Clinical Trial to Determinate Dose, Security and Efficacy or Lenalidomide and Rituximab (LR)-ESHAP in Patients With Diffuse Large B-cell Lymphoma
Condition: Diffuse Large B-cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
Study type: Interventional
Phase: Phase 1/Phase 2

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.

      Lenalidomide:

      Lenalidomide, an analog of thalidomide, is a promising new therapeutic agent that does not
      seem to cause significant somnolence, constipation, and neuropathy, which are usually
      dose-limiting for thalidomide. It has been hypothesized that the mechanism of action of
      lenalidomide includes immunomodulatory, antineoplastic, anti-angiogenic and
      pro-erythropoietic properties. Preclinical as well as clinical observations demonstrate that
      lenalidomide downregulates production of various critical prosurvival cytokines in the tumour
      microenvironment while concurrently promoting activation of T- and natural killer (NK)
      cell-mediated antitumour response. In aggressive lymphomas, lenalidomide was shown to exert
      antiproliferative activity by enhancing the expression of cell cycle regulators, including
      p21 and SPARC, to induce G1 cell cycle arrest, caspase activation, and apoptosis.

      In a recent phase II multicenter trial, 49 patients with relapsed or refractory aggressive
      NHL (diffuse large B-cell, follicular center grade 3, mantle cell, and transformed lymphomas)
      received oral lenalidomide monotherapy, 25 mg once daily on days 1 to 21, every 28 days, for
      52 weeks, until disease progression or intolerance. The most common histology was diffuse
      large B-cell lymphoma. The median age was 65 years (range: 23 to 86). Patients had received a
      median of four prior treatment regimens; 56% were refractory to last therapy and 29% had
      received a prior ASCT. An objective response rate of 35% was observed in 49 treated patients,
      including a 12% rate of complete response/unconfirmed complete response. Responses were
      observed in each aggressive histologic subtype tested (19% ORR in patients with DLBCL). Of
      patients with stable disease or partial response at first assessment, 25% improved with
      continued treatment. Estimated median duration of response was 6.2 months, and median PFS was
      4.0 months. The most common grade 4 adverse events were neutropenia (8.2%) and
      thrombocytopenia (8.2%); the most common grade 3 adverse events were neutropenia (24.5%),
      leukopenia (14.3%), and thrombocytopenia (12.2%). The results of this study show that
      lenalidomide monotherapy is active in relapsed or refractory aggressive NHL, with manageable
      side effects.

      A confirmatory international phase II trial (NHL-003) of single-agent lenalidomide was
      performed for patients with relapsed/refractory aggressive NHL that had received at least one
      prior treatment and had measurable disease. Patients received 25 mg oral lenalidomide once
      daily on days 1-21 of every 28-day cycle and continued therapy until disease progression or
      toxicity. 217 patients enrolled and received lenalidomide. The ORR was 35% (77/217), with 13%
      (29/217) CR, 22% (48/217) PR, and 21% (45/217) with stable disease. The ORR for DLBCL was 28%
      (30/108), 42% (24/57) for mantel-cell lymphoma, 42% (8/19) for grade 3 follicular lymphoma,
      and 45% (15/33) for peripheral T-cell lymphoma. Median progression-free survival for all 217
      patients was 3.7 months [95% confidence interval (CI) 2.7-5.1]. For 77 responders, the median
      response duration lasted 10.6 months (95% CI 7.0-NR). Median response duration was not
      reached in 29 patients who achieved a CR and in responding patients with follicular lymphoma
      (FL)-III or mantle cell lymphoma (MCL). The most common adverse event was myelosuppression
      with grade 4 neutropenia and thrombocytopenia in 17% and 6%, respectively.The results of this
      international study confirm that lenalidomide is active in heavily pre-treated patients with
      relapsed or refractory DLBCL with manageable side effects.

