E7070, Idarubicin and Cytarabine in Relapsed AML and High-Risk Myelodysplastic Syndromes

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01692197
• Collaborator: Eisai Inc. (Industry)
• Enrollment: 43
• Location: 1
• Arm: 1
• Actual Duration (Months): 52.1
• Patients Per Site Per Month: 0.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: E7070; Drug: Idarubicin; Drug: Cytarabine; Drug: Dexamethasone	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of E7070, Idarubicin and Cytarabine in Patients With Relapsed or Refractory Acute Myeloid Leukemia and High-risk Myelodysplastic Syndromes
• Actual Study Start Date: Feb 1, 2013
• Actual Primary Completion Date: Jun 7, 2017
• Actual Study Completion Date: Jun 7, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: E7070 + Idarubicin + Cytarabine 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.

Drug: E7070; 400 mg/m2 intravenously over 1 hour on Day 1 and Day 8 every 3 weeks.; Drug: Idarubicin; 8 mg/m2 by vein over 1 hour daily for 3 days (Days 9-11).; Other Names: Idamycin ; Drug: Cytarabine; 1.0 g/m2 by vein daily on Days 9 - 12 (age <60 years) or Days 9 - 11 (age > 60 years).; Other Names: ARA-C Cytosar DepoCyt Cytosine Arabinosine Hydrochloride ; Drug: Dexamethasone; 10 mg by vein daily for 3 - 4 days with cytarabine.; Other Names: Decadron

Outcome Measures

Primary Outcome Measures

1. Overall Response [2 cycles (60 days)]

   Efficacy measured by overall response - complete response plus complete response with incomplete platelet recovery, plus partial response (Complete remission (CR) + Complete remission without platelet recovery (CRp) + Partial Remission (PR)+ marrow clearance of blast) during cycle 1.

Secondary Outcome Measures

1. Disease-free Survival [Up to 5 years]

   Time from date of treatment start until the date of first objective documentation of disease-relapse.

2. Duration of Response [Up to 5 years]

   Response date to loss of response or last follow up.

3. Overall Survival [Up to 5 years]

   Time from date of treatment start until date of death due to any cause or last follow-up.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. All patients with histologically or cytologically confirmed relapsed or refractory acute myeloid leukemia (AML) [except acute promyelocytic leukemia], or high-risk myelodysplastic syndrome (HRMDS) (Int-2 high risk by International Prostate Symptom Score (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 less than or equal to 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 Principal Investigator (PI) (up to creatinine less than or equal to 2.0), and appropriate dose adjustments will be considered.

5. Patients must have adequate hepatic function (bilirubin less than or equal to 2.0 mg/dl; SGOT or Serum glutamic pyruvic transaminase (SGPT) less than or equal to 3 times the ULN for the reference lab unless due to leukemia or congenital hemolytic disorder or bilirubin). Patients with hepatic dysfunction (SGOT/SGPT up to less than or equal to 5 X ULN) due to organ infiltration by disease may be eligible after discussion with the PI, 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 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 Criteria:

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. 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.

3. Any other medical condition, including mental illness or substance abuse, deemed by the PI 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.

4. Patients must not have received an investigational anti-cancer drug within two weeks of E7070 administration.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Eisai Inc.

Investigators

• Principal Investigator: Gautam Borthakur, MBBS, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 15, 2013

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT01692197
• Other Study ID Numbers: 2009-0570; NCI-2012-02065
• First Posted: Sep 25, 2012
• Last Update Posted: Jul 3, 2018
• Last Verified: Jun 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: 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
• Additional relevant MeSH terms: Leukemia; Preleukemia; Myelodysplastic Syndromes; Cytarabine; Dexamethasone; Idarubicin

Study Results

Participant Flow

Recruitment Details	Recruitment Period: 2/2013 to 06/2014
Pre-assignment Detail	Of the 43 participants registered, three never received the study medication.

