Feasibility Study Of Adding Bortezomib to R-ICE Chemotherapy To Treat Relapsed/ Refractory Diffuse Large B-Cell Lymphoma (SGH652)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Singapore General Hospital
Sponsor:
Collaborator:
Janssen-Cilag Ltd.
Information provided by (Responsible Party):
Singapore General Hospital
ClinicalTrials.gov Identifier:
NCT01226849
First received: October 19, 2010
Last updated: June 18, 2014
Last verified: June 2014
  Purpose

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 Intervention Phase
Diffuse Large B-Cell Lymphoma
Drug: bortezomib, rituximab, ifosphamide, etoposide, carboplatin
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy 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:


Further study details as provided by Singapore General Hospital:

Primary Outcome Measures:
  • 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:
  • 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: 6
Study Start Date: November 2010
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single Arm

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

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

  2. Age between 21-70
  3. Written informed consent
  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  5. Minimum life expectancy of 3 months
  6. Previously treated with chemotherapy containing anthracyclines and rituximab
  7. Negative urine or serum pregnancy test on females of childbearing potential
  8. Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.
  9. Male subject agrees to use an acceptable method for contraception for the duration of the study.
  10. No CNS involvement
  11. Measurable disease on CT scan by international working group response criteria

Exclusion Criteria:

  1. Prior allogeneic transplantation
  2. Prior treatment with bortezomib
  3. Concomitant use of any other anti-cancer therapy
  4. Concomitant use of any other investigational agent
  5. Known infection with human immunodeficiency virus (HIV)
  6. Patient has known clinically active hepatitis B (carriers of hepatitis B are permitted to enter the study)
  7. Contraindication to any drug contained in chemotherapy regimens
  8. Not previously treated with anthracycline-containing regimens
  9. Impaired liver, renal or other organ function not caused by lymphoma, which will interfere with the treatment schedule
  10. Poor bone marrow reserve (neutrophils <1.0 x 109/L or platelets <75 x 10(9)/L unless related to bone marrow infiltration
  11. Subject has a calculated or measured creatinine clearance of <20 mL/minute within 14 days before enrollment.
  12. Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
  13. Clinically significant active infection
  14. Subject has ≥grade 2 peripheral neuropathy or grade 1 with pain within 14 days before enrollment.
  15. Patients who are pregnant or breast-feeding
  16. Coexistent second malignancy or history of prior malignancy within previous 3 years (excluding non-melanoma skin tumors or in situ carcinoma of the cervix)
  17. Any significant medical or psychiatric condition that might prevent the patient from complying with all study procedures.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01226849

Locations
Singapore
Singapore General Hospital Recruiting
Singapore, Singapore, 169608
Contact: Jimmy Ng    63214627    jimmy.ng.y.w@sgh.com.sg@sgh.com.sg   
Contact: Chun Hsien Yeap    63214627    yeap.chun.hsien@sgh.com.sg   
Principal Investigator: Yeow Tee Goh, MBBS MMed         
Sponsors and Collaborators
Singapore General Hospital
Janssen-Cilag Ltd.
Investigators
Principal Investigator: Yeow Tee Goh, MBBS MMed Singapore General Hospital
  More Information

Publications:
Responsible Party: Singapore General Hospital
ClinicalTrials.gov Identifier: NCT01226849     History of Changes
Other Study ID Numbers: SGH652
Study First Received: October 19, 2010
Last Updated: June 18, 2014
Health Authority: Singapore: Health Sciences Authority

Keywords provided by Singapore General Hospital:
diffuse large B-cell lymphoma relapse refractory

Additional relevant MeSH terms:
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Isophosphamide mustard
Bortezomib
Etoposide phosphate
Carboplatin
Ifosfamide
Etoposide
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 19, 2014