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

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

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.

Study Overview

• Status: Completed
• Conditions: Bendamustine; Conditioning Therapy; Autologous Stem Cell Transplant; Aggressive Non Hodgkin's Lymphoma
• Intervention / Treatment: Drug: Bendamustine-EAM

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 Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic I Provincial
  • Barcelona, Spain, 08035
    • Hospital Vall d´hebron
  • Barcelona, Spain
    • H. de la Santa Creu i Sant Pau
  • Madrid, Spain
    • Hospital Ramon y Cajal
  • Madrid, Spain
    • H.U. La Princesa
  • Madrid, Spain
    • H.U. 12 de Octubre,
  • Madrid, Spain
    • H.U. Gregorio Marañón,
  • Madrid, Spain
    • H.U. La Paz
  • Salamanca, Spain
    • H. Clínico Universitario de Salamanca
  • Santander, Spain
    • H. U. Marqués de Valdecilla.
  • Valencia, Spain
    • H. la Fé
  • Valencia, Spain, 46015
    • Hospital Arnau de Vilanova
  • Valencia, Spain, 46010
    • Hospital Clinico de Valencia
  • Zaragoza, Spain, 50009
    • Hospital Clinico Lozano Blesa
  • A Coruña
    • Santiago, A Coruña, Spain, 15706
      • Complejo Hospitalario Universitario de Santiago
  • Asturias
    • Oviedo, Asturias, Spain, 33006
      • Hospital Central de Asturias
  • Cádiz
    • Jerez de la Frontera, Cádiz, Spain, 11407
      • Hospital de Jerez
  • Mallorca
    • Palma de Mallorca, Mallorca, Spain, 07198
      • Hospital Son Llatzer
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Hospital Universitario Virgen de Arrixaca
  • Navarra
    • Pamplona, Navarra, Spain
      • Clinica Universitaria de Navarra
  • Tenerife
    • Santa Cruz de Tenerife, Tenerife, Spain
      • Hospital Universitario de Canarias

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
• Investigators: Principal Investigator: Jorge Gayoso, MD, Gregorio Marañon hospital; 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'Hebron; Principal Investigator: Javier López, MD, Hospital Universitario Ramon Y Cajal; 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 Llatzer; Principal Investigator: Mª José Terol, MD, Hospital Clinico de Valencia

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: February 13, 2011
• First Submitted That Met QC Criteria: February 14, 2011
• First Posted (Estimate): February 15, 2011

Study Record Updates

• Last Update Posted (Estimate): February 17, 2016
• Last Update Submitted That Met QC Criteria: February 15, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: Bendamustine; Autologous Stem Cell Transplant; Conditioning Therapy; Aggressive Non Hodgkin's Lymphoma
• Additional Relevant MeSH Terms: Behavioral Symptoms; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Aggression; Lymphoma; Lymphoma, Non-Hodgkin; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Bendamustine Hydrochloride
• Other Study ID Numbers: Benda-EAM2010-01; 2010-020926-17 (EudraCT Number)