Clinical trial NCT01296256: Bendamustine, Cytarabine, Etoposide and Melphalan (BeEAM) as Conditioning for Autologous Stem Cell Transplant (ASCT) in Aggressive Non Hodgkin's Lymphoma (NHL).
Official title: Bendamustine, Cytarabine, Etoposide and Melphalan as Conditioning for Autologous Stem Cell Transplant in Patients With Aggressive Non Hodgkin's Lymphoma.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Bendamustine
Conditioning Therapy
Autologous Stem Cell Transplant
Aggressive Non Hodgkin's Lymphoma
Keywords: Bendamustine
Conditioning Therapy
Autologous Stem Cell Transplant
Aggressive Non Hodgkin's Lymphoma
Lead sponsor: Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
Sponsor class: OTHER
First posted: 2011-02-15
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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).

Eligibility criteria: Inclusion Criteria:

1. Patients being able to meet all requirements of the clinical trial, according to the investigator's criteria,
2. Patient giving voluntarily written informed consent before performing any essay test that is not part of routine care of patients.
3. Age \>o=18 years and \>0=70 years
4. Candidate for chemotherapy (QT) at high doses and ASCT

   1. Histologically confirmed aNHL:
   2. 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.
   3. 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.
   4. Transformed B cell lymphoma in first CR
   5. Patients with PTCL (other than anaplastic ALK +) in first CR
5. Performance status (ECOG) \<0=2.
6. Adequate renal, hepatic, and bone marrow function (assessed \< 14 days before initiation of the study treatment):

   1. Neutrophil count \<o=1.5 x 109/L
   2. Platelet count \<o=100 x 109/L
   3. Haemoglobin \<o=8.0 g/dL
   4. Creatinine serum \>o=1,5 x ULN mg/dl
   5. Serum bilirubin \<o=1.5 x ULN and alkaline phosphatase \<o=2.5 x ULN
   6. AST, ALT \<o=2.5 x ULN (\<o=5 x ULN in case of liver metastasis).
7. Adequate pulmonary function: forced expiratory volume at 1 second \> 65% of predicted or a diffusing capacity of the lung for CO \>o=50%.
8. Cardiac ejection fraction or greater than 50% by echocardiogram or FEVI.
9. 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:

1. has not undergone hysterectomy or bilateral oophorectomy and
2. 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:

1. Impossibility of collecting, via apheresis, a number of CD34+ cells \>o=2 x 106/kg
2. 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.
3. Known involvement of the central nervous system (CNS) by lymphoma
4. 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.
5. Other serious or uncontrolled medical condition, such as uncontrolled diabetes, uncontrolled active infection, significant cerebrovascular disease or poorly controlled psychiatric disease.
6. Known or suspected hypersensitivity to any of the agents or excipients of the regime under evaluation.
7. Presence of any limitations that compromise the patient's ability to comply with the study treatment.
8. 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.
9. 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.
10. Major surgery procedure within 30 days prior to entering this study.
11. Pregnant or nursing females.

Primary outcomes:
measure: 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.
timeFrame: 18 months follow-up
Secondary outcomes:
measure: 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
timeFrame: 18 months follow-up
Other outcomes:
Locations:
city: Santiago
country: Spain
facility: Complejo Hospitalario Universitario de Santiago
state: A Coruña
city: Oviedo
country: Spain
facility: Hospital Central de Asturias
state: Asturias
city: Jerez de la Frontera
country: Spain
facility: Hospital de Jerez
state: Cádiz
city: Palma de Mallorca
country: Spain
facility: Hospital Son Llátzer
state: Mallorca
city: El Palmar
country: Spain
facility: Hospital Universitario Virgen de Arrixaca
state: Murcia
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra
state: Navarra
city: Santa Cruz de Tenerife
country: Spain
facility: Hospital Universitario de Canarias
state: Tenerife
city: Barcelona
country: Spain
facility: Hospital Vall d´Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial
city: Barcelona
country: Spain
facility: H. de la Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: H.U. 12 de Octubre,
city: Madrid
country: Spain
facility: H.U. Gregorio Marañón,
city: Madrid
country: Spain
facility: H.U. La Paz
city: Madrid
country: Spain
facility: H.U. La Princesa
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Salamanca
country: Spain
facility: H. Clínico Universitario de Salamanca
city: Santander
country: Spain
facility: H. U. Marqués de Valdecilla.
city: Valencia
country: Spain
facility: Hospital Clinico de Valencia
city: Valencia
country: Spain
facility: Hospital Arnau de Vilanova
city: Valencia
country: Spain
facility: H. La Fe
city: Zaragoza
country: Spain
facility: Hospital Clínico Lozano Blesa
Study officials:
affiliation: University of Salamanca
name: Mª Dolores Caballero, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Salamanca
name: Alejandro Martín, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
name: Javier Briones, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Germans Trias i Pujol Hospital
name: Juan Manuel Sancho, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Vall d'Hebrón
name: Cristina Barrenetxea, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Ramon y Cajal
name: Javier López, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario de Canarias
name: Mª José Rodríguez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Gregorio Marañón Hospital
name: Jorge Gayoso, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario La Paz
name: Miguel Ángel Canales, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario 12 de Octubre
name: Carlos Grande, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital La Fe
name: Isidro Jarque, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clínica Universitaria Navarra
name: José Rifón, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Virgen de la Arrixaca
name: Andres Sánchez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Morales Meseguer
name: Cristina Castilla, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Complejo Hospitalario Universitario de Santiago de Compostela
name: José Luis Bello, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospial Clínic de Barcelona
name: Armando López, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Marqués de Valdecilla
name: Eulogio Conde, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fundación de Investigación Biomédica - Hospital Universitario de La Princesa
name: Reyes Arranz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Arnau de Vilanova de Valencia
name: Encarnación Monzó, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Complejo Hospitalario Universitario de A Coruña
name: Rosario Varela, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Jerez de la Frontera
name: Mª José Ramírez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Virgen del Rocío
name: Fátima de la Cruz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Central de Asturias
name: Ana Pilar González, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Clínico de Zaragoza "Lozano Blesa"
name: Luis Palomera, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Son Llátzer
name: Raquel del Campo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Clínico de Valencia
name: Mª José Terol, MD
role: PRINCIPAL_INVESTIGATOR
References: