Azacytidine With Valproic Acid Versus Ara-C in Acute Myeloid Leukemia (AML)/ Myelodysplastic Syndrome (MDS) Patients

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00382590
• Collaborator: (none)
• Enrollment: 11
• Location: 1
• Arms: 2
• Duration (Months): 30
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Primary Objective:

1. To evaluate whether 5 azacytidine (5-aza)/valproic acid (VPA) or low dose ara-C produces longer event free survival time in patients age > or = 60 years with untreated Acute Myeloid Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS) who are typically ineligible for, or not placed on, studies of new agents.

Secondary Objective:

1. To evaluate whether pre-treatment methylation/acetylation status in AML/MDS blasts predicts response to either therapy or whether the ability of the 5 azacytidine + valproic acid combination to induce demethylation or acetylation parallels response.

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia; Myelodysplastic Syndrome; Leukemia	Drug: 5-Azacytidine; Drug: Ara-C; Drug: Valproic Acid (VPA)	Phase 2

Detailed Description

5-aza is a chemotherapy drug with activity in leukemia and MDS. Researchers hope that VPA will increase the effects of 5-aza. Low-dose Cytarabine (ara-C) is considered the standard of care for the treatment of leukemia and MDS in older patients not eligible for other therapies.

Before you can start treatment on this study, you will have what are called "screening tests." These tests will help the doctor decide if you are eligible to take part in the study. You will have blood drawn (about 2 teaspoons) for routine tests. You will also have a bone marrow biopsy and aspiration performed. To collect a bone marrow biopsy/aspirate, an area of the hip or chest bone is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle. Women who are able to have children must have a negative blood or urine pregnancy test.

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to one of two treatment groups. Participants in one group will receive 5-aza and VPA. Participants in the other group will receive ara-C alone. At first, there will be an equal chance of being assigned to either group. As the study goes along, however, the chance of being assigned to the treatment that has worked best so far will increase.

Participants in the 5-aza and VPA group will receive 5-aza as an injection under the skin once a day for 7 days in a row. On these same 7 days, participants in this group will also take VPA by mouth twice a day or 3 times a day based on your weight. Seven (7) days is considered 1 treatment cycle. Both drugs will be taken at the same time. Cycles will be repeated every 4 to 6 weeks.

Participants in the ara-C group will receive ara-c twice a day as an injection under the skin for 10 days (1 cycle). Cycles will be repeated every 4 to 6 weeks.

You will be monitored with routine blood tests (about 1-2 teaspoons each time) 2-3 times a week during this study.

You may receive up to 12 cycles of therapy. You may be taken off study early if the disease gets worse or intolerable side effects occur.

Once you go off study, you will have standard follow-up as is required by your primary physician.

This is an investigational study. 5-aza is approved by the FDA for MDS. VPA is approved by the FDA for epilepsy. Their use together in this study is experimental. Ara-C is approved for acute myelogenous leukemia. About 70 patients will take part in this study. All will be enrolled at M. D. Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study of the Combination of 5-Azacytidine With Valproic Acid (VPA) Versus Low-Dose Ara-C in Patients With AML/MDS Not Eligible for Other Studies
• Study Start Date: Aug 1, 2005
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Feb 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 5-Aza + VPA 5-Azacytidine (5-Aza) 75 mg/m^2 subcutaneously daily + Valproic Acid (VPA) 50 mg/m^2 orally daily, each for 7 days	Drug: 5-Azacytidine; 75 mg/m^2 daily for 7 days (days 1-7) via subcutaneous injection.; Other Names: Azacytidine 5-aza Vidaza 5-AZC AZA-CR Ladakamycin ; Drug: Valproic Acid (VPA); 50 mg/m^2 orally daily days 1-7.; Other Names: VPA Depakene
Active Comparator: Ara-C Low-Dose Ara-C 20 mg twice daily subcutaneously for 10 days.	Drug: Ara-C; 20 mg twice daily via subcutaneous injection for 10 days.; Other Names: Cytarabine Cytosar DepoCyt Cytosine arabinosine hydrochloride

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Response [Evaluated every 3 weeks, following 4 courses (16/24 weeks ) and till study end]

   Patient response defined by: Death, Resistant to Therapy [no major hematologic improvement using International Myelodysplastic Syndromes (MDS) Working Group (Cheson B, Bennett J, Kantarjian H et al, Blood 2006) criteria after a maximum of 4 courses], or Relapse.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients must have untreated AML, or untreated MDS with > 10% blasts in marrow or blood.

2. They must be at least age 60.

3. They must either have a serum creatinine > 1.9 mg/ml, a serum bilirubin > 1.9 mg/ml, or a Zubrod performance status of 3 or 4.

4. Alternatively, they must not be candidates for protocols of higher priority.

5. They must provide written consent.

Exclusion Criteria:

1. Must not have the cytogenetic abnormalities inv (16), t (16;16) t (8;21), or t (15;17). The relatively good prognoses of patients with these findings do not warrant use of 5 azacytidine, + valproic acid or low-dose ara-C (LDAC).

