This study has been transitioned to CTIS with ID 2023-507330-24-00 check the CTIS register for the current data. Part A - Dose Finding/SafetyPrimary Objective:* To determine the recommended pediatric equivalent dose (RPED; based on pharmacokinetic […
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Chronic Graft Versus Host Disease
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoints:
Part A: PK (area under the plasma concentration-time curve [AUC]) to determine
the RPED of ibrutinib for use in pediatric subjects (age >= 1 to
< 12 years) with cGVHD.
Part B: PK (AUC) and safety (treatment-emergent AEs and laboratory
abnormalities) of ibrutinib in pediatric subjects (age >= 1 and < 22 years)
with cGVHD.
Secondary outcome
Secondary Endpoints:
Part A:
* Safety, including treatment-emergent AEs, laboratory abnormalities and other
safety endpoints.
* Pharmacodynamics (Bruton*s tyrosine kinase occupancy)
* For those subjects continuing therapy after dose escalation (Part A
Continuation Cohort), secondary endpoints will be the same as
outlined under Part B below.
Part B:
* Response rate at 24 weeks
* Duration of response
* Overall survival rate
* Growth and development
* Immune reconstitution
Background summary
Although cGVHD is less common in children than in adults, they nonetheless
represent a significant proportion of the overall cGVHD population, and have
substantial morbidity and mortality associated with the disease (Baird 2010).
Based on pediatric-specific data, the pathogenesis of cGVHD, although not yet
fully understood, appears to be essentially the same in adults and pediatric
patients. Recent information implicates B-cells as well as T-cells in the
generation of cGVHD (Sarantopoulos 2015, Allen 2014, Flynn 2014, Johnston
2014). This was
first recognized in adult populations and confirmed in a biomarker study of
children with cGVHD by the Children*s Oncology Group. The investigators
demonstrated that plasma biomarkers influencing both B-cell and T-cell function
were highly expressed when compared to
children who had undergone transplant without cGVHD (Fujii 2008, She 2007).
Children and adolescents develop cGVHD symptomatology in a manner analogous to
that of adults. Clinical manifestations of cGVHD are similar in adults and
children, and most commonly involve the skin, eyes, oral cavity,
gastrointestinal (GI) tract, liver, and lungs (Baird 2010). The primary
difference between the pediatric and adult population is that cGVHD occurs in
children who are still growing and developing and who generally have a longer
life expectancy. For example, cGVHD of the GI tract can lead to malnutrition
and poor weight gain and linear growth while sclerotic skin changes and joint
contractures can lead to musculoskeletal deformities as a child grows.
Complications of cGVHD in children may lead to significant long-term morbidity.
Chronic GVHD Treatment in Pediatric Patients:
Currently, there are no therapies indicated for the treatment of pediatric
patients with cGVHD, and ibrutinib is the only therapy indicated for adult
patients with cGVHD (after failure of one or more lines of systemic therapy). A
significant proportion of pediatric patients do not maintain
sufficient disease control with existing treatments, or experience toxicities
that limit their effectiveness (Jacobsohn 2010). Choice of treatment in
pediatric patients is mostly based on experience in adults, and often includes
prednisone and cyclosporine in the frontline setting
(Baird 2010, Zecca 2002).
Study objective
This study has been transitioned to CTIS with ID 2023-507330-24-00 check the CTIS register for the current data.
Part A - Dose Finding/Safety
Primary Objective:
* To determine the recommended pediatric equivalent dose (RPED; based on
pharmacokinetic [PK] and, if applicable,
pharmacodynamic data) for use in pediatric subjects (age >=1 to <12 years) with
cGVHD as defined by the 2014 NIH Consensus
Development Project Criteria
Secondary Objectives:
* To determine the safety of ibrutinib in pediatric subjects with
cGVHD.
* To assess pharmacodynamics (BTK occupancy) of ibrutinib in pediatric
subjects with cGVHD.
Part A Continuation Cohort
* For those subjects continuing therapy after dose escalation (Part A
Continuation Cohort), secondary endpoints will be the same as
outlined under Part B below.
Part B - Pharmacokinetics and Safety Study
Primary Objective:
* To assess the PK and safety of ibrutinib in pediatric subjects
(age >=1 to <22 years) with cGVHD.
Secondary Objectives:
* To evaluate the efficacy of ibrutinib treatment at 24 weeks in pediatric
subjects with cGVHD.
* To evaluate the duration of response to ibrutinib treatment in pediatric
subjects with cGVHD.
* To evaluate the overall survival rate in pediatric subjects with cGVHD
treated with ibrutinib
* To evaluate safety by assessing the potential impact of ibrutinib on late
effects (including effects on growth and development and
immune reconstitution) in pediatric subjects with cGVHD.
Study design
Open label, multicenter, Phase 1/2 dose finding, safety and efficacy
study of oral ibrutinib in pediatric subjects with moderate or severe cGVHD.
The study is divided into 2 parts:
Part A - dose finding and safety study for subjects >=1 to <12 years, and Part B
- PK, safety and
efficacy study for subjects >=1 to <22 years. Enrollment will be concurrent into
Part A (for subjects < 12 years only),
and into Part B (for subjects >= 12 years old only). Once the RPED (for subjects
< 12 years) has been established in Part A, enrollment for all
subjects (age >= 1 to < 22 years) will continue in Part B. The RPED for subjects
>=1 to <12 years of age with cGVHD is targeted
to be the dose that will achieve approximately the equivalent exposure to that
seen in adult subjects with cGVHD who received 420 mg of
ibrutinib daily. Subjects age >= 12 years will receive the adult fixed dose of
420 mg orally daily in Part B of the study.
