Clinical Trial to Determinate Dose, Security and Efficacy or Lenalidomide and Rituximab (LR)-ESHAP in Patients With Diffuse Large B-cell Lymphoma

NCT02340936 | Completed Phase 1

• 1 other identifier: LR-ESHAP
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 9

Brief Summary

The purpose of the Phase I of the study is to evaluate the safety and the maximum-tolerated dose (MTD) of the combination R-ESHAP with lenalidomide as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma The purpose of the Phase II of the study is to evaluate ORR of LR-ESHAP in patients with relapsed or refractory DLBCL candidates to HDT and ASCT

Conditions

Diffuse Large B-cell Lymphoma

Outcome Measures

Primary Outcomes (2)

• Phase I of the study: to evaluate the safety and the maximum-tolerated dose (MTD) of the combination R-ESHAP with lenalidomide as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma (determine maximum tolerated dose)

  To determine the MTD of the combination R-ESHAP with lenalidomide

  During 3 cycles of treatment (2 months after the initiation of study treatment)

• Phase II of the study: Phase II: to evaluate ORR of LR-ESHAP in patients with relapsed or refractory DLBCL candidates to HDT and ASCT (determine the overall response rate)

  To determine the overall response rate of LR-ESHAP

  After 3 cycles of treatment (2 months after the initiation of study treatment)

Secondary Outcomes (9)

• Phase I of the study: to analyze the adverse events of LR-ESHAP (frequency and severity of the adverse events)

  During study treatment period (3 cycles of LR-ESHAP and ASCT) until end of treatment visit (3 months after ASCT)

• Phase I of the study: preliminarily analyze effectiveness (response rates (CR and PR), duration of response and survival (DFS and OS)

  After 3 cycles of treatment (two months after the initiation of the study treatment) and during follow-up period (36 months)

• Phase I of the study: evaluate haematopoietic progenitor cells mobilization after treatment with LR-ESHAP (Evaluate CD34+ cell count)

  After cycle 2 (5 weeks after the initiation of study treatment) or cycle 3 (9 weeks after the initiation of study treatment)

• Phase I of the study: evaluate hematologic recovery after HSCT (recovery of blood parameters)

  After HSCT (between 5 and 8 weeks after the initiation of the cycle 3 of treatment)

• Phase II of the study: analyze effectiveness (Complete remission (CR) rate (determined by positron emission tomography [PET]/CT), event-free survival (EFS) and overall survival (OS)

  After 3 cycles of treatment (2 months after the initiation of the study treatment) and during follo-up period (36 months)

Study Arms (4)

LR-ESHAP (lenalidomide 5 mg)

EXPERIMENTAL

Intervention: lenalidome 5mg combined with R-ESHAP (3 cycles of treatment every 21 days: lenalidomide 5 mg/day (day 1 to 14 except cycle 2 that will be administered from day 1 to 10), etoposide 40 mg/m2/day (day 1 to day 4), methylprednisolone 500 mg/day (day 1 to day 5), cisplatin 25 mg/m2/day (day 1 to day 4), cytarabine 2000 mg/m2 (day 5) and rituximab 375 mg/m2 (day 1 or 5)).

Drug: LR-ESHAP (lenalidomide 5 mg)

LR-ESHAP (lenalidomide 10mg)

EXPERIMENTAL

Intervention: lenalidome 10mg combined with R-ESHAP( 3 cycles of treatment every 21 days: lenalidomide 10 mg/day (day 1 to 14 except cycle 2 that will be administered from day 1 to 10), etoposide 40 mg/m2/day (day 1 to day 4), methylprednisolone 500 mg/day (day 1 to day 5), cisplatin 25 mg/m2/day (day 1 to day 4), cytarabine 2000 mg/m2 (day 5) and rituximab 375 mg/m2 (day 1 or 5)).

Drug: LR-ESHAP (lenalidomide 10 mg)

LR-ESHAP (lenalidomide 15mg)

EXPERIMENTAL

Intervention: lenalidome 15mg combined with R-ESHAP (3 cycles of treatment every 21 days: lenalidomide 15 mg/day (day 1 to 14 except cycle 2 that will be administered from day 1 to 10), etoposide 40 mg/m2/day (day 1 to day 4), methylprednisolone 500 mg/day (day 1 to day 5), cisplatin 25 mg/m2/day (day 1 to day 4), cytarabine 2000 mg/m2 (day 5) and rituximab 375 mg/m2 (day 1 or 5)).

Drug: LR-ESHAP (lenalidomide 15 mg)

LR-ESHAP (lenalidomide 20mg)

EXPERIMENTAL

Intervention: lenalidome 20mg combined with R-ESHAP (3 cycles of treatment every 21 days: lenalidomide 20 mg/day (day 1 to 14 except cycle 2 that will be administered from day 1 to 10), etoposide 40 mg/m2/day (day 1 to day 4), methylprednisolone 500 mg/day (day 1 to day 5), cisplatin 25 mg/m2/day (day 1 to day 4), cytarabine 2000 mg/m2 (day 5) and rituximab 375 mg/m2 (day 1 or 5)).

