Monoclonal Antibody Plus Chemotherapy in Treating Young Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes

A Dose Finding Study of the Safety of Gemtuzumab Ozogamicin Combined With Conventional Chemotherapy for Patients With Relapsed or Refractory Acute Myeloid Leukemia

RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as gemtuzumab ozogamicin can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining monoclonal antibody therapy with combination chemotherapy may kill more cancer cells.

PURPOSE: Phase I trial to study the effectiveness of combining gemtuzumab ozogamicin with combination chemotherapy in treating children who have relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Leukemia
• Intervention / Treatment: Drug: mitoxantrone hydrochloride; Drug: asparaginase; Drug: cytarabine; Drug: gemtuzumab ozogamicin

Detailed Description

OBJECTIVES:

• Determine the safety and maximum tolerated dose of gemtuzumab ozogamicin in combination with conventional chemotherapy in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndromes.
• Determine the efficacy of this regimen in these patients.
• Correlate the likelihood of leukemic blast cells to undergo apoptosis in vitro with the efficacy of this regimen in these patients.
• Correlate drug resistance as manifested by dye efflux or multiple drug resistance-1 expression by leukemic blast cells with the efficacy of this regimen in these patients.

OUTLINE: This is a dose-escalation, multicenter study of gemtuzumab ozogamicin. Patients are assigned by cohort to 1 of 2 treatment regimens.

• Regimen A: Patients receive cytarabine IV over 2 hours every 12 hours on days 1-4, mitoxantrone IV over 1 hour on days 3-6, and gemtuzumab ozogamicin IV over 2 hours on day 7.
• Regimen B: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 2, 8, and 9, asparaginase intramuscularly on days 2 and 9, and gemtuzumab ozogamicin IV over 2 hours on day 3.

Cohorts of 3-6 patients receive de-escalating doses of gemtuzumab ozogamicin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose below that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed monthly for 6 months, every 2 months for 6 months, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 52 patients will be accrued for this study within 1.5 years.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Princess Margaret Hospital for Children
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital at Hamilton Health Sciences
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Hopital Sainte Justine
    • Montreal, Quebec, Canada, H3H 1P3
      • McGill Cancer Centre at McGill University
    • Ste-Foy, Quebec, Canada, G1V 4G2
      • Centre Hospitalier Universitaire de Québec
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Comprehensive Cancer Center at University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85016-7710
      • Phoenix Children's Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • California
    • Long Beach, California, United States, 90801
      • Jonathan Jaques Children's Cancer Center at Miller Children's Hospital
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Diego, California, United States, 92123-4282
      • Children's Hospital and Health Center - San Diego
    • Stanford, California, United States, 94305
      • Stanford Cancer Center at Stanford University Medical Center
  • Colorado
    • Denver, Colorado, United States, 80218-1088
      • Children's Hospital Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
    • Orlando, Florida, United States, 32803-1273
      • Florida Hospital Cancer Institute at Florida Hospital Orlando
    • St. Petersburg, Florida, United States, 33701
      • All Children's Hospital
    • Tampa, Florida, United States, 33607
      • St. Joseph's Cancer Institute at St. Joseph's Hospital
    • West Palm Beach, Florida, United States, 33407
      • Kaplan Cancer Center at St. Mary's Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital - Atlanta
  • Hawaii
    • Honolulu, Hawaii, United States, 95813
      • Cancer Research Center of Hawaii
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital - Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Cancer Center
    • Indianapolis, Indiana, United States, 46260
      • St. Vincent Indianapolis Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0084
      • Markey Cancer Center at University of Kentucky Chandler Medical Center
  • Maine
    • Bangor, Maine, United States, 04401
      • CancerCare of Maine at Eastern Maine Medial Center
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • Baltimore, Maryland, United States, 21215
      • Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0238
      • C.S. Mott Children's Hospital at University of Michigan
    • Detroit, Michigan, United States, 48201-1379
      • Barbara Ann Karmanos Cancer Institute
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Van Elslander Cancer Center at St. John Hospital and Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Fairview University Medical Center - University Campus
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospital of Minnesota - Minneapolis
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
    • St. Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Cancer Center at Hackensack University Medical Center
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
  • New York
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
  • North Carolina
    • Charlotte, North Carolina, United States, 28232-2861
      • Blumenthal Cancer Center at Carolinas Medical Center
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
  • Ohio
    • Akron, Ohio, United States, 44308-1062
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106-5000
      • Rainbow Babies and Children's Hospital
    • Cleveland, Ohio, United States, 44195-5217
      • Cleveland Clinic Taussig Cancer Center
    • Columbus, Ohio, United States, 43205-2696
      • Columbus Children's Hospital
    • Dayton, Ohio, United States, 45404-1815
      • Children's Medical Center - Dayton
    • Youngstown, Ohio, United States, 44501
      • Tod Children's Hospital - Forum Health
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Medical center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-9786
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina
    • Greenville, South Carolina, United States, 29605
      • Greenville Hospital System Cancer Center
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37232-6310
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech University Health Sciences Center School of Medicine
    • Austin, Texas, United States, 78701
      • Children's Hospital of Austin
    • Dallas, Texas, United States, 75390
      • Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
    • Fort Worth, Texas, United States, 76104-9958
      • Cook Children's Medical Center - Fort Worth
    • Houston, Texas, United States, 77030-4009
      • M.D. Anderson Cancer Center at University of Texas
    • San Antonio, Texas, United States, 78229-3993
      • Methodist Children's Hospital of South Texas
    • San Antonio, Texas, United States, 78284-7811
      • University of Texas Health Science Center at San Antonio
  • Virginia
    • Richmond, Virginia, United States, 23298-0037
      • Massey Cancer Center at Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle
    • Spokane, Washington, United States, 99220-2555
      • Providence Cancer Center at Sacred Heart Medical Center
  • West Virginia
    • Huntington, West Virginia, United States, 25701
      • Edwards Comprehensive Cancer Center at Cabell Huntington Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Comprehensive Cancer Center
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of primary acute myeloid leukemia (AML) or myelodysplastic syndromes

