BeEAM2010-01: Bendamustine, Cytarabine, Etoposide and Melphalan (BeEAM) as Conditioning for Autologous Stem Cell Transplant (ASCT) in Aggressive Non Hodgkin's Lymphoma (NHL).

Sponsor

Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea (Other)

Overall Status

Completed

CT.gov ID

NCT01296256

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

2.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether Bendamustine in combination with Etoposide, Cytarabine and Melphalan (BeEAM) are effective as conditioning followed by ASCT in patients with aggressive lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Bendamustine Conditioning Therapy Autologous Stem Cell Transplant Aggressive Non Hodgkin's Lymphoma	Drug: Bendamustine-EAM	Phase 2

Detailed Description

BCNU (carmustine is a nitrosurea alkylating agent used for many years in the conditioning of patients with lymphoma however this drug is hardly available in some countries in Europe, moreover to improve conditioning regimens in autologous stem cell transplant is important because the anti-tumoral effect of high dose therapy are responsible for this procedure efficacy. Although for many years few advances have been achieved in this area now new drugs can be tested in these patients.

Bendamustine is a unique cytotoxic agent with structural similarities to alkylating agents and antimetabolites, but which is non-cross-resistant with alkylating agents and other drugs in vitro and in the clinic. Early clinical studies conducted in the German Democratic Republic more than 30 years ago suggested promising activity in indolent non-Hodgkin's lymphoma (NHL). Two North American trials reported responses in more than 70% of patients with chemotherapy- and rituximab-refractory disease, suggesting that bendamustine may be the most effective drug available for this patient population. Response rates of 90% to 92%, with complete remission in 55% to 60%, have been reported in patients with follicular and mantle-cell lymphoma with the combination of bendamustine and rituximab.(Cheson 2009) Leone et all have recently reported results on the characterization of the mechanisms of action of bendamustine and its comparison with structurally related compounds as chlorambucil and phosphoramide mustard have demonstrated that bendamustine displays a distinct mechanisms of action including activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. Also bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism.

These data suggest that bendamustine possesses mechanistic features that differentiate it from other alkylating agents and makes this old new drug an attractive one to combine with other agents in the conditioning transplant setting (Leone 2008).

Study Design

Study Type:

Interventional

Actual Enrollment :

60 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Bendamustine, Cytarabine, Etoposide and Melphalan as Conditioning for Autologous Stem Cell Transplant in Patients With Aggressive Non Hodgkin's Lymphoma.

Study Start Date :

May 1, 2011

Actual Primary Completion Date :

Nov 1, 2015

Actual Study Completion Date :

Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bendamustine-EAM	Drug: Bendamustine-EAM Bendamustine 200 mg/m2 starting dose on day -7 and -6 Etoposide 200 mg/m2 from day -5 to day -2 Ara-C 400 mg/m2 from day -5 to day -2 Melphalan 140 mg/m2 on day -1

Arm

Intervention/Treatment

Experimental: Bendamustine-EAM

Drug: Bendamustine-EAM

Bendamustine 200 mg/m2 starting dose on day -7 and -6 Etoposide 200 mg/m2 from day -5 to day -2 Ara-C 400 mg/m2 from day -5 to day -2 Melphalan 140 mg/m2 on day -1

Outcome Measures

Primary Outcome Measures

Evaluate the progression free survival using techniques of image (PET and TC)of Bendamustine in combination with Etoposide, Cytarabine and Melphalan (BeEAM) as conditioning followed by ASCT in patients with aggressive lymphoma. [18 months follow-up]

