CLAG Gleevec in Relapsed or Refractory Acute Myeloid Leukemia (AML)

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00955916
• Collaborator: Novartis (Industry)
• Enrollment: 38
• Location: 1
• Arm: 1
• Duration (Months): 57
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of the study is to find out what effects (good and bad) Gleevec® (Imatinib mesylate) combined with chemotherapy has on participants and their acute myeloid leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: CLAG Regimen; Drug: Gleevec®	Phase 2

Detailed Description

In relapsed or resistant acute myeloid leukemia (a type of blood cancer where immature blood cells are increased, blocking normal blood cell production), different types of chemotherapy are used for treatment. Patients responded to all the chemotherapies in similar ways, but most of the responses did not last long if further stem cell transplantation was not done. Gleevec is believed to work by interfering with the abnormal protein by blocking it from telling the body to keep making more white blood cells that are abnormal.

The CLAG regimen is the standard chemotherapy used for relapsed AML (Acute Myeloid Leukemia). This study will add Gleevec® to the regimen for a period of 14 days. Gleevec® is approved by the Food and Drug Administration (FDA) for the treatment of chronic myeloid leukemia (CML) and some types of acute lymphoblastic leukemia (ALL). Its use in combination with CLAG regimen is considered experimental for the treatment of Acute Myeloid Leukemia/CML blast crisis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of CLAG Regimen in Combination With Imatinib Mesylate (Gleevec) in Relapsed or Refractory Acute Myeloid Leukemia
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: CLAG Regimen with Gleevec® Combined chemotherapy treatment (CLAG regimen) with Gleevec® (imatinib mesylate).

Drug: CLAG Regimen; The CLAG regimen consisted of: Cladribine, 5 mg/m^2 administered via 2 hour IV daily for 5 consecutive days starting on day 2; Cytarabine, 2 mg/m^2 administered through a 4 hour IV starting 2 hours after the ignition of Cladribine for 5 days starting on day 2; granulocyte colony-stimulating factor (G-CSF): 300 mcg subcutaneous (SC) for 6 days starting 12-24 hours (Day 1) before the first dose of Cladribine.; Other Names: cladribine cytarabine neupogen ; Drug: Gleevec®; Imatinib mesylate 400 mg orally twice daily was administered on day 2 to day 15. Re-induction was allowed if participant had partial response (PR).; Other Names: imatinib mesylate

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) [8 weeks per participant]

   Overall Response Rate: Morphologic Complete Remission (CR) + Morphologic Complete Remission with incomplete blood count recovery (CRi) for evaluable participants. CR - Bone Marrow: < 5% blasts without Auer rods with at least 20% cellularity with maturation of all cell lines, No presence of unique phenotype by flow cytometry identical to what was found in the pretreatment specimen, No persistent dysplasia; Peripheral: normal blood counts, absolute neutrophil count (ANC) > 1.0 k/μl and platelets > 100 k/μl ANC > 1.0 k/μl and platelets > 100 k/μl (Peripheral blood counts documenting recovery can be utilized within 4 weeks of the bone marrow); No evidence of extramedullary leukemia. CRi - All CR criteria are met except for residual Neutropenia <1.0 x 10^9/L platelets < 100 k/μl.

Secondary Outcome Measures

1. Median Progression Free Survival (PFS) [Up to 3 years]

   Progression Free Survival is defined as the duration of time from start of treatment to time of progression. Leukemia related failure (progressive disease): Failure to induce bone marrow hypoplasia after 2 cycles or regrowth of leukemic blasts ≥ 20%.

2. Median Overall Survival (OS) [Up to 3 years]

   Overall Survival is defined as the time from randomization until death from any cause.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Men and Women of all ethnic groups whose age is ≥ 18 years old.

• Diagnosis of AML or CML blast crisis, according to World Health Organization (WHO) criteria, except acute promyelocytic leukemia AML-M3 French-American-British (FAB) subgroup. A documentation of relapse is required by a bone marrow/aspirate within 4 weeks of registration.

• Refractory or Relapsed AML. Refractory AML is defined as failure to achieve CR after 2 cycles of induction chemotherapy or persistent (>40%) bone marrow blasts after one cycle of chemotherapy induction.

