Clinical trial NCT01692197
Conditions: Leukemia
Keywords: Leukemia Acute Myeloid Leukemia Acute Myelogenous Leukemia AML Relapsed or Refractory High-Risk Myelodysplastic Syndromes HRMDS E7070 Idarubicin Idamycin Cytarabine Cytarabine (ARA-C) Cytosar DepoCyt Cytosine Arabinosine Hydrochloride Dexamethasone Decadron
Sponsor: M.D. Anderson Cancer Center
Start date: 2013-02-01; Completion date: 2017-06-07
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if E7070 in combination with idarubicin, cytarabine, and dexamethasone can help to control the disease in patients with either AML or high-risk MDS that has relapsed. The safety of the drug combination will also be studied.

Detailed description:
The Study Drugs:

E7070 is designed to stop metabolic ingredients from reaching the cancer cells and to stop the cancer cell from dividing.

Cytarabine is designed to insert itself into DNA (the genetic material of cells) of cancer cells and stop the DNA from repairing itself.

Idarubicin is designed to cause breaks in both strands of DNA (the genetic material of cells).

Dexamethasone is a corticosteroid that is similar to a natural hormone made by your body. Dexamethasone is often given to AML patients in combination with other chemotherapy to treat cancer.

Study Drug Administration:

If you are found eligible to take part in this study, you will receive E7070 by vein over 1 hour on Day 1 and Day 8 (+/- 2 days on Day 8 only) followed by idarubicin by vein over 1 hour on Days 9-11. You will also receive cytarabine by vein over 24 hours each day on Days 9-12. If you are 60 years of age or older, you will only receive cytarabine on Days 9-11. On days that you are receiving the cytarabine infusions, you will also receive dexamethasone by vein over about 30 minutes. You will receive dexamethasone before the cytarabine infusions. Each study cycle is about 28 days.

If your doctor thinks you are benefitting from taking the E7070 in combination with idarubicin, cytarabine, and dexamethasone, you may receive up to 2 additional cycles of the study drug combination.

Study Visits:

During Cycle 1, the following tests and procedures will be performed:

* You will be asked about medications you are taking and side effects you may have had.
* Blood (about 2 teaspoons) will be drawn at least 1 time every week for routine tests and to check your liver and kidney function.
* You will have a bone marrow aspirate on Day 28 (+/- 3 days) to check the status of the disease. You may have additional bone marrow aspirates during Cycle 2 if the doctor thinks it is necessary.
* During Cycle 1 only, you will have an ECG on Day 2 (+/- 1 day) and Day 8 (+/- 2 days).

Treatment cycles beyond Cycle 1, the following tests and procedures will be performed:

* You will be asked about medications you are taking and side effects you may have had.
* Blood (about 2 teaspoons) will be drawn every 2-4 weeks for routine tests.
* You will have a bone marrow aspirate to check the status of the disease whenever the doctor feels it is necessary.

Length of Study:

If the doctor thinks you are benefitting with E7070 in combination with idarubicin, cytarabine and dexamethasone, you may receive 2 additional cycles of therapy (a total of 3 cycles on this study.)

You will be taken off study if the disease gets worse, you experience intolerable side effects, or if the study doctor thinks it is in your best interest.

End-of-Treatment Visit:

At the end of treatment, blood (about 2 teaspoons) will be drawn for routine tests within 30 days (+/- 5 days) of your last dose of the study drug combination. You will also be asked about any side effects you may have had.

Long Term Follow-up (unless you have started on alternative therapy):

Blood (about 1 tablespoon) will be drawn for routine tests every 2-3 months for up to 2 years unless the disease gets worse or you start on another treatment.

This is an investigational study. E7070 is not FDA-approved or commercially available for use in patients with AML or MDS that has relapsed. Its use in this study is considered investigational. Idarubicin, cytarabine, and dexamethasone are FDA-approved and commercially available for use in the treatment of AML. The combination of E7070, idarubicin, cytarabine, and dexamethasone in this study is investigational.

Up to 40 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: E7070 400 mg/m2 IV over 1 hour on day 1 and day 8 (+/- 2 days on Day 8 only) followed by, Idarubicin 8 mg/m2 IV over 1 hour daily for 3 days (days 9-11) and Cytarabine 1.0 g/m2 IV over 24 hours daily on day 9-12 (age \<60 years) or days 9-11 (age \> 60 years). Dexamethasone 10 mg IV daily for 3-4 days with cytarabine.
Interventions: intervention 1: E7070 intervention 2: Idarubicin intervention 3: Cytarabine intervention 4: Dexamethasone
Intervention descriptions: intervention 1: 400 mg/m2 intravenously over 1 hour on Day 1 and Day 8 every 3 weeks. intervention 2: 8 mg/m2 by vein over 1 hour daily for 3 days (Days 9-11). intervention 3: 1.0 g/m2 by vein daily on Days 9 - 12 (age \<60 years) or Days 9 - 11 (age \> 60 years). intervention 4: 10 mg by vein daily for 3 - 4 days with cytarabine.

Protocol documents:
Prot_SAP_000.pdf: 
2009-0570
November 15, 2013
Page 1
Protocol Page
A Phase 2 Study of E7070, Idarubicin and Cytarabine in Patients with Relapsed or 
Refractory Acute Myeloid Leukemia and High-risk Myelodysplastic Syndromes
2009-0570
Core Protocol Information
Short Title 
E7070, idarubicin and cytarabine in relapsed AML and HR MDS
Study Chair: 
Gautam Borthakur
Additional Contact:
Melodie S. England
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-563-1586
Unit:
428
Full Title: 
A Phase 2 Study of E7070, Idarubicin and Cytarabine in Patients with Relapsed or Refractory 
Acute Myeloid Leukemia and High-risk Myelodysplastic Syndromes
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 06/08/2017
Version:
10
Submitted by:
Melodie S. England--3/21/2014 12:20:05 PM
OPR Action:
Accepted by:  Yolanda Shorte -- 4/7/2014 5:52:19 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2009-0570
November 15, 2013
Page 2
Protocol Body
 


 Protocol # 2009-0570         
November 15, 2013 
Page 1 of 25 
Title: A Phase 2, Open-label Study of E7070, Idarubicin and Cytarabine in Patients with 
Relapsed or Refractory Acute Myeloid Leukemia and High-Risk Myelodysplastic 
Syndromes. 
 
Principal Investigator: 
Gautam Borthakur, MD 
 
 
Protocol Number: 
 
 
2009-0570 
 
Date of Protocol: 
 
 
May 25, 2010  
 
Amendment #1: 
 
 
February 9, 2011 
 
 
Amendment #2: 
 
 
July 11, 2012 
 
Amendment #3: 
 
 
October 3, 2012 
 
Amendment #4: 
 
 
March 14, 2013 
 
Amendment #5: 
 
 
June 21, 2013 
 
Amendment #6: 
 
 
November 15, 2013 
 


 Protocol # 2009-0570         
November 15, 2013 
Page 2 of 25 
 
TITLE 
A Phase 2, Open-label Study of E7070, Idarubicin and 
Cytarabine in Patients with Relapsed or Refractory Acute 
Myeloid Leukemia and High-Risk Myelodysplastic 
Syndromes. 
INVESTIGATORS /  
TRIAL LOCATION 
 
Gautam Borthakur, M.D. 
University of Texas M.D. Anderson Cancer Center 
Dept. of Leukemia, 
1515 Holcombe Blvd., Unit 428 
Houston TX  77030 
SUPPORTER 
Eisai, Inc. 
STUDY OBJECTIVES 
 
Primary objective: 
1. To assess the complete response (CR) and CR with 
incomplete platelet recovery (CRp) rates with 
combination therapy of E7070, idarubicin and cytarabine 
in patients with relapsed or refractory acute myeloid 
leukemia (AML) or high-risk myelodysplastic syndromes 
(HRMDS)  
2. To determine the safety and toxicity profile of 
combination therapy with combination therapy of E7070, 
idarubicin and cytarabine in patients with relapsed or 
refractory AML or HRMDS. 
 
