Phase I-II Study of Idarubicin, Cytarabine, and Sorafenib (BAY43-9006)

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00542971
• Collaborator: Bayer (Industry)
• Enrollment: 78
• Location: 1
• Arm: 1
• Duration (Months): 43
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

A primary goal of this clinical research study is to find the highest safe dose of sorafenib that can be given in combination with idarubicin and Ara-C for the treatment of acute myelogenous leukemia (AML) and high-risk, myelodysplastic syndrome (MDS).

Once the highest safe dose is found, researchers will then try to learn if this combination treatment can help control AML and high-risk MDS in newly diagnosed patients. The safety of this treatment combination will also be studied.

Condition or Disease	Intervention/Treatment	Phase
AML; Acute Myeloid Leukemia; Myelodysplastic Disorders	Drug: Idarubicin; Drug: Sorafenib; Drug: Ara-C	Phase 1/Phase 2

Detailed Description

The Study Drugs:

Sorafenib is designed to block the function of important proteins in cancer cells. When active, these proteins help cause abnormal growth and behavior of leukemia cells.

Idarubicin and Ara-C are both designed to insert themselves into DNA (the genetic material of cells) and to stop DNA from repairing itself.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study.

If you are enrolled in the Phase I part of this study, the dose of sorafenib you receive with Ara-C and idarubicin will depend on when you enrolled in this study. Each new group of 3 participants will receive a higher dose level of sorafenib than the previous group until the highest safe dose of sorafenib that can be given in combination with Ara-C and idarubicin is reached.

If you are enrolled in the Phase II portion of this study, you will receive the highest safe dose of sorafenib in combination with Ara-C and idarubicin found in the Phase I part.

Study Drug Administration:

During the study, you will receive treatment over 28-day "cycles." The doses of idarubicin and Ara-C are the same for all study participants.

On Days 1-4 (Days 1-3 if you are older than 60) of each induction cycle (#1 and possibly #2), you will receive Ara-C through a nonstop infusion (through a needle in your vein). You will also receive steroids by mouth or through a vein every day to reduce the risks of side effects, such as rash.

On Days 1-3 of each induction cycle (#1 and possibly #2), you will receive idarubicin by vein over 1 hour once a day.

In general, sorafenib will be taken by mouth twice daily on Days 1-7, unless otherwise instructed. However, the dose of sorafenib may differ among study participants. Sorafenib should be taken with water on an empty stomach. Your study doctor will give you complete instructions on when and how to take sorafenib.

Depending on the side effects that you may have, the dose of sorafenib may be decreased, stopped until side effects go away, or even stopped completely, if your doctor thinks that this is in your best interest.

Study Visits:

During Cycles 1-2, you will have study visits about 2 times a week. You may need to have study visits more often when the study doctor thinks it is necessary. At these visits, you will have the following procedures performed.

• You will be asked about any side effects you may have experienced and any medications you may be taking.

• Blood (about 2 teaspoons) will be drawn for routine tests.

During Cycles 1 and 2, between Days 21-28, you will have a bone marrow aspirate and/or biopsy performed to check the status of the disease.

For Cycle 3 and in further cycles, you will have a bone marrow aspirate as determined necessary by your doctor. If your doctor thinks you have responded to the treatment, you will then have bone marrow aspirates collected every 3-6 months, if your doctor feels this to be necessary.

Consolidation Therapy:

If it is found that the disease is responding to treatment, you may receive 5 additional cycles of therapy. These cycles are called "consolidation" therapy and will be given every 4-6 weeks.

On Days 1-3, Ara-C will be given as a nonstop infusion. You will also receive steroids either by mouth or by vein to help reduce the risk of side effects.

On Days 1-2, idarubicin will be given by vein over 1 hour.

Sorafenib will be taken twice daily by mouth for 7 or more days, at a schedule determined by your study doctor.

After each cycle, about every 4-6 weeks, blood (about 2 teaspoons) will be drawn to check your blood count levels.

Maintenance Therapy:

After 5 cycles of consolidation therapy, and according to your response to consolidation therapy, you may continue on this study to receive "maintenance" treatment, as needed, and as determined by your study doctor for up to 7 more cycles.

You will take sorafenib twice a day every day during the 28-day cycle.

Every 1-4 weeks, blood (about 2 teaspoons) will be drawn for routine tests.

Length of Study:

You may receive up to 14 cycles in total of therapy. You may be taken off this study if the leukemia gets worse, develop another illness that interferes with taking the study drugs, or you have intolerable side effects.

This is an investigational study. Sorafenib is FDA approved and commercially available for the treatment of metastatic renal cancer only. Idarubicin is FDA approved for use in combination with other approved antileukemic drugs for the treatment of acute myeloid leukemia (AML) in adults. Cytarabine is FDA approved for use in the treatment of leukemia. The use of sorafenib combined with idarubicin and Ara-C in the treatment of AML and high-risk MDS is investigational and authorized for use in research only. Up to 75 patients will take part in this study. All patients will be enrolled at M. D. Anderson Cancer Center.

