A MULTICENTER, PHASE III, OPEN-LABEL, RANDOMIZED STUDY IN PREVIOUSLY UNTREATED PATIENTS WITH ADVANCED INDOLENT NON-HODGKIN'S LYMPHOMA EVALUATING THE BENEFIT OF GA101 (RO5072759) PLUS CHEMOTHERAPY COMPARED WITH RITUXIMAB PLUS CHEMOTHERAPY FOLLOWED BY GA101 OR RITUXIMAB MAINTENANCE THERAPY IN RESPONDERS

• Register: EUCTR
• Last refreshed on: 9 October 2012
• Main ID: EUCTR2010-024132-41-IT
• Date of registration: 17/01/2012
• Prospective Registration: No
• Primary sponsor: ROCHE
• Public title: A MULTICENTER, PHASE III, OPEN-LABEL, RANDOMIZED STUDY IN PREVIOUSLY UNTREATED PATIENTS WITH ADVANCED INDOLENT NON-HODGKIN'S LYMPHOMA EVALUATING THE BENEFIT OF GA101 (RO5072759) PLUS CHEMOTHERAPY COMPARED WITH RITUXIMAB PLUS CHEMOTHERAPY FOLLOWED BY GA101 OR RITUXIMAB MAINTENANCE THERAPY IN RESPONDERS
• Scientific title: A MULTICENTER, PHASE III, OPEN-LABEL, RANDOMIZED STUDY IN PREVIOUSLY UNTREATED PATIENTS WITH ADVANCED INDOLENT NON-HODGKIN'S LYMPHOMA EVALUATING THE BENEFIT OF GA101 (RO5072759) PLUS CHEMOTHERAPY COMPARED WITH RITUXIMAB PLUS CHEMOTHERAPY FOLLOWED BY GA101 OR RITUXIMAB MAINTENANCE THERAPY IN RESPONDERS -
• Date of first enrolment: 09/05/2011
• Target sample size: 1400
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-024132-41
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2

Countries of recruitment

Argentina, Australia, Belgium, Bosnia and Herzegovina, Brazil, Canada, Chile, China, Colombia, Czech Republic, El Salvador, Germany, Guatemala, Hungary, Italy, Japan, Mexico, Panama, Peru, South Africa, Spain, Sweden, Taiwan, United Kingdom, United States

Contacts

• Name: Ethics & Administrative Trial Unit
• Affiliation: Roche S.p.A.

• Name: Ethics & Administrative Trial Unit
• Affiliation: Roche S.p.A.

Key inclusion & exclusion criteria

Inclusion criteria:
• Histologically documented,CD20-positive, indolent B-cell NHL consisting of one of the following: follicular lymphoma (Grades 1-3a), splenic MZL, nodal MZL, or extranodal MZL
• Stage III or IV disease, or Stage II bulky disease
• For patients with follicular lymphoma: requirement for treatment, defined as
meeting at least one of the following criteria:
- Bulky disease, defined as a nodal or extranodal (except spleen) mass
=7 cm in the greatest diameter
Local symptoms or compromise of normal organ function due to progressive nodal disease or extranodal tumor mass
Presence of B symptoms (fever, drenching night sweats, or unintentional
weight loss of > 10% of normal body weight over a period of 6 months or less)
- Presence of symptomatic extranodal disease (e.g., pleural effusions,
peritoneal ascites)
- Cytopenias due to underlying lymphoma (i.e., absolute neutrophil count
< 1.0 × 109/L, hemoglobin < 10 g/dL, and/or platelet count < 100 × 109/L)
Involvement of =3 nodal sites, each with a diameter of =3 cm Symptomatic splenic enlargement
• For patients with symptomatic splenic, nodal, or non-gastric extranodal MZL: disease that is de novo or has relapsed following local therapy (i.e., surgery or radiotherapy) and requires therapy, as assessed by the investigator
For patients with symptomatic gastric extranodal MZL:
Helicobacter pylori-negative disease that is de novo or has relapsed following
local therapy (i.e., surgery or radiotherapy) and requires therapy,
as assessed by the investigator, or H. pylori–positive disease that has
remained stable, progressed, or relapsed following antibiotic therapy and
requires therapy, as assessed by the investigator (see Appendix G for
additional details regarding gastric extranodal MZL)
• At least one bi-dimensionally measurable lesion (> 2 cm in its largest
dimension by CT scan or MRI)
In patients with splenic MZL, an enlarged spleen on CT scan or extending
at least 2 cm below the costal margin by physical examination will
constitute measurable disease providing that no explanation other than
lymphomatous involvement is likely. For an enlarged liver to constitute the
only measurable disease parameter, a liver biopsy showing proof of NHL
in the liver is required.
• Able and willing to provide written informed consent and to comply with the
study protocol
• Age =18 years
• ECOG Performance status of 0, 1, or 2 (see Appendix H)
• Adequate hematologic function (unless abnormalities are related to NHL),
defined as follows:
Hemoglobin =9.0 g/dL
Absolute neutrophil count =1.5 x 109/L
Platelet count =75 x 109/L
• For men who are not surgically sterile: agreement to use a barrier method of contraception during the treatment phase and for at least 3 months after the last dose of GA101, rituximab, or bendamustine, or according to institutional guidelines for CHOP or CVP chemotherapy, whichever is longer,and agreement to request that their partners use an additional method ofcontraception, such as oral contraceptives, intrauterine device, barrier method of contraception, or spermicidal jelly
• For women of reproductive potential who are not surgically sterile: agreement to use two adequate methods of contraception, such as oral contraceptives, intrauterine device, or barrier method of contraception in conjunction with spermicidal jelly during the treatment period and for at least 12 months after the last dose of GA101 or rituximab, for at least 3 months after the last dose of bendamustine, or according to institu
Exclusion criteria:
• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (e.g., pts in whom dosing with rituximab would be contraindicated for safety reasons)
• Known hypersensitivity to any of the study drugs
• Known sensitivity to murine products
• History of sensitivity to mannitol
• Central nervous system lymphoma, leptomeningeal lymphoma, or histologic evidence of transformation to a high-grade or diffuse large B-cell lymphoma
• Grade 3b follicular lymphoma, SLL, or WM
• Ann Arbor Stage I disease
• For patients with follicular lymphoma: prior treatment for NHL by chemotherapy, immunotherapy, or radiotherapy
• For patients with non-follicular lymphoma: prior treatment with chemotherapy or immunotherapy
• Regular treatment with corticosteroids during the 4 weeks prior to the start of Cycle 1, unless administered for indications other than NHL at a dose equivalent to = 30 mg/day prednisone
• History of prior malignancy with the exception of curatively treated basal or squamous cell carcinoma of the skin and low-grade in situ carcinoma of the cervix
• Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, severe arrhythmia, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)
• For pts who will be receiving CHOP: left ventricular ejection fraction < 50% by MUGA scan or echocardiogram
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 w. prior to the start of Cycle 1
• Vaccination with a live vaccine within 28 days prior to randomization
• Recent major surgery (within 4 w. prior to the start of Cycle 1), other than for diagnosis
• Any of the following abnormal laboratory values (unless these abnormalities are due to underlying lymphoma):
- Creatinine > 1.5 times the upper limit of normal (ULN) (unless creatinine clearance normal), or calculated creatinine clearance < 40 mL/min (using Cockcroft–Gault formula)
- AST or ALT > 2.5 × ULN
- Total bilirubin > 1.5× ULN (or > 3 × ULN for pts with documented Gilbert’s syndrome)
- INR > 1.5 × ULN in the absence of therapeutic anticoagulation
- PTT > 1.5 × ULN in the absence of a lupus anticoagulant
• Positive test results for chronic hepatitis B infection (defined as positive HBsAg serology). Pts with occult or prior hepatitis B infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing. This population will be limited to 50 pts.
• Positive test results for hepatitis C (hepatitis C virus antibody serology testing). Pts positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
• Known history of HIV seropositive status
• Positive test results for human T-lymphotropic 1 (HTLV 1) virus
• Pregnant or lactating
• Life expectancy < 12 months


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

PREVIOUSLY UNTREATED PATIENTS WITH ADVANCED INDOLENT NON-HODGKIN'S LYMPHOMA
MedDRA version: 14.1 Level: PT Classification code 10029547 Term: Non-Hodgkin's lymphoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Product Name: GA101
Product Code: RO5072759
Pharmaceutical Form: Concentrate for solution for infusion
CAS Number: 949142-50-1
Current Sponsor code: RO5072759/F06
Other descriptive name: GA101
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1000-

Trade Name: Mabthera
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Current Sponsor code: Ro 045-2294/V01
Other descriptive name: MabThera
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Mabthera
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Current Sponsor code: Ro 045-2294/V01
Other descriptive name: MabThera
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Trade Name: Bendamustina
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: BENDAMUSTINE HYDROCHLORIDE
CAS Number: 3543757
Other descriptive name: Ribomustin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Primary Outcome(s)

Main Objective: To evaluate the efficacy of GA101 plus chemotherapy followed by GA101 maintenance therapy compared with rituximab plus chemotherapy followed by rituximab maintenance therapy in
patients with previously untreated advanced follicular lymphoma, as measured b investigator-assessed progression-free survival (PFS).

