Conditions: Small Cell Lung Cancer Extensive-stage Small Cell Lung Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
This is a phase II, open-label, single arm, single-stage study. Both, chemo-sensitive and chemo-resistant patients will be enrolled and treated with 4 cycles of combination of Guadecitabine and carboplatin

Detailed description:

Arms:
arm 1: Each cycle = 28 days; Subjects receive 4 cycles

Interventions: intervention 1: Guadecitabine intervention 2: Carboplatin
Intervention descriptions: intervention 1: Guadecitabine 30 mg/m2 subcutaneously Days 1-5 intervention 2: Carboplatin AUC 4 IV Day 5

Protocol document:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
HCRN LUN17-302 
 
Protocol Title 
A Phase II Study Evaluating Efficacy and Safety of Hypomethylating Agent Guadecitabine in 
Combination with Carboplatin in Extensive Stage Small Cell Lung Cancer 
 
 
Sponsor Investigator 
Shadia Jalal, MD 
Indiana University Melvin and Bren Simon Cancer Center 
 
Co-Investigators 
Lawrence Einhorn, MD 
Nasser Hanna, MD 
Greg Durm, MD 
 
Statistician 
Susan Perkins, PhD 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
500 N. Meridian, Suite 100 
Indianapolis, IN 46204 
 
 
Trial Supported by  
Astex Pharmaceuticals 
 
Investigational New Drug (IND) #: 142701 
 
 
 
 
Initial Protocol Version Date: 20MAR2019 
Protocol Amendment Version Date:  
18MAR2020 
 
 


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PROTOCOL SIGNATURE PAGE 
 
A Phase II Study Evaluating Efficacy and Safety of Hypomethylating Agent Guadecitabine in 
Combination with Carboplatin in Extensive Stage Small Cell Lung Cancer 
 
 
VERSION DATE: 18MAR2020 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable institutional review board(s). 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Site Investigator 
 
 
  
 Date 
 
 
____________________________________ 
 Site Investigator Name (printed) 
 
 
____________________________________ 
 Site Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
 
 
 PLEASE COMPLETE AND EMAIL A COPY TO HCRN 
 
 
 


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SYNOPSIS 
TITLE 
A Phase II Study Evaluating Efficacy and Safety of Guadecitabine in 
Combination with Carboplatin in Extensive Stage Small Cell Lung 
Cancer 
SHORT 
TITLE 
Phase II Study of Guadecitabine in Small Cell Lung Cancer 
PHASE  
II 
OBJECTIVES 
Primary Objective: 
Determine Progression Free Survival (PFS) of the combination of 
Guadecitabine and platinum in patients with extensive stage small cell 
lung cancer previously treated with platinum containing chemotherapy.  
 
Secondary Objectives: 
• Evaluate the toxicity profile of the combination of Guadecitabine 
and carboplatin in patients with extensive stage small cell lung 
cancer patients previously treated with platinum containing 
chemotherapy. 
• Estimate Objective Response Rate (ORR), Disease Control Rate 
(DCR, defined as Complete Response + Partial Response + Stable 
Disease), and Overall Survival (OS) of the combination of 
Guadecitabine and carboplatin in the above mentioned population. 
 
Exploratory Objectives: 
• Measure platinum induced DNA adducts in peripheral blood 
mononuclear cells (PBMCs) and tumor tissue on Cycle 1 Day 1 
and Cycle 2 Day 5 prior to carboplatin treatment. 
• Methylation status change in PBMCs and tumor biopsy for global 
DNA and selected genes in tumor tissue on Cycle 1 Day 1 and 
Cycle 2 Day 5 prior to carboplatin treatment. 
• Analyze IHC expression of EZH2 and EZH2 target genes on 
Cycle 1 Day 1, Cycle 2 Day 5 prior to carboplatin treatment and at 
progression (optional). EZH2 expression changes will be 
correlated with response to Guadecitabine in combination with 
carboplatin.  
• Determine circulating tumor cell (CTC) burden prior to initiating 
treatment. 
 
STUDY 
DESIGN 
Phase II, open-label, single arm, single-stage study. A total of 34 
evaluable patients will be enrolled, of which we expect 70% to be 
chemotherapy sensitive and 30% to be chemotherapy resistant. This study 
is powered for chemotherapy sensitive patients. Chemotherapy resistant 
patients will be enrolled but analyzed separately and descriptively only.


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KEY ELIGIBILITY 
CRITERIA (See 
Section 3 for full 
eligibility criteria) 
Inclusion Criteria 
1. Male or female subjects, age ≥ 18 years.  
2. Histological or cytological diagnosis of small cell lung cancer; 
extensive stage disease.  
3. Patients must have received first line therapy with a platinum-
based chemotherapy. Patients should not have received more 
than 1 prior line of chemotherapy (could have received 
immunotherapy which does not count as chemotherapy) 
4. ECOG PS 0-1 
5. Measurable disease as per RECIST v1.1. Subjects may have 
bone-only disease. 
6. Adequate bone marrow, liver, and renal function, as assessed 
by the following laboratory requirements:  
o Hemoglobin ≥ 9.0 g/dL  
o Absolute neutrophil count (ANC) ≥1,500/mm3  
o Platelet count ≥100,000/mm3  
o Total bilirubin ≤1.5 x upper limit of normal (ULN). For 
subjects with Gilbert’s Disease, Total bilirubin ≤3 x 
ULN  
o ALT and AST ≤2.5 x ULN. For subjects with 
documented liver metastases, ALT and AST ≤5×ULN 
o Estimated glomerular filtration rate (eGFR) ≥ 60 
mL/minute/1.73 m2 as determined using the (by 
Cockcroft-Gault formula) 
7. Male and female subjects of child- bearing potential must agree 
to use contraception as outlined in Section 5.4 from the 
screening visit through 6 months after the last dose of study 
drug.  
 
Exclusion Criteria 
1. Platinum refractory disease defined as disease progression 
during platinum containing chemotherapy. Progression 
following platinum based treatment is not an exclusion. 
2. Prior therapy with a hypomethylating agent. 
3. Previously untreated (non-irradiated), symptomatic brain 
metastases. No prior treatment is required for non-symptomatic 
brain metastases. Previously treated symptomatic brain 
metastases are permitted.  
4. Unstable or clinically significant concurrent medical condition, 
psychiatric illness or social situation that would, in the opinion 
of the investigator, jeopardize the safety of a subject and/or 
their compliance with the protocol.  
5. Clinically significant acute infection requiring systemic 
antibacterial, antifungal, or antiviral therapy. (Suppressive 
therapy for chronic infections allowed, for example: Subjects 
with HIV/AIDS with adequate antiviral therapy to control viral 


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load would be allowed. Subjects with viral hepatitis with 
controlled viral load would be allowed while on suppressive 
antiviral therapy.)  
6. Hypersensitivity to (IMP) or components of the study 
treatment regimen. 
7. Treated with any investigational drug within 3 weeks of first 
dose of study treatment.  
STATISTICAL 
CONSIDERATIONS 
 
Null Hypothesis: Median PFS with combination of Guadecitabine 
with carboplatin in patients with extensive stage small cell lung 
cancer previously treated with platinum containing chemotherapy 
is 3 months or less. 
 
Alternative Hypothesis: Median PFS with combination of 
Guadecitabine with carboplatin in patients with extensive stage 
small cell lung cancer previously treated with platinum containing 
chemotherapy is 6 months or longer. 
 
Acceptable Type I (alpha) error: 10% (one sided) 
Acceptable Type II (beta) error: 20% 
Power: 80% 
 
This study is powered for chemotherapy sensitive 
patients. Chemotherapy resistant patients will be enrolled but 
analyzed separately and descriptively only. For the chemo-
sensitive group, when the sample size is 24, a non-parametric test 
(single-group) with a one-sided 0.10 significance level will have 
80% power to detect the difference between a median survival of 
3.0 months vs 6.0 months. With 24 patients in the chemo-sensitive 
group, we expect to enroll approximate 34 subjects total, thus we 
will have approximately 10 chemo-resistant patients to generate 
pilot data from. 
 
