Gemtuzumab Ozogamicin in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia (AML-19)

Gemtuzumab Ozogamicin (GO) Monotherapy Versus Standard Supportive Care for Previously Untreated AML in Elderly Patients Who Are Not Eligible for Intensive Chemotherapy: A Randomized Phase II/III Trial (AML-19) of the EORTC-LG and GIMEMA-ALWP

RATIONALE: 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. It is not yet known whether gemtuzumab ozogamicin is more effective than standard supportive care in treating older patients who have acute myeloid leukemia.

PURPOSE: This randomized phase II/III trial is studying two different gemtuzumab ozogamicin regimens to see how well they work compared to standard supportive care in treating older patients with previously untreated acute myeloid leukemia.

Study Overview

• Status: Unknown
• Conditions: Leukemia
• Intervention / Treatment: Drug: gemtuzumab ozogamicin

Detailed Description

OBJECTIVES:

• Compare the feasibility, toxicity, and antileukemic activity of two different dosing regimens of gemtuzumab ozogamicin (GO) vs standard supportive care in older patients with previously untreated acute myeloid leukemia who are not candidates for intensive chemotherapy. (phase II)
• Compare the efficacy and toxicity of the best dosing regimen of GO selected from phase II vs standard supportive care, in terms of overall survival, in these patients. (phase III)

OUTLINE: This is a randomized, open-label, multicenter phase II study followed by a phase III study. Patients are stratified according to age (61 to 75 vs 76 to 80 vs 81 and over), CD33-positivity of bone marrow blasts (< 20% vs 20-80% vs > 80% vs unknown), initial WBC before hydroxyurea administration (< 30,000/mm^3 vs ≥ 30,000/mm^3), WHO performance status (0-1 vs 2 vs 3-4), and participating center.

• Phase II: Patients are randomized to 1 of 3 treatment arms.

  • Arm I: Patients receive gemtuzumab ozogamicin (GO) IV over 2 hours on days 1 and 8. Patients with stable or responding disease at day 36 receive GO IV over 2 hours every 4 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity.
  • Arm II: Patients receive GO IV over 2 hours on days 1, 3, and 5. Patients with stable or responding disease at day 36 receive GO IV over 2 hours every 4 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity.
  • Arm III: Patients receive standard supportive care.

• Phase III: Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive the selected treatment (arm I or arm II) from phase II.
  • Arm II: Patients receive standard supportive care. Patients who receive GO treatment are followed monthly for 1 year and then every 3 months thereafter. Patients who receive standard supportive care are followed at least every 4 weeks.

PROJECTED ACCRUAL: A total of 259 patients (75 for phase II [25 per treatment arm] and 184 for phase III [92 per treatment arm]) will be accrued for this study within 2.5 years.

• Study Type: Interventional
• Enrollment (Anticipated): 279
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Hilde Breyssens; Email: hilde.breyssens@eortc.be

Study Locations

• Belgium
  • Antwerp, Belgium, 2020
    • Recruiting
    • Ziekenhuis Netwerk Antwerpen Middelheim
    • Contact: Contact Person; Phone Number: 32-3-280-3111
  • Brugge, Belgium, 8000
    • Recruiting
    • AZ Sint-Jan
    • Contact: Contact Person; Phone Number: 32-50-45-2111
  • Brussels, Belgium, 1000
    • Recruiting
    • Institut Jules Bordet
    • Contact: Contact Person; Phone Number: 32-2-541-3510
  • Brussels, Belgium, 1070
    • Recruiting
    • Hopital Universitaire Erasme
    • Contact: Contact Person; Phone Number: 32-2-555-3806
  • Edegem, Belgium, B-2650
    • Recruiting
    • Universitair Ziekenhuis Antwerpen
    • Contact: Contact Person; Phone Number: 32-03-821-3375
  • Liege, Belgium, B-4000
    • Recruiting
    • CHU Liege - Domaine Universitaire du Sart Tilman
    • Contact: Contact Person; Phone Number: 32-4-366-7111
  • Verviers, Belgium, B-4800
    • Recruiting
    • Centre Hospitalier Peltzer-La Tourelle
    • Contact: Contact Person; Phone Number: 328-721-2111
• Italy
  • Arezzo cap, Italy
    • Recruiting
    • Ospedale S Donato, USL-8
  • Bari, Italy, 70124
    • Recruiting
    • Università degli Studi di Bari
    • Contact: Contact Person; Phone Number: 39-080-547-8660
  • Brescia, Italy
    • Recruiting
    • Universita di Brescia
  • Cagliari, Italy, 09121
    • Recruiting
    • Ospedale Oncologico A. Businco
    • Contact: Contact Person; Phone Number: 39-070-609-5204
  • Cagliari, Italy, 090100
    • Recruiting
    • Ospedale Binaghi
    • Contact: Contact Person; Phone Number: 39-070-609-3149
  • Cantanzaro, Italy
    • Recruiting
    • Ospedale Regionale A Pugliese
  • Catania, Italy, 95124
    • Recruiting
    • Ospedale Ferrarotto
    • Contact: Contact Person; Phone Number: 39-095-743-5915
  • Catanzaro, Italy, 88100
    • Recruiting
    • Ospedale Regionale A. Pugliese
    • Contact: Contact Person; Phone Number: 39-961-883-346
  • Ferrara, Italy, 44100
    • Recruiting
    • Università di Ferrara
    • Contact: Contact Person; Phone Number: 39-532-209-100
  • Lecce, Italy, 73100
    • Recruiting
    • Azienda Ospedaliera Vito Fazzi
    • Contact: Contact Person; Phone Number: 39-083-266-1235
  • Modena, Italy, 41100
    • Recruiting
    • Azienda Ospedaliera - Universitaria di Modena
    • Contact: Contact Person; Phone Number: 39-059-422-4373
  • Montefiascone, Italy, I-01027
    • Recruiting
    • Ospedale Di Montefiascone
    • Contact: Contact Person; Phone Number: 39-07-618-331
  • Naples, Italy, 80127
    • Recruiting
    • Azienda Ospedaliera di Rilievo Nazionale A.Cardarelli
    • Contact: Contact Person; Phone Number: 39-081-747-3011
  • Novara, Italy
    • Recruiting
    • Ospedale Maggiore della Carità
  • Palermo, Italy, 90127
    • Recruiting
    • Azienda Ospedaliera Policlinico Paolo Giaccone
    • Contact: Contact Person; Phone Number: 39-091-655-2321
  • Palermo, Italy
    • Recruiting
    • Ospedale La Maddalena - Palermo
    • Contact: Contact Person; Phone Number: 39-91-680-6111
  • Parma, Italy, 43100
    • Recruiting
    • Azienda Ospedaliera Di Parma
    • Contact: Contact Person; Phone Number: 39-0521-702-441
  • Perugia, Italy, 06122
    • Recruiting
    • Policlinico Monteluce
    • Contact: Massimo F. Martelli, MD; Phone Number: 39-75-5783219; Email: ematol@unipg.it
  • Pesaro, Italy, I-61100
    • Recruiting
    • Ospedale San Salvatore
    • Contact: G. Lucarelli; Phone Number: 0039-0721-36424
  • Pescara, Italy, 65100
    • Recruiting
    • Ospedale Civile Pescara
    • Contact: Contact Person
  • Potenza, Italy
    • Recruiting
    • Ospedale San Carlo
  • Ravenna, Italy, 48100
    • Recruiting
    • Ospedale Sta. Maria Delle Croci
    • Contact: Contact Person; Phone Number: 39-544-285-247
  • Roma, Italy
    • Recruiting
    • Ospedale Sant'Andrea
  • Rome, Italy, 00161
    • Recruiting
    • Azienda Policlinico Umberto Primo
    • Contact: Franco Mandelli; Phone Number: 39-06-85-79-51
  • Rome, Italy, 00133
    • Recruiting
    • Azienda Ospedaliera Universitaria Policlinico Tor Vergata
    • Contact: Contact Person; Phone Number: 39-06-20-901
  • Rome, Italy, 00144
    • Recruiting
    • Ospedale Sant' Eugenio
    • Contact: Contact Person; Phone Number: 39-06-5100-2569
  • Rome, Italy, 00155
    • Recruiting
    • Libero Istituto Universitario Campus Bio-Medico
    • Contact: Contact; Phone Number: 39-06-2254-1366
  • Rome, Italy, 00161
    • Recruiting
    • Istituto Regina Elena
    • Contact: Contact Person; Phone Number: 39-06-4985-2201
  • Rome, Italy, 00168
    • Recruiting
    • Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore
    • Contact: Contact Person; Phone Number: 39-06-3015-5556
  • Rome, Italy, 00184
    • Recruiting
    • H. San Giovanni-Addolorata Hospital
    • Contact: Contact Person
  • Rome, Italy
    • Recruiting
    • Universita Degli Studi "La Sapeinza"
    • Contact: Giuliana Alimena; Phone Number: 39-06-857-951
  • Sassari, Italy, 07100
    • Recruiting
    • Istituto di Ematologia Universita - University di Sassari
    • Contact: Contact Person; Phone Number: 39-79-228-280
  • Siena, Italy, 53100
    • Recruiting
    • Universita di SIENA
    • Contact: Contact Person; Phone Number: 39-0577-586-429
  • Trieste, Italy, 34100
    • Recruiting
    • Ospedale Maggiore dell' Universita
    • Contact: Contact Person; Phone Number: 39-040-399-2232
• Netherlands
  • 's-Hertogenbosch, Netherlands, 5211 NL
    • Recruiting
    • Jeroen Bosch Ziekenhuis
    • Contact: Contact Person; Phone Number: 31-73-699-2000
  • Amsterdam, Netherlands, 1091 HA
    • Recruiting
    • Onze Lieve Vrouwe Gasthuis
    • Contact: Contact Person; Phone Number: 31-20-599-9111
  • Leiden, Netherlands, 2300 RC
    • Recruiting
    • Leiden University Medical Center
    • Contact: Contact Person; Phone Number: 31-71-526-9111
  • Nijmegen, Netherlands, NL-6500 HB
    • Recruiting
    • Universitair Medisch Centrum St. Radboud - Nijmegen
    • Contact: Contact Person

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 61 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed acute myeloid leukemia (AML)

  • At least 20% bone marrow blasts by bone marrow aspiration or biopsy
  • All subtypes except M3 (acute promyelocytic leukemia) are allowed
• Previously untreated primary or secondary disease (including AML after myelodysplastic syndromes)

• Ineligible for intensive chemotherapy, as defined by 1 of the following criteria:

  • 61 to 75 years old AND WHO performance status > 2 AND/OR unwilling to receive intensive chemotherapy
  • Over 75 years old
• No blast crisis of chronic myeloid leukemia
• No AML supervention after other myeloproliferative disease

• WBC < 30,000/mm^3 and meets 1 of the following criteria:

  • WBC < 30,000/mm^3 at diagnosis AND had no prior treatment with hydroxyurea
  • WBC ≥ 30,000/mm^3 at diagnosis AND received mandatory pretreatment with hydroxyurea (up to 14 days duration) until WBC < 30,000/mm^3
• No active CNS leukemia

PATIENT CHARACTERISTICS:

Age

• See Disease Characteristics
• 61 and over

Performance status

• See Disease Characteristics

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• No arrhythmia requiring chronic treatment
• No congestive heart failure
• No symptomatic ischemic heart disease
• No other severe cardiovascular disease

Pulmonary

• No severe pulmonary dysfunction ≥ grade 3

Other

• No alcohol abuse
• No severe neurological or psychiatric disease
• No active uncontrolled infection or severe systemic infection
• No other malignancy
• No psychological, familial, sociological, or geographical condition that would preclude study compliance and follow-up
• HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF)
• No concurrent antiangiogenic drugs

Chemotherapy

• See Disease Characteristics
• Concurrent low-dose cytostatic agents (i.e., thioguanine or mercaptopurine) allowed for palliative care (standard supportive care arm only)

Endocrine therapy

• Prior corticosteroids (duration ≤ 14 days ) for primary or secondary AML allowed

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No other concurrent cytotoxic drugs
• No other concurrent experimental therapy
• No concurrent tyrosine kinase inhibitors

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Proportion of patients able to start continuation therapy (Phase II)
Overall survival (Phase III)

Secondary Outcome Measures

Outcome Measure
Overall survival (Phase II)
Rate of complete remission (CR+CRp)by the end of continuation therapy, for patients in the GO arms (Phase II)
Toxicity (CTCAE grading), including time to hematological recovery (Phase II & III)
Rate of complete remisison (CR+CRp) by the end of induction and by the end of continuation therapy, for patients in GO arm (Phase III)
Disease-free survival for patients who reached CR or CRp (Phase III)
Progression-free survival from randomization for patients in GO arm (Phase III)

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Collaborators: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Investigators: Principal Investigator: Sergio Amadori, MD, EORTC - AZIENDA OSPEDALLERA UNIVERSITARIA - POLICLINICO TOR VERGATA, IT; Principal Investigator: Giuliana Alimena, GIMEMA - Universita Degli Studi "La Sapeinza"

Publications and helpful links

General Publications

• Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, Annino L, Venditti A, Voso MT, Mazzone C, Magro D, De Fabritiis P, Muus P, Alimena G, Mancini M, Hagemeijer A, Paoloni F, Vignetti M, Fazi P, Meert L, Ramadan SM, Willemze R, de Witte T, Baron F. Gemtuzumab Ozogamicin Versus Best Supportive Care in Older Patients With Newly Diagnosed Acute Myeloid Leukemia Unsuitable for Intensive Chemotherapy: Results of the Randomized Phase III EORTC-GIMEMA AML-19 Trial. J Clin Oncol. 2016 Mar 20;34(9):972-9. doi: 10.1200/JCO.2015.64.0060. Epub 2016 Jan 25. Erratum In: J Clin Oncol. 2022 Feb 10;40(5):525.

Study record dates

Study Major Dates

• Study Start: June 1, 2004
• Primary Completion (Anticipated): December 1, 2013

Study Registration Dates

• First Submitted: September 7, 2004
• First Submitted That Met QC Criteria: September 8, 2004
• First Posted (Estimate): September 9, 2004

Study Record Updates

• Last Update Posted (Estimate): July 24, 2012
• Last Update Submitted That Met QC Criteria: July 23, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); secondary acute myeloid leukemia; untreated adult acute myeloid leukemia; adult acute megakaryoblastic leukemia (M7); adult acute minimally differentiated myeloid leukemia (M0); adult acute monoblastic leukemia (M5a); adult acute monocytic leukemia (M5b); adult acute myeloblastic leukemia with maturation (M2); adult acute myeloblastic leukemia without maturation (M1); adult acute myelomonocytic leukemia (M4); adult acute basophilic leukemia; adult acute eosinophilic leukemia; adult erythroleukemia (M6a); adult pure erythroid leukemia (M6b)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Antineoplastic Agents; Antineoplastic Agents, Immunological; Gemtuzumab
• Other Study ID Numbers: EORTC-06031