ECOG 1496 Trial

Proven dosing strategy for helping NHL patients extend remission

ECOG 1496 TRIAL DESIGN1

Chart: ECOG 1496 Trial Desgin
  • *CVP=cyclophosphamide 1 g/m2 on Day 1; vincristine 1.4 mg/m2 on Day 1; prednisone 100 mg/m2 on Days 1–5. After the completion of 6 to 8 twenty-one–day cycles of CVP, patients achieving a CR, PR, or SD were randomized to receive no further treatment or to receive post-induction therapy with RITUXAN. Beginning 4 weeks after completion of induction therapy, patients randomized to RITUXAN received 1 cycle of 4 weekly treatments with 375 mg/m2 RITUXAN, every 6 months for up to 4 cycles.1
  • ECOG=Eastern Cooperative Oncology Group; NHL=non-Hodgkin's lymphoma; IWF=International Working Formulation; CR=complete response; PR=partial response; SD=stable disease; PFS=progression-free survival.

ECOG 1496 dosing strategy based on proven B-cell depletion and recovery

B-CELL DEPLETION AFTER RITUXAN MONOTHERAPY IN THE McLAUGHLIN TRIAL2

Chart: B-cell Depletion after RITUXAN Monotherapy in the McLaughlin Trial
  • McLaughlin P et al. J Clin Oncol. 1998;16:2825-2833.
  • In the McLaughlin monotherapy trial in relapsed or refractory, low-grade or follicular NHL2:
    • RITUXAN 375 mg/m2 was administered once weekly for 4 weeks
    • B cells were rapidly depleted after 4 doses of RITUXAN
    • Recovery began at 6 months and returned to baseline levels by 12 months after completion of a 4-week course of RITUXAN monotherapy
  • B-cell depletion observed in the McLaughlin trial formed the basis for the ECOG 1496 dosing strategy following first-line CVP induction in low-grade NHL2

The ECOG 1496 trial included both low- and high-risk patients

PATIENT CHARACTERISTICS3

Baseline characteristics CVP→R
(n=162)
CVP→Obs
(n=160)
Age range (years) 26-84 26-85
Median age 58 55
Elevated LDH (>1×ULN) 24% 21%
Ann Arbor Stage I/II III/IV 1%
99%
0%
100%
ECOG performance status 01 72%
28%
60%
40%
Bulky disease (>10cm) 19% 24%
Number of extranodal sites 01≥2 19%
52%
30%
15%
43%
42%
CRF-derived IPI score 0-1 2 3-4 38%
41%
21%
36%
43%
21%
  • The IPI score, which ranged from 0 to 5, was derived by assigning 1 point for each of the following risk factors: >60 years of age, Ann Arbor Stage III or IV, extranodal disease involvement at >1 site, ECOG performance status ≥2, and elevated LDH.
  • R=RITUXAN; Obs=observation; LDH=lactate dehydrogenase; ULN=upper limit of normal; CRF=case report form; IPI=International Prognostic Index.
  • The ECOG 1496 trial's diverse patient population included3:
    • Patients across a broad spectrum of age groups (range: 26 to 85 years of age)
    • Higher-risk patients with elevated LDH levels and bulky disease
    • Lower-risk patients with ECOG performance status of 0-1

RITUXAN after first-line CVP induction more than doubled the likelihood of remaining progression-free at 2.3-year follow-up

  • Patients with advanced low-grade NHL were randomized to receive either RITUXAN or no further therapy if they achieved a CR, PR, or SD with CVP induction therapy3
  • At 2.3 year median follow-up, there was a 51% reduction in the risk of relapse, progression, or death with RITUXAN vs observation (p≤0.05)3,4

Single-agent RITUXAN for low-grade NHL after first-line CVP chemotherapy

  • Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the RITUXAN arm compared with those who received no further therapy (4% vs. 1%)
  • The following common adverse reactions were reported more frequently (≥5%) in patients receiving RITUXAN following CVP compared with those who received no further therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepatobiliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%)

References:
  1. Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG 1496 study. J Clin Oncol. 2009;27:1607-1614.
  2. McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:2825-2833.
  3. Data on file, Genentech, Inc.
  4. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2013.

Indications

RITUXAN® (Rituximab) is indicated for the treatment of patients with:

  • Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
  • Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to RITUXAN in combination with chemotherapy, as single-agent maintenance therapy
  • Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy
  • Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens
  • Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC)

RITUXAN is not recommended for use in patients with severe, active infections.

Important Safety Information

BOXED WARNINGS

WARNING: FATAL INFUSION REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

  • Infusion Reactions: RITUXAN administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of RITUXAN infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Monitor patients closely. Discontinue RITUXAN infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion reactions
  • Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving RITUXAN
  • Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with RITUXAN, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with RITUXAN. Discontinue RITUXAN and concomitant medications in the event of HBV reactivation
  • Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving RITUXAN

Warnings and Precautions

Tumor Lysis Syndrome

  • Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12−24 hours after the first infusion of RITUXAN in patients with NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden, confers a greater risk of TLS. Administer aggressive intravenous hydration and anti hyperuricemic therapy in patients at high risk for TLS

Infections

  • Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of RITUXAN-based therapy. Discontinue RITUXAN for serious infections and institute appropriate anti infective therapy

Cardiovascular

  • Discontinue infusions for serious or life threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of RITUXAN for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina

Renal

  • Severe, including fatal, renal toxicity can occur after RITUXAN administration in patients with NHL. Monitor closely for signs of renal failure and discontinue RITUXAN in patients with a rising serum creatinine or oliguria

Bowel Obstruction and Perforation

  • Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving RITUXAN in combination with chemotherapy. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur

Immunization

  • The safety of immunization with live viral vaccines following RITUXAN therapy has not been studied and vaccination with live virus vaccines is not recommended

Laboratory Monitoring

  • Obtain complete blood counts (CBC) prior to each RITUXAN course

Additional Important Safety Information

  • The most common Grade 3 or 4 adverse reactions in clinical trials of NHL and CLL were infusion reactions, neutropenia, leukopenia, anemia, thrombocytopenia, and infections. Additionally, lymphopenia and lung disorder were seen in NHL trials; and febrile neutropenia, pancytopenia, hypotension, and hepatitis B were seen in CLL trials
  • The most common adverse reactions (incidence ≥25%) in clinical trials of NHL and CLL were infusion reactions. Additionally, fever, lymphopenia, chills, infection, and asthenia were seen in NHL trials; and neutropenia was seen in CLL trials
  • Pregnancy: Category C. There are no adequate and well-controlled studies of rituximab in pregnant women

For additional safety information, please see the full prescribing information, including BOXED WARNINGS and Medication Guide.

Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.

You may also report side effects to Genentech at (888) 835-2555.