TOTAL NUMBER 
OF SUBJECTS 
N = 34 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 18 months 
ESTIMATED 
STUDY DURATION  
Estimated 12 months 
 
 
 


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TABLE OF CONTENTS 
 
Schema ............................................................................................................................... 7 
1. 
Background and Rationale ..................................................................................... 8 
2. 
Study Objectives and Endpoints........................................................................... 11 
3. 
Eligibility Criteria .................................................................................................. 12 
4. 
Subject Registration............................................................................................... 14 
5. 
Treatment Plan....................................................................................................... 14 
6. 
Toxicities and Dose Delays/Dose Modifications .................................................. 16 
7. 
Study Calendar & Evaluations ............................................................................. 19 
8. 
Biospecimen Studies and Procedures ................................................................... 22 
9. 
Criteria for Disease Evaluation ............................................................................ 23 
10 
Drug Information ................................................................................................... 27 
11 
Adverse Events ....................................................................................................... 29 
12 
Statistical Methods ................................................................................................. 33 
13 
Trial Management ................................................................................................. 35 
14. Data Handling and Record Keeping .................................................................... 37 
15 
Ethics ....................................................................................................................... 38 
16 
References ............................................................................................................... 39 
 
 
 
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
Treatment Regimen 
Guadecitabine 30mg/m2 subcutaneously Days 1-5 
Carboplatin AUC of 4 intravenously on Day 5 
Continue for 4 cycles; 1 Cycle = 28 Days 
Disease Assessment after completion of 4 cycles of treatment  
Continue follow up per protocol 
• 
ES SCLC patients  
• 
Must have prior treatment with platinum containing chemotherapy regimen 
• 
PS 0-1 
• 
Adequate organ function 
 


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
SCLC General Background 
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early hematogenous 
spread, initial chemotherapy sensitivity followed almost uniformly with rapid resistance and high 
genetic instability(1). The majority of patients present with extensive stage disease and platinum 
based chemotherapy remains the standard first line treatment(2). Chemo-sensitivity is defined as 
a response to initial platinum therapy that lasts ≥90 days. Chemo-resistance is defined as 
response to platinum therapy that lasts <90 days. Initial response rates to platinum based 
chemotherapy in extensive stage SCLC are 65-70%. Second line treatment options for SCLC 
include a number of chemotherapy agents, all with response rates of 20-30% and minimal 
survival benefit(3). Topotecan remains the only FDA approved second line therapy in SCLC 
with low response rates and minimal improvement in survival(4-6). Median survival of extensive 
stage SCLC patients therefore remains less than a year. SCLC has lagged behind many 
malignancies with limited improvements in the development of novel therapies.(7, 8)  
 
The initial remarkable sensitivity of SCLC to platinum, including complete responses in the 
extensive stage setting, suggests a potential role of platinum re-sensitization in the treatment of 
relapsed SCLC.  Platinum resistance is a complex phenomenon with multiple key pathways 
involved including DNA repair pathways(9). Cisplatin exerts its cytotoxicity through the 
formation of DNA adducts that inhibit multiple fundamental cellular processes including DNA 
replication and transcription(10). Adducts lead to a cascade of events that stimulate several 
signal transduction pathways culminating in apoptosis. Increased repair rate of cisplatin induced 
adducts via the nucleotide excision repair and increased tolerance of cisplatin induced adducts 
via the homologous recombination pathway have been tied to platinum resistance(11).  In 
addition, epigenetic changes including alterations in DNA methylation, histone modifications 
and nucleosome positioning have been shown to be involved in the development of platinum 
resistance in lung cancer and other malignancies(12, 13). Several epigenetic disruption of distinct 
biological pathways were observed during the development of platinum resistance in ovarian 
cancer(14).  The exact mechanisms of platinum resistance in SCLC are not well defined. 
However, epigenetics changes likely play a role both in the development of SCLC and in its 
response to platinum based therapy. In fact, a very recent study showed smoking induces 
epigenetic changes in the lungs and are potentially the first step towards the development of lung 
cancer.  Chronic cigarette smoke induced chromatic changes that later manifested as abnormal 
DNA methylation(15).  
 
1.2 
DNA Methylation in SCLC 
DNA methylation is an epigenetic modification involved in gene expression regulation. In 
cancer, the DNA methylation pattern becomes aberrant, causing an array of tumor suppressor 
genes to undergo promoter hypermethylation and become transcriptionally silent. In fact, DNA 
methylation profiles in cancer cells are unique from normal, differentiated cells(16).  In cancer 
cells, widespread methylation occurs throughout the genome and enriched hypermethylation is 
focused in CpG islands. CpG islands are located in the promoters of tumor suppressor genes 
including some of the most commonly mutated genes in cancer in general and small cell lung 
cancer in particular such as retinoblastoma (Rb) gene. In a study of patients with small cell lung 
cancer, significant methylation differences were noted at 62 CpG sites in 52 independent genes 


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in the peripheral blood compared to case controls(17).  DNA methylation patterns were 
evaluated in 18 primary SCLC tumors and 5 SCLC cell lines using a target-specific CpG island 
promoter array. The study identified DNA methylation peaks in 73 genes specific to SCLC with 
a significant representation of neuroendocrine-specifying transcription factor genes. Methylation 
and inactivation of tumor suppressor genes TCF21 and RB1 were described in SCLC in addition 
to BCL2. Methylation patterns identified 3 distinct subtypes of SCLC, yet all shared methylation 
of RB1 and TCF21. The chromatin modifier EZH2 was among the most significantly 
overexpressed genes in SCLC, expressed >12 fold higher than in normal lung. EZH2, a histone 
methyltransferase component of the PRC2 complex, has been implicated in dysregulation of 
DNA methylation in cancer through its effects on histone methylation, particularly histone H3 
lysine 27 tri-methylation. EZH2 is a known target of E2F, which is activated in SCLC by gene 
copy loss and loss of function mutations in RB1, the gene encoding the E2F repressor pRB(18). 
Pharmacologic inhibition of EZH2 in a SCLC patient derived xenograft using EPZ-6438 
suggests hypomethylating agents might have activity in SCLC.  
 
1.3 
Hypomethylating Agents for Treatment of Cancer 
Re-expression of methylation silenced tumor suppressor genes by inhibiting the DNA 
methyltransferases (DNMT11, DNMT3, and DNMT3B) has emerged as an effective strategy 
against cancer(19). The expression of DNA methyltransferase 1 (DNMT1) being high in S phase 
of cell cycle makes it a specific target for methylation inhibition in rapidly dividing cancer cells. 
The first compounds that demonstrated DNA hypomethylation activity in cancer cells were 
cytidine analogs such as 5-Azacyidine which has activity in the treatment of myelodysplastic 
syndrome and acute myelogenous leukemia. Despite the success of 5-azacytidine in hematologic 
malignancies multiple challenges arise due to the instability of the compound and it’s in vivo 
deamination by cytidine deaminase(20). This has led to the development of Guadecitabine. 
 
1.4 
SGI-110 (Guadecitabine) and its role in platinum re-sensitization 
While the FDA-approved demethylating agent decitabine is prone to deamination by cytidine 
deaminase, Guadecitabine (Astex Pharmaceuticals, Inc.), a dinucleotide analogue of decitabine, 
is more stable, less toxic, and a promising alternative to restoring silenced tumor suppression 
genes (TSG) expression in cancer cells by reversal of DNA methylation(21). Guadecitabine is a 
dinucleotide combining 5-aza-dC and deoxyguanosine that has been shown to be more stable 
than 5-aza-dC making it an attractive alternative. Guadecitabine is resistant to cytidine 
deaminase(22).  Guadecitabine is currently under investigation in multiple clinical trials 
including high- risk myelodysplastic syndrome and acute myelogenous leukemia(23). In 
addition, preclinical data has demonstrated the combination of Guadecitabine with cisplatin in 
platinum resistant ovarian models re-sensitized ovarian cancer cells to platinum (24). This re-
sensitization was not a result of inhibition of repair of platinum induced DNA as originally 
thought. DNA damage induced by platinum was increased by Guadecitabine as measured by 
inductively coupled plasma mass spectrometry analysis. A phase I trial of Guadecitabine and 
carboplatin in platinum resistant recurrent ovarian cancer was recently completed (25). 
Guadecitabine was administered once daily subcutaneously on days 1-5 followed by carboplatin 
IV day 8 of every 28 days cycle. The maximum tolerated dose of the combination was 
Guadecitabine at 30mg/m2 SQ days 1-5 in combination with carboplatin AUC 4 on day 8. The 
dose limiting toxicities were grade 4 neutropenia and grade 4 thrombocytopenia. Common 
treatment related adverse events were neutropenia, nausea, fatigue, anemia, injection site 