Drug: LR-ESHAP (lenalidomide 20 mg)

Interventions

LR-ESHAP (lenalidomide 5 mg) DRUG

3 cycles of lenalidomide 5mg, etoposide, methylprednisolone, cisplatin, cytarabine and rituximab every 3 weeks.

Also known as: LR-ESHAP

LR-ESHAP (lenalidomide 5 mg)

LR-ESHAP (lenalidomide 10 mg) DRUG

3 cycles of lenalidomide 10mg, etoposide, methylprednisolone, cisplatin, cytarabine and rituximab every 3 weeks.

Also known as: LR-ESHAP

LR-ESHAP (lenalidomide 10mg)

LR-ESHAP (lenalidomide 15 mg) DRUG

3 cycles of lenalidomide 15mg, etoposide, methylprednisolone, cisplatin, cytarabine and rituximab every 3 weeks.

Also known as: LR-ESHAP

LR-ESHAP (lenalidomide 15mg)

LR-ESHAP (lenalidomide 20 mg) DRUG

3 cycles of lenalidomide 20mg, etoposide, methylprednisolone, cisplatin, cytarabine and rituximab every 3 weeks.

Also known as: LR-ESHAP

LR-ESHAP (lenalidomide 20mg)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The patient must, at the investigator's opinion, be able to meet all requirements of the clinical trial.
• Patients must give voluntarily informed consent before performing any test test that is not part of routine care of patients.
• Age between 18 and 70 years.
• Candidate for treatment with high-dose QT and HSCT .
• Diffuse large B-cell lymphoma (LDCGB) histological diagnosis according to the WHO classification ( see Annex 8).
• Refractory lymphoma or relapsed after 1st line treatment consisting of rituximab combined with a regimen of chemotherapy (CT scan ) including anthracyclines. :
• Relapse is defined as recurrence of lymphoma after obtaining complete response (RC) with 1st line treatment . In these cases, LDCGB histologic confirmation at the time of relapse is recommended
• Refractory lymphoma be considered if it meets one of the following criteria :
• partial response after at least 6 cycles of 1st line regimen . They may also include patients in partial response after 4 cycles if the researcher believes that the response is suboptimal, and patients with stage I- II if they have received 3 cycles of R- QT + affection field radiotherapy .
• stable disease after at least 3 cycles of 1st line regimen . progression during treatment of 1st line , defined as response criteria for malignant lymphoma 2007 (see Annex 9)
• CT scan evidence of at least two clearly demarcated lesions with a diameter of 1.5 cm, or 1 well-defined lesion with a diameter \> 2 cm .
• Evidence of positive lesions by PET, coincident with the anatomical areas affected by CT scan .
• Eastern cooperative oncology group performance status (ECOG) less than or equal to 2.
• Resolution of toxicities caused by the 1st line regimen to less than or equal to grade 1.
• Women of childbearing age ( see Appendix 12) must: Obtain a negative pregnancy test before starting medically supervised therapy study. Must accept continuing pregnancy tests conducted during the course of the study and after the end of study therapy . This applies even if the patient practices complete and continued abstinence .

You may not qualify if:

• \. Patients that previously received any antitumor agent for the treatment of LDCGB except : I ) rituximab in combination with regimen including anthracyclines II ) radiotherapy as part of first-line treatment .
• Previously received any of the following treatments in the 28 days prior to the test regime : I ) antitumor chemotherapeutic agents ; II ) radiotherapy , unless limited to a maximum dose of \< or =10 Gy to control severe life-threatening symptoms ; III ) glucocorticoid except equivalent doses \< or = 1 mg / kg of prednisolone / day with duration \< or = 7 days; iv ) any therapeutic agent under investigation.
• \. Known involvement of the central nervous system (CNS) by lymphoma. 4. Presence of abnormal or clinically significant cardiac disease, such as acute myocardial infarction or unstable angina within 6 months prior to initiation of treatment with LR- ESHAP , grade III or IV heart failure, uncontrolled hypertension or history of poor compliance with antihypertensive treatment , uncontrolled treated arrhythmias, except , with the exception of extra systoles or minor conduction abnormalities.
• \. Any other serious or uncontrolled medical condition , such as diabetes, uncontrolled active infection, significant cerebrovascular disease, poorly controlled psychiatric disease, etc. .
• \. Known or suspected hypersensitivity to any of the agents of the treatment under evaluation.
• \. Presence of any limitations that compromise the patient's ability to comply with treatment .
• \. Positive serology for HIV or Hepatitis B Virus (HBV) surface antigen (HBsAg ) . If negative for HBsAg but HBcAb positive and HBsAb negative, a HB DNA test will be performed and if positive the subject will be excluded. Note: If HBcAb positive and HBsAb positive, which is indicative of a past infection, the subject can be included 9. Active Hepatitis C (RNA positive serum) . If RNA positive result would exclude the patient from the trial in cases of patients with positive serology for Hepatitis C Virus (HCV). If the load ( RNA ) were HCV negative patients could be included in the study.
• \. Prior history of malignancy other than to LDCGB (except basal or squamous cell skin and in situ carcinoma of the cervix or breast ) unless the patient free of disease beyond 5 years are.
• Changes in laboratory values ??that might involve unacceptable risks or compromise compliance with the protocol , including: platelets \< 50 x 109 / L or neutrophils \<1 x 109 / L , unless attributed to infiltration by lymphoma bone marrow (MO) .
• or creatinine \> 1.5 times the normal upper limit . or Total bilirubin \> 2 times the upper limit of normal or alanine aminotransferase (ALT) \> 2.5 times the normal upper limit or alkaline phosphatase \> 2.5 times the normal upper limit , unless it is attributed to hepatic infiltration by lymphoma.
• \. Pregnant or breast-feeding. 13. Females of childbearing potential who do not agree to undergo pregnancy tests or repeated use effective birth control while included in the clinical trial.
• \. Males patients (whose sexual partners are women of childbearing potential ) that not accept use effective birth control methods while included in the clinical trial.

