An Open-Label, Randomized, Phase 2 Study to Assess the Effectiveness of RCHOP With or Without VELCADE in Previously Untreated Patients with Non-Germinal Center B-Cell-like Diffuse Large B-Cell Lymphoma
A central laboratory will perform non-GCB subclassification for all enrolled patients. Clinical centers will consent DLBCL patients and submit their pathology samples to the central laboratory. These samples will be subclassified according to the Hans IHC method with scoring by a certified hematopathologist and the classification results will be returned to the clinical center following sample receipt. Patients classified as non-GCB by the central laboratory may then be enrolled, randomized, and start therapy. Pathology laboratories at some clinical centers routinely perform the GCB/non-GCB classification as part of the initial diagnostic evaluation. A subset of the clinical centers that routinely perform GCB/non-GCB subtyping locally may be allowed to randomize and treat non-GCB patients as classified by their local pathology laboratory. In these cases, lymphoma tissue will also be sent to the central laboratory for confirmation of the subtyping. Only centers that have worked with the sponsor to demonstrate GCB/non-GCB classification consistent with that determined by the central laboratory will be allowed to enroll and treat patients based on subtyping performed by the local pathology laboratory.
It is anticipated that approximately 190 patients, 95 per arm, need to be enrolled in this study to obtain 90 central laboratory confirmed patients with non-GCB DLBCL in each arm.
Patients with the non-GCB subtype of DLBCL will be randomized to receive either RCHOP or Vc-RCHOP. Depending on randomization, VELCADE 1.3 mg/m2 will or will not be administered on Days 1 and 4 of each cycle, with RCHOP administered as follows: rituximab 375 mg/m2 intravenous (IV), cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2 IV, and vincristine 1.4 mg/m2 (maximum total dose 2 mg) IV on Day 1, with prednisone 100 mg/per os (PO) on Days 1 through 5 of a 21-day (3-week) cycle for 6 cycles.
Patients will be evaluated at scheduled visits during screening and treatment, and at the end of treatment (EOT) visit. Patients will be followed every 3 months ((+-) 2 weeks) after the EOT visit until patient withdrawal, death, the study is terminated by sponsor, or until 2 years after the last patient has been enrolled. Patients will discontinue treatment if they experience progressive disease (PD), symptomatic deterioration, or unacceptable AEs. If a patient experiences PD, they will be followed to assess survival status. The maximum duration of treatment will be six 3-week cycles. Patients will attend an EOT visit 30 to 40 days after receiving their last dose of study drug.
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3.0, 09 August 2006. AEs will be assessed and laboratory values (chemistry and hematology) will be obtained to determine the safety and tolerability of Vc-RCHOP.
At screening, all patients will be imaged by computed tomography (CT) and FDG-PET scans. If the screening PET is positive, PET scans will be conducted at the 2 subsequent response assessments (Day 15-21 of Cycle 2 and the EOT visit). Following completion of treatment, patients will be followed with CT scans every 3 months ((+-) 2 weeks) until PD, patient withdrawal, death, the study is terminated by sponsor, or until 2 years after the last patient has been enrolled. Disease status will be assessed using the International Working Group (IWG) revised response criteria for malignant lymphoma.
As part of exploratory research to investigate other candidate biomarkers that may better identify either the non-GCB subtype or patients that benefit from the addition of VELCADE to RCHOP, a baseline serum sample and a genomic DNA sample will be collected at screening. In addition, paraffin-embedded tumor samples will be stored for an analysis of tumor DNA, RNA, and other protein markers.
1. Male or female patient 18 years of age or older
2. Patients with previously untreated DLBCL that has been subclassified as the non-GCB subtype
3. At least 1 measurable tumor mass that is greater than 1.5 cm in the long axis and greater than 1.0 cm in the short axis
4. Availability of paraffin block with sufficient tumor tissue to allow for subtyping that can be submitted for central laboratory analysis
5. No evidence of central nervous system lymphoma
6. Eastern Cooperative Oncology Group (ECOG) performance status <= 2
7. All of the following clinical laboratory values within 21 days before enrollment:
a) Absolute neutrophil count (ANC) > 1000 per uL
b) Platelet count > 70,000 per uL
c) Alanine transaminase (ALT) <= 4 x upper limit of normal (ULN)
d) Aspartate transaminase (AST) <= 4 x ULN
e) Total bilirubin < 1.5 x ULN with a normal direct bilirubin
f) Calculated creatinine clearance >= 20 mL/min
8. Female patients who:
* Are postmenopausal for at least 1 year before the screening visit, OR
* Are surgically sterile, OR
* If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent document through 30 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse
9. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
* Agree to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study drug, OR
* Agree to completely abstain from heterosexual intercourse
10. Patients (or their legally acceptable representative) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.