• Relapsed AML is defined as any evidence of disease recurrence after achieving complete response (CR) (more than 5% myeloblasts). Early relapse is defined as that occurring within 12 months and late relapse is defines as that occurring after 12 months.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Patients must sign a written informed consent.

• Females of childbearing potential (FOCP) must not be pregnant or actively nursing a child. They must have a negative pregnancy test 7 days before initiation of study drug administration

• Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.

• Male and females of reproductive potential must agree to employ an effective barrier method of birth control throughout the duration of the trial and for 3 months following study medication discontinuation.

• Prior allogeneic or autologous stem cell transplantation is allowed.

Exclusion Criteria:

• Abnormal Kidney Functions: creatinine ≥2.5 mg/dL.

• Abnormal Liver Functions: Bilirubin more 3 mg/dL, transaminases (AST/ALT) more than 2.5 times the institutional upper limits of normal (IULN).

• Systemic active infection, unless controlled on active therapy.

• Patients with Grade III/IV cardiac problems as defined by the New York Heart Association (NYHA) Criteria ( i.e., congestive heart failure, myocardial infarction within 6 months of the study), or ejection fraction (EF)< 30%.

• Patient has known chronic liver disease (i.e., chronic active hepatitis, hepatitis B, hepatitis C, and cirrhosis).

• Patient has known diagnosis of human immunodeficiency virus (HIV) infection.

• History of other malignancy, except non-melanotic skin cancers or no disease recurrence/progression for more than 2 years.

• Patients that have received investigational agents within 1 month of study entry.

• History of allergic reaction attributed to compounds of similar chemical or biologic composition to Gleevec or any component of the CLAG regimen

• Prior therapy with CLAG chemotherapy regimen

• Any adverse event attributable to previous chemotherapy regimen must be resolved to grade 1 or less at time of registration.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• Novartis

Investigators

• Principal Investigator: Rami Komrokji, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT00955916
• Other Study ID Numbers: MCC-15787; CSTI571AUS235
• First Posted: Aug 10, 2009
• Last Update Posted: Jun 27, 2014
• Last Verified: Jun 1, 2014

• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: relapsed; refractory; acute; myeloid; AML; CML; blast crisis
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid, Acute; Cytarabine; Imatinib Mesylate; Cladribine

Study Results

Participant Flow

Recruitment Details	Between August 2009 and April 2011, participants were enrolled at Moffitt Cancer Center.

Arm/Group Title	CLAG Regimen With Gleevec®
Arm/Group Description	Combined chemotherapy treatment (CLAG regimen) with Gleevec® (imatinib mesylate). Gleevec®: Imatinib mesylate 400 mg orally twice daily was administered on day 2 to day 15. Re-induction was allowed if participant had partial response (PR). CLAG Regimen: The CLAG regimen consisted of: Cladribine, 5 mg/m^2 administered via 2 hour IV daily for 5 consecutive days starting on day 2; Cytarabine, 2 mg/m^2 administered through a 4 hour IV starting 2 hours after the ignition of Cladribine for 5 days starting on day 2; granulocyte colony-stimulating factor (G-CSF): 300 mcg subcutaneous (SC) for 6 days starting 12-24 hours (Day 1) before the first dose of Cladribine.
Period Title: Overall Study
STARTED	38
COMPLETED	38
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	CLAG Regimen With Gleevec®
Arm/Group Description	Combined chemotherapy treatment (CLAG regimen) with Gleevec® (imatinib mesylate). Gleevec®: Imatinib mesylate 400 mg orally twice daily was administered on day 2 to day 15. Re-induction was allowed if participant had partial response (PR). CLAG Regimen: The CLAG regimen consisted of: Cladribine, 5 mg/m^2 administered via 2 hour IV daily for 5 consecutive days starting on day 2; Cytarabine, 2 mg/m^2 administered through a 4 hour IV starting 2 hours after the ignition of Cladribine for 5 days starting on day 2; granulocyte colony-stimulating factor (G-CSF): 300 mcg subcutaneous (SC) for 6 days starting 12-24 hours (Day 1) before the first dose of Cladribine.
Overall Participants	38
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	23 60.5%
>=65 years	15 39.5%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	16 42.1%
Male	22 57.9%
Region of Enrollment (participants) [Number]
United States	38 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Overall Response Rate: Morphologic Complete Remission (CR) + Morphologic Complete Remission with incomplete blood count recovery (CRi) for evaluable participants. CR - Bone Marrow: < 5% blasts without Auer rods with at least 20% cellularity with maturation of all cell lines, No presence of unique phenotype by flow cytometry identical to what was found in the pretreatment specimen, No persistent dysplasia; Peripheral: normal blood counts, absolute neutrophil count (ANC) > 1.0 k/μl and platelets > 100 k/μl ANC > 1.0 k/μl and platelets > 100 k/μl (Peripheral blood counts documenting recovery can be utilized within 4 weeks of the bone marrow); No evidence of extramedullary leukemia. CRi - All CR criteria are met except for residual Neutropenia <1.0 x 10^9/L platelets < 100 k/μl.
Time Frame	8 weeks per participant