Study Design

• Study Type: Interventional
• Actual Enrollment: 78 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I-II Study of Idarubicin, Cytarabine, and Sorafenib (BAY43-9006), an Oral Vascular Endothelial Growth Factor (VEGF), Rapidly Accelerated Fibrosarcoma (RAF) and FMS-like Tyrosine Kinase 3 (FLT3), in Patients With High-risk MDS and AML
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sorafenib + Idarubicin + Ara-C Sorafenib starting dose 400 mg orally for 7 days; Idarubicin 12 mg/m^2 intravenous (IV) daily (days 1-3); and Ara-C 1.5 g/m^2 IV over 24 hours daily (days 1-4)	Drug: Idarubicin; 12 mg/m^2 IV over 1 hour daily (days 1-3); Other Names: Idamycin® ; Drug: Sorafenib; Starting dose 400 mg by mouth for 7 days; Other Names: Nexavar® ; Drug: Ara-C; 1.5 g/m^2 IV over 24 hours daily (days 1-4); Other Names: Cytarabine Cytosar-U® Arabinosylcytosine

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) [Twice a week for first two 28 day cycles]

   MTD is dose level where grade 3-4 sorafenib-attributable toxicity in <2 of 6 participants. Dose-Limiting Toxicity graded according to the NCI Common Toxicity Criteria version 3.0.

Secondary Outcome Measures

1. Number of Participants With Complete Response [Baseline to 2 years or disease progression.]

   Complete response was defined by the presence of < 5% blasts in the bone marrow (BM) with > 1 x 10^9/L platelets in the peripheral blood (PB).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Diagnosis of 1) AML (World Health Organization classification definition of > 20% blasts), or 2) high risk MDS (defined as the presence of > 10% blasts).

2. Patients aged 15 to 60 years are eligible. Patients older than 60 who are deemed fit to receive intensive chemotherapy by the treating physician are eligible after discussion with the Principal Investigator (PI). For the Phase II portion of the study, patients must be chemo-naïve, i.e. not have received any prior chemotherapy (except hydrea) for AML or MDS. They could have received hypomethylator agents, transfusions, hematopoietic growth factors or vitamins. Temporary prior measures such as pheresis or hydrea are allowed. In the Phase I portion, patients with relapsed or refractory AML/MDS are also eligible.

3. Serum biochemical values with the following limits unless considered due to leukemia:

1. creatinine less than or equal to 2 mg/dl, 2) total bilirubin less than or equal to 2 mg/dL, unless increase is due to hemolysis or congenital disorder, and 3) transaminases (SG PT) less than or equal to 2.5 times upper limit of normal (ULN)

1. Ability to take oral medication.

2. Ability to understand and provide signed informed consent.

3. Baseline test of ejection fraction must be >/=50%.

4. Performance status < 3, unless directly related to the disease process as determined by the principal investigator.

Exclusion Criteria:

1. Patients with Acute promyelocytic leukemia (APL).

2. Any coexisting medical condition that in the judgment of the treating physician is likely to interfere with study procedures or results.

3. Nursing women, women of childbearing potential with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception (such as birth control pills, Intrauterine Device (IUD), diaphragm, abstinence, or condoms by their partner) over the entire course of the study.

4. Any significant, uncontrolled hypertension.

5. Cardiac disease: Congestive heart failure > class II The New York Heart Association (NYHA). Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.

6. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. Sorafenib is contraindicated in patients with known severe hypersensitivity to sorafenib or any of the excipients.

7. Known human immunodeficiency virus (HIV) infection or active Hepatitis B or C.

8. Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.

9. Pulmonary hemorrhage/bleeding event > or = to Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 within 4 weeks of first dose of study drug.

10. Any other hemorrhage/bleeding event > or = to CTCAE Grade 3 within 4 weeks of first dose of study drug.

11. Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.

12. Use of St. John's Wort or rifampin.

13. Known or suspected allergy to sorafenib or any agent given in the course of this trial.

14. Active clinically serious and uncontrolled infection > CTCAE Grade 2

15. Serious non-healing wound, ulcer, or bone fracture

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Texas M.D. Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Bayer

Investigators

• Principal Investigator: Farhad Ravandi-Kashani, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• M.D. Anderson's website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00542971
• Other Study ID Numbers: 2006-0977
• First Posted: Oct 12, 2007
• Last Update Posted: Aug 23, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by M.D. Anderson Cancer Center: Leukemia; AML; High-Risk MDS; Acute Myeloid Leukemia; High-Risk Myelodysplastic Disorder; Idarubicin; Ara-C; Cytarabine; Sorafenib; BAY43-9006
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Cytarabine; Sorafenib; Idarubicin

Study Results

Participant Flow

Recruitment Details	Recruitment Period: October 2007 to February 2009. All participants were registered at The University of Texas M.D. Anderson Cancer Center.
Pre-assignment Detail	Of the 78 participants registered on this study, three (3) were excluded prior to receiving treatment.