Arm/Group Title	E7070 and Idarubicin and Cytarabine
Arm/Group Description	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).
Period Title: Overall Study
STARTED	43
COMPLETED	40
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	E7070 and Idarubicin and Cytarabine
Arm/Group Description	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).
Overall Participants	43
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	25 58.1%
>=65 years	18 41.9%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63
Sex: Female, Male (Count of Participants)
Female	21 48.8%
Male	22 51.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	6 14%
White	36 83.7%
More than one race	0 0%
Unknown or Not Reported	1 2.3%
Region of Enrollment (participants) [Number]
United States	43 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response
Description	Efficacy measured by overall response - complete response plus complete response with incomplete platelet recovery, plus partial response (Complete remission (CR) + Complete remission without platelet recovery (CRp) + Partial Remission (PR)+ marrow clearance of blast) during cycle 1.
Time Frame	2 cycles (60 days)

Outcome Measure Data

Analysis Population Description

Thirty seven patients are evaluable.

Arm/Group Title	E7070 and Idarubicin and Cytarabine
Arm/Group Description	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).
Measure Participants	37
Count of Participants [Participants]	11 25.6%

2. Secondary Outcome

Title	Disease-free Survival
Description	Time from date of treatment start until the date of first objective documentation of disease-relapse.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Thirty seven patients are evaluable.

Arm/Group Title	E7070 + Idarubicin + Cytarabine
Arm/Group Description	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. E7070: 400 mg/m2 intravenously over 1 hour on Day 1 and Day 8 every 3 weeks. Idarubicin: 8 mg/m2 by vein over 1 hour daily for 3 days (Days 9-11). Cytarabine: 1.0 g/m2 by vein daily on Days 9 - 12 (age <60 years) or Days 9 - 11 (age > 60 years). Dexamethasone: 10 mg by vein daily for 3 - 4 days with cytarabine.
Measure Participants	37
Median (Full Range) [months]	1.7

3. Secondary Outcome

Title	Duration of Response
Description	Response date to loss of response or last follow up.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Thirty seven patients are evaluable.

Arm/Group Title	E7070 and Idarubicin and Cytarabine
Arm/Group Description	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).
Measure Participants	37
Median (Full Range) [months]	6.7

4. Secondary Outcome

Title	Overall Survival
Description	Time from date of treatment start until date of death due to any cause or last follow-up.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Thirty seven patients are evaluable.

Arm/Group Title	E7070 and Idarubicin and Cytarabine
Arm/Group Description	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).
Measure Participants	37
Median (Full Range) [months]	5.1

