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

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.

Sex

All

Minimum age

21 Years

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.

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• BACKGROUNDCzuczman MS, Olejniczak S, Gowda A, Kotowski A, Binder A, Kaur H, Knight J, Starostik P, Deans J, Hernandez-Ilizaliturri FJ. Acquirement of rituximab resistance in lymphoma cell lines is associated with both global CD20 gene and protein down-regulation regulated at the pretranscriptional and posttranscriptional levels. Clin Cancer Res. 2008 Mar 1;14(5):1561-70. doi: 10.1158/1078-0432.CCR-07-1254. PMID 18316581
• BACKGROUNDDunleavy K, Pittaluga S, Czuczman MS, Dave SS, Wright G, Grant N, Shovlin M, Jaffe ES, Janik JE, Staudt LM, Wilson WH. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009 Jun 11;113(24):6069-76. doi: 10.1182/blood-2009-01-199679. Epub 2009 Apr 20. PMID 19380866