be given out unless required by law. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
RIGHT TO WITHDRAW 
Taking part in this study is voluntary. You do not have to take part in this research. You 
are free to withdraw your consent at any time. Refusal to take part or to stop taking part 


14 
 
 
in the study will involve no penalty or loss of benefits to which you are otherwise 
entitled. If you decide to stop taking part, or if you have questions, concerns, or 
complaints, or if you need to report a medical injury related to the research, please 
contact the investigator Dr. Maria Baer at (410)328-8708. Also, please send your 
request in writing to the investigator at the following address: 
 
Marlene and Stewart Greenebaum Cancer Center 
Clinical Research Office 
22 South Greene Street 
Baltimore, MD 21201-1595 
 
If you stop being in the study early, the study doctor or study staff may ask you some 
questions about being in the study.  Your decision to leave the study will have no effect 
on your future care by physicians or by this institution. Your decision to leave the study 
will have no adverse consequences (physical, social, economic, legal, or psychological) 
If you withdraw from this study, information that has already been collected may not be 
removed from the study database. You will be asked whether the study doctor can 
collect information from your routine medical care. If you agree, this information will be 
handled the same as research data.  
During the course of the study, any significant new findings that may affect your health, 
welfare, or willingness to stay in this study will be provided by your treating physician. In 
addition, if your treating physician believes that it is in your best interest for you to be 
withdrawn from this trial, she will do so right away, with or without your consent. 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing 
the data from this research throughout the study. We will tell you about the new 
information from this or other studies that may affect your health, welfare, or willingness 
to stay in this study. 
 
CAN I BE REMOVED FROM THE RESEARCH? 
The study doctors, physicians or sponsor may stop the study or remove you from the 
study without your consent at any time if: 
• they judge that it is in your best interest to do so  
• you experience an injury related to the study 
• you need additional or different medication  
• you do not comply with the study plan  
• for various other administrative and medical reasons 
 
UNIVERSITY STATEMENT CONCERNING RESEARCH RISKS  
The University of Maryland, Baltimore (UMB) is committed to providing participants in its 
research the rights due them under State and federal law. You give up none of your 
legal rights by signing this consent form or by participating in the research project. This 
research has been reviewed and approved by the Institutional Review Board (IRB). 
Please call the IRB if you have questions about your rights as a research subject. 
Participating in research may result in an injury, as explained above. If you suffer an 
injury directly related to your participation in this project, UMB and/or one of its affiliated 
institutions or health care groups will help you obtain medical treatment for the specific 
injury and provide referrals to other health care facilities, as appropriate. UMB and/or its 


15 
 
 
affiliated institutions or health care groups will not provide you with financial 
compensation or reimbursement for the cost of care provided to treat a research-related 
injury or for other expenses arising from a research-related injury. The institution or 
group providing medical treatment will charge your insurance carrier, you, or any other 
party responsible for your treatment costs. If you incur uninsured medical costs, they 
are your responsibility. The study staff can give you more information about this if you 
have a study injury. 
By signing this Consent Form, you are not giving up any legal rights. If this research 
project is conducted in a negligent manner and you are injured as a direct result, you 
may be able to recover the costs of care and other damages from the individuals or 
organizations responsible for your injury. 
If you have questions, concerns, complaints, or believe you have been harmed through 
participation in this research study as a result of researcher negligence, you can contact 
members of the IRB or the Human Research Protections Office (HRPO) to ask 
questions, discuss problems or concerns, obtain information, or offer input about your 
rights as a research participant. The contact information for the IRB and the HRPO is: 
University of Maryland Baltimore 
Human Research Protections Office  
620 W. Lexington Street, Second Floor  
Baltimore, MD 21201 
(410) 706-5037 
 
If you need help after hours, you may contact the Patient Assistance line at 
(410) 328-7609. Please reference the study doctor and study number on the first page 
of this consent form. 
 
Signing this consent form indicates that you have read this consent form and 
understand the information in this consent form, that your questions have been 
answered to your satisfaction, and that you voluntarily agree to take part in this study. 
You will receive a copy of this signed consent form. 
 
If you agree to take part in this study, please sign your name below. 
 
 
 
_______________________________ 
 
 
 
_________________________________ 
Patient’s Signature 
 
Signature of Investigator or Designee 
Obtaining Consent  
 
 
 
_______________________________ 
 
 
 
 
_________________________________ 
Patient’s Printed Name 
 
Printed Name of Investigator or Designee 
Obtaining Consent 
 
 
_______________________________ 
 
 
 
_________________________________ 


16 
 
 
Date 
 
Date