Clinical trial NCT00143975: Gemtuzumab Ozogamicin in Combination With A-HAM in Refractory AML (GO-A-HAM)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia, Myeloid, Acute
Keywords: Acute myeloid leukemia
gemtuzumab ozogamicin
refractory disease
Lead sponsor: University of Ulm
Sponsor class: OTHER
First posted: 2005-09-02
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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 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

Primary outcomes:
measure: CR-rate after therapy with GO-A-HAM
timeFrame: day 30
Secondary outcomes:
measure: kind, incidence, severity, temporal sequence and correlation of side effects of the study-drugs
timeFrame: 30 days
measure: rate of veno occlusive disease (VOD) after allogene transplantation
timeFrame: 100 days after allogene transplantation
measure: overall survival
timeFrame: two years
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Department of Hematology / Oncology, University Hospital of Innsbruck
city: Salzburg
country: Austria
facility: St. Johann Hospital, Clinical Center of Salzburg
city: Wien
country: Austria
facility: Medical Department III, Hanusch-Hospital
city: Augsburg
country: Germany
facility: Medical Department II, Central Hospital of Augsburg
city: Bonn
country: Germany
facility: Department of General Internal Medicine, University Hospital of Bonn
city: Essen
country: Germany
facility: Department of Hematology and Oncology, Hospital Essen-Süd, Ev. Hospital of Essen-Werden
city: Frankfurt
country: Germany
facility: Department of Internal Medicine III, City Hospital Frankfurt am Main - Höchst
city: Gießen
country: Germany
facility: Medical Department IV, University Hospital of Gießen
city: Goch
country: Germany
facility: Department of Internal Medicine, Wilhelm-Anton-Hospital gGmbH
city: Göttingen
country: Germany
facility: Centre of Internal Medicine, University Hospital of Göttingen
city: Hamburg
country: Germany
facility: Department of Oncology and Hematology, University Hospital Eppendorf
city: Hanau
country: Germany
facility: Medical Department III, Clinical Center Hanau
city: Hannover
country: Germany
facility: Medical Department III, Clinical Center Hannover-Siloah
city: Hannover
country: Germany
facility: Department of Hematology, Hemostaseology and Oncology, Medizinische Hochschule Hannover
city: Homburg
country: Germany
facility: Department of Internal Medicine I, University Hospital of Saarland
city: Karlsruhe
country: Germany
facility: Medical Department II, City Hospital Karlsruhe gGmbH
city: Kiel
country: Germany
facility: Medical Department II, University Hospital of Kiel
city: Lebach
country: Germany
facility: Department of Internal Medicine / Hematology and Oncology, Caritas Hospital Lebach
city: Luedenscheid
country: Germany
facility: Department of Hematology / Oncology, Clinical center of Lüdenscheid
city: Mainz
country: Germany
facility: Department of Hematology and internal Oncology, University Hospital of Mainz
city: München
country: Germany
facility: Medical Department III, Clinical Center rechts der Isar
city: Oldenburg
country: Germany
facility: Department of Hematology and Oncology, Clinical Center of Oldenburg gGmbH
city: Saarbrucken
country: Germany
facility: Department of Hematology and Oncology / Caritas Hospital St. Theresia
city: Stuttgart
country: Germany
facility: Department of Oncology / Clinical Center of Stuttgart
city: Tübingen
country: Germany
facility: Department of Internal Medicine II, University Hospital of Tübingen
city: Ulm
country: Germany
facility: Department of Internal Medicine III, University of Ulm
city: Wuppertal
country: Germany
facility: Medical Department I, Helios Hospital Wuppertal
Study officials:
affiliation: University of Ulm / Department of Internal Medicine III
name: Richard F Schlenk, Dr. med.
role: PRINCIPAL_INVESTIGATOR
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