Efficacy/Safety Study of R-CHOP vs Bortezomib-R-CAP for Young Patients With Diffuse Large B-cell Lymphoma With Poor IPI.

Diffuse, Large B-Cell, Lymphoma Clinical Trial

Official title:

Multicenter Randomized Phase II Study of Treatment With R-CHOP vs Bortezomib-R-CAP for Young Patients With Diffuse Large B-cell Lymphoma With Poor IPI.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01848132
• Other study ID #: BRCAP-GELTAMO12
• Secondary ID: 2012-005138-12
• Status: Completed
• Phase: Phase 2
• Start date: October 3, 2013
• Est. completion date: August 2018

Study information

• Verified date: September 2018
• Source: Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma, accounting for between 30% and 50% of the patients. Although it is considered a curable disease, still at least 40 % of the patients will fail first line chemotherapy. The International Prognostic Index (IPI) score and the age adjusted IPI (aIPI) has been used since they were published to identify patients with different outcome.

There is not standard therapy for young patients with DLBCL and unfavourable IPI score. The survival of these patients remains poor, with EFS around 40%.

The combination of RCHOP with new drugs is an attractive approach to treat these patients.

The goal is to evaluate the proportion of patients with Event-Free Survival (EFS) after 2 years, with a diagnosis of DLBCL with an aIPI > 1 or an aIPI =1 with increased levels of beta-2-microglobulin (above the Upper Limits of Normal.)

Description:

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma, accounting for between 30% and 50% of the patients. Although it is considered a curable disease, still at least 40 % of the patients will fail first line chemotherapy. The International Prognostic Index (IPI) score and the age adjusted IPI (aIPI) has been used since they were published to identify patients with different outcome.

CHOP chemotherapy administered every 21 days has been for years the standard therapy for advanced DLBCL achieving a long term overall survival (OS) of about 40%. Many studies show that the addition of the monoclonal antibody Rituximab improves the patients survival achieving higher rates of event-free survival in elderly patients with both,favourable and unfavourable IPI score. R-CHOP also improved survival in young patients with favourable IPI score.

There is not standard therapy for young patients with DLBCL and unfavourable IPI score. The survival of these patients remains poor, with EFS around 40%.

The combination of RCHOP with new drugs is an attractive approach to treat these patients.

The investigators propose a phase II randomized clinical trial for young patients with unfavourable IPI score DLBCL using 6 cycles of the combination of subcutaneous Bortezomib with R-CAP (RCHOP without vincristine, to avoid neuropathy) comparing with the standard immunochemotherapy regimen R- CHOP every 21 days.

The goal is to evaluate the proportion of patients with Event-Free Survival (EFS) after 2 years, with a diagnosis of DLBCL with aIPI > 1 or aIPI =1 with increased levels of beta-2-microglobulin (above the Upper Limits of Normal).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 121
• Est. completion date: August 2018
• Est. primary completion date: January 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Patients diagnosed with primary diffuse DLBCL who have never received treatment for this condition.

• Age between 18 and 70 years.

• Age-adjusted IPI (aIPI) higher than 1, or equal 1 with high levels of beta-2-microglobulin (above UNL)

• Cluster of Differentiation 20 (CD20) positive b lymphocytes.

• Eastern Cooperative Oncology Group (ECOG) 0-3.

• More than 12 weeks of life expectancy.

• Signed Informed Consent.

• Nor pregnant women nor breast-feeding women without heterosexual activity during the entire study. Women with heterosexual activity only if they are willing to use two methods of contraceptive. The two contraceptive methods can be, two barrier method or a barrier method combinated with an hormonal contraceptive method to prevent pregnancy, used during the entire study and until 3 months after the study completion.

Exclusion Criteria:

• Pregnant women or in breast-feeding period, or adults in childbearing period not using an effective contraception method.

• Patients with Central Nervous System (CNS) lymphoma.

• Severely impaired renal function (creatinine> 2.5 UNL) or hepatic function impairment (bilirubin or Alanine Amino Transaminase (ALT) / Aspartate Aminotransferase (AST) > 3 UNL), unless it is suspected to be due to the disease.

• Human immunodeficiency virus (HIV) positive patients

• Patient previously treated for the DLBCL

• Positive determination of chronic hepatitis B (defined as positive serology for HBsAg). It will be allowed to enroll patients with hidden or previous hepatitis B (defined as positive antibodies against the core of the hepatitis B virus [HBcAb] and HBsAg negative) if undetectable Hepatitis B Virus (HBV) DNA.

• Positive results for hepatitis C (antibody serology for hepatitis C virus ((HCV)). Patients with HCV positive may only participate if the Polymerase Chain Reaction (PCR) result is negative for HCV RNA.

• History of cardiovascular disease with ventricular ejection fraction < 50%.

• Patients with severe psychiatric conditions that may interfere with their ability to understand the study (including alcoholism or drug addiction).

• Patients with known hypersensitivity to murine proteins or any other components of the study drugs.

• Transformed follicular lymphoma.

• History of other neoplastic malignancy with < 5 year of complete response (except for Squamous Cell Carcinoma of the Skin or cervical Carcinoma in situ).

• Presence of uncontrolled conditions: cardiac, respiratory, neurologic, metabolic etc., not related to lymphoma.

• Uncontrolled hypertension (diastolic blood pressure over 110 mmHg).

Related Conditions & MeSH terms

• Diffuse, Large B-Cell, Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse

Intervention

Drug:
• Bortezomib
Bortezomib: subcutaneous, 1,3 mg/m2, day 1, 8, 15.
• Rituximab
Rituximab: intravenous, 375 mg/m2, day 1
• Cyclophosphamide
Cyclophosphamide: intravenous, 750 mg/m2, day 1
• Doxorubicin
Adriamycin:intravenous, 50 mg/m2, day 1
• Prednisone
Prednisone: oral, 100 mg, days 1-5
• Vincristine
Vincristine: intravenous, 1,4 mg/m2, day 1

Locations

Country	Name	City	State
Spain	Hospital Universitario Fundación Alcorcón	Alcorcón	Madrid
Spain	Institut Català d'Oncologia, Hospital Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Hospital Universitari de Girona Doctor Josep Trueta	Girona
Spain	Hospital de Jerez	Jerez de la Frontera	Cádiz
Spain	Institut Català d'Oncologia, Hospital Duran i Reynals	L'Hospitalet de Llobregat	Barcelona
Spain	Centro Integral Oncológico Clara Campal	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Infanta Leonor	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Hospital Universitario Central de Asturias	Oviedo	Asturias
Spain	Hospital Son Llàtzer	Palma	Islas Baleares
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitario de Canarias	Santa Cruz de Tenerife
Spain	Hospital Universitario Marqués de Valdecilla	Santander	Cantabria
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Spain	Hospital Universitari i Politècnic La Fe	Valencia
Spain	Hospital Universitario Doctor Peset	Valencia
Spain	Complejo Hospitalario Universitario de Vigo	Vigo	Pontevedra
Spain	Hospital Clínico Universitario Lozano Blesa	Zaragoza	Aragón

Sponsors (2)

Lead Sponsor	Collaborator
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea	Janssen-Cilag, S.A.

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Biological project	To explore the mutational profile in a selection of these cases by massive sequencing.; To analyze the impact of the molecular classification of DLBCL based on immunohistochemistry (IHC) (as Hans algorithms, Choi and Meyer) in the prospective series of the patients of this clinical trial.; To explore the effect of the expression of genes, Micro-Ribonucleic Acid (miRNAs) and proteins of interest. Refine the IHC analysis with automatic quantification methods of protein expression.; To explore the effect of frequent cytogenetic alterations in DLBCL.	During recruitment period, after patient randomization.
Primary	Proportion of patients with Event-Free Survival at 2 years.	To evaluate the proportion of patients with event-free survival at 2 years in patients diagnosed of DLBCL with aIPI > 1 or aIPI=1 with elevated levels of beta 2-microglobulin (above UNL).; UNL= Upper Normal Limit.	During treatment period, there will be assessments every 2 cycles. After end of treatment every 3 month the first year, every 6 months the second year and annually from 3rd to 5th year
Secondary	Event-Free survival at 2 years in the different subtypes of DLBCL	Event-free survival at 2 years in the different subtypes of DLBCL subgroups: Germinal center B-cell-like (GCB)/non-GCB.	Once the treatment is started, there will be weekly safety visits, visits before each treatment cycle, at day 60 after the sixth cycle and then follow-up visits every three months during the first 2 years and every 6 months until the 5th year
Secondary	Overall survival at 2 years	Overall survival at 2 years in patients diagnosed of DLBCL with aIPI > 1 or aIPI=1 with elevated levels of beta 2-microglobulin (above UNL)	Once the treatment is started, there will be weekly safety visits, visits before each treatment cycle, at day 60 after the sixth cycle and then follow-up visits every three months during the first 2 years and every 6 months until the 5th year.
Secondary	Overall response rate and complete remissions	Overall response rate and complete remissions in patients diagnosed of DLBCL with aIPI > 1 or aIPI=1 with elevated levels of beta 2-microglobulin (above UNL).	Once the treatment is started, there will be weekly safety visits, visits before each treatment cycle, at day 60 after the sixth cycle and then follow-up visits every three months during the first 2 years and every 6 months until the 5th year.
Secondary	Toxicity according to the CTC criteria	Toxicity according to the Common Toxicity Criteria (CTC) (version 3.0) of the National Cancer Institute (NCI).	Once the treatment is started, there will be weekly safety visits, visits before each treatment cycle, at day 60 after the sixth cycle and then follow-up visits every three months during the first 2 years and every 6 months until the 5th year.
Secondary	To evaluate the predictive value for EFS of interim PET/CT evaluation	To evaluate the predictive value for EFS of interim PET/CT evaluation after 2 and 4 cycles of chemotherapy.; The PET Network group of Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea (GELTAMO), will conduct this blind central review in real-time (qualitative and quantitative, prospective central review of the PET scans performed)	Before treatment, after second cycle, after fourth cycle and after treatment completion.
Secondary	To identify clinical and biological prognostic factors for response and survival.	To identify clinical and biological prognostic factors for response and survival.	Once the treatment is started, there will be weekly safety visits, a visit before each treatment cycle, a visit at day 60 after the sixth cycle and then follow-up visits every three months the first 2 years and every 6 months until the 5th year.