Contacts and Locations

Locations

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

Sponsors and Collaborators

• M.D. Anderson Cancer Center

Investigators

• Principal Investigator: Guillermo Garcia-Manero, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• UT MD Anderson Cancer Center website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00382590
• Other Study ID Numbers: 2005-0177
• First Posted: Sep 29, 2006
• Last Update Posted: Aug 7, 2012
• Last Verified: Aug 1, 2012

• Keywords provided by M.D. Anderson Cancer Center: Acute Myelogenous Leukemia; AML; Myelodysplastic Syndrome; Leukemia; MDS; Azacytidine; 5-Azacytidine; 5-aza; Vidaza; 5-AZC; AZA-CR; Ladakamycin; Ara-C; Cytarabine; Cytosar; DepoCyt; Cytosine arabinosine hydrochloride; Valproic Acid; VPA; Depakene
• Additional relevant MeSH terms: Leukemia; Preleukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Syndrome; Cytarabine; Azacitidine; Valproic Acid

Study Results

Participant Flow

Recruitment Details	Recruitment Period: 09/20/05 through 11/01/06. All participants recruited at UT MD Anderson Cancer Center.
Pre-assignment Detail	Eleven (11) patients were registered, one (1) patient was not eligible and was taken off study prior to receiving study drug.

Arm/Group Title	5-Aza + VPA	Ara-C
Arm/Group Description	5-Azacytidine (5-Aza) 75 mg/m^2 subcutaneously daily + Valproic Acid (VPA) 50 mg/m^2 orally daily, each for 7 days	Low-Dose Cytarabine (Ara-C) 20 mg twice daily subcutaneously for 10 days.
Period Title: Overall Study
STARTED	4	6
COMPLETED	4	6
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	5-Aza + VPA	Ara-C	Total
Arm/Group Description	5-Azacytidine (5-Aza) 75 mg/m^2 subcutaneously daily + Valproic Acid (VPA) 50 mg/m^2 orally daily, each for 7 days	Low-Dose Cytarabine (Ara-C) 20 mg twice daily subcutaneously for 10 days.	Total of all reporting groups
Overall Participants	4	6	10
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	75	76.5	75.5
Sex: Female, Male (Count of Participants)
Female	3 75%	1 16.7%	4 40%
Male	1 25%	5 83.3%	6 60%
Region of Enrollment (participants) [Number]
United States	4 100%	6 100%	10 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Response
Description	Patient response defined by: Death, Resistant to Therapy [no major hematologic improvement using International Myelodysplastic Syndromes (MDS) Working Group (Cheson B, Bennett J, Kantarjian H et al, Blood 2006) criteria after a maximum of 4 courses], or Relapse.
Time Frame	Evaluated every 3 weeks, following 4 courses (16/24 weeks ) and till study end

Outcome Measure Data

Analysis Population Description

The analysis was per intention to treat. One participant was inevaluable for response.

Arm/Group Title	5-Aza + VPA	Ara-C
Arm/Group Description	5-Azacytidine (5-Aza) 75 mg/m^2 subcutaneously daily + Valproic Acid (VPA) 50 mg/m^2 orally daily, each for 7 days	Low-Dose Cytarabine (Ara-C) 20 mg twice daily subcutaneously for 10 days.
Measure Participants	4	5
Death	0 0%	0 0%
Resistant to Therapy	4 100%	5 83.3%
Relapse	0 0%	0 0%

Adverse Events

Time Frame	1 Year 2 months
Arm/Group Title	5-Aza + VPA		Ara-C
Arm/Group Description	5-Azacytidine (5-Aza) 75 mg/m^2 subcutaneously daily + Valproic Acid (VPA) 50 mg/m^2 orally daily, each for 7 days		Low-Dose Cytarabine (Ara-C) 20 mg twice daily subcutaneously for 10 days.
All Cause Mortality
	5-Aza + VPA		Ara-C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	5-Aza + VPA		Ara-C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Elevated liver function test	0/4 (0%)	0	1/6 (16.7%)	1
Anemia	0/4 (0%)	0	2/6 (33.3%)	2
Thrombocytopenia	0/4 (0%)	0	1/6 (16.7%)	1
Pancytopenia	1/4 (25%)	1	0/6 (0%)	0
Cardiac disorders
Congestive Heart Failure	0/4 (0%)	0	1/6 (16.7%)	1
Atrail fibrillation	0/4 (0%)	0	1/6 (16.7%)	1
General disorders
Death	1/4 (25%)	1	2/6 (33.3%)	2
Infections and infestations
Infection	1/4 (25%)	1	1/6 (16.7%)	1
Pneumonia	0/4 (0%)	0	1/6 (16.7%)	1
Nervous system disorders
Confusion	1/4 (25%)	1	1/6 (16.7%)	1
Lethargic fall	1/4 (25%)	1	0/6 (0%)	0
Skin and subcutaneous tissue disorders
Rash	1/4 (25%)	1	0/6 (0%)	0
Vascular disorders
Right periocular hemorrhage	0/4 (0%)	0	1/6 (16.7%)	1
Left ocular hemorrhage	0/4 (0%)	0	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	5-Aza + VPA		Ara-C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/4 (50%)		4/6 (66.7%)
Blood and lymphatic system disorders
Anemia	1/4 (25%)	1	1/6 (16.7%)	1
Leukopenia	1/4 (25%)	1	0/6 (0%)	0
Thrombocytopenia	1/4 (25%)	1	0/6 (0%)	0
Cardiac disorders
Arrythmia	0/4 (0%)	0	1/6 (16.7%)	1
chest pain	0/4 (0%)	0	1/6 (16.7%)	1
Gastrointestinal disorders
fatigue	0/4 (0%)	0	1/6 (16.7%)	1
General disorders
Tumor lysis syndrome	1/4 (25%)	1	0/6 (0%)	0
edema	0/4 (0%)	0	1/6 (16.7%)	1
Infections and infestations
Infection	0/4 (0%)	0	1/6 (16.7%)	1
Nervous system disorders
depression	0/4 (0%)	0	1/6 (16.7%)	1
Renal and urinary disorders
Acute Renal Failure	1/4 (25%)	1	0/6 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/4 (25%)	1	0/6 (0%)	0

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.