Arsenic Trioxide and Gemtuzumab Ozogamicin in Treating Patients With Advanced Myelodysplastic Syndromes

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00274781
• Collaborator: University of Michigan (Other), National Cancer Institute (NCI) (NIH)
• Enrollment: 30
• Location: 1
• Arm: 1
• Duration (Months): 81
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as arsenic trioxide and gemtuzumab ozogamicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving arsenic trioxide together with gemtuzumab ozogamicin works in treating patients with advanced myelodysplastic syndromes.

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Myelodysplastic Syndromes	Drug: arsenic trioxide; Drug: gemtuzumab ozogamicin	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the efficacy of arsenic trioxide and gemtuzumab ozogamicin to achieve complete and partial remissions in patients with advanced myelodysplastic syndromes.

Secondary

• Determine the efficacy of this regimen, in terms of 50% decrease in Red Blood Cell (RBC) transfusion requirements and change in hemoglobin concentration from baseline in patients treated with this regimen.

• Determine the platelet, neutrophil, bone marrow, and cytogenic response in patients treated with this regimen.

• Determine the response duration in patients treated with this regimen.

• Determine the quality of life of patients treated with this regimen.

• Determine the safety and toxicity of this regimen in these patients.

OUTLINE: This is a multicenter, open-label study.

Patients receive arsenic trioxide IV over 1 hour once daily on days 1-5 in week 1 and then twice weekly in weeks 2-12. They also receive gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 12 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, every 12 weeks during study treatment, and then 4 weeks after the completion of study treatment.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Combination Therapy With Arsenic Trioxide (Trisenox) and Gemtuzumab Ozogamicin (Mylotarg) for the Treatment of Adult Patients With Advanced Myelodysplastic Syndrome
• Study Start Date: Feb 1, 2004
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Nov 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: ATO + GO Arsenic Trioxide 0.25 mg/kg D1-5 Week 1/Twice Weekly W2-12 + Gemtuzumab Ozogamicin 3 mg/m^2 D8 for 1 or 2 Cycles of 12 Weeks each

Drug: arsenic trioxide; Arsenic trioxide will be administered at a dose of 0.25 mg/kg/day IV over 1-2 hours for 5 consecutive days during the first week. Subsequently, arsenic trioxide will be given at a dose of 0.25mg/kg/day twice a week for 11 additional weeks (weeks 2-12).; Other Names: Trisenox ; Drug: gemtuzumab ozogamicin; Gemtuzumab ozogamicin consists of a 2 hr infusion at a dose of 3mg/m2 on day 8 of each 12-week cycle. Gemtuzumab ozogamicin should be administered at a minimum of one hour after the completion of the arsenic trioxide infusion; Other Names: Mylotarg

Outcome Measures

Primary Outcome Measures

1. Complete and Partial Remission Per the International Working Group (IWG) Criteria for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML) [at 12 weeks post treatment]

   The null hypothesis to be tested was the percentage who will respond to combination arsenic trioxide (ATO) and gemtuzumab ozogamicin (GO) therapy is <10%. A total of >/= 9 responses observed in 30 evaluable patients was taken as evidence warranting further study of the regimen, provided the toxicity profile also appears favorable. The IWG Criteria standardizes the clinical responses in MDS and AML based upon hematologic improvement, quality of life and cytogenic improvement. These standardizations allow for the responses to be determined as either complete responses or partial responses.

Secondary Outcome Measures

1. Overall Survival [From date of enrollment to a minimum of three years for survival]

   Patient's Overall Survival from date of enrollment to a minimum of three years for survival.

2. Tolerability [12 Weeks]

   Tolerability of Therapy was assessed through use of the National Cancer Institute Common Toxicity Criteria (version 3.0). Treatment tolerability was determined based upon whether or not the physician determined therapy was in the patient's best interest, whether the patient wanted to continue therapy or not, whether patients discontinued treatment due to progressive disease, or whether patients discontinued treatment due to toxicity.

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Diagnosis of one of the following hematologic malignancies:

• Myelodysplastic syndromes (MDS) of one of the following French-American-British (FAB) classifications:

• Refractory anemia with excess blasts (RAEB) (WHO RAEB-1)

• RAEB in transformation (RAEB-t) (RAEB-2)

• Chronic myelomonocytic leukemia (CMML) with > 5% myeloblasts (WHO CMML-2)

• International Prognostic Scoring System (IPSS) score of intermediate-2 or higher in the setting of > 5% myeloblasts

• Acute myeloid leukemia that has evolved from MDS

• Must not be a candidate for bone marrow transplantation as first-line therapy or must have declined bone marrow transplantation

PATIENT CHARACTERISTICS:

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Life expectancy of at least 4 months

• Serum potassium ≥ 4.0 milliequivalent (mEq/dL) and serum magnesium ≥ 1.8 mg/dL (supplemental electrolytes allowed)