Secondary objectives:  
To determine the: 
1. duration of response; 
2. disease-free survival; and 
3. overall survival 
STUDY DESIGN 
Phase 2 
STUDY POPULATION 
 
Eligibility criteria: 
Inclusion: 
1. All patients with histologically or cytologically confirmed 
relapsed or refractory AML [except acute promyelocytic 
leukemia], or HRMDS (Int-2 high risk by IPSS or >10% blasts 
in marrow). 
2. Patients must be 18 years or older. 
3. Patients must have a performance status of 0-2 (Zubrod 
scale). 
4. Patients must have adequate renal function (serum creatinine 
≤ 1.3 mg/dL and/or creatinine clearance > 40 mL/min). 
Patients with renal dysfunction due to organ infiltration by 
disease may be eligible after discussion with the P.I., (up to 
creatinine ≤ 2.0) and appropriate dose adjustments will be 
considered.  
5. Patients must have adequate hepatic function (bilirubin ≤ 2.0 
mg/dl; SGOT or SGPT ≤ 3X the ULN for the reference lab 
unless due to leukemia or congenital hemolytic disorder or 
bilirubin) excretion disorder. Patients with hepatic dysfunction 
(SGOT/SGPT up to ≤ 5X ULN) due to organ infiltration by 
disease may be eligible after discussion with the P.I., and 
appropriate dose adjustments will be considered. 
6. Patients must have normal cardiac ejection fraction. 
7. QTc interval ≤ 480 msecs.  
8. Patients must sign an informed consent form indicating that 
they are aware of the investigational nature of this study, in 


 Protocol # 2009-0570         
November 15, 2013 
Page 3 of 25 
keeping with the policies of the hospital. 
9. Female patients must not be pregnant or lactating. Female 
patients of childbearing potential (including those <1 year 
post-menopausal) and male patients must agree to use 
contraception. 
Exclusion: 
1. Patients must not have untreated or uncontrolled life-
threatening infection. 
2. Patients must not have received chemotherapy and/or 
radiation therapy within 2 weeks. Hydroxyurea is allowed up 
to 48 hours prior to starting therapy in the setting of rapidly 
proliferating disease.  For details of allowance of hydroxyurea 
use after the start of study drug, please refer to section VI. 
3. Patients must not have received an investigational anti-
cancer drug within two weeks of E7070 administration.   
4. Any other medical condition, including mental illness or 
substance abuse, deemed by the Investigator to be likely to 
interfere with a patient’s ability to sign informed consent or 
cooperate and participate in the study or with the 
interpretation of the results. 
TOTAL EXPECTED NUMBER OF 
PATIENTS 
Up to 40 
STUDY DRUGS 
 
E7070 
Idarubicin 
Cytarabine 
Dexamethasone 
ROUTE OF ADMINISTRATION 
IV 
DOSE REGIMEN 
E7070 400 mg/m2 intravenously (IV) approximately over 1 hour 
on day 1 and day 8: 
Idarubicin 8 mg/m2 IV approximately over 1 hour daily x 3 (days 
9-11) 
Cytarabine 1.0 g/m2 IV approximately over 24 hours daily on day 
9-12 (age <60 years) or days 9-11 (age ≥ 60 years). 
Dexamethasone 10 mg IV daily for 3-4 days with cytarabine 
(Duration is approximately 28 days). 
EVALUATION CRITERIA 
Toxicity will be evaluated using the National Cancer Institute 
(NCI) Version 4.0 criteria.  
DURATION OF STUDY PERIOD 
Patients will continue on study until death, disease progression, 
unacceptable toxicity, patient refusal, or withdrawal from study.    
 


 Protocol # 2009-0570         
November 15, 2013 
Page 4 of 25 
 
Table of Contents 
I. Objective 
5 
II. Background 
5 
III. Background Drug Information 
A. E7070 
B. Cytarabine 
C. Idarubicin 
5 
5 
7 
7 
IV. Study Design 
A. Treatment Plan 
B. Dose Modifications 
9 
9 
10 
V. Patient Eligibility 
10 
VI. Concomitant Medications 
11 
VII. Pretreatment Evaluation 
11 
VIII. Evaluation During Study 
12 
IX. End-of-Treatment Visit 
12 
X. Long Term Followup 
12 
XI. Outside Physician Participation During Treatment 
13 
XII. Schedule of Assessments 
14 
XIII. Criteria for Response for Acute Leukemias and MDS 
15 
XIV. Criteria for Removal from Study 
16 
XV. Adverse Events, Serious Adverse Events and Reporting 
A. Adverse Event 
B. Reporting of Adverse Event 
C. Assessing Severity of Adverse Event 
D. Assessing Relationship to Study Treatment 
E. Classification of Causality 
F. Reporting Requirements 
G. Expedited Reporting 
H. Unexpected Adverse Event 
16 
16 
17 
18 
18 
19 
19 
21 
21 
XVI. Drug Accountability 
22 
XVII. Protocol Administration 
23 
XVIII. Ethical and Regulatory Standards 
23 
XIX. Laboratory Tests 
24 
XX. Statistical Considerations 
24 
XXI. References 
25 
 


 Protocol # 2009-0570         
November 15, 2013 
Page 5 of 25 
I. 
OBJECTIVES 
Primary Objectives 
1. 
To assess the complete response (CR) and CR with incomplete platelet recovery 
(CRp) rates with combination therapy of E7070, idarubicin and cytarabine in patients 
with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic 
syndromes (HRMDS), and. 
2. 
To determine the safety and toxicity profile of combination therapy with combination 
therapy of E7070, idarubicin and cytarabine in patients with relapsed or refractory AML 
or HRMDS. 
Secondary Objectives 
Determine the duration of response, disease-free survival, and overall survival. 
II. 
BACKGROUND 
The Disease 
The cure rates for patients with relapsed or refractory hematological malignancies are dismal.  
Therefore, new agents need to be identified, tested in clinical trials, and incorporated into 
effective regimens to improve the prognosis of these patients.  This study is designed for 
patients with relapsed/refractory AML and HRMDS whose duration of first CR was less than 1 
year.  Once front-line therapy fails, patients’ therapeutic options are limited.  This population of 
patients with disease that has relapsed or is refractory to established frontline therapies has 
response rates of less than 10% to 20%.1  Even if a small proportion of these patients achieve 
a remission, the remissions are short lasting. 
Rationale for Proposed Therapy 
Idarubicin and Cytarabine 
While a combination of an anthracycline (daunorubicin or idarubicin) and cytarabine is 
standard ‘induction’ regimen for patients with newly diagnosed AML, the ‘best’ salvage 
regimen for patients with relapsed disease is unclear. While patients with initial CR duration of 
over 1 year clearly benefit from high-dose cytarabine (HDAC) based regimens, the probability 
of achieving a second CR for patients with shorter first CR duration is very low. Cytogenetics, 
age, failure of prior salvage attempts add to the poor outcome of these patients. Investigational 
agents alone or in combination with traditional chemotherapy in clinical trials should be the 
most appropriate approach for these patients.   
 