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	CLAG Regimen With Gleevec®
Arm/Group Description	Combined chemotherapy treatment (CLAG regimen) with Gleevec® (imatinib mesylate). Gleevec®: Imatinib mesylate 400 mg orally twice daily was administered on day 2 to day 15. Re-induction was allowed if participant had partial response (PR). CLAG Regimen: The CLAG regimen consisted of: Cladribine, 5 mg/m^2 administered via 2 hour IV daily for 5 consecutive days starting on day 2; Cytarabine, 2 mg/m^2 administered through a 4 hour IV starting 2 hours after the ignition of Cladribine for 5 days starting on day 2; granulocyte colony-stimulating factor (G-CSF): 300 mcg subcutaneous (SC) for 6 days starting 12-24 hours (Day 1) before the first dose of Cladribine.
Measure Participants	38
Number [percentage of participants]	37 97.4%

2. Secondary Outcome

Title	Median Progression Free Survival (PFS)
Description	Progression Free Survival is defined as the duration of time from start of treatment to time of progression. Leukemia related failure (progressive disease): Failure to induce bone marrow hypoplasia after 2 cycles or regrowth of leukemic blasts ≥ 20%.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	CLAG Regimen With Gleevec®
Arm/Group Description	Combined chemotherapy treatment (CLAG regimen) with Gleevec® (imatinib mesylate). Gleevec®: Imatinib mesylate 400 mg orally twice daily was administered on day 2 to day 15. Re-induction was allowed if participant had partial response (PR). CLAG Regimen: The CLAG regimen consisted of: Cladribine, 5 mg/m^2 administered via 2 hour IV daily for 5 consecutive days starting on day 2; Cytarabine, 2 mg/m^2 administered through a 4 hour IV starting 2 hours after the ignition of Cladribine for 5 days starting on day 2; granulocyte colony-stimulating factor (G-CSF): 300 mcg subcutaneous (SC) for 6 days starting 12-24 hours (Day 1) before the first dose of Cladribine.
Measure Participants	38
Median (95% Confidence Interval) [months]	11.1

3. Secondary Outcome

Title	Median Overall Survival (OS)
Description	Overall Survival is defined as the time from randomization until death from any cause.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	CLAG Regimen With Gleevec®
Arm/Group Description	Combined chemotherapy treatment (CLAG regimen) with Gleevec® (imatinib mesylate). Gleevec®: Imatinib mesylate 400 mg orally twice daily was administered on day 2 to day 15. Re-induction was allowed if participant had partial response (PR). CLAG Regimen: The CLAG regimen consisted of: Cladribine, 5 mg/m^2 administered via 2 hour IV daily for 5 consecutive days starting on day 2; Cytarabine, 2 mg/m^2 administered through a 4 hour IV starting 2 hours after the ignition of Cladribine for 5 days starting on day 2; granulocyte colony-stimulating factor (G-CSF): 300 mcg subcutaneous (SC) for 6 days starting 12-24 hours (Day 1) before the first dose of Cladribine.
Measure Participants	38
Median (95% Confidence Interval) [months]	4.9

