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Leukemia, Myeloid, AcutePhase 2NCT00143975

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

A Phase 2 study testing Cytarabine, Mitoxantrone and Gemtuzumab Ozogamicin in people with Leukemia, Myeloid, Acute, run by University of Ulm at 27 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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 Read more about this study

Who is it for?
Ages 18 to 60 years
Conditions the study is for
Leukemia, Myeloid, Acute
What is being tested?
Cytarabine, Mitoxantrone and Gemtuzumab Ozogamicin
Type of treatment
Injection or infusion
How many people
95 participants
Where
27 sitesin 2 countries
Study dates
Jun 2004to Jun 2009
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 60 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

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

Who cannot join

  • 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

Trial locations and contacts

27 sites in 2 countries.

27 sites in 2 countries

Germany24 sites

  • Medical Department II, Central Hospital of Augsburg

    Augsburg, 86156

  • Department of General Internal Medicine, University Hospital of Bonn

    Bonn, 53127

  • Department of Hematology and Oncology, Hospital Essen-Süd, Ev. Hospital of Essen-Werden

    Essen, 45239

  • Department of Internal Medicine III, City Hospital Frankfurt am Main - Höchst

    Frankfurt, 65929

  • Medical Department IV, University Hospital of Gießen

    Giessen, 35392

  • Department of Internal Medicine, Wilhelm-Anton-Hospital gGmbH

    Goch, 47574

  • Centre of Internal Medicine, University Hospital of Göttingen

    Göttingen, 37075

  • Department of Oncology and Hematology, University Hospital Eppendorf

    Hamburg, 20246

  • Medical Department III, Clinical Center Hanau

    Hanau, 63450

  • Medical Department III, Clinical Center Hannover-Siloah

    Hanover, 30449

  • Department of Hematology, Hemostaseology and Oncology, Medizinische Hochschule Hannover

    Hanover, 30625

  • Department of Internal Medicine I, University Hospital of Saarland

    Homburg, 66421

  • Medical Department II, City Hospital Karlsruhe gGmbH

    Karlsruhe, 76133

  • Medical Department II, University Hospital of Kiel

    Kiel, 24116

  • Department of Internal Medicine / Hematology and Oncology, Caritas Hospital Lebach

    Lebach, 66822

  • Department of Hematology / Oncology, Clinical center of Lüdenscheid

    Lüdenscheid, 58515

  • Department of Hematology and internal Oncology, University Hospital of Mainz

    Mainz, 55101

  • Medical Department III, Clinical Center rechts der Isar

    München, 81675

  • Department of Hematology and Oncology, Clinical Center of Oldenburg gGmbH

    Oldenburg, 26133

  • Department of Hematology and Oncology / Caritas Hospital St. Theresia

    Saarbrücken, 66113

  • Department of Oncology / Clinical Center of Stuttgart

    Stuttgart, 70174

  • Department of Internal Medicine II, University Hospital of Tübingen

    Tübingen, 72076

  • Department of Internal Medicine III, University of Ulm

    Ulm, 89070

  • Medical Department I, Helios Hospital Wuppertal

    Wuppertal, 42283

Other trials in Germany

Austria3 sites

  • Department of Hematology / Oncology, University Hospital of Innsbruck

    Innsbruck, A-6020

  • St. Johann Hospital, Clinical Center of Salzburg

    Salzburg, A-5020

  • Medical Department III, Hanusch-Hospital

    Vienna, A-1140

Other trials in Austria

About this study

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

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

Read the 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.

Being tested
Cytarabine, Mitoxantrone, Gemtuzumab Ozogamicin, All-trans-Retinoid Acid
Keywords
Acute myeloid leukemia, gemtuzumab ozogamicin, refractory disease
Medical subject headings
Leukemia, Myeloid, Acute, Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CytarabineDrug

    3 g/m2 bid. i.v day 1-3

  • MitoxantroneDrug

    12 mg/m2 i.v. day 2 and 3

  • Gemtuzumab OzogamicinDrug

    3mg/m² i.v. day 1

  • All-trans-Retinoid AcidDrug

    45 mg/m2 p.o. day 4-6 15 mg/m2 p.o. day 7-28

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. CR-rate after therapy with GO-A-HAM

    Measured: day 30

Secondary outcomes (3)

  1. kind, incidence, severity, temporal sequence and correlation of side effects of the study-drugs

    Measured: 30 days

  2. rate of veno occlusive disease (VOD) after allogene transplantation

    Measured: 100 days after allogene transplantation

  3. overall survival

    Measured: two years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Sep 2005 (estimated)
  2. Study startJun 2004
  3. Primary completionJul 2007
  4. Study completionJun 2009

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
95 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00143975
Sponsor's protocol ID
AMLSG05-04
Status last verified
Aug 2010
First submitted
31 Aug 2005
Last updated
12 Aug 2010
Results posted
No

Publications

  • Schlenk RF, Benner A, Hartmann F, del Valle F, Weber C, Pralle H, Fischer JT, Gunzer U, Pezzutto A, Weber W, Grimminger W, Preiss J, Hensel M, Frohling S, Dohner K, Haas R, Dohner H; AML Study Group Ulm (AMLSG ULM). Risk-adapted postremission therapy in acute myeloid leukemia: results of the German multicenter AML HD93 treatment trial. Leukemia. 2003 Aug;17(8):1521-8. doi: 10.1038/sj.leu.2403009.