  • Relapsed (remission duration less than 1 year) OR
  • Failed induction (failed to achieve an initial complete response)
• Patients with AML as a second malignant neoplasm allowed provided no other prior therapy for AML
• M2 or M3 bone marrow aspirate at time of study entry
• No Fanconi's anemia
• No known CNS leukemia

PATIENT CHARACTERISTICS:

Age:

• 21 and under

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Bilirubin no greater than 1.5 times normal
• AST or ALT less than 2.5 times upper limit of normal
• No history of veno-occlusive disease of the liver defined as weight increase of more than 5% over baseline and serum bilirubin greater than 5 mg/dL within 20 days after receipt of chemotherapy

Renal:

• Creatinine no greater than 1.5 times normal OR
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) at least 70 mL/min OR
• Equivalent GFR by institutional normal range

Cardiovascular:

• Shortening fraction more than 27% by echocardiogram or normal for institution OR
• Ejection fraction more than 50% by MUGA

Other:

• Not pregnant or nursing

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 180 days since prior hematopoietic stem cell transplantation

Chemotherapy:

• Not specified

Endocrine therapy:

• Not specified

Radiotherapy:

• Not specified

Surgery:

• Not specified

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Event Free Survival	Length of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity	Toxicity will be monitored through study chair notification and end course reports
Remission Rate	The remission rate in each arm will be estimated by the proportion of patients who achieved remission among patients who received GMTZ at the MTD level.	Length of study
Prognostic Factor Analysis	The predictive value of the likelihood of leukemia blast cells to undergo apoptosis and drug resistance of leukemia blast cells will be assessed by logistic regression

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Richard Aplenc, MD, MSCE, Children's Hospital of Philadelphia

Publications and helpful links

General Publications

• Aplenc R, Alonzo TA, Gerbing RB, Lange BJ, Hurwitz CA, Wells RJ, Bernstein I, Buckley P, Krimmel K, Smith FO, Sievers EL, Arceci RJ; Children's Oncology Group. Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia: a report from the Children's Oncology Group. J Clin Oncol. 2008 May 10;26(14):2390-3295. doi: 10.1200/JCO.2007.13.0096.

Study record dates

Study Major Dates

• Study Start: July 1, 2002
• Primary Completion (Actual): September 1, 2006
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: January 4, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): February 20, 2014
• Last Update Submitted That Met QC Criteria: February 18, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: previously treated myelodysplastic syndromes; secondary acute myeloid leukemia; recurrent childhood acute myeloid leukemia
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Cytarabine; Asparaginase; Mitoxantrone; Gemtuzumab
• Other Study ID Numbers: AAML00P2; COG-AAML00P2 (Other Identifier: Children's Oncology Group); CDR0000069145 (Other Identifier: ClinicalTrials.gov)