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reaction, thrombocytopenia, leukopenia and vomiting. The combination of Guadecitabine and 
platinum is currently being investigated in platinum refractory testicular cancer and seems to be 
potentially promising with a response rate of 35%(26). In SCLC, re-sensitization of a platinum 
resistant SCLC was recently demonstrated using RRx-001, an agent that epigenetically 
modulates DNA methylation and histone deacetylation(27). This data provides proof of concept 
of the potential role of Guadecitabine in platinum re-sensitization in SCLC. A common 
characteristic between testicular cancer, ovarian cancer and small cell lung cancer is their initial 
exquisite sensitivity to platinum. Guadecitabine has been shown to prime hepatocellular 
carcinoma cells to oxaliplatin in vitro(28). Guadecitabine is currently under investigation in 
combination with durvalumab/tremelimumab in SCLC. This will be the first study combining 
Guadecitabine with platinum in SCLC. This study is unique as guadecitabine has been mainly 
studied as a radio-sensitizer in acquired platinum resistance. Some of the patients on this study 
will be platinum resistant and guadecitabine could re-sensitize them to platinum. However, some 
of the patients will have low sensitivity to platinum and guadecitabine could potentially serve as 
an “enhancer” rather than ‘re-sensitizer” to platinum sensitivity in these patients.  
 
1.5 
Rationale for Combining Guadecitabine with Carboplatin 
The DNA methylation changes described in SCLC in addition to the potential role of 
hypomethylating agents in reversal of platinum resistance suggest a potential role for hypo-
methylating agents in the treatment of SCLC. EPZ-6438 (a histone methyltransferase inhibitor) 
profoundly inhibited SCLC growth in vivo(18). Guadecitabine had single agent activity and 
reduced tumor burden by 35% in a non-small cell lung cancer in an in vivo model. In addition 
Guadecitabine induced genome wide promoter region demethylation and impacted the 
expression of a number of EZH2-target genes(29). This finding has the potential to be pertinent 
in SCLC with overexpression of EZH2(30).  
 
The goal of this study is to explore the potential for the epigenetic agent Guadecitabine in re-
sensitizing SCLC patients who have progressed following a platinum based doublet regimen. 
Progression free survival will be the primary endpoint. A longer PFS than noted with first line 
platinum doublet would suggest this combination is promising in SCLC.  
 
There are no optimal drugs for the treatment of recurrence SCLC. SCLC has been shown to 
respond to platinum re-challenge(31). In fact, there have been at least two studies that compared 
platinum re-challenge in SCLC to topotecan or Amrubicin. The response rate to platinum re-
challenge was higher than topotecan and comparable to amrubicin. Re-challenging patients with 
platinum is therefore a reasonable treatment for recurrent SCLC(32, 33).  Current evidence in 
ovarian cancer shows Guadecitabine re-sensitizes patients to platinum re-treatment. It is unclear 
if guadecitabine or hypomethylators enhance the response to a second platinum exposure.  We 
will analyze that potential benefit in this study.  
 
 
 


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SGI-110  
Days 1-5 
SGI-110  
Days 1-5 
Biopsy and 
CTCs  
Prior to C1D1 
SGI-110  
Days 1-5 
Carboplatin 
Day 5
SGI-110  
Days 1-5 
Carboplatin 
Day 5 
Cycle 1 
Cycle 2 
Cycle 3
Cycle 4 
Biopsy, 
PBMCs 
 Prior to C2D5
Progression
Biopsy (optional), 
PBMCs, CTCs 
Carboplatin 
Day 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
Determine Progression Free Survival (PFS) of the combination of Guadecitabine and platinum in 
patients with extensive stage small cell lung cancer previously treated with platinum containing 
chemotherapy.  
 
2.1.2 Secondary Objectives 
• Evaluate the toxicity profile of the combination of Guadecitabine and carboplatin in 
patients with extensive stage small cell lung cancer patients previously treated with 
platinum containing chemotherapy. 
• Estimate Objective Response Rate (ORR) of the combination of Guadecitabine and 
carboplatin in the above mentioned population. 
• Estimate disease Control Rate of the combination of Guadecitabine and carboplatin in the 
above mentioned population. 
• Estimate Overall Survival (OS) of the combination of Guadecitabine and carboplatin in 
the above mentioned population. 
 
2.1.3 Correlative/Exploratory Objectives 
• Measure platinum induced DNA adducts in peripheral blood mononuclear cells (PBMCs) 
and tumor tissue on Cycle 1 Day 1 and Cycle 2 Day 5 prior to carboplatin treatment. 
• Methylation status change in PBMCs and tumor biopsy for global DNA and selected 
genes in tumor tissue on Cycle 1 Day 1 and Cycle 2 Day 5 prior to carboplatin treatment. 
• Analyze IHC expression of EZH2 and EZH2 target genes on Cycle 1 Day 1, Cycle 2 Day 
5 prior to carboplatin treatment and at progression (optional). EZH2 expression changes 
will be correlated with response to Guadecitabine in combination with carboplatin. 
• Determine circulating tumor cell (CTC) burden prior to initiating treatment. 
Carboplatin 
Day 5


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2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
• PFS as defined as the time from Day 1 of treatment until the criteria for disease 
progression is met as defined by RECIST 1.1, MD Anderson (MDA) criteria or death as a 
result of any cause, whichever occurs first. 
 
2.2.2 Secondary Endpoints 
• Occurrence of all treatment related toxicities as defined by the NCI Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 
• ORR will include confirmed complete response (CR) + confirmed partial response (PR) 
and will be determined as per RECIST 1.1 or MDA criteria.  
• DCR defined as CR + PR + Stable Disease (SD) per RECIST 1.1 or MDA criteria  
• OS as defined as the time from Day 1 of treatment until death from any cause 
 
3. 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Male or female subjects, age ≥ 18 years.  
 
2. Histological or cytological diagnosis of small cell lung cancer. Subjects must have 
extensive stage disease, defined as disease beyond the ipsilateral hemithorax, 
mediastinum and ipsilateral supraclavicular area and including malignant pleural or 
pericardial effusion or hematogenous metastases. 
 
3. Patients must have received first line therapy with a platinum-based chemotherapy. 
Patients should not have received more than 1 prior line of chemotherapy (could have 
received immunotherapy which does not count as chemotherapy). 
 
4. ECOG PS 0-1 
 
5. Measurable disease as per RECIST v1.1. Subjects may have bone-only disease. NOTE: 
Bone-only subjects are eligible if their disease can be documented/evaluated by bone 
scans, CT or MRI. Their disease will be assessed using MD Anderson criteria.(34) 
NOTE: Previously irradiated lesions are eligible as a target lesion only if there is 
documented progression of the lesion after irradiation. 
 
6. Adequate bone marrow, liver, and renal function, as assessed by the following laboratory 
requirements:  
o Hemoglobin ≥ 9.0 g/dL  
o Absolute neutrophil count (ANC) ≥ 1,500/mm3  
o Platelet count ≥ 100,000/mm3  
o Total bilirubin ≤ 1.5 x upper limit of normal (ULN). For subjects with Gilbert’s 
Disease, total bilirubin ≤ 3 x ULN  


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o ALT and AST ≤ 2.5 x ULN. For subjects with documented liver metastases, ALT 
and AST ≤ 5×ULN 
o Estimated glomerular filtration rate (eGFR) ≥ 60 mL/minute/1.73 m2 as 
determined using the Cockcroft-Gault formula.  
 
7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a 
negative pregnancy test at screening. 
 
8. Male and female subjects of child- bearing potential must agree to use contraception as 
outlined in Section 5.4 from the screening visit through 6 months after the last dose of 
study drug.  
 
3.2 
Exclusion Criteria 
 
1. Platinum refractory disease defined as disease progression during first line platinum 
containing chemotherapy regimen. Progression following platinum based therapy is 
allowed. 
 
2. Prior therapy with a hypomethylating agent. 
 
3. Previously untreated (non-irradiated), symptomatic brain metastases. No prior treatment 
is required for non-symptomatic brain metastases. Previously treated symptomatic brain 
metastases are permitted.  
 
4. Unstable or clinically significant concurrent medical condition, psychiatric illness or 
social situation that would, in the opinion of the investigator, jeopardize the safety of a 
subject and/or their compliance with the protocol.  
 
