Prospective Study of Mylotarg and G-CSF in Acute Myeloid Leukemia Treatment - Full Text View

Purpose

Acute myeloid leukemia (AML) is a neoplasm of immature hematopoietic cells (blasts) with altered ripening capacity. Due to excessive proliferation, the blasts displace normal hematopoietic cells and bone marrow failure appears. Leukemic cells also infiltrate extramedullary tissues.

Following the standard chemotherapy treatment, the CR rate achieved is around 65-75% for all patients and 15% lower when considering only patients over 65 years. Modifications to the standard regimen consist of replacing the DNR for a cytotoxic one, modifying the dose of ara-C or adding a third drug.

Gemtuzumab ozogamicin (Mylotarg ®) is an immunoconjugate between anti-CD33 antibody and a cytotoxic antitumor antibiotic, calicheamicin. Mylotarg ® antibody specifically binds to CD33, a sialic acid-dependent adhesion protein expressed in over 90% of LMA10. Mylotarg ® selectively transports the cytotoxic agent calicheamicin into leukemic cells and hematopoietic progenitors differentiated from the myelomonocytic line, while respecting the pluripotent hematopoietic stem cells. Calicheamicin is released only after the fixation of the antibody anti-CD33 and its internalization by the cell, after which binds to and damages the DNA.

Mylotarg ® is approved in the U.S. for the treatment of CD33 positive AML in first relapse, for patients older than 60 years non-candidates for other intensive treatment modalities.

Since the efficacy of Mylotarg ® is equivalent and its toxicity profile less than the conventional therapy, it is logical to conduct a phase II trial exploring the role of Mylotarg ® in the early stages of treatment of AML.

Previous experience with gemtuzumab ozogamicin in relapsed patients led to its use combined with induction chemotherapy. The aim was to improve the CR rate reached with the latter and reduce relapse after achieving greater leukemic cytoreduction.

Recent data from the HOVON group support that the administration of G-CSF before and during induction chemotherapy decreases the incidence of relapse in patients with AML, particularly those considered to have intermediate risk.

Everything mentioned above justifies to investigate the combination of GO combined with chemotherapy with IDR and ara-C in standard 3x7 scheme and analyze the effect of sensitization with G-CSF in patients with AML de novo. If the treatment proposed here is effective and presents an acceptable toxicity it should be investigated.

Condition	Intervention	Phase
Novo Acute Myeloid Leukemia	Drug: Mylotarg	Phase 2

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Treatment of de Novo Acute Myeloid Leukemia With the Combination of Idarubicin, Cytarabine, and Gemtuzumab Ozogamicin (Mylotarg ®), Associated or Not Priming With G-CSF. Prospective Study of Efficacy and Toxicity

Resource links provided by NLM:

Genetics Home Reference related topics: familial acute myeloid leukemia with mutated CEBPA

MedlinePlus related topics: Acute Myeloid Leukemia Leukemia

Drug Information available for: Cytarabine Idarubicin hydrochloride Idarubicin Granulocyte colony-stimulating factor Gemtuzumab ozogamicin

U.S. FDA Resources

Further study details as provided by Grupo Cooperativo de Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias:

Primary Outcome Measures:

Complete Remission of the Disease [ Time Frame: 28 days after chemotherapy ] [ Designated as safety issue: No ]
Bone marrow normocellular or slightly hypocellular with proportion of blasts <5%, including the erythroid cell count (and including promonocytes in case of M5), no Auer rods, no extramedullary leukemia, neutrophils and platelets rising. The persistence of minimal residual disease in immunophenotypic study will not invalidate the standard cytogenetic complete remission

Secondary Outcome Measures:

Secondary Toxicity to Mylotarg(R) [ Time Frame: Baseline, weekly during treatment and at month 3 and month 6 after first induction. ] [ Designated as safety issue: Yes ]
Hematological toxicity, hepatic and gastrointestinal toxicity, fever and infections, pulmonary complications, duration of hospitalization
Mortality and Induction [ Time Frame: Weekly during treatment, at third month and at 6 months after last administration of Mylotarg ] [ Designated as safety issue: Yes ]
all deaths occurring after the first administration of MylotargTM until the time of transplantation with no leukemic relapse has occurred, and all deaths in the 6 first months after administration of the second dose of MylotargTM with no leukemic relapse occurred.
Capacity to obtain hematopoietic progenitor cells (HPC) for autotransplantation [ Time Frame: One month before transplant, expected at 9 months after end of treatment. ] [ Designated as safety issue: No ]
Relapse after 6 months [ Time Frame: 6 months from complete remission ] [ Designated as safety issue: No ]
Rate of patients that have relapse after 6 months of obtained complete remission.
Survival after 6 months [ Time Frame: 6 months after complete remission ] [ Designated as safety issue: No ]
rate of patients alive within 6 months of obtained complete remission