III. 
BACKGROUND DRUG INFORMATION 
A. 
E7070 
(Information detailed in Investigator’s Brochure: all references in parentheses are Eisai reports 
outlined in Investigator’s Brochure) 
E7070 is a sulfonamide anticancer agent that was selected out by G1 cell-cycle arrest effect in 
murine leukemia P388 cells and antitumor effect in human tumor xenograft models in mice. 
E7070 induces G1 cell-cycle arrest and delay in G1/S transition in both P388 cells (P1&P2) 


 Protocol # 2009-0570         
November 15, 2013 
Page 6 of 25 
and the colorectal cancer CRC cell line HCT116 (P3).  Cell cycle arrest in these cases is 
followed by induction of apoptosis at higher dose (P2).  These effects of E7070 on cell cycle 
progression and apoptosis were found to be time-dependent (P2). 
Gene expression analysis using high-density oligonucleotide microarrays has revealed that 
E7070 treatment causes characteristic repression of subsets of genes involved in redox 
metabolism, cell cycle control, immune response, and signal transduction (P5). A significant 
reduction in DNA topoisomerase II alpha and glutathione synthetase transcripts may provide a 
molecular basis for combination therapy with irinotecan (CPT-11) and platinum agents, 
respectively. 
Proteomic studies using E7070-based affinity matrixes have identified cytosolic malate 
dehydrogenase (cMDH) as a specific binding protein of E7070.  cMDH is a critical metabolic 
enzyme involved in the malate-aspartate shuttle, gluconeogenesis, and glycolysis. It catalyses 
the reversible conversion of oxaloacetate to malate using nicotinamide adenine dinucleotides 
(NAD and NADH) as cofactors.  The core structure of E7070 competes with NADH in binding 
to cMDH at a physiologically relevant concentration (P6). It has yet to be demonstrated that 
this binding property is a prerequisite for the antitumor activity of E7070. 
Potential interactions with other medications 
Human liver microsomal studies have shown that there is potential for CYP450 (CYP2C9, 
2C19 and 3A4) inhibition by indisulam.  As a consequence, there is a hypothetical chance of 
an interaction between indisulam and a number of drugs.  Some drugs with which this 
interaction may be observed have a relatively narrow therapeutic index and so are of potential 
concern.  The most important of these are listed below:  
• 
oral anticoagulants 
• 
terfenadine, cisapride, cyclosporin, tacrolimus 
• 
theophylline 
• 
diazepam 
• 
sulphonylurea anti-diabetics 
• 
phenytoin and carbamazepine.   
There have been reports of drug interactions between E7070 and oral anticoagulants. Three 
patients from the Phase I program who were receiving chronic therapy with the oral 
anticoagulant acenocoumarol experienced bleeding and/or a further prolongation of the 
prothrombin time following treatment with E7070 at a dose of 700 mg/m2 given as a 1-hour 
infusion.  A pharmacokinetic study was performed to investigate this interaction further. The 
results indicate that E7070 may primarily interact with acenocoumarol by reducing its systemic 
clearance.  Displacement of adenocoumarol’s plasma protein binding by E7070 may also 
occur, but to a minor extent.  In view of these findings, clinicians are advised to exercise 
caution during the introduction and after the withdrawal of E7070 therapy in patients stabilized 
on oral anticoagulation. 
Pre-clinical work outlined below indicates synergy of E7070 with traditional chemotherapeutic 
agents. 
E7070 Dosing 
 
Section 5.4.1 Table 34 in the Investigator’s Brochure is the summary for recommended phase 
2 doses for single agent E7070 and for the weekly schedule, 400 mg/m2 weekly times four is 


 Protocol # 2009-0570         
November 15, 2013 
Page 7 of 25 
the recommended dose. In our proposed study, the dose of E7070 is scheduled at 400 mg/m2 
weekly times two to allow for the addition of chemotherapy and to avoid undue toxicity with the 
combination.  
 
Moreover, in a phase 2 study (E7070-E044-214) combining E7070 with chemotherapy, the 
dose of E7070 was 400 mg/m2 with irinotecan 125 mg/m2 on days 1 and 8 in a 21 day cycle 
(Table 5.5.5 Page 93 of Investigator Brochure) and this was tolerated with acceptable level of 
toxicity (diarrhea, vomiting, cytopenias being most frequent toxicities). 
 
These data has been used to arrive at the proposed doses in the current protocol.   
 
The doses of idarubicin and cytarabine to be administered are lower than the usual 12mg and 
1.5 gram per meter squared that is usually used, to avoid undue toxicity when combined with 
E7070. 
 
B. 
Cytarabine 
 
Cytarabine (Ara-C, Cystosar) is commercially available from Pharmacia, ON, Canada L4W 
5J5 or other manufacturers. 
 
Cytarabine is an antimetabolite that is cell cycle specific. It is a pyrimidine analogue that 
affects rapidly dividing cells in the S phase and inhibits cell development from G1 to S phase. 
Cytarabine is primarily metabolized in the liver, with a half-life of 1 to 3 hours. Eighty to ninety 
percent of the drug is excreted in the bile. Moderate amounts of the drug cross the blood-brain 
barrier, and cytarabine has been shown to cross the placental barrier.  
 
How Supplied: Cytarabine is available in a freeze-dried preparation in multi-dose vials, 100 mg 
and 500 mg. The solution pH is 5.0 when reconstituted. 
 
Solution preparation: Five ml of bacteriostatic H2O for injection (made with 5% dextrose or 
normal saline) should be added to 100 mg to get 50 mg cytarabine per ml. Diluents containing 
benzyl alcohol should not be used. 
 
Stability and storage: Before mixing, cytarabine is stable at room temperature. After mixing, 
reconstituted solutions are chemically stable at room temperature for eight days. 
 
Route of administration: Intravenous. 
 
Overdosage: Doses up to 3 gm/m2 for six doses have been used.  
PRECAUTIONS: Dexamethasone 0.1% eye drops (1-2 drops every 6 hours for 2-7 days) 
should be administered to all patients to ameliorate conjunctivitis. 
C. 
Idarubicin  
 
Idarubicin is commercially available and will not be supplied for this protocol. Please see 
package insert for further information.  
 
