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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

Phase 1
21 Years
Open (Enrolling)
Diffuse Large B-cell Lymphoma

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Trial Information

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

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.

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

13. Clinically significant active infection

14. Subject has ≥grade 2 peripheral neuropathy or grade 1 with pain within 14 days before

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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate number of participants with adverse events with R-ICE plus bortezomib (VR-ICE)

Outcome Description:

To evaluate the feasibility, safety and maximum tolerated dose (MTD) of R-ICE plus bortezomib (VR-ICE) in previously treated patients with DLBCL.

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Daryl Tan, MBBS MRCP

Investigator Role:

Principal Investigator

Investigator Affiliation:

Singapore General Hospital


Singapore: Health Sciences Authority

Study ID:




Start Date:

November 2010

Completion Date:

December 2012

Related Keywords:

  • Diffuse Large B-Cell Lymphoma
  • diffuse large B-cell lymphoma relapse refractory
  • Lymphoma
  • Lymphoma, B-Cell
  • Lymphoma, Large B-Cell, Diffuse