5. Clinically significant acute infection requiring systemic antibacterial, antifungal, or 
antiviral therapy. (Suppressive therapy for chronic infections allowed, for example: 
Subjects with HIV/AIDS with adequate antiviral therapy to control viral load would be 
allowed. Subjects with viral hepatitis with controlled viral load would be allowed while 
on suppressive antiviral therapy.)  
 
6. Hypersensitivity to (IMP) or components of the study treatment regimen. 
 
7. Treated with any investigational drug within 3 weeks of first dose of study treatment. 
 
8. Pregnant or breastfeeding. 
 
9. Second malignancy currently requiring active therapy except breast or prostate cancer 
stable on or responding to endocrine therapy. 
 
 
 


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4. 
SUBJECT REGISTRATION 
All subjects must be registered through HCRN’s electronic data capture (EDC) system prior to 
starting protocol therapy. Subjects must begin therapy within 7 business days of registration.  
 
Registered patients will be assigned to chemo-sensitive or chemo-resistant group based on the 
time of disease progression since the completion of platinum containing chemotherapy. Chemo-
sensitivity is defined as a response to initial platinum therapy that lasts ≥ 90 days. Chemo-
resistance is defined as response to platinum therapy that lasts < 90 days. 
 
5. 
TREATMENT PLAN 
This is a phase II, open-label, single arm, single-stage study. Both, chemo-sensitive and chemo-
resistant patients will be enrolled and treated with 4 cycles of combination of Guadecitabine and 
carboplatin as detailed in the study schema. Premedication and hydration will be provided as per 
institutional standards for administration of carboplatin.  
 
5.1 
Drug Administration 
Drug 
Dose1 
Route 
Schedule2 
Cycle 
Length 
Guadecitabine 
30 mg/m2  
Subcutaneously (SC) 
Days 1-5 
4 weeks  
(28 days) 
Carboplatin 
AUC 4 
Intravenously (IV) 
Day 5 
1 Body surface area (BSA) should be recalculated when weight changes based on institutional guidelines 
2 A window of ± 3 days may be applied to all Day 1 and 5 visits to accommodate observed holidays, 
inclement weather, scheduling conflicts etc. Date and time of each drug administration should be clearly 
documented in subject’s chart and electronic case report forms (eCRFs).
 
5.2 
Concomitant Medications 
 
5.2.1 Allowed Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. 
 
5.2.2 Prohibited Concomitant Medications 
Drug-drug interaction studies have not been conducted with guadecitabine. In vitro studies 
suggest guadecitabine is unlikely to inhibit or induce human cytochrome p450 (CYP) enzymes 
and is not a substrate for CYPs, indicating that CYP-mediated drug-drug interactions with 
guadecitabine are unlikely to occur. Neither guadecitabine, nor the active metabolite decitabine 
inhibit major human drug transporters.  Therefore, no specific concomitant medications are 
prohibited. 
 
5.3 
Supportive Care 
Institutional standards should be followed for supportive care such as symptom management, 
hydration and transfusions. Filgrastim should be utilized based on NCCN guidelines.  
 
 


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5.4 
Contraception 
The following restrictions apply while the patient is receiving study treatment and for the specified 
times before and after: 
 
Female patient of child-bearing potential 
• Females of childbearing potential who are sexually active with a non-sterilized male 
partner must use at least 1 highly effective method of contraception from the time of 
screening and must agree to continue using such precautions for 180 days after the last 
dose of durvalumab + guadecitabine. Non-sterilized male partners of a female patient 
must use male condom plus spermicide throughout this period. Cessation of birth control 
after this point should be discussed with a responsible physician. Not engaging in sexual 
activity for the total duration of the drug treatment and the drug washout period is an 
acceptable practice; however, periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of birth control. Female subjects should 
also refrain from breastfeeding throughout this period. 
 
Male subjects with a female partner of childbearing potential 
• Non-sterilized males who are sexually active with a female partner of childbearing 
potential must use a male condom plus spermicide from screening through 180 days after 
receipt of the final dose of durvalumab + guadecitabine or. Not engaging in sexual 
activity is an acceptable practice; however, occasional abstinence, the rhythm method, 
and the withdrawal method are not acceptable methods of contraception. Male subjects 
should refrain from sperm donation throughout this period. 
• Female partners (of childbearing potential) of male subjects must also use a highly 
effective method of contraception throughout this period.  
 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.  
 
Women will be considered post-menopausal if they have been amenorrheic for 12 months without 
an alternative medical cause. The following age-specific requirements apply:  
• Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone levels 
in the post-menopausal range for the institution or underwent surgical sterilization 
(bilateral oophorectomy or hysterectomy).  
• Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 
 
Highly effective methods of contraception, defined as one that results in a low failure rate (i.e., 
less than 1% per year) when used consistently and correctly are described in the table below. 
Note that some contraception methods are not considered highly effective (e.g. male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 


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spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action; and triphasic 
combined oral contraceptive pills). 
 
Highly Effective Methods of Contraception (<1% Failure Rate) 
Barrier/Intrauterine methods 
Hormonal Methods
Copper T intrauterine device 
Levonorgestrel-releasing intrauterine 
system (e.g., Mirena®)a 
 
Etonogestrel implants: e.g. Implanon 
Intravaginal device: e.g. ethinylestradiol 
and etonogestrel 
Medroxyprogesterone injection: e.g. 
Depo-Provera  
Normal and low dose combined oral 
contraceptive pill 
Norelgestromin/ethinylestradiol 
transdermal system 
a 
This is also considered a hormonal method 
 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 will be used to 
grade adverse events. Subjects enrolled in this study will be evaluated clinically and with 
standard laboratory tests before and at regular intervals during their participation in this study as 
specified in Study Calendar & Evaluations. Subjects will be evaluated for adverse events (all 
grades), serious adverse events, and adverse events requiring study drug interruption or 
discontinuation as specified in Study Calendar & Evaluations.   
 
6.1 
Dose Delays/Dose Modifications 
Unless otherwise noted in the dose modification tables below, treatment may be delayed ≤ 2 
weeks from the expected day of the next treatment for any reason. If treatment is delayed ≥ 2 
weeks, subjects will proceed with the next cycle of treatment at the dose level recommended 
according to the tables below. 
 
6.2 
Dose Levels for Dose Reductions 
 
Dose level 
Dose of carboplatin 
Dose of Guadecitabine 
Starting Dose 
AUC 4 
30mg/m2 
Dose level (-1) 
AUC 4 
24mg/m2 
 
 
 


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Dose Modification Guidance Table (applies to Day 1 for all cycles except for Cycle 1) 
 
Neutropenia (absolute neutrophil count [ANC]) 
Toxicity 
Grade 
Stipulations 
Suggested Action 
 
G3 
500 - 999/mm3 
(w/out fever [>38.3°C 
or 101.0°F]) 
≤ 14 days of 
interruption/delay 
• 
hold treatments until ANC 
>1000/mm3 
• 
Prophylaxis with granulocyte 
colony stimulating factor (G-CSF) 
starting with next cycle should be 
considered by treating physician. 
In these patients GCSF support 
will be given on Day 6 through an 
on-body injector (neulasta onpro) 
• 
no change in Guadecitabine or 
carboplatin dose 
G3 
500 - 999/mm3  
(w/out fever) 
> 14 days of 
interruption/delay 
• 
hold treatments until ANC 
>1000/mm3 
• 
Prophylaxis with granulocyte 
colony stimulating factor (G-CSF) 
starting with next cycle should be 
considered by treating physician. 
In these patients GCSF support 
will be given on Day 6 through an 
on-body injector (neulasta onpro) 
• 
reduce Guadecitabine by one dose 
level 
 
G3 
500 - 999/mm3  
(w/ fever) 
 
• 
hold treatments until ANC 
>1000/mm3 
• 
Prophylaxis with granulocyte 
colony stimulating factor (G-CSF) 
starting with next cycle should be 
considered by treating physician. 
In these patients GCSF support 
will be given on Day 6 through an 
on-body injector (neulasta onpro) 
• 
reduce Guadecitabine by one dose 
level 
G4 (w/out fever) 
Lasting ≤ 14 days 
Any 
episode 
G4 (w/out fever) 
G4 lasting > 14 days 
• 
discontinue subject from study 
 
 
 
 


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Thrombocytopenia  
Toxicity 
Grade 
Suggested Action 
1 
G3 25,000 - 50,000/mm3 
• 
hold treatments until plt ≥ 50,000/mm3 
• 
reduce Guadecitabine by one dose level 
G4 < 25,000/mm3 
• 
discontinue subject from study 
 
6.3 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined above, a subject will 
also be discontinued from protocol therapy and followed per protocol under the following 
circumstances outlined below.  The reason for discontinuation of protocol therapy will be 
documented on the electronic case report form (eCRF)   
• Documented disease progression.   
• 
Site investigator determines a change of therapy would be in the best interest of the 
subject 
• 
Subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or 
for other reasons 
o In a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if he or she may still be contacted for further 
scheduled study assessments. The outcome of that discussion should be documented 
in both the medical records and in the eCRF. 
• 
Female subject becomes pregnant  
• 
Protocol therapy is interrupted for ≥ 6 weeks.  
 
