Feasibility Study Of Adding Bortezomib to R-ICE Chemotherapy To Treat Relapsed/ Refractory Diffuse Large B-Cell Lymphoma

This study is currently recruiting participants.
Verified November 2010 by Singapore General Hospital

First Received on October 19, 2010.  
Last Updated on November 21, 2010  
History of Changes
This Clinical Trial Sponsored By: Singapore General Hospital
Collaborator: Janssen-Cilag Ltd.
Information provided by: Singapore General Hospital
ClinicalTrials.gov Identifier: NCT01226849
 

Purpose for Clinical Trial

Incorporation of rituximab to conventional chemotherapy (R-CHOP) has revolutionalized the frontline treatment of diffuse large B-cell lymphoma (DLBCL), one of the commonest subtype of lymphoma. Although the majority of patients are cured, there still remains a substantial number patients (20-30%) who will relapse despite upfront R-CHOP therapy. Recent studies have informed that in the rituximab era, the ability to salvage patients with relapsed DLBCL with the conventional salvage regimens like R-ICE or R-DHAP is significantly poorer than expected. For a patients who has been exposed to rituximab in the frontline, the response rate of conventional salvage chemotherapy is now a mere 51% (Coral Study). This suggests that relapses after rituximab exposure are more severe, strongly implying the presence of rituximab-resistant disease in additional to the selection of more aggressive subtypes of DLBCL which R-CHOP may not have a significant impact on. As R-CHOP is currently the frontline standard of care, more has to be done to augment the current available salvage regimens as a response rate of 51% is unacceptable.

Incorporation of agents targeting rituximab-resistance and also the more aggressive subtype of DLBCL ( ABC subtype) is prudent in the salvage regimen. Bortezomib, a targeted novel agent has potent anti-tumor effects on its own. It has also been show clinically to be able to overcome the adverse risk conferred by the ABC subtype of DLBCL. In addition, preclinical studies have also demonstrated that bortezomib may enhance the biologic activity of rituximab through upregulation of CD20, the target of rituximab.

The investigators hypothesize that adding bortezomib to salvage regimen of DLBCL will be more efficacious. Increasing the response rate will then allow more eligible patients to go on to autologous stem cell transplantation. The investigators intend to test the tolerability and efficacy of the combination of bortezomib with the R-ICE regimen, and attempt to correlate responses with histopathological and gene expression studies of tumor specimens.

Condition Study Intervention Clinical Trial Phase
Diffuse Large B-cell Lymphoma Drug: bortezomib, rituximab, ifosphamide, etoposide, carboplatin Phase 1

Study Type: Study Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Study Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Pilot Study To Investigate Feasibility and Safety Of Using Bortezomib, Rituximab, Ifosfamide, Carboplatin, Etoposide As Salvage Regime In Previously Treated Patients With Diffuse Large B-Cell Lymphoma

Resource links provided by NLM:

MedlinePlus related topics:
Lymphoma
Drug Information available for:
Ifosfamide
Etoposide
Carboplatin
Etoposide phosphate
Rituximab
Bortezomib

U.S. FDA Resources

Further study details as provided by Singapore General Hospital:

Primary Outcome Measures For Clinical Trial:

  • To evaluate number of participants with adverse events with R-ICE plus bortezomib (VR-ICE) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    To evaluate the feasibility, safety and maximum tolerated dose (MTD) of R-ICE plus bortezomib (VR-ICE) in previously treated patients with DLBCL.

Secondary Outcome Measures For Clinical Trial:

  • Response rate [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    Response rate at the end of 3 cycles of induction chemotherapy treatment will be assessed. The ability of stem cells mobilization with the regimen and the engraftment rate will also be studied. Lastly, Time to progression or relapse and overall survival will be determined. Biomarkers assessment & correlation of response to subtype DLBCL will be attempted.

Estimated Enrollment: 12
Study Start Date: November 2010
Estimated Study Completion Date: December 2012
Estimated Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Study Intervention Details:

    Drug: bortezomib, rituximab, ifosphamide, etoposide, carboplatin

    Rituximab 375mg/m2 day 1 Etoposide 100mg/m2 day 1-3 Carboplatin AUC (5) max 800 days 2 Ifosfamide continuous infusion + Mesna 5/m2/24hr day2 Bortezomib 1.3mg/m2 days 1,4,8,11 G-CSF (SC) recommended
    Other Names:
    • velcade,
    • rituxan,
    • mabtera

Detailed Description:

The most commonly used regimen for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is the R-ICE regime (rituximab, ifosphamide, cisplatin and etoposide). It was previously reported to give an overall response rate (RR) of close to 70%, and a complete response rate of 53%. As most DLBCL patients are now treated in the frontline with R-CHOP regimen, the validity of RRs with R-ICE needs to be reevaluated. Results of the CORAL study, a prospective randomized phase III trial comparing R-DHAP vs R-ICE in relapsed DLBCL were recently presented. It was shown that there was no difference in RR between R-ICE and R-DHAP. However, the RR of patients who had received prior rituximab in the frontline setting was significantly lower at 51%, compared with rituximab-naïve patients at 83%. This suggests that relapses after rituximab exposure are more severe. In addition to the risk of more aggressive subtype of DLBCL (activated B-cell [ABC]) that may not be abrogated by rituximab, the presence of rituximab-resistant disease is also strongly implicated. As R-CHOP is currently the frontline standard of care, more has to be done to augment the current available salvage regimens. Incorporation of agents targeting the activated B-cell (ABC)subtype and rituximab-resistance is prudent in the salvage regimen. Bortezomib, a proteosome inhibitor impacts on many cellular processes relevant to the pathogenesis of DLBCL, including inhibition of nuclear factor-kappa B. Preclinical studies have also demonstrated that bortezomib displayed significant antitumor activity against various lymphomas, and in particular the ABC subtype of DLBCL. It is also capable of enhancing the biologic activity of rituximab through upregulation of CD20 in preclinical studies. Demonstration of synergism in these 2 agents, in part due to their dependence on overlapping pathways, suggests that they should be explored as a combination.

On this basis, the investigators aim to conduct a pilot study of adding intravenous bortezomib to R-ICE as a salvage regime for adult patients with relapsed/refractory DLBCL.

  Eligibility

Ages Eligible for Study:   21 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically proven diffuse large B-cell lymphoma in first relapse after CR, less than PR or PR to first line treatment De Novo DLBCL, DLBCL arising from transformed follicular lymphoma or chronic lymphocytic leukaemia are allowed.

    Prior rituximab is allowed Prior radiation is allowed Prior autologous stem cell transplant is allowed CD20 negative relapses are allowed

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