Adverse Events

Time Frame	Adverse Events will be collected beginning from the time the subject signs the study consent until resolution or for 30 days after the participants last study visit.
Arm/Group Title	E7070 and Idarubicin and Cytarabine
Arm/Group Description	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).
All Cause Mortality
	E7070 and Idarubicin and Cytarabine
	Affected / at Risk (%)	# Events
Total	11/40 (27.5%)
Serious Adverse Events
	E7070 and Idarubicin and Cytarabine
	Affected / at Risk (%)	# Events
Total	30/40 (75%)
Blood and lymphatic system disorders
Intracranial Hemorrhage	1/40 (2.5%)	1
Pulmonary edema	1/40 (2.5%)	1
Thromboembolic event	1/40 (2.5%)	1
Cardiac disorders
Atrial Fibrillation	1/40 (2.5%)	2
Cardiac Arrest	1/40 (2.5%)	1
Chest Pain	1/40 (2.5%)	1
Heart Failure	1/40 (2.5%)	1
Hypotension	1/40 (2.5%)	1
General disorders
Allergic Reaction	1/40 (2.5%)	1
Back Pain	1/40 (2.5%)	1
Bone Marrow Hypocellular	1/40 (2.5%)	1
Bone Pain	1/40 (2.5%)	1
Death	2/40 (5%)	2
Fall	1/40 (2.5%)	1
Fatigue	1/40 (2.5%)	1
Fever	1/40 (2.5%)	1
Multi-Organ Failure	1/40 (2.5%)	1
Infections and infestations
Infective Endocarditis	1/40 (2.5%)	1
Febrile Neutropenia	14/40 (35%)	18
Joint Infection	1/40 (2.5%)	2
Lung Infection	11/40 (27.5%)	15
Pelvic Infection	1/40 (2.5%)	1
Sepsis	9/40 (22.5%)	10
Skin Infection	3/40 (7.5%)	3
Upper Respiratory Infection	1/40 (2.5%)	1
Wound Infection	1/40 (2.5%)	1
Investigations
Injection Site Reaction	1/40 (2.5%)	1
Nervous system disorders
Syncope	1/40 (2.5%)	1
Renal and urinary disorders
Hematuria	1/40 (2.5%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/40 (2.5%)	1
Other (Not Including Serious) Adverse Events
	E7070 and Idarubicin and Cytarabine
	Affected / at Risk (%)	# Events
Total	38/40 (95%)
Blood and lymphatic system disorders
Edema	14/40 (35%)	16
Epistaxis	3/40 (7.5%)	3
Hematoma	2/40 (5%)	2
Cardiac disorders
Atrial Fibrillation	3/40 (7.5%)	3
Increased Cardiac Troponin I	2/40 (5%)	2
Chest Pain	3/40 (7.5%)	3
Hypertension	2/40 (5%)	6
Hypotension	5/40 (12.5%)	5
Sinus Tachycardia	5/40 (12.5%)	5
Eye disorders
Eye Disorders	2/40 (5%)	2
Gastrointestinal disorders
Anorexia	11/40 (27.5%)	11
Constipation	13/40 (32.5%)	16
Dehydration	3/40 (7.5%)	3
Diarrhea	17/40 (42.5%)	17
Dry Mouth	2/40 (5%)	2
Dysgeusia	4/40 (10%)	4
Gastroesophageal reflux disease	2/40 (5%)	2
Gastrointestinal disorders	8/40 (20%)	11
Hemorrhoids	2/40 (5%)	2
Hiccups	3/40 (7.5%)	3
Oral Mucositis	3/40 (7.5%)	3
Nausea	21/40 (52.5%)	26
Sore Throat	2/40 (5%)	2
Vomiting	9/40 (22.5%)	12
General disorders
Pain	6/40 (15%)	7
Chills	2/40 (5%)	2
Dizziness	7/40 (17.5%)	7
Fatigue	16/40 (40%)	17
Fever	8/40 (20%)	10
Headache	7/40 (17.5%)	8
Insomnia	6/40 (15%)	6
Lethargy	2/40 (5%)	2
malaise	3/40 (7.5%)	3
Nasal Congestion	2/40 (5%)	2
Infections and infestations
Neutropenic Fever	10/40 (25%)	13
Metabolism and nutrition disorders
Increased Alanine Aminotransferase	9/40 (22.5%)	15
Increased Alkaline Phosphatase	6/40 (15%)	12
Increased Aspartate Aminotransferase	8/40 (20%)	11
Hyperbilirubinemia	14/40 (35%)	28
Increased Creatinine	9/40 (22.5%)	12
Hypercalcemia	2/40 (5%)	2
Hyperglycemia	13/40 (32.5%)	29
Hyperkalemia	4/40 (10%)	6
Hypernatremia	3/40 (7.5%)	3
Hypoalbuminemia	10/40 (25%)	33
Hypocalcemia	12/40 (30%)	23
Hypokalemia	17/40 (42.5%)	33
Hypomagnesemia	16/40 (40%)	20
Hyponatremia	10/40 (25%)	20
Hypophosphatemia	10/40 (25%)	20
Musculoskeletal and connective tissue disorders
Arthralgia	2/40 (5%)	3
Nervous system disorders
Agitation	2/40 (5%)	2
Anxiety	2/40 (5%)	2
Confusion	4/40 (10%)	4
Depression	3/40 (7.5%)	3
Hallucinations	3/40 (7.5%)	3
Renal and urinary disorders
Acute Kidney injury	2/40 (5%)	2
Urinary Retention	2/40 (5%)	3
Respiratory, thoracic and mediastinal disorders
Cough	7/40 (17.5%)	7
Dyspnea	11/40 (27.5%)	11
Hypoxia	3/40 (7.5%)	3
Pleural Effusion	4/40 (10%)	4
Respiratory Failure	2/40 (5%)	2
Respiratory disorders	3/40 (7.5%)	4
Wheezing	2/40 (5%)	2
Skin and subcutaneous tissue disorders
Alopecia	2/40 (5%)	2
Skin and Subcutaneous tissue disorders	13/40 (32.5%)	14
Surgical and medical procedures
Surgical and Medical Procedures	3/40 (7.5%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.