Secondary Outcome Measures

Evaluate safety BeEAM chemotherapy followed of reinfusion of autologous hematopoietic stem cells by considering the incidence of adverse event (with CTCAE).Evaluate % patients in CR.Evaluate response of ASCT using PET, TC.Evaluate overall survival [18 months follow-up]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients being able to meet all requirements of the clinical trial, according to the investigator's criteria,
Patient giving voluntarily written informed consent before performing any essay test that is not part of routine care of patients.
Age >o=18 years and >0=70 years
Candidate for chemotherapy (QT) at high doses and ASCT
Histologically confirmed aNHL:
Patients with DLBCL or grade 3 b Follicular lymphoma or PTCL (including anaplastic ALK +) in sensitive relapse, so, in second complete or partial response, after a minimum of 2 cycles of the rescue regimen.
Patients with DLBCL or grade 3 b Follicular lymphoma or PTCL (including anaplastic ALK +) in first complete or partial response, if more than one treatment line have been required to reach this first complete or partial response.
Transformed B cell lymphoma in first CR
Patients with PTCL (other than anaplastic ALK +) in first CR
Performance status (ECOG) <0=2.
Adequate renal, hepatic, and bone marrow function (assessed < 14 days before initiation of the study treatment):
Neutrophil count <o=1.5 x 109/L
Platelet count <o=100 x 109/L
Haemoglobin <o=8.0 g/dL
Creatinine serum >o=1,5 x ULN mg/dl
Serum bilirubin <o=1.5 x ULN and alkaline phosphatase <o=2.5 x ULN
AST, ALT <o=2.5 x ULN (<o=5 x ULN in case of liver metastasis).
Adequate pulmonary function: forced expiratory volume at 1 second > 65% of predicted or a diffusing capacity of the lung for CO >o=50%.
Cardiac ejection fraction or greater than 50% by echocardiogram or FEVI.
A woman capable of gestation (see definition below) should:

Have two medically supervised negative pregnancy test (minimum sensitivity of 25 mIU / ml) before starting study therapy (the first pregnancy test should be completed in 10 to 14 days prior to initiating bendamustine and the latter pregnancy test 24 hours before the start of this drug).
Commit to a continued abstinence of heterosexual relationship or agree to use reliable contraception without interruption, 28 days before starting the study therapy, during the study therapy and for 28 days after stopping therapy study.

A woman capable of gestation is defined as sexually mature woman who:

has not undergone hysterectomy or bilateral oophorectomy and
is not naturally postmenopausal (amenorrhea as a result of cancer treatment does not rule the reproductive potential) for at least 24 consecutive months (i.e., menses at any time during the previous 24 consecutive months).

Exclusion Criteria:

Impossibility of collecting, via apheresis, a number of CD34+ cells >o=2 x 106/kg
To receive any of the following treatments in the 28 days before the start the study treatment:

i.chemotherapeutic or antitumor agents ii.radiation therapy, except in limited fields, to a maximum dose of <o=10 Gy to control serious life-threatening symptoms iii.glucocorticoids, except doses equivalent to <o=1 mg / kg of prednisolone / day with a duration <o=7 days iv.any therapeutic agent under investigation.