Enrollment:	40
Study Start Date:	October 2009
Estimated Study Completion Date:	February 2013
Estimated Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Single arm, two cohorts Idarubicin, cytarabine, Mylotarg, G-CSF.	Drug: Mylotarg Cohort 1 (20 evaluable patients): GO: 3 mg/m^2 (maximum 5 mg), IV infusion, 2 hours, day 1. Idarubicin: 12 mg/m^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine (cytosine arabinoside): 100 mg/m^2 IV continuous infusion on days 1 to 7, to begin 4 hours after the administration of GO. Cohort 2 (20 evaluable patients): G-CSF: 150 mcg/m^2, SC, days 0 to 7, to begin 12 to 18 hours before treatment with Gemtuzumab. GO: 3 mg/m^2 (maximum 5 mg), IV infusion, 2 hours, day 1. Idarubicin: 12 mg/m^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine (cytosine arabinoside): 100 mg/m^2 IV continuous infusion on days 1 to 7, to begin 4 hours later after the administration of GO.

Arms

Assigned Interventions

Experimental: Single arm, two cohorts

Idarubicin, cytarabine, Mylotarg, G-CSF.

Drug: Mylotarg

Cohort 1 (20 evaluable patients):

GO: 3 mg/m^2 (maximum 5 mg), IV infusion, 2 hours, day 1. Idarubicin: 12 mg/m^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine (cytosine arabinoside): 100 mg/m^2 IV continuous infusion on days 1 to 7, to begin 4 hours after the administration of GO.

Cohort 2 (20 evaluable patients):

G-CSF: 150 mcg/m^2, SC, days 0 to 7, to begin 12 to 18 hours before treatment with Gemtuzumab. GO: 3 mg/m^2 (maximum 5 mg), IV infusion, 2 hours, day 1.

Idarubicin: 12 mg/m^2, IV, 30 minutes, on days 2, 3, 4. Cytarabine (cytosine arabinoside): 100 mg/m^2 IV continuous infusion on days 1 to 7, to begin 4 hours later after the administration of GO.

Eligibility

Ages Eligible for Study:	18 Years to 70 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients with primary or "de novo" AML, different than promyelocytic or M3 subtype.
Age 18 to 70 years.
Written informed consent form

Exclusion Criteria:

Acute leukemia appeared after a myeloproliferative process or a myelodysplastic syndrome longer than 6 months, AML arising after another cured malignant disease (e.g. Hodgkin's disease), and secondary AML treated with alkylating agents or radiation.
Acute promyelocytic leukemia.
Relevant history of liver disease. Significant impaired liver function (bilirubin, AST or ALT ≥ 2.5 times the normal value) not attributable to leukemic infiltration.
Patients with prior heart failure.
Symptomatic chronic respiratory failure.
Positive serology for HIV, hepatitis C virus or its surface antigen.
Estimated life expectancy less than 3 months, despite treatment.
Pregnancy or breastfeeding at the time of inclusion in the study.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01698879

Locations

Spain
Hospital Germans Trias i Pujol
Badalona, Barcelona, Spain, 08916
Hospital de la Santa Creu i Sant Pau
Barcelona, Spain, 08025
Hospital Clinic Barcelona
Barcelona, Spain, 08036
Hospital Clinico Universitario de Salamanca
Salamanca, Spain, 37007
Hospital Universitario Virgen del Rocio
Sevilla, Spain, 41013
Hospital Clínico Universitario de Valencia
Valencia, Spain, 496010

Sponsors and Collaborators

Grupo Cooperativo de Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias

Investigators

Study Chair:

Jordi Sierra, MD

Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

More Information

No publications provided

Responsible Party:	Grupo Cooperativo de Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias
ClinicalTrials.gov Identifier:	NCT01698879 History of Changes
Other Study ID Numbers:	ICOG-07, 2007-006295-11
Study First Received:	July 23, 2012
Last Updated:	October 1, 2012
Health Authority:	Spain: Spanish Agency of Medicines

Additional relevant MeSH terms:

Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Gemtuzumab
Idarubicin
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
Antibiotics, Antineoplastic

ClinicalTrials.gov processed this record on May 16, 2013