A Multicenter, Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton*s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Rituximab versus Placebo in Combination with Rituximab in Treatment Naïve Subjects with Follicular Lymphoma

Pharmacyclics LLC (Sponsor) is studying ibrutinib in combination with rituximab
in participants with follicular lymphoma. Ibrutinib (IMBRUVICA®) has been
approved in many regions, including the United States (US) for indications of
cancer other than follicular lymphoma (FL), which is your type of cancer.
Rituximab (Rituxan®) is approved by the US FDA for the treatment of follicular
lymphoma and other diagnoses. However, the two study medications ibrutinib and
rituximab have not been approved for use in combination to treat follicular
lymphoma. Please read carefully the sections on risks and benefits of the study
later in this consent form.
Ibrutinib is a type of drug called a *kinase inhibitor*. *Kinases* are proteins
inside cells that help cells live and grow. The specific kinase inhibited or
*blocked* by ibrutinib is believed to help blood cancer cells live and grow. By
inhibiting the activity of this specific kinase, it is possible that the
ibrutinib may kill the cancer cells or stop them from growing.
Rituximab is a type of drug called a *monoclonal antibody*. It is believed that
rituximab works by using the body*s immune system to attack the cancer.
Rituximab may work by attaching to the cancer cells (lymphocytes) and causing
the cells to die or by signaling your immune system to destroy the cancer
cells.

This study has been transitioned to CTIS with ID 2023-507271-21-00 check the CTIS register for the current data.

Analysis Study:
To evaluate whether the addition of ibrutinib to rituximab will result in
prolongation of progression-free survival (PFS) when compared with rituximab
alone in treatment naïve subjects with follicular lymphoma.

This is a randomized, double-blind, placebo-controlled Phase 3 study designed
to assess the efficacy and safety of ibrutinib in combination with rituximab
compared to placebo in combination with rituximab in treatment naïve subjects
with follicular lymphoma.

Subjects randomized to the investigational arm (Arm A) will receive ibrutinib
560 mg PO daily continuously in combination with rituximab 375 mg/m2 IV once
weekly for the first 4 weeks of study treatment (Cycle 1: Days 1, 8, 15, and
22) and as maintenance therapy beginning Cycle 3, Day 1 given as a single dose
of 375 mg/m2 IV every 8 weeks for up to 12 additional doses (approximately 2
years). In the control arm (Arm B) subjects will receive placebo PO daily
continuously in combination with rituximab 375 mg/m2 IV once weekly for the
first 4 weeks of study treatment (Cycle 1: Days 1, 8, 15, and 22), and as
maintenance therapy beginning with Cycle 3, Day 1 given as a single dose of 375
mg/m2 IV every 8 weeks up to 12 additional doses (approximately 2 years).

Administration of study treatment will continue until disease progression or
unacceptable toxicity. Subjects who discontinue study treatment in the absence
of disease progression will continue to be followed for response. Subjects who
discontinue study treatment due to any reason and have not withdrawn consent
for follow up, will be followed for overall survival. Subsequent anticancer
therapies, best response to therapy, and information about other malignancies
will be collected.

Given the toxicity seen with standard combination treatment regimens in
patients who are elderly or infirm, an initial chemotherapy- free regimen such
as rituximab and ibrutinib may be an attractive treatment option if found to be
well tolerated and to have significant anti-tumor activity. Data from clinical
trials in high-risk
CLL and MCL have shown that the combination of ibrutinib and rituximab has a
favorable
safety profile with enhanced efficacy.