      The results from these phase II studies demonstrate the activity of oral lenalidomide
      monotherapy in patients with relapsed or refractory aggressive NHL and warrant further
      investigation of lenalidomide therapy, alone or in combination, in the treatment of patients
      with aggressive NHL. It was recently reported that when used in combination, lenalidomide
      (maximum-tolerated dose [MTD] 20 mg/day, 21 of 28 days) and rituximab produce a robust
      response rate in relapsed or refractory mantle cell lymphoma, with a favourable toxicity
      profile. In multiple myeloma (MM) patients, several phase 1/2 trials have evaluated
      lenalidomide in conjunction with chemotherapy, such as melphalan and prednisone (MTD 10
      mg/day, 21 days every 4 to 6 weeks), doxorubicin and dexamethasone (MTD 25 mg/day with
      G-Colony-stimulating factors (CSF), 21 of 28 days), or doxorubicin, vincristine and
      dexamethasone (MTD 10 mg/day, 21 days every 4 to 6 weeks). These combinations provide a
      considerable proportion of high-quality responses with substantial durability in patients
      with MM and overcomes several well-known adverse prognostic factors. A phase 1 study showed
      that lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for
      aggressive B-cell lymphomas. Preliminary results of ongoing phase 2 suggest that the addition
      of lenalidomide to rituximab, cyclophosphamide, adriamycin, vincristine and prednisone
      (RCHOP) could overcome the negative prognostic impact of the non-germinal center B-cell (GCB)
      phenotype on outcome.

      Thus, we propose an open-label, non-randomized, multicentre, escalating-dose, Phase I trial,
      to investigate the safety and the maximum-tolerated dose of the combination R-ESHAP with
      lenalidomide as salvage therapy for patients with relapsed or refractory diffuse large B-cell
      lymphoma candidates to stem-cell transplantation. We expect haematological toxicity as the
      main form of toxicity, as shown in previous studies. We must also take into account the
      possible adverse influence of lenalidomide treatment on stem cell mobilization. In patients
      with MM, prior lenalidomide therapy has been associated with high rates of failure in stem
      cell mobilization with filgrastim. Remobilization with chemotherapy and filgrastim is usually
      successful in these patients.

      After selection of the maximum-tolerated dose of the combination R-ESHAP with lenalidomide a
      phase 2 of the study will be performed in order to evaluate the ORR of LR-ESHAP.

      Partial data verification will be performed. A Clinical Research Organization (Dynamic
      Science S.L) Standard Operating Procedures will be used to manage the clinical trial.

      Categorical variables were show by absolute and relative frequencies, including the
      confidence interval of 95%.

      For the description of the continuous variables will be use the mean, standard deviation,
      median, mode, minimum and maximum, including the total number of valid values.

      In the case of compare subgroups of patients, will be use for quantitative variables
      parametric tests or nonparametric as characteristics of the variables under study. For
      qualitative variables will be use Chi-square test.

      Statistical analysis was planned with the Statistical Analysis System (SAS) package version
      9.1 or later.
    

Intervention name(s): LR-ESHAP (lenalidomide 5 mg); LR-ESHAP (lenalidomide 10 mg); LR-ESHAP (lenalidomide 15 mg); LR-ESHAP (lenalidomide 20 mg)
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 3 cycles of lenalidomide 5mg, etoposide, methylprednisolone, cisplatin, cytarabine and rituximab every 3 weeks.; 3 cycles of lenalidomide 10mg, etoposide, methylprednisolone, cisplatin, cytarabine and rituximab every 3 weeks.; 3 cycles of lenalidomide 15mg, etoposide, methylprednisolone, cisplatin, cytarabine and rituximab every 3 weeks.; 3 cycles of lenalidomide 20mg, etoposide, methylprednisolone, cisplatin, cytarabine and rituximab every 3 weeks.
Other intervention name(s): LR-ESHAP; LR-ESHAP; LR-ESHAP; LR-ESHAP
Intervention MeSH terms: Lenalidomide
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment