Gemtuzumab Ozogamicin in Combination With A-HAM in Refractory AML (GO-A-HAM)

This study has been completed.
Sponsor:
Information provided by:
University of Ulm
ClinicalTrials.gov Identifier:
NCT00143975
First received: August 31, 2005
Last updated: August 11, 2010
Last verified: August 2010
  Purpose

GO-A-HAM:

Gemtuzumab Ozogamicin 3g/m² day 1 Cytarabine 3g/m² bid days 1-3 Mitoxantrone 12mg/m² days 2,3 All-trans Retinoic acid 45mg/m² days 4-6 and 15 mg/m² days 7-28


Condition Intervention Phase
Leukemia, Myeloid, Acute
Drug: Cytarabine
Drug: Mitoxantrone
Drug: Gemtuzumab Ozogamicin
Drug: All-trans-Retinoid Acid
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study on Gemtuzumab Ozogamicin in Combination With All-trans-Retinoic Acid, High-dose Cytarabine and Mitoxantrone in Patients With Primary Refractory Acute Myeloid Leukemia

Resource links provided by NLM:


Further study details as provided by University of Ulm:

Primary Outcome Measures:
  • CR-rate after therapy with GO-A-HAM [ Time Frame: day 30 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • kind, incidence, severity, temporal sequence and correlation of side effects of the study-drugs [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
  • rate of veno occlusive disease (VOD) after allogene transplantation [ Time Frame: 100 days after allogene transplantation ] [ Designated as safety issue: Yes ]
  • overall survival [ Time Frame: two years ] [ Designated as safety issue: No ]

Enrollment: 95
Study Start Date: June 2004
Study Completion Date: June 2009
Primary Completion Date: July 2007 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Cytarabine
    3 g/m2 bid. i.v day 1-3
    Drug: Mitoxantrone
    12 mg/m2 i.v. day 2 and 3
    Drug: Gemtuzumab Ozogamicin
    3mg/m² i.v. day 1
    Drug: All-trans-Retinoid Acid
    45 mg/m2 p.o. day 4-6 15 mg/m2 p.o. day 7-28
Detailed Description:

Primary refractory AML is associated with an extremely poor prognosis [1,2]. In the AMLHD93 trial conducted by the AMLSG ULM, patients refractory to the first induction therapy with ICE (idarubicin, cytarabine, etoposide) had an overall survival of 12% after 5 years [1]. All patients alive in this cohort had received allogeneic transplantation. Therefore, we assigned allogeneic transplantation in our consecutive trial, AMLHD98A, to all primary refractory patients [3]. However, the main problem in this patient group remains achieving a partial (PR) or complete (CR) remission to a salvage therapy. Additionally, the pre-transplant disease status is an important prognostic factor in most studies of allogeneic transplantation, regardless dose intensified or dose reduced conditioning regimens are used [4,5,6]. Since 1993, in all studies of the German-Austrian-AMLSG response-adapted treatment strategies had been used. Within the AMLHD93 trial, refractory patients were assigned to an intensified second induction regimen with S-HAM (age<55 years) [7] or HAM (age 55 to 60 years) [1], and in the AMLHD98A trial, with A-HAM [3]. The incorporation of all-trans-retinoic acid was based on in vitro data [8-13] and by our randomised AMLHD98B study for elderly AML-patients showing a benefit in primary response and survival for patients assigned to standard induction therapy in combination with ATRA [14].

To compare the different salvage therapy strategies, we performed an as-treated analysis in primary refractory patients of the different cohorts. Although refractory to the first induction therapy with ICE, nine patients received a second cycle ICE. The results summarized in table 1 showed an improved response rate (CR and PR) for patients treated with the A-HAM protocol and thus leading to a higher proportion of patients receiving an allogeneic transplantation. Survival analysis showed so far no difference between the 4 different groups. Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 conjugated to Calicheamicin. The efficacy and the toxicity profile has been evaluated in several studies, so far the substance is approved for the monotherapy in relapsed AML-patients in a dose of 9mg/m² q 14d [15]. However, used as a single agent the efficacy is limited and not durable. Therefore, several trials have evaluated GO in combination with conventional chemotherapy [16,17]. In the MRC study a dose of 6 mg/m² given once at day 1 was associated with an increased liver toxicity and therefore the study continues with a dose of 3 mg/m² once at day 1 of induction therapy [17]. In summary, the available data for combination therapy showed efficacy of GO in phase II trials. The dose limiting toxicity was defined in the MRC trial at 6 mg/m². Therefore we consider GO in combination with A-HAM for primary refractory adult AML patients. Because all primary refractory patients are candidates for an allogeneic transplantation special considerations have to be taken with respect to the development of VOD after allogeneic transplantation. One recent report suggests a substantial risk for VOD for patients receiving an allogeneic transplantation after a therapy with GO [18]. In this report the odds ratio for VOD after a therapy with GO within 3.5 months before allogeneic transplantation was 21.6 (95%-confidence interval 4.2-112.2%). However, this report is based on 62 patients and the dosage of GO used was 6mg/m² and 9mg/m². Therefore, holding in mind the risk of VOD after GO exposure and the extremely poor prognosis of primary refractory patients the treatment approach combining A-HAM with GO with a dose of 3mg/m² is justified.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Acute myeloid leukemia defined according the WHO classification not responding to first induction therapy
  • Age 18-60 years
  • Written informed consent

