Phase 2 Study of Temozolomide to Treat Poor Risk / Refractory Acute Myeloid Leukemia

• Sponsor: Bruno C. Medeiros (Other)
• Overall Status: Completed
• CT.gov ID: NCT00611247
• Collaborator: Schering-Plough (Industry)
• Enrollment: 42
• Location: 1
• Arms: 2
• Duration (Months): 25
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

Open-label, non-randomized, parallel assignment, phase 2 trial assessing the safety and efficacy of distinct temozolomide treatment regimens for patients with AML and poor prognosis

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid	Drug: Temozolomide	Phase 2

Detailed Description

This is a single institution phase 2 clinical trial evaluating the efficacy, safety, and tolerability of tailored temozolomide therapy for patients with acute myeloid leukemia (AML) and poor risk features.

Patients will be assigned to 1 of 2 parallel treatment groups based on their AGAT promoter region methylation status, as determined by PCR.

Patients achieving a complete remission after 1 to 2 cycles of chemotherapy will be eligible to receive up to an additional 5 cycles of temozolomide of 5 or 19 days, depending on the methylation status of the AGAT promoter (consolidation phase).

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Two Distinct Tailored Temozolomide Regimens for Patients With Acute Myeloid Leukemia Age > 60 Years and Poor Risk/Refractory Disease
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Jan 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Methylated AGAT Promoter (Group 1) Induction: 200 mg/m2/day oral Temozolomide x 7 days	Drug: Temozolomide; Priming, Group 2 only, 100 mg/m2/day temozolomide. Induction (both arms) 200 mg/m2/day temozolomide; Other Names: Temodar, Temodal
Experimental: Un-Methylated AGAT Promoter (Group 2) Priming: 100 mg/m2/day oral Temozolomide x 14 days, followed by Induction: 200 mg/m2/day oral Temozolomide x 7 days	Drug: Temozolomide; Priming, Group 2 only, 100 mg/m2/day temozolomide. Induction (both arms) 200 mg/m2/day temozolomide; Other Names: Temodar, Temodal

Outcome Measures

Primary Outcome Measures

1. Response Rate (CR + CRi + LFS) [up to 2 months]

   Response determined per European LeukemiaNet response criteria: CR = bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count > 1.0 x 10e9/L; platelet count > 100 x 10e9/L; and independence of red cell transfusions. CRi = all CR criteria except for residual neutropenia (< 1.0 x 10e9/L) or thrombocytopenia (< 100 x 10e9/L)]. Morphologic leukemia-free state (LFS) = bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; with no hematologic recovery required. Relapse = bone marrow blasts >5%; reappearance of blasts in the blood; or development of extramedullary disease.

Secondary Outcome Measures

1. Toxicity Profile: Total Number of Drug-related Serious Adverse Events [12 months]

2. Toxicity Profile: Individual Subjects With Drug-related SAEs [12 months]

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 histologically or cytologically confirmed Acute Myeloid Leukemia, as defined by the WHO classification.

2. Patients must be considered unfit for conventional induction chemotherapy, unwilling to receive such treatment or have evidence of disease relapse or refractory disease.

3. For patients who have received no prior conventional chemotherapy, one of the following must be present:

• Poor risk cytogenetics (complex abnormalities, deletions of chromosome 7 or 5, 11q23 abnormalities, inv[3])

• Secondary leukemia (prior hematologic disorder or therapy-related leukemia).

1. Age > 60 years of age.

2. Life expectancy of greater than 3 months.

3. ECOG performance status greater than 2.

4. Patients must have normal organ and marrow function as defined below:

5. Adequate hepatic function: Total bilirubin 1.5mg/dL, AST(SGOT)/ALT(SGPT) 2.5 X institutional upper limit of normal.

6. Adequate renal function: serum creatinine within normal institutional limits or Calculated creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

7. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.

