A Randomized, Open-label, Safety and Efficacy Study of Ibrutinib in Pediatric and Young Adult Patients With Relapsed or Refractory Mature B-cell non-Hodgkin Lymphoma.

Ibrutinib (IMBRUVICA®; PCI-32765; JNJ-54179060) is an orally-administered,
covalently-binding small molecule Bruton*s tyrosine kinase (BTK) inhibitor
currently being co-developed by Janssen Research & Development, LLC and
Pharmacyclics LLC for the treatment of B-cell malignancies.

In children, mature B-cell non-Hodgkin lymphomas (NHLs) occur rarely; the most
common types are Burkitt lymphoma (BL) and diffuse large B-cell lymphoma
(DLBCL). Although these are aggressive lymphomas that are fatal in weeks to
months if untreated, the cure rate in children with BL and DLBCL is between 85%
to 90% after initial treatment. Given this high cure rate, the incidence of
relapsed or refractory BL and DLBCL within the broader pediatric population of
NHL is very small.Relapse of pediatric BL most commonly occurs within 6 months
of the end of treatment and has a poor prognosis. A review of children with
mature B-cell NHL who relapsed or progressed following treatment with frontline
pediatric B cell NHL protocols had survival rates of less than 20%; however,
these data were not summarized by the individual subtypes of BL or DLBCL.
Despite the reported overall response rate (ORR) of over 50% in most of these
series, the overall mortality of this population is high and the 1- and 2-year
event-free survival (EFS) rates are approximately 40% and 20%, respectively.
Long-term survival beyond 2 years is poor, with only 10% to 20% of these
patients surviving, underscoring the unmet medical need in this patient
population.

Historically, RICE has been the most commonly used treatment regimen for DLBCL
and BL in the relapsed/refractory pediatric population. However, among members
of the European Intergroup Collaboration for Childhood non-Hodgkin Lymphoma
(EICNHL), an alternative treatment regimen (the rituximab, vincristine,
ifosfamide, carboplatin, and idarubicin [RVICI] regimen) is being increasingly
used in BL patients.

As described above, long-term survival for patients with relapsed or refractory
BL and DLBCL is poor, with only 10% to 20% of these patients surviving beyond 2
years, underscoring the unmet medical need in this patient population.
Ibrutinib is an oral agent with an acceptable safety profile and novel
mechanism of action. The drug inhibits the B-cell receptor pathway via BTK
inhibition, thereby overcoming the B-cell receptor (BCR)- and
chemokine-controlled retention of malignant B cells in their supportive
microenvironments. It has been shown to disrupt the pathogenesis of several
B-cell malignancies. Therefore, the addition of ibrutinib to a salvage regimen
like RICE/RVICI may provide some advantages for the pediatric population given
its non-overlapping mechanism of action and toxicity profile. Although there is
no clinical pediatric experience with ibrutinib, translational models
demonstrate activity of ibrutinib in BL and DLBCL. Clinical data also
demonstrate the safety and activity of ibrutinib in adult subjects with
relapsed DLBCL. No effect of the R-CHOP regimen (rituximab, cyclophosphamide,
doxorubicin, vincristine, and prednisone) on ibrutinib pharmacokinetics was
observed, nor did ibrutinib affect the pharmacokinetics of vincristine, also a
CYP3A substrate. Therefore, an open label study of ibrutinib in combination
with RICE/RVICI in pediatric subjects with relapsed or refractory BL or DLBCL
is planned. The available safety and pharmacokinetic information combined with
the unmet medical need support foregoing a stepwise approach and support
starting treatment using the body surface area (BSA)-derived equivalent of the
560 mg ibrutinib dose used in adults with lymphomas. In all 3 pediatric age
groups, the first 2 evaluable subjects will start treatment with the equivalent
of 420 mg, followed by up titration to the 560 mg equivalent guided by safety
and pharmacokinetic evaluation.

Run-in Part (Part 1)
Objectives
Primary
* Confirm that the pharmacokinetics in pediatric subjects is consistent with
that in adults
Secondary
* Evaluate the safety and tolerability of ibrutinib in combination with RICE or
RVICI background therapy in pediatric subjects with B-cell malignancies
* Assess anti-tumor activity of ibrutinib as add on to RICE or RVICI regimens
* Assess disease-specific biomarkers
* Assess the pharmacodynamic response
* Acceptability and palatability assessment of all ibrutinib formulations
Exploratory
* Evaluate other response biomarkers
* Explore the exposure-response relationships

