Feasibility Study Of Adding Bortezomib to R-ICE Chemotherapy To Treat Relapsed/ Refractory Diffuse Large B-Cell Lymphoma (SGH652)
Recruitment status was Recruiting
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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 |
- 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.
- 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) |
-
Drug: bortezomib, rituximab, ifosphamide, etoposide, carboplatin
- velcade,
- rituxan,
- mabtera
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 |
Inclusion Criteria:
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
- Age between 21-70
- Written informed consent
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Minimum life expectancy of 3 months
- Previously treated with chemotherapy containing anthracyclines and rituximab
- Negative urine or serum pregnancy test on females of childbearing potential
- 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.
- Male subject agrees to use an acceptable method for contraception for the duration of the study.
- No CNS involvement
- Measurable disease on CT scan by international working group response criteria
Exclusion Criteria:
- Prior allogeneic transplantation
- Prior treatment with bortezomib
- Concomitant use of any other anti-cancer therapy
- Concomitant use of any other investigational agent
- Known infection with human immunodeficiency virus (HIV)
- Patient has known clinically active hepatitis B (carriers of hepatitis B are permitted to enter the study)
- Contraindication to any drug contained in chemotherapy regimens
- Not previously treated with anthracycline-containing regimens
- Impaired liver, renal or other organ function not caused by lymphoma, which will interfere with the treatment schedule
- Poor bone marrow reserve (neutrophils <1.0 x 109/L or platelets <75 x 10(9)/L unless related to bone marrow infiltration
- Subject has a calculated or measured creatinine clearance of <20 mL/minute within 14 days before enrollment.
- 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.
- Clinically significant active infection
- Subject has ≥grade 2 peripheral neuropathy or grade 1 with pain within 14 days before enrollment.
- Patients who are pregnant or breast-feeding
- Coexistent second malignancy or history of prior malignancy within previous 3 years (excluding non-melanoma skin tumors or in situ carcinoma of the cervix)
- Any significant medical or psychiatric condition that might prevent the patient from complying with all study procedures.
Contacts and Locations| Singapore | |
| Singapore General Hospital | Recruiting |
| Singapore, Singapore, 169608 | |
| Contact: Melissa Tan, BSC 63214627 melissa.tan.y.l@sgh.com.sg | |
| Contact: Daryl Tan, MBBS MRCP 63266604 daryl.tan@sgh.com.sg | |
| Principal Investigator: Daryl Tan, MBBS MRCP | |
| Sub-Investigator: Yeow Tee Goh, MBBS | |
| Sub-Investigator: Yvonne Loh, MBBs MRCP | |
| Principal Investigator: | Daryl Tan, MBBS MRCP | Singapore General Hospital |
More Information
Publications:
| Responsible Party: | Daryl Tan, MD, Singapore General Hospital |
| ClinicalTrials.gov Identifier: | NCT01226849 History of Changes |
| Other Study ID Numbers: | SGH652 |
| Study First Received: | October 19, 2010 |
| Last Updated: | November 21, 2010 |
| Health Authority: | Singapore: Health Sciences Authority |
Keywords provided by Singapore General Hospital:
|
diffuse large B-cell lymphoma relapse refractory |
Additional relevant MeSH terms:
|
Lymphoma Lymphoma, B-Cell Lymphoma, Large B-Cell, Diffuse Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Lymphoma, Non-Hodgkin Etoposide Etoposide phosphate Isophosphamide mustard Rituximab Bortezomib |
Ifosfamide Carboplatin Antineoplastic Agents, Phytogenic Antineoplastic Agents Therapeutic Uses Pharmacologic Actions Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Protease Inhibitors Enzyme Inhibitors |
ClinicalTrials.gov processed this record on May 19, 2013