2. Patients may not be receiving any other investigational agents.

3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or DTIC

4. History of gastrointestinal disease or significant bowel resection that could interfere with drug absorption.

5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

6. Prior allogeneic stem cell transplantation.

7. Inability to swallow tablets

8. Prior radiation up to more than 25% of bone marrow.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• Bruno C. Medeiros
• Schering-Plough

Investigators

• Principal Investigator: Bruno Carneiro de Medeiros, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bruno C. Medeiros, PI, Stanford University
• ClinicalTrials.gov Identifier: NCT00611247
• Other Study ID Numbers: IRB-07815; 97611; SU-12142007-936; HEMAML0004; NCT00426309
• First Posted: Feb 8, 2008
• Last Update Posted: Jun 15, 2018
• Last Verified: May 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Temozolomide

Study Results

Participant Flow

Recruitment Details	42 subjects consented to screening for this study.
Pre-assignment Detail	6 of 42 subjects did not meet eligibility criteria and did not receive induction therapy. Of these, 1 subject had no evidence of AML; 1 had acute lymphoblastic leukemia, and 4 had disease progression and death before induction. None of the 6 were stratified to a treatment group, and were not treated on study.

Arm/Group Title	Methylated AGAT Promoter (Group 1)	Un-Methylated AGAT Promoter (Group 2)
Arm/Group Description	Induction: 200 mg/m2/day oral Temozolomide x 7 days	Priming: 100 mg/m2/day oral Temozolomide x 14 days, followed by Induction: 200 mg/m2/day oral Temozolomide x 7 days
Period Title: Overall Study
STARTED	5	31
COMPLETED	3	10
NOT COMPLETED	2	21

Baseline Characteristics

Arm/Group Title	Methylated AGAT Promoter (Group 1)	Un-Methylated AGAT Promoter (Group 2)	Total
Arm/Group Description	Induction: 200 mg/m2/day oral Temozolomide x 7 days	Priming: 100 mg/m2/day oral Temozolomide x 14 days, followed by Induction: 200 mg/m2/day oral Temozolomide x 7 days	Total of all reporting groups
Overall Participants	5	31	36
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	77	75	75
Sex: Female, Male (Count of Participants)
Female	2 40%	11 35.5%	13 36.1%
Male	3 60%	20 64.5%	23 63.9%

Outcome Measures

1. Primary Outcome

Title	Response Rate (CR + CRi + LFS)
Description	Response determined per European LeukemiaNet response criteria: CR = bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count > 1.0 x 10e9/L; platelet count > 100 x 10e9/L; and independence of red cell transfusions. CRi = all CR criteria except for residual neutropenia (< 1.0 x 10e9/L) or thrombocytopenia (< 100 x 10e9/L)]. Morphologic leukemia-free state (LFS) = bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; with no hematologic recovery required. Relapse = bone marrow blasts >5%; reappearance of blasts in the blood; or development of extramedullary disease.
Time Frame	up to 2 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Methylated AGAT Promoter (Group 1)	Un-Methylated AGAT Promoter (Group 2)
Arm/Group Description	Induction: 200 mg/m2/day oral Temozolomide x 7 days	Priming: 100 mg/m2/day oral Temozolomide x 14 days, followed by Induction: 200 mg/m2/day oral Temozolomide x 7 days
Measure Participants	5	31
Number [participants]	3 60%	10 32.3%

2. Secondary Outcome

Title	Toxicity Profile: Total Number of Drug-related Serious Adverse Events
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Methylated AGAT Promoter (Group 1)	Un-Methylated AGAT Promoter (Group 2)
Arm/Group Description	Induction: 200 mg/m2/day oral Temozolomide x 7 days	Priming: 100 mg/m2/day oral Temozolomide x 14 days, then followed by Induction: 200 mg/m2/day oral Temozolomide x 7 days
Measure Participants	5	31
Number [events]	4	27

3. Secondary Outcome

Title	Toxicity Profile: Individual Subjects With Drug-related SAEs
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Methylated AGAT Promoter (Group 1)	Un-Methylated AGAT Promoter (Group 2)
Arm/Group Description	Induction: 200 mg/m2/day oral Temozolomide x 7 days	Priming: 100 mg/m2/day oral Temozolomide x 14 days, then followed by Induction: 200 mg/m2/day oral Temozolomide x 7 days
Measure Participants	5	31
Number [participants]	4 80%	13 41.9%