Known involvement of the central nervous system (CNS) by lymphoma
Abnormalities in cardiac function or clinically significant heart disease such as acute myocardial infarction or unstable angina within 6 months prior to the start of study treatment, heart failure NYHA class III or IV, uncontrolled hypertension or a history of antihypertensive treatment poor compliance, uncontrolled arrhythmias with treatment, except extrasystoles or minor conduction disorders.
Other serious or uncontrolled medical condition, such as uncontrolled diabetes, uncontrolled active infection, significant cerebrovascular disease or poorly controlled psychiatric disease.
Known or suspected hypersensitivity to any of the agents or excipients of the regime under evaluation.
Presence of any limitations that compromise the patient's ability to comply with the study treatment.
Positive serology for HIV, HCV or HBV surface antigen (HBsAg). If the HBsAg is negative but anti-core antibodies (HBcAb) are positive and antibody against surface antigen (HBsAb) are negative, there will be a HBV DNA test; If positive results the patient may not be included in the trial. If both types of antibodies HBcAb and HBsAb are positive (indicative of past infection), the patient may be included in the study.
Previous history of malignancies other than lymphoma (except basal cell or squamous cell skin carcinoma and carcinoma in situ of the cervix or breast) unless the patient is free of disease beyond 5 years.
Major surgery procedure within 30 days prior to entering this study.
Pregnant or nursing females.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Complejo Hospitalario Universitario de Santiago	Santiago	A Coruña	Spain	15706
2	Hospital Central de Asturias	Oviedo	Asturias	Spain	33006
3	Hospital de Jerez	Jerez de la Frontera	Cádiz	Spain	11407
4	Hospital Son Llátzer	Palma de Mallorca	Mallorca	Spain	07198
5	Hospital Universitario Virgen de Arrixaca	El Palmar	Murcia	Spain	30120
6	Clinica Universitaria de Navarra	Pamplona	Navarra	Spain
7	Hospital Universitario de Canarias	Santa Cruz de Tenerife	Tenerife	Spain
8	Hospital Vall d´Hebron	Barcelona		Spain	08035
9	Hospital Clinic i Provincial	Barcelona		Spain	08036
10	H. de la Santa Creu i Sant Pau	Barcelona		Spain
11	H.U. 12 de Octubre,	Madrid		Spain
12	H.U. Gregorio Marañón,	Madrid		Spain
13	H.U. La Paz	Madrid		Spain
14	H.U. La Princesa	Madrid		Spain
15	Hospital Ramon y Cajal	Madrid		Spain
16	H. Clínico Universitario de Salamanca	Salamanca		Spain
17	H. U. Marqués de Valdecilla.	Santander		Spain
18	Hospital Clinico de Valencia	Valencia		Spain	46010
19	Hospital Arnau de Vilanova	Valencia		Spain	46015
20	H. La Fe	Valencia		Spain
21	Hospital Clínico Lozano Blesa	Zaragoza		Spain	50009

Sponsors and Collaborators

Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea

Investigators

Principal Investigator: Mª Dolores Caballero, MD, University of Salamanca
Principal Investigator: Alejandro Martín, MD, University of Salamanca
Principal Investigator: Javier Briones, MD, Hospital Santa Creu i Sant Pau
Principal Investigator: Juan Manuel Sancho, MD, Germans Trias i Pujol Hospital
Principal Investigator: Cristina Barrenetxea, MD, Hospital Vall d'Hebrón
Principal Investigator: Javier López, MD, Hospital Universitario Ramon y Cajal
Principal Investigator: Mª José Rodríguez, MD, Hospital Universitario de Canarias
Principal Investigator: Jorge Gayoso, MD, Gregorio Marañón Hospital
Principal Investigator: Miguel Ángel Canales, MD, Hospital Universitario La Paz
Principal Investigator: Carlos Grande, MD, Hospital Universitario 12 de Octubre
Principal Investigator: Isidro Jarque, MD, Hospital La Fe
Principal Investigator: José Rifón, MD, Clínica Universitaria Navarra
Principal Investigator: Andres Sánchez, MD, Hospital Virgen de la Arrixaca
Principal Investigator: Cristina Castilla, MD, Hospital Morales Meseguer
Principal Investigator: José Luis Bello, MD, Complejo Hospitalario Universitario de Santiago de Compostela
Principal Investigator: Armando López, MD, Hospial Clínic de Barcelona
Principal Investigator: Eulogio Conde, MD, Hospital Marqués de Valdecilla
Principal Investigator: Reyes Arranz, MD, Hospital La Princesa
Principal Investigator: Encarnación Monzó, MD, Hospital Arnau de Vilanova de Valencia
Principal Investigator: Rosario Varela, MD, Complejo Hospitalario Universitario de A Coruña
Principal Investigator: Mª José Ramírez, MD, Hospital Jerez de la Frontera
Principal Investigator: Fátima de la Cruz, MD, Hospital Virgen del Rocío
Principal Investigator: Ana Pilar González, MD, Hospital Central de Asturias
Principal Investigator: Luis Palomera, MD, Hospital Clínico de Zaragoza "Lozano Blesa"
Principal Investigator: Raquel del Campo, MD, Hospital Son Llátzer
Principal Investigator: Mª José Terol, MD, Hospital Clínico de Valencia