6.4 
Protocol Discontinuation  
If a subject decides to discontinue from the protocol (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as possible. A 
complete final evaluation at the time of the subject’s protocol withdrawal should be made with 
an explanation of why the subject is withdrawing from the protocol. If the reason for removal of 
a subject from the study is an adverse event, it will be recorded on the eCRF. 


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7. 
STUDY CALENDAR & EVALUATIONS 
 
Study Evaluation  
Cycle = 28 days 
Screening 
On Treatment Cycle 1-4 
Safety follow up 
visit9 
Long-term Follow 
up10 
-28 days 
Day 1 
± 3 days 
Day 5 
± 3 days 
30 days 
post last dose 
(± 7 days)
Every 2 months  
(±14 days) 
REQUIRED ASSESSMENTS 
Informed Consent 
X
 
Medical History1 
X
 
Physical Exam 
X
X
 
X
Vital signs and ECOG Performance Status2 
X
X
X 
X
AEs & concomitant medications 
X
X
X 
X
LABORATORY ASSESSMENTS 
 
Complete Blood Cell Count with diff (CBC)
X
X8 
X 
X
Comprehensive Metabolic Profile (CMP)
X
X8 
X 
X
Pregnancy test (urine or serum) (WOCBP)3 
X
 
DISEASE ASSESSMENT 
CT or PET CT of chest4 
X
Prior to C3D1 
 
X
X
CT, PET CT or MRI of abdomen and pelvis4 
X
Prior to C3D1 
 
X
X
Bone Scan4 
X
Prior to C3D1 
 
X
X
TREATMENT EXPOSURE 
Guadecitabine 
Daily D1-D5 
Carboplatin 
X 
SPECIMEN COLLECTION  
Archival Tumor Tissue or Fresh Tissue5 
X5 
X5 
C2D5 
X
Whole blood for somatic baseline and CTCs6
C1D1
 
Whole blood for PBMCs6 
C1D1 
C2D5 
X 
BANKING SAMPLES 
Whole blood7 
C1D1
Whole blood for plasma and serum7 
C1D1
 
X
FOLLOW-UP 
Survival Status, Subsequent Therapy 
 
 
 
 
X 
 


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CBC with differential and platelet to include: WBC, ANC, Hgb, Hct, PLT. CMP to include sodium, potassium, chloride, creatinine, blood urea 
nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline phosphatase and LDH 
 
Key to Footnotes  
 
1: Medical History; other data to obtain during this assessment includes: diagnosis and staging to include pathology report and staging 
documentation. A smoking history questionnaire and trial awareness question. Prior anti-cancer treatment should be documented including 
medications (chemotherapy, checkpoint inhibitors, etc) radiation or surgery.   
 
2: Vital signs to include blood pressure, temperature, pulse, oxygen saturation, weight, and height (screening only) and ECOG performance status.   
 
3: For women of childbearing potential (WOCBP): urine or serum βhCG if clinically appropriate. If a urine test is done and it is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required. Testing is required at screening. 
 
4: Tumor response assessment will consist of evaluation by CT or PET CT scan of chest. An MRI, CT or PET CT scan of the abdomen and pelvis 
may be done if there is measurable disease that is not detectable by CT or PET CT of the chest. A bone scan may be used for subjects with bone 
only disease or if there is suspicion of bone metastasis. Imaging will be performed at screening, prior to Cycle 3 and at the D30 safety follow up 
visit (± 7 days). Imaging selected for each subject should remain the same throughout the study. If tumor assessments are available for subjects 
who have not yet experienced progressive disease (PD) at the time treatment is discontinued, the follow-up tumor evaluations will be documented 
in the eCRF until PD or death is confirmed, or until another treatment is initiated.  
 
5: Archival tissue is required if available and should be identified at screening and shipped by C2D1. If archival tissue is not available, subjects 
may still be eligible.  Biopsies will be obtained prior to C1D1 from 15 patients with easily accessible disease regardless of availability of archival 
tissue. These same 15 patients will be required to undergo a repeat biopsy prior to treatment on C2D5 if clinically feasible. These same 
subjects will have the option to undergo a biopsy at progression/safety visit. See Correlative Laboratory Manual (CLM) for detailed 
instructions.  
 
6: Whole blood will be collected for somatic baseline and CTCs prior to treatment C1D1. Whole blood will be collected prior to treatment C1D1, 
C2D5 and at progression/Safety Follow Up visit for isolation of peripheral blood mononuclear cells. See CLM for detailed instructions. 
 
7: Samples for banking for future unspecified cancer related research include: Whole blood: collected prior to treatment on Cycle 1 Day 1. Whole 
blood for Serum and Plasma: collected prior to treatment on Cycle 1 Day 1 and at the 30-day Safety Follow-up visit. See CLM for detailed 
instructions. 


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8: CBC and CMP to be performed during screening for eligibility and on C1D1 prior to treatment. For the remainder of the Cycles, CBC and CMP 
may be performed within 4 days prior to Day 1 of treatment.  
 
9: The safety follow-up visit should only occur when subjects permanently stop study treatment for whatever reasons (toxicity, progression, or at 
discretion of site investigator) and should be performed 30 days (± 7 days) after the last dose of treatment. Subjects who have an ongoing Grade ≥ 
2 or serious AE (SAE) at this visit will continue to be followed until the AE resolves to ≤ Grade 1 or baseline, deemed clinically insignificant, 
and/or until a new anti-cancer treatment starts, whichever is earlier. 
 
10: Long-term follow up will occur in all subjects until documented disease progression. Radiology imaging should be performed every 2 months 
(± 7 days). Subjects who discontinue treatment for any reason without documented disease progression will be followed every 2 months for 1 year 
(± 14 days). Once disease progression is documented, subjects will enter a survival follow up period every 3 months for 1 year from the time of 
documented progression. Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate.   
 
 
 
 


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8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
Please refer to the Correlative Laboratory Manual (CLM) for additional details on studies 
outlined below. 
 
8.1 
Tissue 
 
8.1.1 Archival Tissue 
Archival tissue is required if available. Archival tissue should be identified at screening, 
requested after registration and shipped by C2D1. If archival tissue is not available, subjects may 
still be eligible.  This tissue will be used to analyze EZH2 expression. 
 
8.1.2 Fresh Biopsy Tissue 
For 15 patients with easily accessible disease, biopsies are required Cycle 1 Day 1 (regardless of 
archival tissue availability) and Cycle 2 Day 5 to assess methylation changes, EZH2 expression, 
and platinum-induced DNA adducts. A biopsy at progression is optional for the same 15 patients 
and similar analysis will be performed. 
 
8.2 
Peripheral Blood Samples  
 
8.2.1 Somatic Baseline 
Whole blood will be collected for somatic baseline prior to treatment C1D1. This sample is 
required. 
 
8.2.2 Circulating Tumor Cells (CTCs) 
Whole blood will be collected for CTCs prior to treatment C1D1. This sample is required and 
will be used to determine circulating tumor cell (CTC) burden prior to initiating treatment. 
 
8.2.3 Peripheral Blood Mononuclear cells 
Whole blood will be collected prior to treatment on C1D1, C2D5 and at progression for isolation 
of peripheral blood mononuclear cells. Changes in LINE1 methylation levels in PBMCs will be 
assessed. In addition, platinum induced DNA lesions will be quantified. DNA will be extracted 
and ICP-MS performed to determine global DNA lesions. 
 