Sponsors & Collaborators

• Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea: lead
• Celgene Corporation: collaborator
• Dynamic Science S.L.: collaborator
• Thermo Fisher Scientific, Inc: collaborator

Study Sites (9)

ICO- Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, 08916, Spain

Location

ICO- Hospital Duran i Reynals

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

Location

Hospital del Mar

Barcelona, 08003, Spain

Location

Hospital Clinic i Provincial de Barcelona

Barcelona, 08036, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Regional Universitario de Málaga

Málaga, 29010, Spain

Location

Alejandro Martín

Salamanca, 37007, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

Hospital Universitario La Fe

Valencia, 46026, Spain

Location

Related Publications (6)

• Harting R, Venugopal P, Gregory SA, O'brien T, Bogdanova E. Efficacy and safety of rituximab combined with ESHAP chemotherapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Clin Lymphoma Myeloma. 2007 May;7(6):406-12. doi: 10.3816/CLM.2007.n.019.

  PMID: 17621406 BACKGROUND

• Feldman T, Mato AR, Chow KF, Protomastro EA, Yannotti KM, Bhattacharyya P, Yang X, Donato ML, Rowley SD, Carini C, Valentinetti M, Smith J, Gadaleta G, Bejot C, Stives S, Timberg M, Kdiry S, Pecora AL, Beaven AW, Goy A. Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma. Br J Haematol. 2014 Jul;166(1):77-83. doi: 10.1111/bjh.12846. Epub 2014 Mar 25.

  PMID: 24661044 BACKGROUND

• Chiappella A, Tucci A, Castellino A, Pavone V, Baldi I, Carella AM, Orsucci L, Zanni M, Salvi F, Liberati AM, Gaidano G, Bottelli C, Rossini B, Perticone S, De Masi P, Ladetto M, Ciccone G, Palumbo A, Rossi G, Vitolo U; Fondazione Italiana Linfomi. Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi. Haematologica. 2013 Nov;98(11):1732-8. doi: 10.3324/haematol.2013.085134. Epub 2013 Jun 28.

  PMID: 23812930 BACKGROUND

• Nowakowski GS, LaPlant B, Habermann TM, Rivera CE, Macon WR, Inwards DJ, Micallef IN, Johnston PB, Porrata LF, Ansell SM, Klebig RR, Reeder CB, Witzig TE. Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study. Leukemia. 2011 Dec;25(12):1877-81. doi: 10.1038/leu.2011.165. Epub 2011 Jul 1.

  PMID: 21720383 BACKGROUND

• Wang M, Fowler N, Wagner-Bartak N, Feng L, Romaguera J, Neelapu SS, Hagemeister F, Fanale M, Oki Y, Pro B, Shah J, Thomas S, Younes A, Hosing C, Zhang L, Newberry KJ, Desai M, Cheng N, Badillo M, Bejarano M, Chen Y, Young KH, Champlin R, Kwak L, Fayad L. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia. 2013 Sep;27(9):1902-9. doi: 10.1038/leu.2013.95. Epub 2013 Apr 2.

  PMID: 23545991 BACKGROUND

• Martin Garcia-Sancho A, Baile M, Rodriguez G, Dlouhy I, Sancho JM, Jarque I, Gonzalez-Barca E, Salar A, Espeso M, Grande C, Bergua J, Montes-Moreno S, Redondo A, Enjuanes A, Campo E, Lopez-Guillermo A, Caballero D. Lenalidomide in combination with R-ESHAP in patients with relapsed or refractory diffuse large B-cell lymphoma: A phase 2 study from GELTAMO. Br J Haematol. 2023 Oct;203(2):202-211. doi: 10.1111/bjh.18989. Epub 2023 Jul 23.

  PMID: 37485564 DERIVED

Related Links

• Sponsor web page

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

Lenalidomide

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Alejandro Martin

  University of Salamanca

  PRINCIPAL INVESTIGATOR

• Dolores Caballero

  University of Salamanca

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2015
• First Posted: January 19, 2015
• Study Start: January 1, 2011
• Primary Completion: September 1, 2016
• Study Completion: February 20, 2019
• Last Updated: January 10, 2020

Record last verified: 2018-02

Locations

ES (9)