Synonyms: 4-Demethoxydaunorubicin; 4-DMDR, Idarubicin Hydrochloride, IDR: IMI 30; NSC-
256439, SC 33428, Idamycin  
 


 Protocol # 2009-0570         
November 15, 2013 
Page 8 of 25 
Use: Treatment of acute leukemias (AML, ANLL, ALL), accelerated phase or blast crisis of 
chronic myelogenous leukemia (CML), breast cancer  
 
Contraindications: Hypersensitivity to idarubicin, other anthracyclines, or any component of the 
formulation; bilirubin >5 mg/dl; pregnancy  
 
Warnings/Precautions: The U.S. FDA currently recommends that procedures for proper 
handling and disposal of antineoplastic agents be considered. Can cause myocardial toxicity 
and is more common in patients who have previously received anthracyclines or have 
preexisting cardiac disease; reduce dose in patients with impaired hepatic function.  
 
Adverse Reactions: >10%: Cardiovascular: Transient EKG abnormalities (supraventricular 
tachycardia, S-T wave changes, atrial or ventricular extrasystoles); generally asymptomatic 
and self-limiting. Congestive heart failure, dose-related. The relative cardiotoxicity of idarubicin 
compared to doxorubicin is unclear. Some investigators report no increase in cardiac toxicity 
at cumulative oral idarubicin doses up to 540 mg/m2; other reports suggest a maximum 
cumulative intravenous dose of 150 mg/ m2. Other cardiovascular side effects include 
arrhythmias, chest pain, and myocardial infarction.  
Central nervous system: Headache  
Dermatologic: Alopecia (25% to 30%), radiation recall, skin rash (11%), urticaria  
Oral: mucositis 10-20%  
Gastrointestinal: Nausea, vomiting (30% to 60%); diarrhea (9% to 22%); stomatitis (11%); GI 
hemorrhage (30%)  
Genitourinary: Discoloration of urine (darker yellow)  
Hematologic: Myelosuppression, primarily leukopenia; thrombocytopenia and anemia. Nadir: 
10-15 days Recovery: 21-28 days  
Hepatic: Elevations of bilirubin and transaminases (44%) 1% to 10%:  
Central nervous system: Seizures  
Neuromuscular & skeletal: Peripheral neuropathy <1%: Hyperuricemia  
 
Overdosage/Toxicology: Symptoms of overdose include severe myelosuppression and 
increased GI toxicity. Treatment is supportive. It is unlikely that therapeutic efficacy or toxicity 
would be altered by conventional peritoneal or hemodialysis.  
 
Drug Interactions: Patients may experience impaired immune response to vaccines; possible 
infection after administration of live vaccines in patients receiving immunosuppressants  
 
Stability: Store intact vials of solution under refrigeration (2°C to 8°C/36°F to 46°F); protect 
from light. Solutions diluted in D5W or NS for infusion are stable for 4 weeks at room 
temperature and 7 days under refrigeration.  
 
Mechanism of Action: Similar to doxorubicin and daunorubicin; inhibition of DNA and RNA 
synthesis by intercalation between DNA base pairs  
 
Pharmacodynamics/Kinetics: Absorption: Oral: Variable (4% to 77%; mean: ~30%) 
Distribution: Vd: 64 L/kg (some reports indicate 2250 L)  
 
Metabolism: Hepatic to idarubicinol (pharmacologically active)  
 
Half-life elimination: Oral: 14-35 hours; I.V.: 12-27 hours Time to peak, serum: 1-5 hours  
 
Excretion: Oral: Urine (~5% of dose; 0.5% to 0.7% as unchanged drug, 4% as idarubicinol); 
hepatic (8%) 


 Protocol # 2009-0570         
November 15, 2013 
Page 9 of 25 
 
I.V.: Urine (13% as idarubicinol, 3% as unchanged drug); hepatic (17%)  
 
Dosage: Refer to individual protocols.  
I.V.:  Leukemia induction: 12 mg/m2/day for 3 days  
Leukemia consolidation: 4-8 mg2/m/day for 2 days  
 
Extravasation management: Topical cooling may be achieved using ice packs or cooling with 
circulating ice water. Cooling of site for 24 hours as tolerated by the patient. Elevate and rest 
extremity 24-48 hours, then resume normal activity as tolerated. Application of cold inhibits 
vesicant's cytotoxicity. Application of heat can be harmful and is contraindicated. If pain, 
erythema, and/or swelling persist beyond 48 hours, refer patient immediately to plastic 
surgeon for consultation and possible debridement.  
 
IV. 
STUDY DESIGN 
This is a phase 2 study of E7070 in combination with idarubicin and cytarabine in patients with 
relapsed/refractory AML with a particular focus towards patients with primary refractory 
disease or who are receiving first salvage therapy or beyond. Patients with newly diagnosed 
AML who do not qualify for front-line induction studies will also be eligible.  HRMDS patients 
will also be eligible. Patients will be treated according to the schedule below: 
 
A. 
Treatment Plan 
 
E7070 400 mg/m2 intravenously (IV) approximately over 1 hour on day 1 and day 8 (± 2 
days on Day 8 only) followed by:  
 
• Idarubicin 8 mg/m2 IV approximately over 1 hour daily x 3 (days 9-11) and 
• Cytarabine 1.0 g/m2 IV approximately over 24 hours daily on day 9-12 (age <60 
years) or days 9-11 (age ≥ 60 years). 
• Dexamethasone 10 mg IV daily for 3-4 days with cytarabine 
 
Variations in infusion times due to minor differences in IV bag overfill/underfill and 
institutional procedure on flushing chemotherapy lines will not result in protocol 
deviation. 
 
Patient will undergo disease assessment on day 28 ± 3 days at the discretion of 
treating physician. This assessment can be repeated or delayed at the discretion of 
treating physician if there is ground to believe that the patient is benefiting from study 
drug. Patients who derive clinical benefit e.g. CR, CRp, PR or marrow clearance of 
blasts may receive up to two additional cycles of E7070 in combination with 
chemotherapy at the above doses. Each cycle will be approximately 28 days (+/- 2 
days). Dose modifications and delays are allowed for persistent cytopenias or non-
hematological toxicities.   
 
Patients not achieving less than an objective response after cycle 1 may receive 
another cycle of therapy if considered to be in best interest by investigator. If such a 
patient achieves an objective response as defined in response criteria after the second 
cycle may receive one more cycle of therapy on study. If a patient does not achieve an 
objective response after two cycles of therapy, the patient will be removed from study 
for lack of response. 
 


 Protocol # 2009-0570         
November 15, 2013 
Page 10 of 25 
 
 
 
 
 
B. 
Dose modification will be according to Table 1: 
 
Table 1 
 
Dose level 0 
Dose level -1 
Dose level -2 
E7070 
400 mg/m2 
25% reduction
50% reduction 
Cytarabine 
1 gm/m2 
0.75 gm/m2 
0.5 gm/m2 
Idarubicin 
8 mg/m2 
6 mg/m2 
4 mg/m2 
 
V. 
PATIENT ELIGIBILITY:   
 
INCLUSION: 
1. All patients with histologically or cytologically confirmed relapsed or refractory AML [except 
acute promyelocytic leukemia], or HRMDS (Int-2 high risk by IPSS2 or >10% blasts in 
marrow). 
 
2. Patients must be 18 years or older. 
 
3. Patients must have a performance status of 0-2 (Zubrod scale). 
 
4. Patients must have adequate renal function (serum creatinine ≤ 1.3 mg/dL and/or 
creatinine clearance > 40 mL/min). Patients with renal dysfunction due to organ infiltration 
by disease may be eligible after discussion with the P.I., (up to creatinine ≤ 2.0) and 
appropriate dose adjustments will be considered.  
 
