PRIMA Trial

Helping patients extend the remission achieved with initial R-CHEMO therapy

PRIMA TRIAL DESIGN1,2

Chart: Prima Trial Design
  • To ensure that all patients received an equal number of courses of RITUXAN prior to maintenance randomization, an additional 2 courses of RITUXAN were given to R-CHOP– and R-FCM–treated patients. For the R-CHOP patients, the 2 additional courses were given on Day 1 of Cycles 7 and 8; for the R-FCM patients, the 2 additional courses were given on Day 15 of Cycles 1 and 4.2
  • PRIMA=Primary RItuximab and MAintenance; R=RITUXAN; NHL=non-Hodgkin’s lymphoma; CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; CVP=cyclophosphamide, vincristine, and prednisone; FCM=fludarabine, cyclophosphamide, and mitoxantrone; PFS=progression-free survival; PR=partial response; CR=complete response; CRu=complete response, unconfirmed.

The PRIMA dosing schedule was chosen based in part on its potential to maintain a target serum level of RITUXAN. This level was derived from pharmacokinetic data in the pivotal McLaughlin trial in relapsed or refractory low-grade or follicular lymphoma.2-4

  • At 3 months post-RITUXAN treatment, median serum levels in responding and non-responding patients were 25.4 μg/mL and 5.9 μg/mL, respectively (p<0.001)2
  • Based on these pharmacokinetic data, a once-every-2-months PRIMA dosing regimen was developed to help increase the likelihood of patients maintaining a serum concentration of 25 μg/mL2

Patient population was diverse and well balanced across both arms

PATIENT CHARACTERISTICS2

Baseline characteristics before induction* RITUXAN
(n=505)
Observation
(n=513)
Age Median (range) 57
(26-79)
55
(22-84)
Sex Female Male 47%
53%
49%
51%
Bone marrow involvement Involved Not involved Unspecified Not done 54%
43%
2%
<1%
56%
42%
1%
2%
Extranodal involvement <2 sites ≥2 sites 57%
43%
54%
46%
ECOG performance status 0 1 2 64%
32%
4%
66%
30%
3%
FLIPI score ≤1 2 ≥3 21%
36%
43%
21%
36%
42%
Induction therapy R-CHOP R-CVP R-FCM 76%
22%
3%
75%
22%
3%
  • *For patients (N=1,018) who were randomized to the maintenance portion of the trial.2
  • Percentages are rounded and may not add up to 100%.
  • ECOG=Eastern Cooperative Oncology Group; FLIPI=Follicular Lymphoma International Prognostic Index.
  • The PRIMA trial’s diverse patient population included2:
    • Patients with bulky disease—98% of the PRIMA population had bulky disease prior to induction therapy
    • Higher-risk patients—43% had a FLIPI score of ≥3
    • Lower-risk patients—57% had a FLIPI score of ≤2

RITUXAN maintenance following first-line R-CHEMO nearly doubled the likelihood of remaining progression-free at 2-year median follow-up

PFS AT 2-YEAR MEDIAN FOLLOW-UP (IRC ANALYSIS)1,2

Chart: PFS at 2-Year Median Follow-Up (IRC ANALYSIS)
  • CI=confidence interval.
  • At 2-year median follow-up, RITUXAN maintenance provided a 46% reduction in the risk of progression, relapse, or death (p<0.0001)2
  • RITUXAN maintenance significantly improved PFS at 2 years—78% vs 62%2
    • Results from the investigator analysis showed a similar 2-year PFS improvement in the RITUXAN maintenance arm

In a Kaplan-Meier PFS curve, when the patient population gets smaller, either due to availability for analysis or progression, a single event can result in a drastic drop in the curve. PFS assessment after 27 months is based on <10% of the patient population and the plot cannot be used to reliably predict PFS beyond this time point.

PRIMA was designed to include an interim analysis, which occurred at a median follow-up of 25 months. An IRC assessment of the full trial results at this time point formed the basis for FDA approval of RITUXAN maintenance in the first-line treatment of follicular NHL.2

Single-agent RITUXAN as maintenance for follicular NHL after first-line RITUXAN-based chemotherapy

  • Detailed safety data collection was limited to Grade ≥2 infections, Grade ≥3 adverse reactions, and serious adverse reactions
  • The most common Grade 3-4 adverse reactions occurring at a higher incidence (≥2%) in the RITUXAN arm than in the observation arm were infections (4% vs. 1%) and neutropenia (4% vs. <1%)
  • The most frequently reported adverse reaction was infections. In patients receiving RITUXAN as single-agent maintenance therapy following RITUXAN plus chemotherapy, infections were reported more frequently compared with the observation arm (37% vs. 22%)

References:
  1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2013.
  2. Data on file, Genentech, Inc.
  3. 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.
  4. Berinstein NL, Grillo-López AJ, White CA, et al. Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol. 1998;9:995-1001.

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.