Adverse Events

Time Frame	1 year, 10 months
Arm/Group Title	CLAG Regimen With Gleevec®
Arm/Group Description	Combined chemotherapy treatment (CLAG regimen) with Gleevec® (imatinib mesylate). Gleevec®: Imatinib mesylate 400 mg orally twice daily was administered on day 2 to day 15. Re-induction was allowed if participant had partial response (PR). CLAG Regimen: The CLAG regimen consisted of: Cladribine, 5 mg/m^2 administered via 2 hour IV daily for 5 consecutive days starting on day 2; Cytarabine, 2 mg/m^2 administered through a 4 hour IV starting 2 hours after the ignition of Cladribine for 5 days starting on day 2; granulocyte colony-stimulating factor (G-CSF): 300 mcg subcutaneous (SC) for 6 days starting 12-24 hours (Day 1) before the first dose of Cladribine.
All Cause Mortality
	CLAG Regimen With Gleevec®
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	CLAG Regimen With Gleevec®
	Affected / at Risk (%)	# Events
Total	8/38 (21.1%)
General disorders
Death not associated with CTCAE term - Disease progression NOS	1/38 (2.6%)	1
Pain - Abdomen NOS	1/38 (2.6%)	1
Pain - Cardiac/heart	1/38 (2.6%)	1
Hepatobiliary disorders
Liver dysfunction/failure (clinical)	1/38 (2.6%)	1
Infections and infestations
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils - Blood	1/38 (2.6%)	1
Metabolism and nutrition disorders
Potassium, serum-low (hypokalemia)	1/38 (2.6%)	1
Respiratory, thoracic and mediastinal disorders
Hemorrhage, pulmonary/upper respiratory - Lung	1/38 (2.6%)	1
Adult Respiratory Distress Syndrome (ARDS)	1/38 (2.6%)	1
Dyspnea (shortness of breath)	1/38 (2.6%)	1
Vascular disorders
Thrombosis/embolism (vascular access-related)	1/38 (2.6%)	1
Other (Not Including Serious) Adverse Events
	CLAG Regimen With Gleevec®
	Affected / at Risk (%)	# Events
Total	38/38 (100%)
Blood and lymphatic system disorders
Edema: limb	32/38 (84.2%)	35
Lymphatics - Other	8/38 (21.1%)	8
Edema: head and neck	2/38 (5.3%)	2
Cardiac disorders
Cardiac General - Other	4/38 (10.5%)	5
Hypertension	3/38 (7.9%)	3
Hypotension	3/38 (7.9%)	3
Cardiac troponin T (cTnT)	2/38 (5.3%)	2
Left ventricular systolic dysfunction	2/38 (5.3%)	2
Eye disorders
Dry eye syndrome	3/38 (7.9%)	3
Vision-blurred vision	3/38 (7.9%)	3
Ocular/Visual - Other	2/38 (5.3%)	2
Muscle weakness, generalized or specific area (not due to neuropathy) - Extraocular	2/38 (5.3%)	2
Gastrointestinal disorders
Diarrhea	29/38 (76.3%)	30
Nausea	28/38 (73.7%)	29
Vomiting	20/38 (52.6%)	22
Anorexia	12/38 (31.6%)	12
Constipation	9/38 (23.7%)	10
Mucositis/stomatitis (clinical exam) - Oral cavity	8/38 (21.1%)	8
Taste alteration (dysgeusia)	3/38 (7.9%)	3
Dehydration	2/38 (5.3%)	2
Gastrointestinal - Other	2/38 (5.3%)	2
Hemorrhage, GI - Lower GI NOS	3/38 (7.9%)	3
General disorders
Rigors/chills	17/38 (44.7%)	24
Insomnia	7/38 (18.4%)	7
Fatigue (asthenia, lethargy, malaise)	5/38 (13.2%)	5
Constitutional Symptoms - Other	2/38 (5.3%)	2
Fever (in the absence of neutropenia)	2/38 (5.3%)	2