5. Patients must have adequate hepatic function (bilirubin ≤ 2.0 mg/dl; SGOT or SGPT ≤ 3X 
the ULN for the reference lab unless due to leukemia or congenital hemolytic disorder or 
bilirubin). Patients with hepatic dysfunction (SGOT/SGPT up to ≤ 5X ULN) due to organ 
infiltration by disease may be eligible after discussion with the P.I., and appropriate dose 
adjustments will be considered.  
 
6. Patients must have normal cardiac ejection fraction. 
 
7. QTc interval ≤ 480 msecs. 
 


 Protocol # 2009-0570         
November 15, 2013 
Page 11 of 25 
8. Patients must sign an informed consent form indicating that they are aware of the 
investigational nature of this study, in keeping with the policies of the hospital. 
 
9. Female patients must not be pregnant or lactating. Female patients of childbearing 
potential (including those <1 year post-menopausal) and male patients must agree to use 
contraception. 
 
EXCLUSION: 
1. Patients must not have untreated or uncontrolled life-threatening infection. 
 
2. Patients must not have received chemotherapy and/or radiation therapy within 2 weeks. 
Hydroxyurea is allowed up to 48 hours prior to starting therapy in the setting of rapidly 
proliferating disease. (For details of allowance of hydroxyurea use after the start of study 
drug please refer to section VI 
 
3. Patients must not have received an investigational anti-cancer drug within two weeks of 
E7070 administration.   
 
4. Any other medical condition, including mental illness or substance abuse, deemed by the 
Investigator to be likely to interfere with a patient’s ability to sign informed consent or 
cooperate and participate in the study or with the interpretation of the results. 
 
VI. 
CONCOMITANT MEDICATIONS:  
Use of hydroxyurea to control proliferative disease will be allowed starting from day 2 until day 
7 Cycle 1. Maximum dose of hydroxyurea allowed daily is 5 gram and hydroxyurea must be 
discontinued once administration of idarubicin and cytarabine is started. 
VII  
PRETREATMENT EVALUATION (within 7 days of start of study drug except 
where noted) 
 
• 
History and Physical Examination to include vital signs and weight.   
 
• 
CBC with differential platelets, glucose, total protein, albumin, electrolytes [sodium, 
potassium, chloride, CO2], calcium, phosphorus, magnesium, uric acid, bilirubin (total, 
direct), SGPT (ALT) or SGOT (AST), alkaline phosphatase, lactate dehydrogenase, 
creatinine, blood urea nitrogen. 
 
• 
Record all concomitant medications and baseline adverse events. 
 
• 
Bone marrow aspirate and/or biopsy (within one month), and cytogenetics, unless these 
tests were done within 3 months. 
 
• 
Chest x-ray (PA and lateral) [at or within one month of screening]. 
 
• 
Electrocardiogram [at or within 1 month of screening]. 
 
• 
Evaluation of cardiac ejection fraction (MUGA or ECHO) (at or within 1 month of 
screening). 
 


 Protocol # 2009-0570         
November 15, 2013 
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• 
Urine or blood pregnancy test for women of childbearing potential (within 7 days prior to 
day 1). 
 
• 
ECOG assessment. 
 
 
VIII. 
EVALUATION DURING STUDY 
 
• 
CBC, differential (if WBC > 109/L), every 4-7 days during Cycle 1 and every 1 to 4 weeks 
during Cycle 2. 
 
• 
Record all concomitant medications and adverse events: continuously during study. 
 
• 
Disease assessment: Cycle 1, Day 28 (+/- 3 days) 
 
• 
Electrocardiogram on Day 2 (+/- 1 day) and Day 8 (+/- 2 days) of Cycle 1 done at least 1 
hour after completion of E7070 infusion. 
 
• 
Bone marrow aspiration on day 28 (+/- 3 days) and as indicated at the discretion of the 
treating physician until documentation of response.  Bone marrow examinations may be 
omitted in patients where there is clear evidence of active disease (e.g., increasing blasts 
in peripheral blood). 
 
• 
Creatinine, total bilirubin, electrolytes, AST and/or ALT once every week during induction 
Cycle 1, then every 2-4 weeks during Cycle 2. 
 
• 
Safety lab assessments (CBC, differential, platelets, creatinine, total bilirubin, electrolytes, 
AST and/or ALT) can be performed by local physician, see Section X.  
 
IX. 
END-OF-TREATMENT VISIT (30 days [+/- 5 days] after the last dose of study 
drug), unless the patient has started on alternative therapy 
 
• 
CBC, platelet count, differential 
• 
Serum chemistries (creatinine, total bilirubin, electrolytes, AST and/or ALT) 
• 
Record adverse events  
 
 
X. 
LONG TERM FOLLOW-UP (unless the patient has started on alternative therapy) 
 
Patients will have blood counts and chemistry studies every 2-3 months for up to 2 years.  
These can be done by a local physician.  If the counts are abnormal and relapse is suspected, 
patients will return to M. D. Anderson for additional evaluation of their disease. See Section X. 
 


 Protocol # 2009-0570         
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XI. 
OUTSIDE PHYSICIAN PARTICIPATION DURING TREATMENT AND LONG-TERM 
FOLLOW-UP 
• 
MDACC Physician communication with the outside physician is required prior to the patient 
returning to the local physician. This will be documented in the patient record 
• 
A letter to the local physician outlining the patient's participation in a clinical trial will 
request local physician agreement to supervise the patient's care (Appendix H) 
• 
Protocol required evaluations outside MDACC will be documented by telephone, fax or e-
mail.  Fax and/or e-mail will be dated and signed by the MDACC physician, indicating that 
they have reviewed it. 
• 
Changes in drug dose and/or schedule must be discussed with and approved by the 
MDACC physician investigator, or their representative prior to initiation, and will be 
documented in the patient record. 
• 
A copy of the informed consent, protocol abstract, treatment schema and evaluation during 
treatment will be provided to the local physician. 
• 
Documentation to be provided by the local physician will include drug administration 
records, progress notes, reports of protocol required laboratory and diagnostic studies and 
documentation of any hospitalizations. 
• 
The home physician will be requested to report to the MDACC physician investigator all life 
threatening events within 24 hours of documented occurrence. 
• 
Patients will return to MDACC every month for evaluation prior to subsequent cycles. 
       


