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

Leukemia, Myeloid, Acute Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00143975
• Other study ID #: AMLSG05-04
• Status: Completed
• Phase: Phase 2
• First received: August 31, 2005
• Last updated: August 11, 2010
• Start date: June 2004
• Est. completion date: June 2009

Study information

• Verified date: August 2010
• Source: University of Ulm
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 95
• Est. completion date: June 2009
• Est. primary completion date: July 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Cytarabine
3 g/m2 bid. i.v day 1-3
• Mitoxantrone
12 mg/m2 i.v. day 2 and 3
• Gemtuzumab Ozogamicin
3mg/m² i.v. day 1
• All-trans-Retinoid Acid
45 mg/m2 p.o. day 4-6 15 mg/m2 p.o. day 7-28

Locations

Country	Name	City	State
Austria	Department of Hematology / Oncology, University Hospital of Innsbruck	Innsbruck
Austria	St. Johann Hospital, Clinical Center of Salzburg	Salzburg
Austria	Medical Department III, Hanusch-Hospital	Wien
Germany	Medical Department II, Central Hospital of Augsburg	Augsburg
Germany	Department of General Internal Medicine, University Hospital of Bonn	Bonn
Germany	Department of Hematology and Oncology, Hospital Essen-Süd, Ev. Hospital of Essen-Werden	Essen
Germany	Department of Internal Medicine III, City Hospital Frankfurt am Main - Höchst	Frankfurt
Germany	Medical Department IV, University Hospital of Gießen	Gießen
Germany	Department of Internal Medicine, Wilhelm-Anton-Hospital gGmbH	Goch
Germany	Centre of Internal Medicine, University Hospital of Göttingen	Göttingen
Germany	Department of Oncology and Hematology, University Hospital Eppendorf	Hamburg
Germany	Medical Department III, Clinical Center Hanau	Hanau
Germany	Department of Hematology, Hemostaseology and Oncology, Medizinische Hochschule Hannover	Hannover
Germany	Medical Department III, Clinical Center Hannover-Siloah	Hannover
Germany	Department of Internal Medicine I, University Hospital of Saarland	Homburg
Germany	Medical Department II, City Hospital Karlsruhe gGmbH	Karlsruhe
Germany	Medical Department II, University Hospital of Kiel	Kiel
Germany	Department of Internal Medicine / Hematology and Oncology, Caritas Hospital Lebach	Lebach
Germany	Department of Hematology / Oncology, Clinical center of Lüdenscheid	Luedenscheid
Germany	Department of Hematology and internal Oncology, University Hospital of Mainz	Mainz
Germany	Medical Department III, Clinical Center rechts der Isar	München
Germany	Department of Hematology and Oncology, Clinical Center of Oldenburg gGmbH	Oldenburg
Germany	Department of Hematology and Oncology / Caritas Hospital St. Theresia	Saarbrucken
Germany	Department of Oncology / Clinical Center of Stuttgart	Stuttgart
Germany	Department of Internal Medicine II, University Hospital of Tübingen	Tübingen
Germany	Department of Internal Medicine III, University of Ulm	Ulm
Germany	Medical Department I, Helios Hospital Wuppertal	Wuppertal

Sponsors (1)

Lead Sponsor	Collaborator
University of Ulm

Countries where clinical trial is conducted

Austria,  Germany, 

References & Publications (17)

Benito A, Grillot D, Nuñez G, Fernández-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. — View Citation

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. — View Citation

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, Döhner 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. — View Citation

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.

Hiddemann W, Büchner 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. — View Citation

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. — View Citation

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

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, Fröhling S, Döhner K, Haas R, Döhner 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. — View Citation

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

Schlenk RF, Fröhling S, Hartmann F, Fischer JT, Glasmacher A, del Valle F, Grimminger W, Götze 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, Döhner K, Haas R, Döhner 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. — View Citation

Schlenk RF, Hartmann F, Hensel M, Jung W, Weber-Nordt R, Gabler A, Haas R, Ho AD, Trümper L, Döhner 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. — View Citation

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. — View Citation

Sievers EL, Larson RA, Stadtmauer EA, Estey E, Löwenberg 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. — View Citation

Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, Ho V, Alyea EP, Antin JH, Stone RM, Soiffer RJ, DeAngelo DJ. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood. 2003 Sep 1;102(5):1578-82. Epub 2003 May 8. — View Citation

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. — View Citation

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. — View Citation

Zheng A, Mäntymaa P, Säily M, Savolainen E, Vähäkangas 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. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	CR-rate after therapy with GO-A-HAM		day 30	No
Secondary	kind, incidence, severity, temporal sequence and correlation of side effects of the study-drugs		30 days	Yes
Secondary	rate of veno occlusive disease (VOD) after allogene transplantation		100 days after allogene transplantation	Yes
Secondary	overall survival		two years	No

External Links

•   Study office, Department of Internal Medicine III, University of Ulm