Exclusion Criteria:

  • Acute promyelocytic leukemia
  • Uncontrolled infection
  • Transfusion-refractory thrombocytopenia
  • Pregnancy, breast-feeding, insufficient contraception
  • Organ insufficiency: kidneys, liver, lungs, heart
  • Severe neurological and psychiatrical interfering with informed consent
  • No consent for the registration, storage and processing of data concerning the characteristics of the AML and the individual course
  • Performance status > grad 2 according the WHO classification
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00143975

Locations
Austria
Department of Hematology / Oncology, University Hospital of Innsbruck
Innsbruck, Austria, A-6020
St. Johann Hospital, Clinical Center of Salzburg
Salzburg, Austria, A-5020
Medical Department III, Hanusch-Hospital
Wien, Austria, A-1140
Germany
Medical Department II, Central Hospital of Augsburg
Augsburg, Germany, 86156
Department of General Internal Medicine, University Hospital of Bonn
Bonn, Germany, 53127
Department of Hematology and Oncology, Hospital Essen-Süd, Ev. Hospital of Essen-Werden
Essen, Germany, 45239
Department of Internal Medicine III, City Hospital Frankfurt am Main - Höchst
Frankfurt, Germany, 65929
Medical Department IV, University Hospital of Gießen
Gießen, Germany, 35392
Department of Internal Medicine, Wilhelm-Anton-Hospital gGmbH
Goch, Germany, 47574
Centre of Internal Medicine, University Hospital of Göttingen
Göttingen, Germany, 37075
Department of Oncology and Hematology, University Hospital Eppendorf
Hamburg, Germany, 20246
Medical Department III, Clinical Center Hanau
Hanau, Germany, 63450
Department of Hematology, Hemostaseology and Oncology, Medizinische Hochschule Hannover
Hannover, Germany, 30625
Medical Department III, Clinical Center Hannover-Siloah
Hannover, Germany, 30449
Department of Internal Medicine I, University Hospital of Saarland
Homburg, Germany, 66421
Medical Department II, City Hospital Karlsruhe gGmbH
Karlsruhe, Germany, 76133
Medical Department II, University Hospital of Kiel
Kiel, Germany, 24116
Department of Internal Medicine / Hematology and Oncology, Caritas Hospital Lebach
Lebach, Germany, 66822
Department of Hematology / Oncology, Clinical center of Lüdenscheid
Luedenscheid, Germany, 58515
Department of Hematology and internal Oncology, University Hospital of Mainz
Mainz, Germany, 55101
Medical Department III, Clinical Center rechts der Isar
München, Germany, 81675
Department of Hematology and Oncology, Clinical Center of Oldenburg gGmbH
Oldenburg, Germany, 26133
Department of Hematology and Oncology / Caritas Hospital St. Theresia
Saarbrucken, Germany, 66113
Department of Oncology / Clinical Center of Stuttgart
Stuttgart, Germany, 70174
Department of Internal Medicine II, University Hospital of Tübingen
Tübingen, Germany, 72076
Department of Internal Medicine III, University of Ulm
Ulm, Germany, 89070
Medical Department I, Helios Hospital Wuppertal
Wuppertal, Germany, 42283
Sponsors and Collaborators
University of Ulm
Investigators
Principal Investigator: Richard F Schlenk, Dr. med. University of Ulm / Department of Internal Medicine III
  More Information

Additional Information:
Publications:
Schlenk RF, Fröhling S, Del Valle F, Dreger P, Fischer JTh, Glasmacher A, Götze K, Grimminger W, Germing U, Hartmann F, Koller E, Mergenthaler HG, Salwender H, Waterhouse C, Döhner K, Bunjes D, Döhner H. Early Allogeneic Transplantation in Patients with High Risk Acute Myeloid Leukemia Defined by Karyotype and Response To Induction Therapy: First Results of the AML HD98A Trial. Blood 98: 2822, abstract
De Angelo, D., et al., Interim analysis of a phase II study of the safety and efficacy of Gemtuzumab Ozogamicin (Mylotarg) given in combination with Cytarabine and Daunorubicin in patients< 60years old with untreated acute myeloid leukemia. Blood 100:745a.
Jonathan W. Kell, Alan K. Burnett, Raj Chopra, John Yin, Dominic Culligan, Richard Clark, Ann Hunter, Ama Rohatiner, Don W. Milligan, Nigel Russell, Archie Prentice. Dept of Haematology, MRC AML Pilot Group, United Kingdom Mylotarg (Gemtuzumab Ozogamicin: GO) Given Simultaneously with Intensive Induction and/or Consolidation Therapy for AML Is Feasible and May Improve the Response Rate. Blood 100:746a

Responsible Party: Prof. Dr. Reinhard Marre, University of Ulm
ClinicalTrials.gov Identifier: NCT00143975     History of Changes
Other Study ID Numbers: AMLSG05-04
Study First Received: August 31, 2005
Last Updated: August 11, 2010
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by University of Ulm:
Acute myeloid leukemia
gemtuzumab ozogamicin
refractory disease

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Gemtuzumab
Mitoxantrone
Tretinoin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Keratolytic Agents
Dermatologic Agents

ClinicalTrials.gov processed this record on August 28, 2014