Independent Data Monitoring Committee Recommends Early Stopping of Phase 3 Study of Ibrutinib in Relapsed/Refractory CLL/SLL

  Independent Data Monitoring Committee Recommends Early Stopping of Phase 3
Study of Ibrutinib in Relapsed/Refractory CLL/SLL Patients Based on a Planned
                               Interim Analysis

PR Newswire

RARITAN, N.J., Jan. 7, 2014

RARITAN, N.J., Jan. 7, 2014 /PRNewswire/ --Janssen Research & Development,
LLC today announced the early stopping of PCYC-1112-CA, the Phase 3 study of
IMBRUVICA™ (ibrutinib) in the treatment of chronic lymphocytic leukemia and
small lymphocytic lymphoma (CLL/SLL), based on the recommendation of an
Independent Data Monitoring Committee (IDMC), which concluded that the study
showed a significant difference in progression-free survival (PFS) as compared
to the control, the primary endpoint of the study.

Study PCYC-1112-CA (RESONATE) is an international, randomized, open-label
Phase 3 clinical study including 391 patients with relapsed or refractory
CLL/SLL with measurable nodal disease and who were not eligible for treatment
with purine analog-based therapy, who had received at least one prior therapy.
Patients were randomized to receive 420 mg of ibrutinib orally once daily or
intravenous doses of ofatumumab, an approved treatment for relapsed/refractory
CLL, over the course of 24 weeks. Both treatments were administered until
disease progression or unacceptable toxicity.

The primary endpoint of the study is PFS; overall survival (OS) is a key
secondary endpoint; others included overall response rate and safety.

"We're delighted with this outcome, and look forward to sharing these results
with the scientific community and Health Authorities," said Peter F. Lebowitz,
MD, PhD, Oncology Therapeutic Area Head, Janssen Research & Development, LLC.
"This Phase 3 randomized study provides a useful head-to-head comparison of
single agent ibrutinib versus ofatumumab, and builds upon the early evidence
of clinical benefit observed in the ibrutinib Phase 2 program."

The IDMC unanimously recommended stopping the study early based on a planned
interim analysis, in which statistically significant differences in PFS (as
assessed by an independent review committee) and OS were observed.The IDMC
agreed that these results suggest evidence of clinical benefit as well as a
tolerable safety profile in patients receiving ibrutinib as compared to
intravenous doses of ofatumumab. The IDMC also recommended that the sponsor
provide access to ibrutinib to patients in the ofatumumab arm.

These results will be presented at an upcoming medical meeting and also will
be submitted for publication in a peer-reviewed journal.

AboutIbrutinib (IMBRUVICA™)

Ibrutinib was approved in November 2013 in the U.S. under the tradename
IMBRUVICA™, as a single agent for the treatment of patients with mantle cell
lymphoma (MCL) who have received at least one prior therapy. This indication
is based on overall response rate. An improvement in survival or
disease-related symptoms has not been established.



Hemorrhage – Five percent (5%) of patients with MCL had Grade 3 or higher
bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria).
Bleeding events including bruising of any grade occurred in 48% of patients
with MCL treated with 560 mg daily. The mechanism for the bleeding events is
not well understood. Consider the benefit-risk of ibrutinib in patients
requiring antiplatelet or anticoagulant therapies and the benefit-risk of
withholding ibrutinib for at least 3 to 7 days pre and post-surgery depending
upon the type of surgery and the risk of bleeding.

Infections – Fatal and non-fatal infections have occurred. At least 25% of
patients with MCL had infectionsgreater than or equal toGrade 3, according
to NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor
patients for fever and infections and evaluate promptly.

Myelosuppression – Treatment-emergent Grade 3 or 4 cytopenias were reported in
41% of patients. These included neutropenia (29%), thrombocytopenia (17%) and
anemia (9%). Monitor complete blood counts monthly.

Renal Toxicity – Fatal and serious cases of renal failure have occurred.
Treatment-emergent increases in creatinine levels up to 1.5 times the upper
limit of normal occurred in 67% of patients and from 1.5 to 3 times the upper
limit of normal in 9% of patients. Periodically monitor creatinine levels.
Maintain hydration.

Second Primary Malignancies – Other malignancies (5%) have occurred in
patients with MCL who have been treated with IMBRUVICA, including skin cancers
(4%), and other carcinomas (1%).

Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause
fetal harm when administered to a pregnant woman. Advise women to avoid
becoming pregnant while taking IMBRUVICA. If this drug is used during
pregnancy or if the patient becomes pregnant while taking this drug, the
patient should be apprised of the potential hazard to a fetus.

Adverse Reactions – The most commonly occurring adverse reactions (greater
than or equal to 20%) in the clinical trial were thrombocytopenia*, diarrhea
(51%), neutropenia*, anemia*, fatigue (41%), musculoskeletal pain (37%),
peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%),
bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain
(24%), vomiting (23%) and decreased appetite (21%).

* Treatment-emergent decreases (all grades) of platelets (57%), neutrophils
(47%) and hemoglobin (41%) were based on laboratory measurements and adverse

The most common Grade 3 or 4 non-hematological adverse reactions (greater than
or equal to 5%) were: pneumonia (7%), abdominal pain (5%), atrial
fibrillation, diarrhea (5%), fatigue (5%), and skin infections (5%).
Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients.

Ten patients (9%) discontinued treatment due to adverse reactions in the trial

The most frequent adverse reaction leading to treatment discontinuation was
subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred
in 14% of patients.

Drug Interactions:

CYP3A Inhibitors – Avoid concomitant administration with strong or moderate
inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the

CYP3A Inducers – Avoid co-administration with strong CYP3A inducers.

Special Populations – Hepatic Impairment – Avoid use in patients with baseline
hepatic impairment.

For the full prescribing information, visit

Ibrutinib has been submitted to the European Medicines Agency (EMA) for the
treatment of adult patients with relapsed or CLL/SLL or adult patients with
relapsed or refractory MCL. Use of ibrutinib in markets and for indications in
which it has not been approved is investigational.

Ibrutinib is being jointly developed and commercialized by Janssen and
Pharmacyclics, Inc. Pharmacyclics sponsored the study.

For more information, visit

About Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
Chronic Lymphocytic Leukemia (CLL) is a slow-growing cancer of the white blood
cells (lymphocytes), most commonly B cells. CLL is the most common adult
leukemia. Small Lymphocytic Lymphoma (SLL) is a slow-growing lymphoma in which
too many immature white blood cells cause lymph nodes to become larger than

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include a focus on hematologic malignancies, prostate cancer and lung cancer;
cancer interception with the goal of developing products that interrupt the
carcinogenic process; biomarkers that may help guide targeted, individualized
use of our therapies; as well as safe and effective identification and
treatment of early changes in the tumor microenvironment.

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