Timepoint(s) of evaluation of this end point: PFS in patients with follicular lymphoma, is defined as the time from randomization to the first occurrence of progression or relapse as assessed by the investigator according to the Revised Response
Criteria for Malignant Lymphoma, or death from any cause. PFS for patients without disease progression, relapse, or death will be censored at the time of the last tumor assessment, or if no tumor assessments were performed after the baseline visit, at the time of randomization.

Primary end point(s): The primary efficacy endpoint, PFS in patients with follicular lymphoma, is defined as the time from randomization to the first occurrence of progression or relapse as assessed by the investigator according to the Revised Response Criteria for Malignant Lymphoma, or death from any cause. PFS for patients without disease progression, relapse, or death will be censored at the time of the last tumor assessment, or if no tumor assessments were performed after the baseline visit, at the time of randomization.

Secondary Objective: overall population:
• To evaluate and compare investigator-assessed PFS between the two arms
For overall population and follicular population, to evaluate and compare:
• Independent Review Committee (IRC)–assessed PFS between thetwo arms
• overall response and complete response (CR) after the end of induction treatment, as assessed by the investigator, between the two arms
• overall response and CR after the end of induction treatment, as assessed by the IRC, between the two arms
• overall survival, event-free survival (EFS), disease-free survival (DFS), duration of response, and time to next anti-lymphoma treatment between the two arms; EFS, DFS and duration of response will be based on investigator assessment.
• the safety profiles between the two arms during induction and maintenance
• To assess patient-reported outcomes
• To evaluate medical resource utilization

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: • OS=the time from randomization to death from any cause
• EFS=the time from randomization to disease progression/relapse as assessed by the investigator, death from any cause, or start of a new anti-lymphoma therapy
a documented CR to disease progression as assessed by the investigator or death from any cause
• Duration of response, defined for patients with a best overall response of CR or PR as the time from first occurrence of a documented CR or PR to disease progression/relapse as assessed by the investigator or death from any cause
• Time to next anti-lymphoma treatment, defined as the time from randomization to start of new non-protocol anti-lymphoma therapy or death from any cause

Secondary end point(s): overall population:
• Investigator-assessed PFS
overall population and follicular population:
• IRC-assessed PFS
• CR and overall response (CR or PR) at the end of induction, as assessed by the investigator
• CR and overall response (CR or PR) at the end of induction, as assessed by the IRC
• Overall survival, defined as the time from randomization to death from any cause
• EFS, defined as the time from randomization to disease progression/relapse as assessed by the investigator, death from any cause, or start of a new anti-lymphoma therapy a documented CR to disease progression as assessed by the investigator or death from any cause
• Duration of response, defined for patients with a best overall response of CR or PR as the time from first occurrence of a documented CR or PR to disease progression/relapse as assessed by the investigator or death from any cause
• Time to next anti-lymphoma treatment, defined as the time from random. to start of new non-protocol anti-lymphoma therapy or death from any cause
• Change from baseline to the end of study in PROs based on the FACT-Lym instrument, as outlined below.
- Change from baseline in all domains of the FACT-G
- Change from baseline in the total outcome index (ranges from 0 to 116): sum of physical well-being (7 items), functional well-being (7 items), and Lym subscale (15 items) scores
- Change from baseline in the FACT-Lym subscale score (ranges from 0 to 60): 15 lymphoma-specific items
- Change from baseline in the FACT-Lym total score (ranges from 0 to 168): sum of physical well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), functional well-being (7 items), and Lym subscale (15 items) scores
• EQ-5D summary scores at baseline, during treatment, after treatment, at the last assessment prior to progression, and at the first assessment after progression
• Medical resource utilization, including number of hospitalizations, length of hospital stay, types of subsequent drug therapies, and types of medical and surgical procedures (i.e., blood transfusions, bone marrow transplantation, or stem-cell transplantation)

Secondary ID(s)

BO21223

2010-024132-41-BE

Source(s) of Monetary Support

F. Hoffman - La Roche Ltd.

Genentech Inc.