Adverse Events

Arm/Group Title	Methylated AGAT Promoter (Group 1)		Un-Methylated AGAT Promoter (Group 2)
Arm/Group Description	Induction: 200 mg/m2/day oral Temozolomide x 7 days		Priming: 100 mg/m2/day oral Temozolomide x 14 days, then followed by Induction: 200 mg/m2/day oral Temozolomide x 7 days
All Cause Mortality
	Methylated AGAT Promoter (Group 1)		Un-Methylated AGAT Promoter (Group 2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Methylated AGAT Promoter (Group 1)		Un-Methylated AGAT Promoter (Group 2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/5 (80%)		28/31 (90.3%)
Blood and lymphatic system disorders
Anemia	1/5 (20%)	1	1/31 (3.2%)	1
Febrile neutropenia	4/5 (80%)	5	13/31 (41.9%)	21
Blood and lymphatic system disorders - Other, Pancytopenia	0/5 (0%)	0	1/31 (3.2%)	1
Hypoalbuminemia	0/5 (0%)	0	1/31 (3.2%)	1
Cardiac disorders
Atrial fibrillation	1/5 (20%)	1	1/31 (3.2%)	1
Gastrointestinal disorders
Abdominal pain	1/5 (20%)	1	1/31 (3.2%)	1
Arthralgia	1/5 (20%)	1	0/31 (0%)	0
Rectal hemorrhage	0/5 (0%)	0	1/31 (3.2%)	1
Oral Pain	1/5 (20%)	1	0/31 (0%)	0
General disorders
Multi-organ failure	0/5 (0%)	0	1/31 (3.2%)	1
Sudden death NOS	0/5 (0%)	0	2/31 (6.5%)	2
Death NOS	1/5 (20%)	1	3/31 (9.7%)	3
Infections and infestations
Mucosa infection	0/5 (0%)	0	1/31 (3.2%)	1
Sepsis	0/5 (0%)	0	2/31 (6.5%)	2
Injury, poisoning and procedural complications
Fall	0/5 (0%)	0	1/31 (3.2%)	1
Investigations
Creatinine increased	0/5 (0%)	0	1/31 (3.2%)	1
Platelet count decreased	1/5 (20%)	2	10/31 (32.3%)	14
Neutrophil count decreased	1/5 (20%)	3	12/31 (38.7%)	17
White blood cell decreased	1/5 (20%)	3	6/31 (19.4%)	6
Metabolism and nutrition disorders
Hyponatremia	0/5 (0%)	0	1/31 (3.2%)	1
Nervous system disorders
Depressed level of consciousness	0/5 (0%)	0	1/31 (3.2%)	1
Renal and urinary disorders
Urinary tract infection	0/5 (0%)	0	1/31 (3.2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/5 (0%)	0	1/31 (3.2%)	1
Pulmonary fibrosis	0/5 (0%)	0	1/31 (3.2%)	1
Respiratory, thoracic and mediastinal disorders - Other, fever/pneumonia	0/5 (0%)	0	1/31 (3.2%)	1
Respiratory, thoracic and mediastinal disorders - Other, Multilobar pneumonia	0/5 (0%)	0	1/31 (3.2%)	1
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other, Rash	0/5 (0%)	0	1/31 (3.2%)	1
Vascular disorders
Hypotension	0/5 (0%)	0	1/31 (3.2%)	1
Other (Not Including Serious) Adverse Events
	Methylated AGAT Promoter (Group 1)		Un-Methylated AGAT Promoter (Group 2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/5 (60%)		23/31 (74.2%)
Blood and lymphatic system disorders
Anemia	2/5 (40%)	5	19/31 (61.3%)	36
Blood and lymphatic system disorders - Not otherwise specified	1/5 (20%)	1	1/31 (3.2%)	2
Febrile neutropenia	1/5 (20%)	1	3/31 (9.7%)	3
Lymph node pain	1/5 (20%)	1	0/31 (0%)	0
Hemolysis	0/5 (0%)	0	2/31 (6.5%)	2
Cardiac disorders
Atrial fibrillation	0/5 (0%)	0	2/31 (6.5%)	2
Cardiac disorders - Not otherwise specified	1/5 (20%)	1	1/31 (3.2%)	1
Eye disorders