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XII. 
SCHEDULE OF ASSESSMENTS 
Procedure 
Pre 
treatment 
(Within 7 days 
of start of 
study drug  
except where 
noted) 
Cycle 1 
Cycle 2-3 
End-of-
Treatment 
(30 days [+/- 5 
days] after the 
last dose of 
study drug) 
Long Term 
Follow-up 
(unless the 
patient has 
started on 
alternative 
therapy) 
Medical History 
X 
 
 
 
 
Physical 
examination11 
 
X 
 
 
 
 
ECOG 
assessment 
X 
 
 
 
 
Hematology1 
X 
Every 4-7 days
Every 1-4 
weeks 
X 
Every 2-3 
months for 
up to 2 
years2 
Serum Chemistry 
X3 
Once each 
week4 
X4
X 
Every 2-3 
months for 
up to 2 
years2,4 
Bone Marrow 
aspirate and/or 
biopsy 
 
X5 
Day 28  
(+/- 3 days)6 
 
 
 
Chest x-ray 
X7 
 
 
 
 
Electrocardiogram 
X7 
Day 2  
(+/-1 day) and  
Day 8  
(+/-2 days)8 
 
 
 
Evaluation of 
cardiac ejection 
fraction (MUGA or 
ECHO) 
 
X7 
 
 
 
 
Urine or blood 
pregnancy test 
X9 
 
 
 
 
Dosing  
(see Study 
Design) 
 
Day 1 and Day 
812 
(+/- 2 days) 
Day 1 and 
Day 8 
(+/- 2 days) 
 
 
 
Disease 
Assessment 
 
Day  28 
(+/- 3 days)10 
 
 
 
Adverse Events 
X 
Continuous 
 
Concomitant  
Medications 
X 
Continuous 
 
 
1 To include CBC with differential platelets 
2 Tests can be performed by local physician.   
3 To include glucose, total protein, albumin, electrolytes [sodium, potassium, chloride, CO2], calcium, phosphorus, 
magnesium, uric acid, bilirubin (total, direct), SGPT (ALT) or SGOT (AST), alkaline phosphatase, lactate dehydrogenase, 
creatinine, blood urea nitrogen will be performed at least weekly. 
4 Creatinine, total bilirubin, electrolytes, AST and/or ALT once every week during Cycle 1, then every 2-4 weeks during 
Cycles 2-3. 
5 Within one month, to include cytogenetics, unless these tests were done within 3 months.  
6 And as indicated until documentation of response.  Bone marrow examinations may be omitted in patients where there is 
clear evidence of active disease (e.g., increasing blasts in peripheral blood) 
7 At or within 1 month of screening 
8 Done at least 1 hour after completion of E7070 infusion if EKG is done on the day of the E7070 infusion day 
 9 For women of childbearing potential within 7 days prior to day 1 


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10 If patient is found to be CR, CRp, PR or marrow clearance of blasts, may receive up to 2 additional cycles of E7070 in 
combination with chemotherapy 
11To include vital signs and weight 
12 Approximately every 28 days to 2 additional cycles 
 
XIII. 
CRITERIA FOR RESPONSE FOR ACUTE LEUKEMIAS AND MDS 
International Working Group Criteria3, 4 will be used to define response. 
 
1. Complete remission (CR):  The patient must be free of all symptoms related to leukemia 
and have an absolute  neutrophil count ≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L, and 
normal bone marrow differential (≤ 5% blasts). 
 
2. Complete remission without platelet recovery (CRp): As per CR but platelet count  < 100 x 
109/L. 
 
3. Partial remission (PR): CR with 6 to 25% abnormal cells in the marrow or 50% decrease in 
bone marrow blasts.   
 
4. Marrow CR:  Bone marrow:   ≤5% myeloblasts and decrease by ≥ 50% over pre-treatment 
(MDS only) 
 
5. Morphologic leukemia-free state:  Normal marrow differential (<5% blasts); neutrophil and 
platelet counts are not considered.  (AML only) 
 
6. Hematologic Improvement (HI):  HI should be described by the number of individual, 
positively affected cell lines (e.g. HI-E; HI-E + HI-N; HI-E + HI-P +HI-N) 
 
a) Erythroid response (HI-E):   
 
• 
Major response:  For patients with pretreatment hemoglobin less than 11 g/dL, 
greater than 2 g/dL increase in hemoglobin; for RBC transfusion-dependent 
subjects, transfusion independence. 
• 
Minor response:  For patients with pretreatment hemoglobin less than 11 g/dL, 1 to 
2 g/dL increase in hemoglobin; for RBC transfusion-dependent patients, 50% 
decrease in transfusion requirements.  
 
b) Platelet response (HI-P): 
• 
Major response:  For patients with a pretreatement platelet count less than 100 x 
109/L, an absolute increase of 30 x 109/L or more; for platelet transfusion-
dependent patients, stabilization of platelet transfusion independence. 
• 
Minor response:  For patients with a pretreatment platelet count less than 100 x 
109/L, a 50% or more increase in platelet count with a net increase greater than 10 
x 109/L but less than 30 x 109/L. 
 
c) Neutrophil response (HI-N): 
• 
Major response:  For absolute neutrophil count (ANC) less than 1.5 x 109/L before 
therapy, at least a 100% increase, or an absolute increase of more than 0.5 x 
109/L, whichever is greater. 
• 
Minor response:  For ANC less than 1.5 x 109/L before therapy, ANC increase of at 
least 100%, but absolute increase less than 0.5 x 109/L. 
 


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7. Progression/relapse after HI:  One or more of the following:  a 50% or greater decrement 
from maximum response levels in granulocytes or platelets, a reduction in hemoglobin 
concentration by at least 2 g/dL, or transfusion. 
 
 
XIV. 
CRITERIA FOR REMOVAL FROM THE STUDY 
 
The investigator may remove patients from the study for any of the following reasons: 
 
• 
Clinically significant progressive disease 
• 
Failure to achieve any clinically significant response after two cycles of therapy  
• 
Unacceptable adverse events/toxicities 
• 
Investigator thinks a change of therapy would be in the best interest of the patient (e.g. 
potential for worsening of existing infection or other toxicities) 
• 
The patient has an intercurrent, non-leukemia-related illness that would, in the judgment 
of the investigator, affect assessments of clinical status to a significant degree and require 
discontinuation of protocol therapy 
• 
Patient request 
• 
Patient is non-compliant with protocol requirements 
 
 
XV. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND REPORTING 
 
A. Adverse Event (AE): Any untoward medical occurrence in a subject or clinical 
investigation subject administered an investigational product.  An AE does not 
necessarily have a causal relationship with the medicinal product.  For this study, 
the medicinal product is E7070. 
The criteria for identifying AEs are: 
• Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product 
• Any new disease or exacerbation of an existing disease 
• Any deterioration in non-protocol-required measurements of laboratory value or 
other clinical test (e.g., ECG or X-ray) that results in symptoms, a change in 
treatment, or discontinuation from study drug 
• Recurrence of an intermittent medical condition (e.g. headache) not present at 
Baseline. 
An abnormal laboratory test result may be considered as an adverse event if the 
identified laboratory abnormality leads to any type of intervention whether 
prescribed in the protocol or not. 


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A laboratory result should be considered by the Investigator to be an adverse event 
if it: 
• results in the withdrawal of study treatment 
• results in withholding of study treatment pending some investigational outcome 
• medical evaluation, results in the initiation of an intervention (e.g. potassium 
supplement for hypokalemia) 
• Any out of range laboratory value that in the Investigator’s judgment, fulfills the 
definitions of an AE with regards to subject’s medical profile 
• Increases in severity compared to Baseline by ≥ 2 NCI grades (see Appendix A 
for NCI CTCAE Ver 4.0 criteria), with the exception of lymphocytes, albumin, 
cholesterol, glucose and phosphate.  For these tests, a change of ≥ 2 grades 
will be evaluated by the Investigator to determine if they are of clinical 
significance and if so, will be considered an adverse event. 
Abnormal laboratory values should not be listed as separate AEs if they are 
considered to be part of the clinical syndrome that is being reported as an AE.  Any 
laboratory abnormality considered to constitute an adverse event should be 
reported on the Adverse Event Case Report Form (CRF). 
It is the responsibility of the Investigator to review all laboratory findings in all 
subjects and determine if they constitute an adverse event.  Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
B. Reporting of Adverse Events 
Adverse events will be recorded by the research personnel on a MDACC Adverse 
Event log.  The Investigator or physician designee is responsible for verifying and 
providing source documentation for all adverse events and assigning the attribution 
for each event for all subjects enrolled on the trial.  Adverse event logs will be 
scanned into Clinic Station when a patient is removed from study or approximately 
every 6 months. 
 