8.3 
Samples for future unspecified cancer related  
Subject consent will be obtained to collect additional samples for future unspecified cancer 
related research. Hoosier Cancer Research Network will manage the banked samples. Samples 
will be banked indefinitely in the Hoosier Cancer Research Network Biorepository until they are 
used up. Collection of samples is optional. 
 
This includes: 
• Whole blood: Whole blood will be collected prior to treatment on Cycle 1 Day 1.  
• Pre- and Post-treatment plasma: Whole blood for plasma will be collected prior to treatment 
on Cycle 1 Day 1 and at the 30-day Safety Follow-up visit.  
• Pre- and Post-treatment serum: Whole blood for serum will be collected prior to treatment on 
Cycle 1 Day 1 and at the 30-day Safety Follow-up visit. 
 


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Please refer to the Correlative Laboratory Manual (CLM) for all sample collection, processing, 
labeling, and shipping instructions. 
 
8.4 
Storage of Biospecimens 
Any specimens remaining (leftover) once protocol described biospecimen-based studies are 
complete will be stored for future unspecified cancer related research. Permission to store these 
samples will be obtained during informed consent. 
 
8.5 
Confidentiality of Biospecimens 
Samples that are collected will be identified by a subject’s sequence ID assigned at the time of 
registration to the trial. Any material issued to collaborating researchers will be anonymized and 
only identified by the subject’s study number. 
 
9. 
CRITERIA FOR DISEASE EVALUATION 
 
9.1 
Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
9.1.1 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
 
9.2 
Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
 
9.3 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 


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lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
 
9.4 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
9.5 
Evaluation of Target Lesions 
NOTE: In addition to the information below, also see section 4.3.2 in the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 
1.1 (Eur J Cancer 45;2009:228-247) for special notes on the assessment of target lesions.  
 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm.
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note:  the appearance of one or 
more new lesions is also considered progressions). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study
 
 
9.6 
Evaluation of Non-Target Lesions 
 
Complete 
Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (<10 mm short axis) 
NOTE:  If tumor markers are initially above the upper normal limit, they must 
normalize for a subject to be considered in complete clinical response. 
Non-CR/ Non-
PD 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits
Progressive 
Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status 
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Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor investigator. 
 
9.7 
Evaluation of Best Overall Response 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR
No
CR 
CR 
Non-CR/ Non-PD
No
PR 
CR 
Not evaluated
No
PR 
PR 
Non-PD/ or not all evaluated
No
PR 
SD 
Non-PD or not all evaluated
No
SD 
Not all evaluated 
Non-PD
No
Non-evaluable
PD 
Any
Yes or No
PD 
Any 
PD*
Yes or No
PD 
Any 
Any
Yes
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
9.8 
Definitions for Response Evaluation – RECIST 1.1 
 
9.8.1 Objective Response Rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR according 
to RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded since the start of 
treatment). 
 
9.8.2 
Disease Control Rate 
The disease control rate is the proportion of all subjects with stable disease (SD) for 8 weeks, or 
partial response (PR), or complete response (CR) according to RECIST 1.1, from the start of 
treatment until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the start of treatment). 
 


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9.8.3 Progression Free Survival 
A measurement from Day 1 of treatment until the criteria for disease progression is met as 
defined by RECIST 1.1 or death, whichever occurs first. Subjects who have not progressed will 
be right-censored at the date of the last disease evaluation. 
 
9.8.4 Overall Survival 
Overall survival is defined by the duration from day 1 of treatment to date of death from any 
cause. 
 
9.9 
Definitions for Response Criteria for patients with bone-only metastases; MD 
Anderson (MDA) criteria36 
 
Complete Response (CR) 
• Complete sclerotic fill-in of lytic lesions on XR or CT 
• Normalization of bone density on XR or CT 
• Normalization of signal intensity on MRI 
• Normalization of tracer uptake on SS
Partial Response (PR) 
• Development of a sclerotic rim or partial sclerotic fill-in of 
lytic lesions on XR or CT 
• Osteoblastic flare - Interval visualization of lesions with 
sclerotic rims or new sclerotic lesions in the setting of other 
signs of PR and absence of progressive bony disease 
• ≥ 50% decrease in measurable lesions on XR, CT, or MRI 
• ≥ 50% subjective decrease in the size of ill-defined lesions 
on XR, CT, or MRI 
• ≥ 50% subjective decrease in tracer uptake on SS 
Progressive Disease (PD) 
• > 25% increase in size of measurable lesions on XR, CT, or 
MRI 
• > 25% subjective increase in the size of ill-defined lesions 
on XR, CT, or MRI 
• > 25% subjective increase in tracer uptake on SS 
• New bone metastases
Stable Disease (SD) 
• No change 
• < 25% increase or < 50% decrease in size of measurable 
lesions 
• < 25% subjective increase or < 50% subjective decrease in 
size of ill-defined lesions 
• No new bone metastases
Abbreviations: XR: radiography; CT: computed tomography; SS: skeletal scintigraphy; MRI: 
magnetic resonance imaging. 
 
Measurements are based on the sum of a perpendicular, bi-dimensional measurement of the 
greatest diameters of each individual lesion. 
 
 
 


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10 
DRUG INFORMATION 
 
10.1 
Guadecitabine; SGI-110 
Guadecitabine is a potent inhibitor of DNA methylation that has been shown to induce a dose-
dependent decrease of global DNA and gene-specific methylation in many different human 
cancer cell lines. 
 
10.1.1 Supplier/How Supplied 
Astex Pharmaceuticals will supply Guadecitabine at no charge to subjects participating in this 
clinical trial.  
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
 
10.1.2 Preparation 
Guadecitabine is available as a two-vial system, referred to as (1) Guadecitabine for Injection, 
100mg and (2) Guadecitabine Diluent for Reconstitution, 3mL or 1.2mL: 
• Guadecitabine for Injection, 100mg contains guadecitabine, 100mg as a dry lyophilized 
powder  
• Guadecitabine Diluent for Reconstitution, 3mL contains 3mL of a non-aqueous diluent 
for constitution. 1.2mL contains 1.2mL of a non-aqueous diluent. 
 
The diluent is comprised of 3 commonly used excipients, propylene glycol, glycerin and ethanol, 
which are generally recognized as safe. All 3 excipients are pharmaceutically acceptable solvents 
previously in drug productions approved for SC administration. Guadecitabine solution is 
reconstituted at a maximum concentration of 100mg/mL for SC administration. 
 
Both product and diluent are contained in clear glass vials stoppered with a latex-free rubber 
stopper and capped with an aluminum flip-off seal. 
 
10.1.3 Storage and Stability 
Guadecitabine for Injection, 100mg vial is stored at 2ºC to 8 ºC in the original packaging until 
use. Guadecitabine Diluent for Reconstitution, 3mL is stored at 2ºC to 30 ºC, and 1.2 mL is 
stored at 2°C to 8°C, both in an upright position until use. Both vials are preservative free and for 
single use only. 
 
10.1.4 Handling and Disposal 
Occupational Safety and Health Administration (OSHA) Guidelines for handling cytotoxic drugs 
outlined in the American Journal of Hospital Pharmacy should be followed. As with other 
potentially toxic anti-cancer agents, care should be exercised in the handling and preparation of 
guadecitabine. The use of gloves and protective garments is recommended. Preparation should 
occur in a vertical laminar flow biological hood using proper aseptic technique. Reconstituted 
drug product is intended for SC administration at a recommended concentration of 100 mg/mL. 
 
 
 


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10.1.5 Dispensing 
Guadecitabine must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Guadecitabine be stored in a secure area according to local 
regulations. It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to subjects.  
 
10.1.6 Adverse Events 
Please refer to the current version of the Investigator’s Brochure (IB) for additional information 
regarding this drug. 
 
10.2 
Carboplatin 
Please see product package insert for complete details regarding Carboplatin. 
 
10.2.1 Availability  
Carboplatin is commercially available.  
 
10.2.2 Chemical Name  
Carboplatin (carboplatin for injection or platinum diamine [1,1-cyclobutane- decarbozxylate 
(2—0,0’)-,(SP-4-2)]) is a platinum compound used as a chemotherapeutic agent. It will be 
supplied commercially.  
 
10.2.3 Formulation  
Carboplatin is available as a sterile lyophilized powder in single-dose vials containing 50 mg, 
150 mg, or 450 mg of carboplatin. Each vial contains equal parts by weight of carboplatin and 
mannitol. Commercial supplies of carboplatin will be used in this study.  
 