Sweating (diaphoresis)	2/38 (5.3%)	2
Weight gain	2/38 (5.3%)	2
Pain - Head/headache	8/38 (21.1%)	8
Pain - Back	5/38 (13.2%)	5
Pain - Abdomen NOS	4/38 (10.5%)	4
Pain - Extremity-limb	4/38 (10.5%)	4
Pain - Joint	4/38 (10.5%)	5
Pain-Cardiac/heart	3/38 (7.9%)	3
Pain - Chest/thorax NOS	2/38 (5.3%)	2
Pain - Neck	2/38 (5.3%)	2
Dizziness	3/38 (7.9%)	3
Memory impairment	3/38 (7.9%)	3
Syncope (fainting)	2/38 (5.3%)	2
Hemorrhage/Bleeding - Other	4/38 (10.5%)	4
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	5/38 (13.2%)	5
Infections and infestations
Febrile neutropenia	22/38 (57.9%)	31
Infection with Grade 3 or 4 neutrophils - Blood	12/38 (31.6%)	12
Infection - Other	10/38 (26.3%)	11
Infection with Grade 3 or 4 neutrophils - Small bowel NOS	6/38 (15.8%)	6
Infection with Grade 3 or 4 neutrophils - Urinary tract NOS	5/38 (13.2%)	5
Infection with Grade 3 or 4 neutrophils - Colon	4/38 (10.5%)	4
Infection with normal ANC or Grade 1 or 2 neutrophils - Lung (pneumonia)	3/38 (7.9%)	3
Infection with normal ANC or Grade 1 or 2 neutrophils - Blood	2/38 (5.3%)	2
Infection with normal ANC or Grade 1 or 2 neutrophils - Mucosa	2/38 (5.3%)	2
Infection with normal ANC or Grade 1 or 2 neutrophils - Urinary tract NOS	2/38 (5.3%)	2
Infection with unknown AND - Lung (pneumonia)	2/38 (5.3%)	2
Metabolism and nutrition disorders
Potassium, serum-low (hypokalemia)	15/38 (39.5%)	17
Glucose, serum-high (hyperglycemia)	11/38 (28.9%)	11
ALT, SGPT (serum glutamic pyruvic transaminase)	8/38 (21.1%)	8
Magnesium, serum-low (hypomagnesemia)	8/38 (21.1%)	8
Bilirubin (hyperbilirubinemia)	6/38 (15.8%)	6
AST, SGOT (serum glutamic oxaloacetic transaminase)	5/38 (13.2%)	5
Acidosis (metabolic or respiratory)	3/38 (7.9%)	3
Calcium, serum-low (hypocalcemia)	2/38 (5.3%)	2
Sodium, serum-low (hyponatremia)	2/38 (5.3%)	2
Psychiatric disorders
Mood alteration - Anxiety	12/38 (31.6%)	12
Confusion	7/38 (18.4%)	7
Psychosis (hallucinations/delusions)	5/38 (13.2%)	6
Mood alteration - Depression	4/38 (10.5%)	4
Mental status	3/38 (7.9%)	3
Renal and urinary disorders
Renal failure	6/38 (15.8%)	6
Renal/Genitourinary - Other	2/38 (5.3%)	2
Respiratory, thoracic and mediastinal disorders
Infection with Grade 3 or 4 neutrophils - Lung (pneumonia)	16/38 (42.1%)	18
Dyspnea (shortness of breath)	5/38 (13.2%)	5
Hiccoughs (hiccups, singultus)	5/38 (13.2%)	5
Cough	3/38 (7.9%)	3
Adult Respiratory Distress Syndrome (ARDS)	2/38 (5.3%)	2
Pleural effusion (non-malignant)	2/38 (5.3%)	2
Hemorrhage, pulmonary/upper respiratory - Nose	5/38 (13.2%)	5
Skin and subcutaneous tissue disorders
Infection with Grade 3 or 4 neutrophils - Skin (cellulitis	3/38 (7.9%)	3
Dermatology/Skin - Other	14/38 (36.8%)	14
Pruritus/itching	6/38 (15.8%)	6
Rash/desquamation	4/38 (10.5%)	4
Rash: dermatitis associated with radiation - Chemoradiation	3/38 (7.9%)	3
Hair loss/alopecia (scalp or body)	2/38 (5.3%)	2

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.