For this protocol, adverse events and protocol specific data will be entered into 
PDMS/CORe.  PDMS/CORe will be used as the electronic case report form for this 
protocol. 
All AEs encountered during the clinical study will be reported on the CRF.  All AEs, 
regardless of relationship to study drug or procedure, should be collected 
beginning from the time the subject signs the study consent.  Adverse events in 
clinical investigation subjects include any change in the subject’s condition.  This 
includes symptoms, physical findings, or clinical syndromes. 
Subjects with AEs that are ongoing at the subject’s last study visit must be followed 
until resolution or for 30 days after the subject’s last study visit, whichever comes 


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first.  Adverse events that are reported during the Follow-up Period will be recorded 
on the Adverse Events CRF and followed until resolution or for up to the 30 days 
after the subject’s last study visit, whichever comes first, with the exception that 
SAEs will be followed until the event resolves or the event or sequelae stabilize. 
Every effort must be made by the Investigator to categorize each AE 
according to its severity and its relationship to the study treatment. 
C. Assessing Severity of Adverse Events 
The National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE Ver 4.0) is used to assign severity scales to AEs (Appendix A).  
They are: 
Grade 1 = Mild 
Grade 2 = Moderate 
Grade 3 = Severe 
Grade 4 = Life Threatening 
Grade 5 = Death 
AEs that are not defined in the NCI CTCAE should be evaluated for severity 
according to the following scale: 
Grade 1 = Mild 
Grade 2 = Moderate 
Grade 3 = Severe 
In addition, all AEs reported using the NCI CTCAE classification and graded as 4 
or 5 are to be considered serious. 
The criteria for assessing severity are different than those used for seriousness. 
D. Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study 
treatment are: 
• Temporal relationship of the onset of the event to the initiation of the study 
treatment 
• The course of the event, considering especially the effect of discontinuation of 
study treatment or reintroduction of study treatment, as applicable 
• Whether the event is known to be associated with the study treatment, or with 
other similar treatments 
• The presence of risk factors in the study subject known to increase the 
occurrence of the event 


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• The presence of non-study treatment related factors which are known to be 
associated with the occurrence of the event 
E. Classification of Causality 
Not Related:  A causal relationship between the study treatment and the AE is not 
a reasonable possibility. 
Related:  A causal relationship between the study treatment and the AE is a 
reasonable possibility. The Investigator must further qualify the degree of certainty 
as “possible” or “probable.” 
F. REPORTING REQUIREMENTS  
Reporting requirements will be as per institutional guidelines. 
Adverse events (AE) related to study conditions 
The serious adverse event (SAE) reporting period will begin with the signing of the 
informed consent.   
AEs should be followed to resolution or stabilization, and reported as SAEs if they 
become serious.  This also applies to patients experiencing AEs that cause 
interruption or discontinuation of investigational product, or those experiencing AEs 
that are present at the end of their participation in the study.  Such patients should 
receive post-treatment follow-up as appropriate. 
 
Serious Adverse Event Reporting (SAE)  
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience that, 
had it occurred in a more severe form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32). 
 


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• 
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
• 
All events occurring during the conduct of a protocol and meeting the definition of a 
SAE must be reported to the IRB in accordance with the timeframes and procedures 
outlined in “The University of Texas M. D. Anderson Cancer Center Institutional Review 
Board Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs 
and Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or 
unexpected, must be reported to the IND Office, regardless of attribution (within 5 
working days of knowledge of the event). 
• 
All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office.   
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete 
and laboratory tests have returned to baseline, progression of the event has stabilized, 
or there has been acceptable resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may include 
the development of a secondary malignancy. 
 
Reporting to FDA: 
 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional 
Review Board policy. 
 
G. Expedited Reporting 
Eisai, Inc. must inform Investigators and regulatory authorities of reportable events, 
in compliance with applicable regulatory requirements, on an expedited basis (i.e., 
within specific timeframes).  For this reason, it is imperative that investigational 
sites provide complete SAE information in the manner described above. 
H. An Unexpected Adverse Event is one that is not listed in the current Clinical 
Investigator’s Brochure (CIB) / Package Insert or that differs from the event 
mentioned in the CIB / Package Insert because of greater severity or specificity.  
 
Causality is a determination of whether there is a reasonable possibility that the 
drug may have caused or contributed to an adverse event. It includes assessing 
temporal relationships, dechallenge/rechallenge information, association (or lack of 


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association) with underlying diseases, and the presence (or absence) of one or 
more likely causes. 
 
The investigator must attempt to determine whether an adverse event is in some 
way related to the use of the study drug.  This relationship should be described as 
follows: 
 
Unlikely:  The event is clearly due to causes distinct from the use of the study 
drug, such as a documented pre-existing condition, the effect of a concomitant 
medication, or a new condition that, based on the pathophysiology of the condition 
and the pharmacology of the study drug, is unlikely to be related to the use of the 
study drug. 
 
Possible: The event follows a reasonable temporal sequence from administration 
of the study drug or the event follows a known response pattern to the study drug, 
but the event could have been produced by a concomitant medication or an 
intercurrent medical condition which, based on the pathophysiology of the condition 
and the pharmacology of the study drug, is unlikely to be related to the use of the 
study drug.  
 
Probable: The event follows a reasonable temporal sequence from administration 
of the study drug and the event follows a known response pattern to the study drug 
and the event cannot be reasonably explained by an intercurrent medical condition 
or the event cannot be the effect of a concomitant medication. 
 
Definite: The event follows a reasonable temporal sequence from administration 
of the study drug, the event follows a known response pattern to the study drug, 
and based on the known pharmacology of the study drug, the event is clearly 
related to the effect of the study drug. 
 
Unknown:  Based on the evidence available, causality cannot be ascribed. 
 
Please see Appendix G regarding data capturing of adverse events and adverse 
events source documentation. 
 
XVI. 
DRUG ACCOUNTABILITY 
 
The Investigator and study staff will be responsible for the accountability of all clinical 
supplies (dispensing, inventory, and record keeping) following Eisai, Inc. instructions 
and adhere to GCP guidelines as well as local and / or regional requirements.  
 
Under no circumstances will the Investigator allow the study drug to be used other 
than as directed by this protocol. Clinical supplies will not be administered to any 
individual who is not enrolled in the study.  
 
An accurate and timely record of the receipt of all clinical supplies, administration of 
study drug to the subject, and subsequent destruction of all used and unused study 


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drug must be maintained. This includes, but may not be limited to: (a) documentation 
of receipt of clinical supplies, (b) study drug dispensing/return reconciliation log, 
(unused vials will be shipped back, all used vials should be destroyed on-site per 
MDACC institutional policy) (c) study drug accountability log, and (d) all shipping 
service receipts. All forms will be provided by Eisai, Inc. Any comparable forms that 
the investigational site wishes to use must be approved by Eisai, Inc.  
 