10.2.4 Preparation 
Immediately before use, the contents of a carboplatin vial must be reconstituted with either 
sterile water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride injection, USP. 
The following shows the proper diluent volumes to be used to obtain a carboplatin concentration 
of 10 mg/mL. Carboplatin solution can be further diluted to concentrations as low as 0.5 mg/mL 
with D5W or 0.9% normal saline. Carboplatin reacts with aluminum to form a precipitate and 
cause a loss of potency. Therefore, needles or intravenous sets containing aluminum parts that 
may come in contact with the drug must not be used for the preparation or administration of 
carboplatin.  
 
10.2.5 Storage and Stability 
Intact vials of carboplatin are stable for the period indicated on the package when stored at room 
temperature (15-30°C or 59-86°F) and protected from light.  When prepared as described above, 
carboplatin solutions are stable for 8 hours at room temperature if protected from light. The 
solution should be discarded after 8 hours since no antibacterial preservative is contained in the 
formulation. 
 
10.2.6 Adverse Events Associated with Carboplatin 
Incidence rates of adverse events associated with carboplatin are provided in the product package 
insert.  


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11 
ADVERSE EVENTS 
The descriptions and grading scales found in the NCI CTCAE v5.0 will be utilized for AE 
assessment. A copy of the CTCAE v5.0 can be downloaded from the CTEP website at 
http://ctep.cancer.gov. All forms for AE/SAE recording and reporting can be found in the EDC 
system (Documents and Information Tab). 
 
11.1 
Definitions 
 
11.1.1 Adverse Event  
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
• Unintended or unfavorable sign or symptom 
• A disease temporally associated with participation in the protocol 
• An intercurrent illness or injury that impairs the well-being of the subject 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
 
11.1.2 Serious Adverse Event (SAE) 
A SAE is an adverse event that: 
• Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
• Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 


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11.1.3 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, prescribing information or when it is not included in 
the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.   
 
11.1.4 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  
 
11.2 
Reporting 
 
11.2.1 Adverse Events  
• AEs will be recorded from time of signed informed consent until 30 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
• AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
• All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
• AEs considered related to study drug(s) will be followed until resolution to        
 ≤ Grade 1 or baseline, deemed clinically insignificant, and/or until a new anti-cancer 
treatment starts, whichever occurs first. 
• Asymptomatic laboratory abnormalities that do not require treatment will not be collected 
as adverse events. 
 
11.2.2 Serious Adverse Events (SAEs) 
 
11.2.2.1 
Site Requirements for Reporting SAEs and SUSAR’s to HCRN 
• SAEs will be reported from time of signed informed consent until 30 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
• SAEs will be reported on the SAE Submission Form within 1 business day of discovery 
of the event.   
• SAEs include events related and unrelated to the study drug(s).  


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• All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
• All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 
1 or baseline and/or deemed clinically insignificant and/or until a new anti-cancer 
treatment starts, whichever occurs first. 
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that qualify for 
mandatory expedited reporting to regulatory authorities where the SAE is suspected to be caused 
by the study treatment and is considered unexpected (ie, not defined as expected in the current IB 
clinical study protocol, or approved labeling for marketed drugs). After sponsor-investigator 
assessment, HCRN will report to the relevant regulatory authorities and forward a formal 
notification describing the SUSAR to investigators, according to regulatory requirements. Each 
investigator must then notify his or her IRB/IEC of the SUSAR as required by local regulatory 
authorities and in accordance with IRB/IEC policy. 
 
The site will submit the completed SAE Submission Form to HCRN within 1 business day of 
discovery of the event. The form may be submitted to HCRN electronically to 
safety@hoosiercancer.org. The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies as per local requirements.  The original copy of the SAE Submission 
Form and the email correspondence must be kept within the study file at the study site. 
 
Once the SAE has resolved (see resolution guidelines listed above), sites must submit a follow-
up SAE Submission Form within a reasonable timeframe to HCRN electronically to 
safety@hoosiercancer.org.   
 
11.2.2.2 
HCRN Requirements for Reporting SAEs and SUSARS to Astex   
HCRN will report all SAEs to Astex Drug Safety at drugsafety@astx.com within 1 business 
day of receipt of the SAE Submission Form from a site. If the event is classified as a SUSAR, 
please clearly state in the notification to Astex as such, and include the date of SUSAR 
submission to regulatory agency. Follow-up information will be provided to Astex as it is 
received from site. Every quarter, Astex will provide a list of all SAEs to HCRN that were 
reported to Astex. HCRN will be asked to reconcile this list with the site’s records, and report 
any discrepancies to Astex. 
 
11.3 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.   
 
11.4 
Overdose 
Record the actual dose of study drug administered in the source document and on the appropriate 
eCRF. Record any adverse clinical signs and symptoms associated with a potential overdose on 
the AE eCRFs. Report signs and symptoms of a potential overdose that meet SAE criteria to 
HCRN on the SAE form within 1 business day. Treat any AE (including SAE) based on 
standard care for the specific signs and symptoms. HCRN will report to Astex within 1 business 
day. 


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11.5 
Pregnancy 
Report any pregnancy that occurs in a subject or male subject's female partner during the time 
between the first dose of study treatment and 30 days after the last dose of study treatment. 
Record any occurrence of pregnancy on the Pregnancy Form and send information on the baby 
until the baby is 1 year old to HCRN who will report the information to Astex.  
 
A subject must immediately inform the investigator if the subject or subject's partner becomes 
pregnant during the time between the first dose of study treatment and 30 days after the last dose 
of study treatment. Any female subjects receiving (study treatment) who become pregnant must 
immediately discontinue study treatment. The investigator should counsel the subject, discussing 
any risks of continuing the pregnancy and any possible effects on the fetus. Report any abortion 
and the reason for it, whether therapeutic, elective or spontaneous, to HCRN within 1 business 
day who will report to Astex within 1 business day. 
 
11.6 
HCRN Responsibilities to FDA 
HCRN will manage the Investigational New Drug Application (IND) associated with this 
protocol on behalf of the sponsor-investigator. HCRN will cross-reference this submission to the 
Astex’s parent IND at the time of submission. Additionally, HCRN will submit a copy of these 
documents to Astex and IU DSMC at the time of submission to FDA. 
 
For protocols conducted under an IND, HCRN will be responsible for all communication with 
the FDA in accordance with 21CFR312 including but not limited to the 7 and 15 Day Reports, as 
well as an Annual Progress Report. Additionally, HCRN will submit a copy of these reports to 
Astex and IU DSMC at the time of submission to FDA. 
 
11.7 
IND Safety Reports Unrelated to this Trial 
Astex will provide to HCRN IND safety reports from external studies that involve the study 
drug(s) per their guidelines.  HCRN will forward safety reports to the sponsor-investigator who 
will review these reports and determine if revisions are needed to the protocol or consent. HCRN 
will forward these reports to participating sites within 1 business day of receiving the sponsor-
investigator’s review.  Based on the sponsor-investigator’s review, applicable changes will be 
made to the protocol and informed consent document (if required).  All IND safety reports will 
also be made available to sites via the EDC system.    
 
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
 
 


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12 
STATISTICAL METHODS 
Statistical analysis of this study will be the responsibility of the Department of Biostatistics at 
Indiana University School of Medicine. Parameter estimates and relevant summary statistics will 
be reported for both efficacy and safety outcomes. Continuous variables will be summarized by 
means, medians, minima, maxima, and standard deviations. Categorical variables will be 
summarized by frequencies and percentages. Missing data will not be imputed. Additional 
exploratory analysis will be conducted when appropriate. Changes from the analysis plan will 
not require an amendment to the protocol unless it changes a significant feature in the protocol; 
however, all changes from the original analysis plan will be documented in the final study report. 
The statistical analysis methods are outlined below. 
 
12.1 
Study Design 
This is a Phase II study evaluating the efficacy and safety of Guadecitabine in combination with 
carboplatin in Extensive Stage Small Cell Lung Cancer. The statistical analyses will be primarily 
in the chemotherapy-sensitive group. Chemotherapy-resistant patients will also be enrolled but 
will be described separately. Chemo-sensitivity is defined as a response to initial platinum 
therapy that lasts ≥ 90 days. Chemo-resistance is defined as response to platinum therapy that 
lasts < 90 days. 
 