• Absolute corrected QT interval (QTc) interval < 460 msec

• No serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the patient at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent

• Not pregnant or nursing

• Fertile patients must be willing to use adequate contraception (barrier method with spermicidal jelly, intrauterine device (IUD), or oral contraceptives)

• Negative pregnancy test

• Creatinine > 2.5 mg/dL

• serum glutamate oxaloacetate transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) > 1.5 times upper limit of normal

• Bilirubin > 2.0 mg/dL

• No history of malignancy within the past 3 years other than MDS except basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast

• Arsenic trioxide is contraindicated in patients who are hypersensitive to arsenic

PRIOR CONCURRENT THERAPY:

• No prior bone marrow transplantation

• Must not receive another investigational or approved therapy for MDS within 4 weeks of study enrollment, including growth factors (within 1 week of study enrollment)

• No prior arsenic trioxide or gemtuzumab ozogamicin

• No other concurrent cytotoxic drugs or investigational agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• The Cleveland Clinic
• University of Michigan
• National Cancer Institute (NCI)

Investigators

• Study Chair: Mikkael A. Sekeres, MD, MS, The Cleveland Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT00274781
• Other Study ID Numbers: CCF6818; P30CA043703; CCF-6818
• First Posted: Jan 11, 2006
• Last Update Posted: Jul 10, 2015
• Last Verified: Jul 1, 2015

• Keywords provided by The Cleveland Clinic: refractory anemia with excess blasts in transformation; refractory anemia with excess blasts; chronic myelomonocytic leukemia; secondary acute myeloid leukemia; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; de novo myelodysplastic syndromes
• Additional relevant MeSH terms: Leukemia; Preleukemia; Myelodysplastic Syndromes; Syndrome; Arsenic Trioxide; Gemtuzumab

Study Results

Participant Flow

Recruitment Details	Patients were enrolled at Cleveland Clinic and the University of Michigan from February 2004 through June 2006.

Arm/Group Title	ATO (0.25mg/kg) and GO (3mg/m2)
Arm/Group Description	ATO dosing was based on the phase 2 European Union regimen at a dose of 0.25 mg/kg administered intravenously on Days 1 through 5 during Week 1 and then twice weekly during Weeks 2 to 12, and GO at a dose of 3mg/m2 on Day 8 for 1 or 2 cycles of 12 weeks each.
Period Title: Overall Study
STARTED	30
COMPLETED	30
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	ATO (0.25mg/kg) and GO (3mg/m2)
Arm/Group Description	ATO dosing was based on the phase 2 European Union regimen at a dose of 0.25 mg/kg administered intravenously on Days 1 through 5 during Week 1 and then twice weekly during Weeks 2 to 12, and GO at a dose of 3mg/m2 on Day 8 for 1 or 2 cycles of 12 weeks each.
Overall Participants	30
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	69
Sex: Female, Male (Count of Participants)
Female	9 30%
Male	21 70%
Region of Enrollment (participants) [Number]
United States	30 100%

Outcome Measures

1. Primary Outcome

Title	Complete and Partial Remission Per the International Working Group (IWG) Criteria for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML)
Description	The null hypothesis to be tested was the percentage who will respond to combination arsenic trioxide (ATO) and gemtuzumab ozogamicin (GO) therapy is <10%. A total of >/= 9 responses observed in 30 evaluable patients was taken as evidence warranting further study of the regimen, provided the toxicity profile also appears favorable. The IWG Criteria standardizes the clinical responses in MDS and AML based upon hematologic improvement, quality of life and cytogenic improvement. These standardizations allow for the responses to be determined as either complete responses or partial responses.
Time Frame	at 12 weeks post treatment

Outcome Measure Data

Analysis Population Description

Responses According to IWG MDS Criteria (n=30) Responses According to IWG AML Criteria (n=12)

Arm/Group Title	ATO + GO
Arm/Group Description	Arsenic Trioxide 0.25 mg/kg D1-5 Week 1/Twice Weekly W2-12 + Gemtuzumab Ozogamicin 3 mg/m^2 D8 for 1 or 2 Cycles of 12 Weeks each arsenic trioxide: Arsenic trioxide will be administered at a dose of 0.25 mg/kg/day IV over 1-2 hours for 5 consecutive days during the first week. Subsequently, arsenic trioxide will be given at a dose of 0.25mg/kg/day twice a week for 11 additional weeks (weeks 2-12). gemtuzumab ozogamicin: Gemtuzumab ozogamicin consists of a 2 hr infusion at a dose of 3mg/m2 on day 8 of each 12-week cycle. Gemtuzumab ozogamicin should be administered at a minimum of one hour after the completion of the arsenic trioxide infusion
Measure Participants	30
Responses according to IWG MDS Criteria	30
Responses according to IWG AML Criteria	25
Responses according to Both Criteria	10

2. Secondary Outcome

Title	Overall Survival
Description	Patient's Overall Survival from date of enrollment to a minimum of three years for survival.
Time Frame	From date of enrollment to a minimum of three years for survival

