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

Sponsor

University of Ulm (Other)

Overall Status

Completed

CT.gov ID

NCT00143975

Collaborator

(none)

Enrollment

Locations

Duration (Months)

3.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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

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

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

95 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (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

Study Start Date :

Jun 1, 2004

Actual Primary Completion Date :

Jul 1, 2007

Actual Study Completion Date :

Jun 1, 2009

Outcome Measures

Primary Outcome Measures

CR-rate after therapy with GO-A-HAM [day 30]

Secondary Outcome Measures

kind, incidence, severity, temporal sequence and correlation of side effects of the study-drugs [30 days]
rate of veno occlusive disease (VOD) after allogene transplantation [100 days after allogene transplantation]
overall survival [two years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	Country	Postal Code
1	Department of Hematology / Oncology, University Hospital of Innsbruck	Innsbruck	Austria	A-6020
2	St. Johann Hospital, Clinical Center of Salzburg	Salzburg	Austria	A-5020
3	Medical Department III, Hanusch-Hospital	Wien	Austria	A-1140
4	Medical Department II, Central Hospital of Augsburg	Augsburg	Germany	86156
5	Department of General Internal Medicine, University Hospital of Bonn	Bonn	Germany	53127
6	Department of Hematology and Oncology, Hospital Essen-Süd, Ev. Hospital of Essen-Werden	Essen	Germany	45239
7	Department of Internal Medicine III, City Hospital Frankfurt am Main - Höchst	Frankfurt	Germany	65929
8	Medical Department IV, University Hospital of Gießen	Gießen	Germany	35392
9	Department of Internal Medicine, Wilhelm-Anton-Hospital gGmbH	Goch	Germany	47574
10	Centre of Internal Medicine, University Hospital of Göttingen	Göttingen	Germany	37075
11	Department of Oncology and Hematology, University Hospital Eppendorf	Hamburg	Germany	20246
12	Medical Department III, Clinical Center Hanau	Hanau	Germany	63450
13	Medical Department III, Clinical Center Hannover-Siloah	Hannover	Germany	30449
14	Department of Hematology, Hemostaseology and Oncology, Medizinische Hochschule Hannover	Hannover	Germany	30625
15	Department of Internal Medicine I, University Hospital of Saarland	Homburg	Germany	66421
16	Medical Department II, City Hospital Karlsruhe gGmbH	Karlsruhe	Germany	76133
17	Medical Department II, University Hospital of Kiel	Kiel	Germany	24116
18	Department of Internal Medicine / Hematology and Oncology, Caritas Hospital Lebach	Lebach	Germany	66822
19	Department of Hematology / Oncology, Clinical center of Lüdenscheid	Luedenscheid	Germany	58515
20	Department of Hematology and internal Oncology, University Hospital of Mainz	Mainz	Germany	55101
21	Medical Department III, Clinical Center rechts der Isar	München	Germany	81675
22	Department of Hematology and Oncology, Clinical Center of Oldenburg gGmbH	Oldenburg	Germany	26133
23	Department of Hematology and Oncology / Caritas Hospital St. Theresia	Saarbrucken	Germany	66113
24	Department of Oncology / Clinical Center of Stuttgart	Stuttgart	Germany	70174
25	Department of Internal Medicine II, University Hospital of Tübingen	Tübingen	Germany	72076
26	Department of Internal Medicine III, University of Ulm	Ulm	Germany	89070
27	Medical Department I, Helios Hospital Wuppertal	Wuppertal	Germany	42283