12.2 
Endpoints 
 
12.2.1 Definition of Primary Endpoint 
PFS is defined as the time from Day 1 of treatment until the criteria for disease progression is 
met as defined by RECIST 1.1, MDA criteria or death as a result of any cause. 
 
12.2.2 Definition of Secondary Endpoints 
• 
Toxicities will be defined by the NCI Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v5. 
• 
Objective response rate (CR+PR) will be assessed via RECIST 1.1 or MDA criteria. 
• 
Disease Control Rate (CR+PR+SD > 8 weeks) will be assessed via RECIST 1.1 or MDA 
criteria. 
• 
Overall survival will be defined as the time from Day 1 of treatment until death from any 
cause. 
 
12.3 
Sample Size and Accrual 
For the chemo-sensitive group, when the sample size is 24, a non-parametric test (single-group) 
with a one-sided 0.10 significance level will have 80% power to detect the difference between a 
median survival of 3.0 months vs 6.0 months assuming an accrual period of approximately 12 
months and maximum follow-up of 24 months (i.e. would allow for up to 12 months of follow-
up after accrual ends).  With 24 in the chemo-sensitive group, we expect to enroll approximate 
34 subjects total, thus will have approximately 10 chemo-resistant patients to generate pilot data.   
 
12.4 
Assessment of Safety 
The safety population will be comprised of all subjects who receive at least one dose of study 
drug.  Safety will be assessed by the NCI CTCAE V5. Please refer to the Study Calendar for the 
schedule of toxicity assessment. 


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12.5 
Assessment of Efficacy 
The efficacy evaluable population will be comprised of all subjects who receive at least one dose 
of study drug and either undergo at least one post-baseline assessment or die before any 
evaluation.  Efficacy will be evaluated using RECIST 1.1 or MDA criteria (for subjects with 
bone only disease). 
 
12.6 
Data Analysis Plans 
 
12.6.1 Analysis Plans for Primary Objective 
In the efficacy evaluable population, in the chemo-sensitive group only the primary endpoint of 
PFS will be separately compared to the historical control rate of 3 months using a one-sided Sign 
Test for censored data (35).  In both the chemo-sensitive and -resistant groups, PFS overall will 
be estimated with a Kaplan-Meier curve and median PFS with a 95% confidence interval.   
 
12.6.2 Analysis Plans for Secondary Objectives 
In the efficacy evaluable population, Objective Response and Disease Control Rate will be 
estimated with 95% confidence intervals.  Overall survival (OS) will be estimated with a Kaplan-
Meier curve and median OS with a 95% confidence interval. Toxicities will be tabulated in the 
Safety Population. All analyses will be separate for the chemo-sensitive and chemo-resistant 
groups. 
 
12.6.3 Analysis Plans for Exploratory Objectives 
Platinum induced DNA adducts in PBMCs and tumor tissue on Cycle 2 Day 5 will be analyzed. 
These will be compared to platinum induced DNA lesions isolated from PBMCs of a control 
group of patients that have completed standard of care treatment with 4 cycles of carboplatin (+ 
etoposide) enrolled under a separate protocol using two-sample t-tests. LINE1 methylation levels 
in PBMCs and baseline tumor biopsy for global DNA methylation status and selected genes, 
IHC expression of EZH2 will be described with box plots and means/standard deviations or 
median/quartiles, as appropriate, at each time point collected and with line plots over-time if 
appropriate. Paired t-tests or Wilcoxon signed-rank tests will be used to compare baseline 
measures to post-treatment measures (for LINE1 in PBMCs, IHC expression of EZH2).   
 
12.6.4 Other Planned Analyses 
For the enrolled population (all subjects who are enrolled onto the trial), descriptive statistics 
will be used to characterize subject demographic and clinical characteristics, disposition, and 
significant protocol violations. In the safety population, concomitant medications and exposure 
will be described. 
 
 
 


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13 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted in accordance with the Indiana University Melvin and Bren Simon 
Cancer Center’s (IUSCC) DSMP for High Risk Safety Lead-In/Phase II Trials.  
 
HCRN oversight activities include: 
• Review and processing of all adverse events requiring expedited reporting as defined in 
the protocol 
• Provide trial accrual progress, safety information and data summary reports to the 
sponsor-investigator, including a weekly update of aggregate AE data. 
• Investigators will conduct continuous review of data and patient safety. For any increase 
in frequency of grade 3 or above adverse events (above the rate reported in the 
Investigator Brochure or package insert), the sponsor investigator will notify HCRN who 
will notify the DSMC Chair immediately. The notification will include the incidence of 
study adverse events, grades, and attributions, as well as investigator statements 
regarding comparison with risks per the IB/ package insert.    
• Notify participating sites of adverse events potentially requiring expedited reporting and 
subsequent DSMC recommendations for study modifications. 
• Investigators will conduct continuous review of data and patient safety.  
• Coordinate monthly meetings which will include representation from each accruing site.  
o These meetings should include review of data, the number of subjects and 
significant toxicities as described in the protocol. HCRN should maintain 
meeting minutes and attendance for submission to the DSMC upon request. 
• Conduct the trial across all participating sites in accordance with the requirements set 
forth in the IUSCC DSMP. 
 
13.2 
Indiana University Melvin and Bren Simon Cancer Center’s Data Safety 
Monitoring Committee 
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of 
subject safety, regulatory compliance, and data integrity for this trial. The DSMC will review 
this study to assess toxicity, compliance, data integrity, and accrual per the Institutional DSMP. 
Trials managed by HCRN are not routinely audited or monitored by IUSCC; however, the 
IUSCC DSMC retains the right to audit HCRN trials on a for cause basis.  
 
The IUSCC DSMC will review study data semi-annually during the active treatment and safety 
follow-up portion of the trial per the IUSCC DSMP. 
 
In preparation for the IUSCC DSMC review, HCRN will provide the following: 
1. Monthly Summary Reports 
2. Reports of the following, if not already included in the Monthly Summary Report: 
o Adverse event summary report (including serious adverse events) 
o Study accrual patterns  
o Protocol deviations 
• Audit and/or monitoring results, if applicable 
• Data related to stopping/decision rules described in study design 


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3. HCRN weekly (Phase I) or monthly (Phase II) study update meeting minutes/ attendance  
 
Documentation of DSMC reviews will be provided to sponsor-investigator (SI) and HCRN.  The 
IUSCC DSMC will notify the sponsor-investigator and other regulatory bodies, as appropriate, 
for issues of immediate concern. The sponsor-investigator will work with HCRN to address the 
DSMC’s concerns as appropriate. 
 
At any time during the conduct of the trial, if it is the opinion of the sponsor-investigator that 
the risks (or benefits) to the patient warrant early closure of the study, this recommendation 
should be made in writing to the DSMC Chair and Compliance Officer. Alternatively, the 
DSMC may initiate suspension or early closure of the study at any time based on its review of 
the study reports.   
 
13.2.1 IND Annual Reports 
For trials with an IND held locally by the IU principal investigator or university, the IND Annual 
Report will be prepared and submitted to the Compliance Team. This report will be reviewed by 
the DSMC at the time of FDA submission. 
 
13.3 
Data Quality Oversight Activities 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study. Automated edit check listings will be used to generate queries in the EDC 
system and transmitted to the site to address in a timely fashion. Corrections will be made by the 
study site personnel.  
 
13.3.1 Onsite Monitoring 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. Additional for cause visits may occur as necessary. Selected source 
documents will be reviewed for verification of agreement with data entered into the EDC system.  
It is important for the site investigator and their relevant personnel to be available for a sufficient 
amount of time during the monitoring visits or audit, if applicable. The site investigator and 
institution guarantee access to source documents by HCRN or its designee. 
 
The trial site may also be subject to quality assurance audit by Astex Pharmaceuticals or its 
designee as well as inspection by appropriate regulatory agencies. 
 
13.4 
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-investigator 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. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects 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 study 
site contact information.   


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14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform (EDC system), a system compliant with Good 
Clinical Practices and Federal Rules and Regulations.  HCRN personnel will coordinate and 
manage data for quality control assurance and integrity. Select data will be collected and entered 
into the EDC system by study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in EDC system or other secure database(s). If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, Astex Pharmaceuticals, IRB, or government agencies, 
like the FDA, may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
 
 


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15 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB to HCRN 
before he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require.  
 
Progress reports and notifications of serious and unexpected adverse events will be provided to 
the IRB according to local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject.  
 
 
 


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