Arm/Group Title	Sorafenib + Idarubicin + Ara-C
Arm/Group Description	Sorafenib starting dose 400 mg orally for 7 days; Idarubicin 12 mg/m2 intravenous (IV) daily (days 1-3); and Ara-C 1.5 g/m2 IV over 24 hours daily (days 1-4)
Period Title: Overall Study
STARTED	75
COMPLETED	75
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Sorafenib + Idarubicin + Ara-C
Arm/Group Description	Sorafenib starting dose 400 mg orally for 7 days; Idarubicin 12 mg/m2 intravenous (IV) daily (days 1-3); and Ara-C 1.5 g/m2 IV over 24 hours daily (days 1-4)
Overall Participants	75
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	52
Sex: Female, Male (Count of Participants)
Female	38 50.7%
Male	37 49.3%
Region of Enrollment (participants) [Number]
United States	75 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD)
Description	MTD is dose level where grade 3-4 sorafenib-attributable toxicity in <2 of 6 participants. Dose-Limiting Toxicity graded according to the NCI Common Toxicity Criteria version 3.0.
Time Frame	Twice a week for first two 28 day cycles

Outcome Measure Data

Analysis Population Description

10 participants were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination.

Arm/Group Title	Sorafenib + Idarubicin + Ara-C
Arm/Group Description	Sorafenib starting dose 400 mg orally for 7 days; Idarubicin 12 mg/m2 intravenous (IV) daily (days 1-3); and Ara-C 1.5 g/m2 IV over 24 hours daily (days 1-4)
Measure Participants	10
Number [milligrams/twice a day (BID)]	400

2. Secondary Outcome

Title	Number of Participants With Complete Response
Description	Complete response was defined by the presence of < 5% blasts in the bone marrow (BM) with > 1 x 10^9/L platelets in the peripheral blood (PB).
Time Frame	Baseline to 2 years or disease progression.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sorafenib + Idarubicin + Ara-C
Arm/Group Description	Sorafenib starting dose 400 mg orally for 7 days; Idarubicin 12 mg/m2 intravenous (IV) daily (days 1-3); and Ara-C 1.5 g/m2 IV over 24 hours daily (days 1-4)
Measure Participants	75
Complete Response	54 72%
No Complete Response	21 28%

Adverse Events

Time Frame	2 years, 4 months.
Arm/Group Title	Sorafenib + Idarubicin + Ara-C
Arm/Group Description	Sorafenib starting dose 400 mg orally for 7 days; Idarubicin 12 mg/m2 intravenous (IV) daily (days 1-3); and Ara-C 1.5 g/m2 IV over 24 hours daily (days 1-4)
All Cause Mortality
	Sorafenib + Idarubicin + Ara-C
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Sorafenib + Idarubicin + Ara-C
	Affected / at Risk (%)	# Events
Total	8/78 (10.3%)
Cardiac disorders
Hypertension	2/78 (2.6%)	2
Atrial Fibrillation	1/78 (1.3%)	1
Gastrointestinal disorders
Diarrhea	1/78 (1.3%)	1
Death	3/78 (3.8%)	3
Infections and infestations
Infection	2/78 (2.6%)	2
Metabolism and nutrition disorders
Hyperbilirubinemia	2/78 (2.6%)	2
Elevated Alanine Aminotransferase	1/78 (1.3%)	1
Other (Not Including Serious) Adverse Events
	Sorafenib + Idarubicin + Ara-C
	Affected / at Risk (%)	# Events
Total	47/75 (62.7%)
Blood and lymphatic system disorders
Hemorrhage Bleeding	4/75 (5.3%)	4
edema	5/75 (6.7%)	5
Cardiac disorders
Hypertension	3/75 (4%)	4
Cardiac Arrhythmia	1/75 (1.3%)	1
Cardiac General	1/75 (1.3%)	1
Left Ventricular Systolic Dysfunction	2/75 (2.7%)	2
Hypotension	1/75 (1.3%)	1
Cardiac Ischemia/Infarct	1/75 (1.3%)	1
Gastrointestinal disorders
Diarrhea	23/75 (30.7%)	26
Mucositis	7/75 (9.3%)	7
Nausea	5/75 (6.7%)	5
Anorexia	3/75 (4%)	3
Colitis	1/75 (1.3%)	1
Constipation	1/75 (1.3%)	1
Dysphasia	1/75 (1.3%)	1
General disorders
Death	1/75 (1.3%)	1
Pain	3/75 (4%)	7
Tumor Lysis Syndrome	1/75 (1.3%)	1
Hepatobiliary disorders
Pancreatitis	2/75 (2.7%)	2
Infections and infestations
Febrile Neutropenia	27/75 (36%)	40
Opportunistic Infection	12/75 (16%)	12
Infection	8/75 (10.7%)	9
Metabolism and nutrition disorders
Elevated Alanine Aminotransferase	2/75 (2.7%)	2
Elevated Creatinine	1/75 (1.3%)	1
Bilirubin	6/75 (8%)	6
Nervous system disorders
Mood Alteration	1/75 (1.3%)	1
Seizures	1/75 (1.3%)	1
Syncope	1/75 (1.3%)	1
Renal and urinary disorders
Renal Failure	1/75 (1.3%)	1
Skin and subcutaneous tissue disorders
Skin Rash	1/75 (1.3%)	1
Rash Hand Foot Reaction	9/75 (12%)	11
Rash Desquamation	15/75 (20%)	15

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.