Eye disorders - Not otherwise specified	1/5 (20%)	1	0/31 (0%)	0
Gastrointestinal disorders
Abdominal distension	0/5 (0%)	0	3/31 (9.7%)	4
Abdominal pain	0/5 (0%)	0	5/31 (16.1%)	8
Constipation	0/5 (0%)	0	8/31 (25.8%)	11
Diarrhea	0/5 (0%)	0	6/31 (19.4%)	7
Mucositis oral	0/5 (0%)	0	3/31 (9.7%)	3
Nausea	0/5 (0%)	0	10/31 (32.3%)	13
Rectal hemorrhage	0/5 (0%)	0	2/31 (6.5%)	2
Rectal Pain	0/5 (0%)	0	2/31 (6.5%)	2
Vomiting	0/5 (0%)	0	5/31 (16.1%)	7
General disorders
Edema limbs	0/5 (0%)	0	6/31 (19.4%)	11
Fatigue	3/5 (60%)	7	19/31 (61.3%)	24
Fever	1/5 (20%)	3	2/31 (6.5%)	2
Localized edema	1/5 (20%)	1	0/31 (0%)	0
Pain	0/5 (0%)	0	3/31 (9.7%)	4
Infections and infestations
Lip infection	1/5 (20%)	1	0/31 (0%)	0
Infections and infestations - Not otherwise specified	0/5 (0%)	0	4/31 (12.9%)	5
Injury, poisoning and procedural complications
Bruising	0/5 (0%)	0	2/31 (6.5%)	2
Investigations
Activated partial thromboplastin time prolonged	1/5 (20%)	2	0/31 (0%)	0
Alanine aminotransferase increased	0/5 (0%)	0	4/31 (12.9%)	7
Alkaline phosphatase increased	1/5 (20%)	2	4/31 (12.9%)	4
Blood bilirubin increased	1/5 (20%)	1	0/31 (0%)	0
Creatinine increased	2/5 (40%)	4	8/31 (25.8%)	11
Neutrophil count decreased	1/5 (20%)	1	3/31 (9.7%)	7
Platelet count decreased	1/5 (20%)	2	13/31 (41.9%)	19
Weight loss	1/5 (20%)	1	4/31 (12.9%)	4
White blood cell decreased	1/5 (20%)	2	9/31 (29%)	19
Aspartate aminotransferase increased	0/5 (0%)	0	2/31 (6.5%)	3
Metabolism and nutrition disorders
Anorexia	1/5 (20%)	2	8/31 (25.8%)	9
Hyperglycemia	2/5 (40%)	5	13/31 (41.9%)	18
Hypoalbuminemia	2/5 (40%)	4	10/31 (32.3%)	17
Hypocalcemia	1/5 (20%)	2	5/31 (16.1%)	5
Hypokalemia	1/5 (20%)	4	0/31 (0%)	0
Hypomagnesemia	1/5 (20%)	1	2/31 (6.5%)	2
Hyponatremia	1/5 (20%)	2	7/31 (22.6%)	9
Musculoskeletal and connective tissue disorders
Arthralgia	0/5 (0%)	0	3/31 (9.7%)	3
Nervous system disorders
Dizziness	0/5 (0%)	0	3/31 (9.7%)	3
Memory impairment	0/5 (0%)	0	2/31 (6.5%)	2
Headache	1/5 (20%)	2	0/31 (0%)	0
Syncope	1/5 (20%)	1	0/31 (0%)	0
Psychiatric disorders
Confusion	1/5 (20%)	1	0/31 (0%)	0
Depression	0/5 (0%)	0	3/31 (9.7%)	3
Insomnia	1/5 (20%)	1	1/31 (3.2%)	3
Renal and urinary disorders
Chronic kidney disease	1/5 (20%)	1	3/31 (9.7%)	3
Urinary incontinence	0/5 (0%)	0	2/31 (6.5%)	2
Reproductive system and breast disorders
Vaginal hemorrhage	1/5 (20%)	1	0/31 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	2/5 (40%)	3	6/31 (19.4%)	6
Dyspnea	1/5 (20%)	2	3/31 (9.7%)	3
Hypoxia	1/5 (20%)	1	2/31 (6.5%)	3
Pharyngolaryngeal pain	0/5 (0%)	0	2/31 (6.5%)	2
Pleural effusion	0/5 (0%)	0	2/31 (6.5%)	2
Pneumonitis	1/5 (20%)	1	2/31 (6.5%)	2
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/5 (0%)	0	3/31 (9.7%)	5
Pruritus	0/5 (0%)	0	2/31 (6.5%)	2
Purpura	0/5 (0%)	0	5/31 (16.1%)	5
Rash maculo-papular	0/5 (0%)	0	2/31 (6.5%)	2
Skin ulceration	0/5 (0%)	0	2/31 (6.5%)	2
Vascular disorders
Hypertension	0/5 (0%)	0	2/31 (6.5%)	2

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.