National, Open-label, Multicentre Phase I-II Study of Combination R-ESHAP With Lenalidomide as Salvage Therapy for Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma Candidates to Stem-cell Transplantation
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Enrollment
- 53
- Locations
- 9
- Primary Endpoint
- 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)
Study Overview
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
Detailed Description
Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of non-Hodgkin's lymphoma (NHL), comprising approximately 30% of new cases. Treatment results of DLBCL have significantly improved after the introduction of rituximab (R) into CHOP-like, anthracycline-based, treatment schedules, and it is now the standard of care. Nevertheless, even with current R-CHOP-like treatment, approximately 30-40% of patients will ultimately relapse or progress.
To date, high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is the reference treatment for patients with relapsed or primary refractory aggressive B-cell NHL, provided the disease is sensitive to second-line chemotherapy. Among patients with chemosensitive disease, the remission status at transplant has a significant impact on the outcome, because patients in complete remission (CR) before HDT achieve better long-term progression-free survival (PFS) than patients who undergo transplantation in partial remission (PR). Standard salvage chemotherapy for aggressive lymphoma does not exist. Commonly used second-line regimens include dexamethasone, cytarabine, cisplatin (DHAP), ESHAP (etoposide, methylprednisone, cytarabine, cisplatin), mini-BEAM (carmustine, etoposide, cytarabine, melphalan) and ICE (ifosfamide, carboplatin, etoposide). These regimens produce an overall response rate (ORR) of around 60%, and CR rates of 25% to 35%. More effective salvage regimens are needed in order to maximize the number of patients in CR prior to ASCT.
Increasing evidence suggests that rituximab added to salvage chemotherapy improves response rates and outcomes in relapsed DLBCL. In a recent randomized phase 3 study, the efficacy of adding rituximab to the DHAP-VIM-DHAP regimen was tested in 239 rituximab-naïve patients with relapsed or primary refractory aggressive cluster of differentiation 20 (CD20)+ B-cell NHL. In 225 evaluable patients, the addition of rituximab to second-line chemotherapy resulted in a significant improvement of ORR (75% versus 54%, p=.01) and PFS (52% versus 31% at two years, p<.002). Other small phase II trials (with a range of 35-55 patients) investigating rituximab in combination with ICE, DHAP or EPOCH have also shown encouraging results. However, the patients in these studies had not been previously exposed to rituximab, while at present, almost all patients with aggressive B-cell NHL receive rituximab combined with first-line chemotherapy.
In a recent multicenter retrospective study, we analyzed the influence of prior exposure to rituximab on response rates and outcomes in 163 patients with relapsed or refractory DLBCL who received Rituximab-ESHAP (R-ESHAP) as salvage therapy with a curative purpose. In this study, prior exposure to rituximab did not have an independent effect on response rates to R-ESHAP. However, a high proportion (57.4%) of patients who had received prior rituximab treatment experienced disease relapse or progression, that translated into a significantly worse PFS (17 v 57% at 3 years) and OS (38% v 67% at 3 years) as compared with rituximab-naïve patients. This observation was independent of other prognostic factors with an impact upon these outcomes, such as disease status at R-ESHAP, age-adjusted International Prognostic Index (IPI) or response to R-ESHAP. Results of the CORAL randomised trial comparing R-ICE with R-DHAP in 396 patients with relapsed or refractory DLBCL confirmed that exposure to rituximab prior to salvage therapy is associated with a worse outcome . Rituximab naïve patients had a 83% response rate and 47% 3-year event-free survival (EFS) compared with a 51% response rate and 21% EFS for patients who had received prior rituximab treatment.
These results suggest that the use of highly effective rituximab-containing primary therapy in DLBCL makes it more difficult to salvage patients who are refractory or who relapse. Thus, prospective studies incorporating new agents are needed for these patients.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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
- •Resolution of toxicities caused by the 1st line regimen to less than or equal to grade
- •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 .
- •They must either commit to continued abstinence or heterosexual sex (which should be reviewed monthly ) or agree to use and be capable of complying with effective contraception without interruption, 28 days before starting the study drug during the study therapy (including during periods of dose interruptions ) , and for 28 days after discontinuation of study therapy .
- •12 male patients ( see Appendix 12) must:
- •Accept to use a latex condom during any sexual relations with women of childbearing potential , even if they have had a vasectomy , while participating in this study, during dose interruptions and after discontinuation of treatment .
- •Accept refrain from donating sperm while participating in this study and for a time after cessation of treatment (see specific data ) .
- •All patients must: Understand that the study drug could potentially have a teratogenic risk . Agree to abstain from donating blood while they are taking the treatment and after discontinuation of study drug therapy .
- •Agree not to share study medication with anyone else. For advice on precautions against pregnancy and potential risks of fetal exposure
Exclusion Criteria
- •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 .
- •2 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.
- •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
- •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.
- •11 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.
- •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.
Arms & Interventions
LR-ESHAP (lenalidomide 5 mg)
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)).
Intervention: LR-ESHAP (lenalidomide 5 mg) (Drug)
LR-ESHAP (lenalidomide 10mg)
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)).
Intervention: LR-ESHAP (lenalidomide 10 mg) (Drug)
LR-ESHAP (lenalidomide 15mg)
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)).
Intervention: LR-ESHAP (lenalidomide 15 mg) (Drug)
LR-ESHAP (lenalidomide 20mg)
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)).
Intervention: LR-ESHAP (lenalidomide 20 mg) (Drug)
Outcomes
Primary Outcomes
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)
Time Frame: During 3 cycles of treatment (2 months after the initiation of study treatment)
To determine the MTD of the combination R-ESHAP with lenalidomide
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)
Time Frame: After 3 cycles of treatment (2 months after the initiation of study treatment)
To determine the overall response rate of LR-ESHAP
Secondary Outcomes
- 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))
- Phase II of the study: rate of transplanted patients (number of patients that undergo HSCT)(6-8 weeks aftter the initiation of cycle 3)
- Phase II of the study: to analyze the adverse events of LR-ESHAP and ASCT. (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 II of the study: influence of clinical and biological prognostic factors on response rates and survival (influence of clinical and biological (such as cell of origin) prognostic factors on response rates and survival.)(During study treatment (2 months) until end of treatment visit (3 months after ASCT) and during follow-up period (36 months))
- Phase II of the study: evaluate mobilization after treatment with LR-ESHAP (number of stem cells (2 x 106/Kg Hematopoietic progenitor cell antigen (CD34)+ cells) collected after the salvage therapy.)(After cycle 2 (5 weeks after the initiation of study treatment) or cycle 3 (9 weeks after the initiation of study treatment))