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Phase 2 Trial of Single-Agent Ibrutinib (PCI-32765) in Relapsed or Refractory Follicular Lymphoma

Phase 2
18 Years
Open (Enrolling)
Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma

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Trial Information

Phase 2 Trial of Single-Agent Ibrutinib (PCI-32765) in Relapsed or Refractory Follicular Lymphoma


I. Evaluate the overall response rate of ibrutinib in patients with relapsed or refractory
follicular lymphoma.


I. Assess the safety and tolerability of ibrutinib in patients with follicular lymphoma.

II. Evaluate overall survival, time to response, duration of response, progression-free
survival, time to treatment failure, and time to subsequent treatment.


I. Describe the relationship between interim positron emission tomography (PET)/computed
tomography (CT) scan results, CT response, and response duration.

II. Biomarker studies including exploring associations between ibrutinib response and
somatic mutations identified in follicular lymphoma, whole transcriptome shotgun sequencing
(ribonucleic acid-sequencing [RNA-seq]), exploration of inhibition of Bruton's tyrosine
kinase (BTK) and other kinases, expression of cytokines, chemokines, and other proteins with
an aim to develop predictors of response and resistance.

III. Assess changes in various cancer-derived molecules in the blood over the course of
treatment with ibrutinib.

IV. As part of ongoing research for Phase II Consortium (P2C) studies, we are banking
paraffin-embedded tissue blocks/slides and blood products for future studies.


Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months until
progressive disease, and then every 6 months for 5 years.

Inclusion Criteria:

- Histologically confirmed diagnosis of follicular lymphoma, grade 1, 2, or 3a; NOTE:
Fresh (frozen) tumor biopsy must be available or attempted; a frozen tumor biopsy
equivalent to a minimum of four at least 16 gauge needle cores is an important
component of this study; patients without adequate frozen material should have a
biopsy performed to obtain material; if biopsy is performed and does not yield
adequate material, the patient is still eligible for the study; if a biopsy cannot be
done safely, the patient may still be eligible for the study if permission is granted
in writing (email) by the Study Chair (Dr. Nancy Bartlett) or her designees; Dr.
Bartlett may be consulted to discuss situations involving invasive biopsy procedures
that may pose an increased risk to the patient

- Measureable disease as defined by a lymph node or tumor mass that is >= 1.5 cm in at
least one dimension by CT or the CT portion of the PET/CT

- Relapsed or refractory follicular lymphoma which has progressed during or following 1
or more prior chemotherapy regimens for lymphoma

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

- Absolute neutrophil count >= 750/mm^3 (0.75 x 10^9/L)

- Hemoglobin >= 8.0 g/dL

- Platelets >= 30,000/mm^3 (30 x 10^9/L)

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) unless Gilbert's
syndrome or disease infiltration of the liver is present

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.0 x institutional ULN

- Creatinine =< 2.0 x institutional ULN and creatinine clearance (est. glomerular
filtration rate [GFR] [Cockcroft-Gault]) >= 30 mL/min

- Negative serum pregnancy test done =< 7 days prior to registration for women of
childbearing potential only

- Willingness to provide biologic samples for correlative research purposes

Exclusion Criteria:

- Any of the following:

- Chemotherapy/systemic therapy =< 4 weeks prior to registration

- Radiotherapy =< 4 weeks prior to registration

- Nitrosoureas or mitomycin C =< 6 weeks prior to registration

- Those who have not recovered from adverse events due to agents administered more
than 4 weeks earlier

- Major surgery =< 10 days prior to registration or minor surgery =< 7 days prior
to registration.

- Prior therapy with ibrutinib or another Bruton's tyrosine kinase inhibitor

- Receiving any other investigational agents

- Active central nervous system (CNS) involvement; NOTE: Because of their poor
prognosis and because they often develop progressive neurologic dysfunction that
would confound the evaluation of neurologic and other adverse events, patients should
be excluded

- Receiving any medications or substances that are strong inhibitors or inducers of
cytochrome P450 (CYP)3A4/5; NOTE: Because the lists of these agents are constantly
changing, it is important to regularly consult a frequently-updated list such as; medical reference texts such as
the Physicians' Desk Reference may also provide this information; as part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate

- NOTE: The effects of ibrutinib on the developing human fetus are unknown;
for this reason and because tyrosine kinase inhibitors as well as other
therapeutic agents used in this trial may be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation; should a woman become
pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician
immediately; men treated or enrolled on this protocol must also agree to
use adequate contraception prior to the study, for the duration of study
participation, and 4 months after completion of ibrutinib administration

- NOTE: Because there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the mother with ibrutinib,
breastfeeding should be discontinued if the mother is treated with

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy; NOTE: HIV-positive patients on antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with ibrutinib; in addition, these
patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy; appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated; NOTE: HIV-positive
patients who are not on anti-viral medications that are strong CYP3A4/5 inhibitors
and who do not have cluster of differentiation (CD)4 counts less than the lower limit
of normal by institutional criteria are eligible; no patients with CD4 counts below
institutional normals are eligible

- Known active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)

- Known histological transformation from follicular lymphoma to diffuse large B-cell
lymphoma; NOTE: A prior history of adequately treated transformed lymphoma does not
exclude a patient if the current active disease is biopsy-proven follicular lymphoma

- History of stroke or intracranial hemorrhage =< 6 months prior to the first dose of
study drug

- Requires anticoagulation with warfarin or similar vitamin K antagonist; NOTE:
Warfarin or similar vitamin K antagonist must have been discontinued at least 28 days
prior to study entry

- Patient has the inability to swallow tablets

- Uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection,

- Uncontrolled diabetes mellitus

- Cardiac disease

- Psychiatric illness/social situations that would limit compliance with study

- "Currently active" second malignancy, other than non-melanoma skin cancers; NOTE:
Patients are not considered to have a "currently active" malignancy if they have
completed anti-cancer therapy, and are considered by their physician to be at less
than 30% risk of relapse

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ibrutinib

- Concurrent treatment with therapeutic doses (> 20 mg prednisone or equivalent) of
systemic steroids within 14 days of start of protocol therapy

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall response rate defined as a partial response (PR) or complete response (CR) as the objective status at any time during treatment, evaluated using the Cheson et al. Revised Response Criteria for Malignant Lymphoma

Outcome Description:

Ninety-five percent binomial confidence intervals for the true success proportion will be calculated.

Outcome Time Frame:

Up to 5 years

Safety Issue:


Principal Investigator

Nancy Bartlett

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

April 2013

Completion Date:

Related Keywords:

  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Lymphoma
  • Lymphoma, Follicular



Washington University School of Medicine Saint Louis, Missouri  63110