2.1.2. Randomized Part (Part 2)
Objectives
Primary
* Assess efficacy (EFS) of ibrutinib in combination with RICE or RVICI
background therapy compared to RICE or RVICI background therapy alone *
Difference in EFS between the 2 treatment groups (an event is defined as the
time from randomization to death, disease progression, or lack of CR or PR
after 3 cycles of treatment based on blinded independent event review)
Secondary
* Evaluate the safety and tolerability of ibrutinib in combination with RICE or
RVICI background therapy in pediatric subjects and young adults with B-cell
malignancies * Safety parameters, including gastrointestinal effects, immune
function, intensified cardiac monitoring (in particular, after previous
anthracycline exposure)
* Determine the ORR * The proportion of subjects who achieve CR, (including
CRb and CRu) and PR
* Evaluate tumor volume reduction at Day 14 * Percent decrease in the sum of
the products of the lesion diameters at Day 14
* Determine the number and proportion of subjects who proceed to stem cell
transplantation * Number and proportion of subjects who proceed to stem cell
transplantation
* Evaluate the time to response * The time interval from the first dose of
ibrutinib to the first documented response for those subjects who respond
* Measure the duration of response * Duration calculated from the date of
initial documentation of a response (CR or PR) to the date of first documented
evidence of PD or death
* Evaluate long-term survival (EFS at 2 and 3 years) * Proportion of subjects
with EFS at 2 and 3 years
* Evaluate overall survival * The duration from the date of randomization to
the date of the subject*s death
* Assess disease-specific biomarkers * Phosphor-BTK, as well as SYK, STAT3,
caspase-3, BCL-xL, and cIAP1 expression at baseline and during treatment
* BCR/CD79B, CARD11, and MYD mutations
* c-MYC, immunoglobulin, and T-cell receptor gene rearrangements at baseline
* Assess the pharmacodynamic response, if deemed appropriate based on Part 1
results * BTK occupancy
* Assess the population pharmacokinetics of ibrutinib in pediatric subjects and
young adults * Population pharmacokinetic parameters and derived systemic
exposure to ibrutinib such as AUC
* Relationship between pharmacokinetic parameters and age or measure of body
size
* Acceptability and palatability assessment of all ibrutinib formulations *
Visual analog scale score for palatability
Exploratory
* Evaluate other response biomarkers * Other biomarkers, as applicable
* Explore the exposure-response relationships * Potential relationships between
systemic exposure and response

This is a 2-part, multicenter study. A safety and pharmacokinetic run-in part
(Part 1) will be conducted before starting the randomized part (Part 2) of the
study. Part 2 is a randomized, open-label, Phase 3 study to compare the safety
and efficacy of ibrutinib in combination with CIT (RICE or RVICI) versus CIT
alone in children and young adult subjects with relapsed or refractory mature
B-cell NHL. All subjects in Part 1 will receive ibrutinib in combination with
CIT (investigator choice of RICE or RVICI); 6 to 12 pediatric subjects (1 to
<18 years) will be enrolled to allow confirmation of the dose regimen. In Part
2, approximately 72 additional subjects will be randomized in a 2:1 ratio to
receive ibrutinib in combination with CIT (investigator choice of RICE or
RVICI) or CIT alone; at least 40 subjects are targeted to be of age 1 to <18
years and at least 10 of the 40 subjects are targeted to be age <11 years.
Subjects will be stratified by histology (Burkitt lymphoma [BL]/Burkitt
leukemia [B AL] versus other) and by background therapy (RICE versus RVICI).
Pharmacokinetic samples will be obtained during Part 2 of the study to
characterize the pharmacokinetics in pediatric subjects.
Part 1 and Part 2 of the study will be conducted in 3 phases: a Pretreatment
(Screening) Phase, a Treatment Phase, and a Posttreatment Phase. The Treatment
Phase will extend from enrollment/randomization until 1 of the following: 1)
completion of 3 cycles of therapy, 2) transplantation, if clinically indicated,
or 3) disease progression, whichever comes first. Subjects will begin the
Posttreatment Phase after completion of combination therapy. During the
Posttreatment Phase, subjects on ibrutinib with a response of PR or better and
have completed 3 cycles of combination treatment will continue on ibrutinib
monotherapy for up to three 28-day cycles as described below (see Dosage and
Administration). All subjects will be followed to assess disease progression as
described below (see Efficacy Evaluations/Endpoints). The Posttreatment Phase
will continue until death, loss to follow up, consent withdrawal, or study end,
whichever occurs first. The end of study is defined as when approximately 60
EFS events have occurred in Part 2 (death, disease progression, or lack of CR
or PR after 3 cycles of treatment based on blinded independent event review),
or the sponsor terminates the study, whichever comes first.

An Independent Data Monitoring Committee (IDMC) will be commissioned for this
study. The IDMC will review the safety and
efficacy data during the study and make recommendations as to the further
conduct of the study.

Safety evaluations will include adverse events (AEs) (incidence, intensity, and
type), vital sign measurements, clinical
laboratory test results, and limited physical examinations.