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ATO (0.25mg/kg) and GO (3mg/m2)
Arm/Group Description	ATO dosing was based on the phase 2 European Union regimen at a dose of 0.25 mg/kg administered intravenously on Days 1 through 5 during Week 1 and then twice weekly during Weeks 2 to 12, and GO at a dose of 3mg/m2 on Day 8 for 1 or 2 cycles of 12 weeks each.
Measure Participants	30
Overall Survival	9.7
Responders Overall Survival	28.6
Nonresponders Overall Survival	7.6

3. Secondary Outcome

Title	Tolerability
Description	Tolerability of Therapy was assessed through use of the National Cancer Institute Common Toxicity Criteria (version 3.0). Treatment tolerability was determined based upon whether or not the physician determined therapy was in the patient's best interest, whether the patient wanted to continue therapy or not, whether patients discontinued treatment due to progressive disease, or whether patients discontinued treatment due to toxicity.
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ATO (0.25mg/kg) and GO (3mg/m2)
Arm/Group Description	ATO dosing was based on the phase 2 European Union regimen at a dose of 0.25 mg/kg administered intravenously on Days 1 through 5 during Week 1 and then twice weekly during Weeks 2 to 12, and GO at a dose of 3mg/m2 on Day 8 for 1 or 2 cycles of 12 weeks each.
Measure Participants	30
Patients Who Completed 1 12-Week Cycle (C1)	17 56.7%
Patients Who Completed 2 12-Week Cycles (C2)	7 23.3%
Discontinue Tx During C1: Patient/Physician Choice	5 16.7%
Discontinue Tx During C1: Progressive Disease	5 16.7%
Discontinue Tx During C1:Treatment Toxicity	3 10%
Discontinue Tx After C1: Progressive Disease	8 26.7%
Discontinue Tx After C1: Treatment Toxicity	2 6.7%

Adverse Events

Time Frame	12 Weeks of Therapy
Arm/Group Title	ATO (0.25mg/kg) and GO (3mg/m2)
Arm/Group Description	ATO dosing was based on the phase 2 European Union regimen at a dose of 0.25 mg/kg administered intravenously on Days 1 through 5 during Week 1 and then twice weekly during Weeks 2 to 12, and GO at a dose of 3mg/m2 on Day 8 for 1 or 2 cycles of 12 weeks each.
All Cause Mortality
	ATO (0.25mg/kg) and GO (3mg/m2)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	ATO (0.25mg/kg) and GO (3mg/m2)
	Affected / at Risk (%)	# Events
Total	19/30 (63.3%)
Blood and lymphatic system disorders
Neutropenia	19/30 (63.3%)
Anemia	11/30 (36.7%)
Cardiac disorders
QT / QTc Interval Prolongation	3/30 (10%)
Gastrointestinal disorders
Nausea / Vomiting / Dyspepsia	1/30 (3.3%)
Diarrhea / Constipation	1/30 (3.3%)
Infections and infestations
Pneumonia	5/30 (16.7%)
Musculoskeletal and connective tissue disorders
Fatigue	4/30 (13.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	4/30 (13.3%)
Vascular disorders
Thrombocytopenia	14/30 (46.7%)
Other (Not Including Serious) Adverse Events
	ATO (0.25mg/kg) and GO (3mg/m2)
	Affected / at Risk (%)	# Events
Total	28/30 (93.3%)
Blood and lymphatic system disorders
Neutropenia	20/30 (66.7%)
Anemia	22/30 (73.3%)
Edema	9/30 (30%)
Ecchymosis / Petechiae	5/30 (16.7%)
Cardiac disorders
Cardiac Arrhythmia	8/30 (26.7%)
QT / QTc Interval Prolongation	4/30 (13.3%)
Gastrointestinal disorders
Nausea / Vomiting / Dyspepsia	18/30 (60%)
Diarrhea / Constipation	20/30 (66.7%)
General disorders
Insomnia	4/30 (13.3%)
Immune system disorders
Pyrexia	15/30 (50%)
Chills / Rigors	16/30 (53.3%)
Infections and infestations
Catheter / Infusion Site Disorders / Infections	4/30 (13.3%)
Pneumonia	8/30 (26.7%)
Metabolism and nutrition disorders
Anorexia / Decreased Appetite	10/30 (33.3%)
Musculoskeletal and connective tissue disorders
Fatigue	28/30 (93.3%)
Pain	16/30 (53.3%)
Abdominal Pain	6/30 (20%)
Nervous system disorders
Headache	11/30 (36.7%)
Dizziness / Vertigo	6/30 (20%)
Neuropathy	2/30 (6.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	15/30 (50%)
Cough	11/30 (36.7%)
Skin and subcutaneous tissue disorders
Rash / Pruritis	12/30 (40%)
Vascular disorders
Thrombocytopenia	16/30 (53.3%)

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.