    PubMed 12886238

  • Wheatley K, Burnett AK, Goldstone AH, Gray RG, Hann IM, Harrison CJ, Rees JK, Stevens RF, Walker H. A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United Kingdom Medical Research Council's Adult and Childhood Leukaemia Working Parties. Br J Haematol. 1999 Oct;107(1):69-79. doi: 10.1046/j.1365-2141.1999.01684.x.

    PubMed 10520026

  • 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

  • Bunjes D, Buchmann I, Duncker C, Seitz U, Kotzerke J, Wiesneth M, Dohr D, Stefanic M, Buck A, Harsdorf SV, Glatting G, Grimminger W, Karakas T, Munzert G, Dohner H, Bergmann L, Reske SN. Rhenium 188-labeled anti-CD66 (a, b, c, e) monoclonal antibody to intensify the conditioning regimen prior to stem cell transplantation for patients with high-risk acute myeloid leukemia or myelodysplastic syndrome: results of a phase I-II study. Blood. 2001 Aug 1;98(3):565-72. doi: 10.1182/blood.v98.3.565.

    PubMed 11468151

  • Schlenk RF, Hartmann F, Hensel M, Jung W, Weber-Nordt R, Gabler A, Haas R, Ho AD, Trumper L, Dohner H. Less intense conditioning with fludarabine, cyclophosphamide, idarubicin and etoposide (FCIE) followed by allogeneic unselected peripheral blood stem cell transplantation in elderly patients with leukemia. Leukemia. 2002 Apr;16(4):581-6. doi: 10.1038/sj.leu.2402423.

    PubMed 11960336

  • Sierra J, Storer B, Hansen JA, Martin PJ, Petersdorf EW, Woolfrey A, Matthews D, Sanders JE, Storb R, Appelbaum FR, Anasetti C. Unrelated donor marrow transplantation for acute myeloid leukemia: an update of the Seattle experience. Bone Marrow Transplant. 2000 Aug;26(4):397-404. doi: 10.1038/sj.bmt.1702519.

    PubMed 10982286

  • Hiddemann W, Buchner T, Essink M, Koch O, Stenzinger W, van de Loo J. High-dose cytosine arabinoside and mitoxantrone: preliminary results of a pilot study with sequential application (S-HAM) indicating a high antileukemic activity in refractory acute leukemias. Onkologie. 1988 Feb;11(1):10-2. doi: 10.1159/000216471.

    PubMed 3283619

  • Hu ZB, Minden MD, McCulloch EA. Direct evidence for the participation of bcl-2 in the regulation by retinoic acid of the Ara-C sensitivity of leukemic stem cells. Leukemia. 1995 Oct;9(10):1667-73.

    PubMed 7564507

  • Bradbury DA, Aldington S, Zhu YM, Russell NH. Down-regulation of bcl-2 in AML blasts by all-trans retinoic acid and its relationship to CD34 antigen expression. Br J Haematol. 1996 Sep;94(4):671-5. doi: 10.1046/j.1365-2141.1996.d01-1838.x.

    PubMed 8826891

  • Benito A, Grillot D, Nunez G, Fernandez-Luna JL. Regulation and function of Bcl-2 during differentiation-induced cell death in HL-60 promyelocytic cells. Am J Pathol. 1995 Feb;146(2):481-90.

    PubMed 7856757

  • Yang GS, Minden MD, McCulloch EA. Influence of schedule on regulated sensitivity of AML blasts to cytosine arabinoside. Leukemia. 1993 Jul;7(7):1012-9.

    PubMed 7686602

  • Zheng A, Mantymaa P, Saily M, Savolainen E, Vahakangas K, Koistinen P. p53 pathway in apoptosis induced by all-trans-retinoic acid in acute myeloblastic leukaemia cells. Acta Haematol. 2000;103(3):135-43. doi: 10.1159/000041036.

    PubMed 10940651

  • Schlenk RF, Frohling S, Hartmann F, Fischer JT, Glasmacher A, del Valle F, Grimminger W, Gotze K, Waterhouse C, Schoch R, Pralle H, Mergenthaler HG, Hensel M, Koller E, Kirchen H, Preiss J, Salwender H, Biedermann HG, Kremers S, Griesinger F, Benner A, Addamo B, Dohner K, Haas R, Dohner H; AML Study Group Ulm. Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia. 2004 Nov;18(11):1798-803. doi: 10.1038/sj.leu.2403528.

    PubMed 15385923

  • Sievers EL, Larson RA, Stadtmauer EA, Estey E, Lowenberg B, Dombret H, Karanes C, Theobald M, Bennett JM, Sherman ML, Berger MS, Eten CB, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR; Mylotarg Study Group. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001 Jul 1;19(13):3244-54. doi: 10.1200/JCO.2001.19.13.3244.

    PubMed 11432892

  • 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.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Cytarabine, Mitoxantrone and Gemtuzumab Ozogamicin in people with Leukemia, Myeloid, Acute, run by University of Ulm at 27 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 Aug 2010. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 27 sites in Germany, Austria. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

CR-rate after therapy with GO-A-HAM (time frame: day 30). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00143975, which also lists 18 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Aug 2010.

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