The supplies and inventory records must be made available, upon request, for 
inspection by the designated representative of Eisai, Inc., a representative of the Food 
and Drug Administration, or a representative of a non-U.S. health authority. All used 
and unused study drug, including empty containers, are to be accounted for and 
destroyed according to site policy and procedure throughout the course of the trial.  
 
The CRAs will review drug accountability during investigational site visits and at the 
completion of the study.  
 
 
XVII. PROTOCOL ADMINISTRATION 
 
Study Organization 
 
Institution:  
The University of Texas M. D. Anderson Cancer Center 
Address: 
Department of Leukemia 
1515 Holcombe Blvd, Unit 428 
 
 
 
Houston, TX 77030 
 
 
 
Principal Investigator:  
Gautam Borthakur, M.D. 
 
 
 
 
 
Phone: (713)  563-1586 
 
 
 
 
 
Fax:   (713)  794-4297 
 
 
 
 
 
Email: gborthak@mdanderson.org  
 
 
 
 
 
XVIII. ETHICAL AND REGULATORY STANDARDS 
 
Ethical Principles 
 
The study will be conducted according to the principles outlined by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments; the International Conference on 
Harmonization Guidelines for Good Clinical Practice; and FDA regulations regarding the 
conduct of clinical trials and the protection of human subjects.  
 
Informed Consent 
 
It is the responsibility of the Investigator to obtain written informed consent from a patient or a 
patient’s legal representative before any study-related procedures are performed.  The 
Investigator will provide an informed consent in compliance with ICH, GCP, and U.S. FDA 
guidelines (21 CFR 50).  The informed consent document must clearly describe the potential 


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risks and benefits of the trial, and each prospective participant must be given adequate time to 
discuss the trial with the Investigator or site staff and to decide whether or not to participate.  
The informed consent must be approved by the IRB prior to being presented to a potential 
patient.    
 
One copy of the patient's signed, dated, and witnessed written consent will be kept in the 
patient’s medical record, and one copy will be given to the patient or the patient’s legal 
representative. 
 
Institutional Review Board (IRB) Approval 
 
The Investigator must obtain approval of the protocol, the informed consent document, and 
any other material used to inform the patient about the nature of the trial from the local IRB in 
the form of a written letter.  In the approval letter, which must be signed by the Chairperson of 
the IRB or the Chairperson’s designee, the following items should be clearly stated:  trial title, 
protocol number and version, study-related documents (protocol, informed consent material, 
advertisement when applicable), IRB review date, and IRB decision.  The trial should not start 
until a copy of this written approval has been received by the Investigator. 
 
If the Investigator is a member of the IRB, the Investigator may participate in any discussion of 
the study but may not participate in the final vote deciding whether to approve the study.  
 
Annually, or more often if stipulated by the IRB, and at the completion or termination of the 
study, the Investigator will report the progress of the trial to the IRB. 
 
Additional Responsibilities of the Investigator 
 
The Investigator(s) agrees to perform the study in accordance with ICH Good Clinical Practice 
and FDA regulations.  The Investigator is required to ensure compliance with respect to the 
investigational drug schedule, visit schedule, and procedures required by the protocol.  
 
The Investigator should be able to recruit the required number of suitable patients and should 
have sufficient time to properly conduct and complete the trial.  The Investigator should have 
available an adequate number of qualified staff and adequate facilities for the duration of the 
trial and should ensure that all persons assisting with the trial are adequately informed about 
the protocol, the protocol-defined procedures, protocol therapy, and trial-related duties and 
functions. 
 
The Investigator should be responsible for all trial-related medical decisions.  During and 
following a patient’s participation in a trial, the investigator should ensure that adequate 
medical care is provided to a patient for any adverse events related to the trial.   
 
 
Confidentiality 
 
It is the responsibility of the Investigator to ensure that the confidentiality of all patients 
participating in the trial and all of their medical information is maintained.  Case report forms 
must never contain the name of a trial patient.  All case report forms and any identifying 
information must be kept in a secure location, with access limited to the study staff directly 
participating in the trial.  Personal medical information may be reviewed by a representative of 
Eisai, Inc., of the IRB, or of regulatory authorities in the course of auditing the trial.  Every 
reasonable effort will be made to maintain such information as confidential. 
 


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XIX. 
LABORATORY TESTS 
 
All labs for eligibility determination and bone marrow aspirations and/or biopsy for disease 
evaluation will be done at MD Anderson Cancer Center.  Safety labs and Long Term Follow-up 
labs may be done with patients’ local physician.   See Section XI. 
 
 
 
XX. 
STATISTICAL CONSIDERATIONS 
 
The objective of this study is to assess the efficacy and safety of treatment of E7070 with 
chemotherapy in Leukemia patients. The efficacy will be measured by the overall response 
(CR + CRp + PR+ marrow clearance of blast) during Cycle 1. The sample size and stopping 
rules will be determined according to Simon’s two-stage design. 
 
The efficacy will be assessed based on the Simon’s two-stage Minmax design. The new 
treatment will be considered promising if the response rate is 25% or higher, and will be 
considered unworthy of further investigation if response rate is 10% or less.  The maximum 
sample size of 40 patients is chosen to differentiate between response rates of 10% and 25% 
with 90% power at a significance level of 0.1. In particular, 27 patients will be enrolled at the 
first stage. If there are two or fewer patients with response, the trial will be terminated; 
otherwise another 13 patients will be treated for a total of 40 patients. If, among 40 patients, 
there are 6 or fewer patients with response, the treatment will be concluded ineffective. The 
probability of early termination due to futility is 0.48. 
 
A Bayesian sequential monitoring method5 will be used to monitor the toxicity. We stop the trial 
if the toxicity is likely to be greater than 33%. That is, stop the trial if  
Prob {toxicity rate > 33% | data} > 0.80. 
The prior distribution of toxicity rate is assumed to be beta (0.67, 1.33).  Following this rule, the 
trial will be terminated due to toxicity if [# toxicity]/[# patients evaluated] ≥  2/3, 3/5, 4/7, 5/10, 
6/13, 7/15, 8/18, 9/20, 10/23, 11/26, 12/28, 13/31, 14/34, 15/37, or 16/40. 
 
A toxic event will be defined as death or a CTCAE 4.0 grade 3/4 non-hematological toxicity 
related to study drug lasting or 7 days or more. 
 
Descriptive statistical analysis will be calculated, including histograms or box-plots, 
proportions, range, means and standard deviations. Fisher’s exact test and Wilcoxon rank test 
will be used in univariate analyses of categorical and continuous variables, respectively. 
Overall response (CR + CRp + PR) rate and its 95% confidence interval will be estimated 
using a binomial distribution. Overall survival and progression free survival functions will be 
estimated using the Kaplan-Meier method. The two-sided log-rank test will be used to examine 
the difference of survival functions among different groups. Toxicity will be reported by type, 
frequency and severity. Worst toxicity grades per patient will be tabulated for selected adverse 
events and laboratory measurements. 
 


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November 15, 2013 
Page 25 of 25 
XXI. 
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