On April 21,
2020, the Food and Drug Administration expanded the indication of ibrutinib
(IMBRUVICA, Pharmacyclics LLC) to include its combination with rituximab for
the initial treatment of adult patients with chronic lymphocytic leukemia (CLL)
or small lymphocytic lymphoma (SLL).
This review was
conducted under Project Orbis, an initiative of the FDA
Oncology Center of Excellence. Project Orbis provides a framework for concurrent
submission and review of oncology drugs among international partners. For this
application, a modified Project Orbis was undertaken because of the timing of
submission to other regulatory agencies. Nevertheless, the FDA is collaborating
with the Australian Therapeutic Goods Administration, Health Canada, and
Swissmedic as they review the application.
Approval was
based on the E1912 trial (NCT02048813), a 2:1 randomized, multicenter,
open-label, actively controlled trial of ibrutinib with rituximab compared to
fludarabine, cyclophosphamide, and rituximab (FCR) in 529 adult patients 70
years or younger with previously untreated CLL or SLL requiring systemic
therapy. Patients with 17p deletion were excluded. Ibrutinib was administered
at 420 mg daily until disease progression or unacceptable toxicity.
The main
efficacy outcome measure was progression-free survival (PFS). The trial
demonstrated a statistically significant improvement in PFS for patients
receiving ibrutinib plus rituximab compared with those receiving FCR (HR 0.34;
95% CI: 0.22, 0.52; p<0.0001). Median PFS was not reached in either arm
after a median follow-up duration of 37 months.
The most common
adverse reactions (≥30%) in patients with CLL/SLL receiving ibrutinib are
thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash,
anemia, bruising, and nausea.
The recommended
ibrutinib dose is 420 mg taken orally once daily with a glass of water.
Rituximab was initiated in Cycle 2 and administered at 50 mg/m2 on Day 1, 325
mg/m2 on Day 2, and 500 mg/m2 on Day 1 of 5 subsequent cycles, for a total
of 6 cycles.
FDA used
the Real-Time Oncology Review and Assessment Aid Pilot Programs for this
application and the application was granted priority review. The Assessment Aid
is being used to facilitate discussions among the regulatory agencies
participating in Project Orbis. A description of FDA expedited programs is in
the Guidance for Industry: Expedited Programs for Serious
Conditions-Drugs and Biologics.
Healthcare
professionals should report all serious adverse events suspected to be
associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling
1-800-FDA-1088.
For assistance
with single-patient INDs for investigational oncology products, healthcare
professionals may contact OCE’s Project Facilitate at 240-402-0004 or
email OncProjectFacilitate@fda.hhs.gov.
For information
on the COVID-19 pandemic, see the following resources:
- FDA:
Coronavirus Disease 2019 (COVID-19)
- NCI: Coronavirus: What People With Cancer Should
Know
- CDC: Coronavirus (COVID-19)
Follow
the Oncology
Center of Excellence on Twitter @FDAOncologyExternal Link Disclaimer.
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