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

NCT01226849 | Completed Phase 1 DMC

• 1 other identifier: SGH652
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Diffuse Large B-Cell Lymphoma

Keywords

diffuse large B-cell lymphoma relapse refractory

Outcome Measures

Primary Outcomes (1)

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

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

  2 years

Secondary Outcomes (1)

• Response rate

  2 years

Study Arms (1)

Single Arm

EXPERIMENTAL

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

Interventions

bortezomib, rituximab, ifosphamide, etoposide, carboplatin DRUG

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

Also known as: velcade,, rituxan,, mabtera

Single Arm

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Singapore General Hospital: lead
• Janssen-Cilag Ltd.: collaborator

Study Sites (1)

Singapore General Hospital

Singapore, 169608, Singapore

Location

Related Publications (3)

• Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Briere J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. doi: 10.1200/JCO.2010.28.1618. Epub 2010 Jul 26.

  PMID: 20660832 BACKGROUND

• Czuczman 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 BACKGROUND

• Dunleavy 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 BACKGROUND

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

Bortezomib; Rituximab; Etoposide; Carboplatin

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Coordination Complexes

Study Officials

• Yeow Tee Goh, MBBS MMed

  Singapore General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 19, 2010
• First Posted: October 22, 2010
• Study Start: November 1, 2010
• Primary Completion: November 1, 2014
• Study Completion: November 1, 2014
• Last Updated: April 27, 2017

Record last verified: 2017-04

Locations

SG (1)