Part A - Dose Finding/Safety Study
A minimum of 12 subjects >=1 to <12 years with moderate or severe
cGVHD after failure of 1 or more lines of systemic therapy will be
enrolled. Intra-subject dose escalation will occur in order to determine
the RPED. Subjects will receive oral ibrutinib once daily, starting with a
dose of 120 mg/m2 (equivalent to approximately 50% of the adult
cGVHD dose calculated using mg/m2) and escalate to 240 mg/m2
(approximately 100% of the adult cGVHD dose) after 14 days of
treatment at the lower dose level, provided there are no safety concerns.
Doses may exceed an absolute dose of 420 mg.
Pharmacokinetic data and, if applicable, pharmacodynamic data, from Part A will
be used to determine the RPED to be carried forward for
subjects >=1 to <12 years in Part B. If analysis of PK data after the initial 3
subjects treated at the 50% dose level confirms sub-therapeutic
exposure, then dose levels may be adjusted for all subsequent subjects who
begin Part A.
The RPED will be determined after PK (and, if applicable, pharmacodynamic) data
are evaluated on a minimum of 12 subjects in
Part A (>=1 to<12 years) including a minimum of 3 subjects in the younger age
group (>=1 to < 6 years). If the older age group (age >=6 to
<12 years) enrolls 9 subjects before 3 subjects in the younger age group are
enrolled, RPED will be determined based on available data, and
subsequent enrollment for the older age group will be in Part B while the
younger age group continues to recruit subjects in Part A. Safety
will be monitored until 30 days after the last ibrutinib dose.
Part A Continuation Cohort:
Subjects participating in Part A may continue receiving daily ibrutinib at the
240 mg/m2 dose (or maximal achieved dose) until the RPED is
determined, at which time their dose may be adjusted. This cohort will be
treated and evaluated in the same fashion as for Part B subjects.
Evaluation of these subjects will include safety and efficacy as in Part B
subjects.
Part B - Pharmacokinetics, Safety, and Efficacy
Part B will enroll a minimum of 10 and up to 32 subjects with moderate or
severe cGVHD after failure of 1 or more lines of systemic therapy or
with newly diagnosed moderate or severe cGVHD. Efficacy assessments will be
made at weeks 5, 13, 25 and every 12 weeks
subsequently. PK and pharmacodynamic data will be assessed on Week 3 Day 1.
Treatment with ibrutinib will continue until:
* The subject*s cGVHD no longer requires treatment (subject has received at
least 36 weeks of ibrutinib and has been off
immunosuppressants for a minimum of 12 weeks)
* The subject begins a new systemic immunosuppressive agent for treatment of
cGVHD
* Progressive cGVHD
* Unacceptable toxicity
* Recurrence of the underlying disease, or
* Subject dies
In addition to regular assessments of safety and efficacy, subjects in Part A
and B will continue to be followed every 12 months until 60
months post-enrollment, to assess for potential late effects of
ibrutinib,including effects on growth and development as well as immune
reconstitution.
Intervention
see section study design
Study burden and risks
Chronic GVHD Treatment in Pediatric Patients
Currently, there are no therapies indicated for the treatment of pediatric
patients with cGVHD, and ibrutinib is the only therapy indicated for adult
patients with cGVHD (after failure of one or more lines of systemic therapy). A
significant proportion of pediatric patients do not maintain
sufficient disease control with existing treatments, or experience toxicities
that limit their effectiveness (Jacobsohn 2010). Choice of treatment in
pediatric patients is mostly based on experience in adults, and often includes
prednisone and cyclosporine in the frontline setting
(Baird 2010, Zecca 2002).
Gateway Boulevard 1000
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Listed location countries
Age
Inclusion criteria
1. Part A: Subjects with moderate or severe cGVHD after failure of 1
or more lines of systemic therapy.
2. Part B: Subjects with moderate or severe cGVHD after failure of 1
or more lines of systemic therapy, or subjects with new onset
moderate or severe cGVHD and in need of systemic
immunosuppression.
a. Subjects with new onset moderate or severe cGVHD must not
have received previous systemic therapy for cGVHD with the
exception of corticosteroids received within 72 hours prior to
signing the informed consent form.
b. Subjects with newly diagnosed cGVHD may be receiving
other immunosuppressants for the prophylaxis or treatment of
acute GVHD, but if the subject is receiving prednisone for
prophylaxis or treatment of acute GVHD it must be at or below
0.5 mg/kg/d at the time of enrollment.
3. History of allogeneic stem cell transplantation
4. Age
• Part A: >=1 to <12 years of age at the time of enrollment
• Part B: >=1 to <22 years of age at the time of enrollment
5.Written informed consent or parental or guardian permission and
assent of children capable of understanding the nature of the study,
per country-specific or site-specific standards
6. Ability of subject or, if a minor, parent/guardian to understand the
purpose and risks of the study and to provide a signed and dated
parental permission and authorization to use protected health
information (in accordance with national and local subject privacy
regulations); willingness of child to provide an assent, if
developmentally able to do so.
Exclusion criteria
Disease-Related
1. Presence of single organ genito-urinary involvement as the only
manifestation of cGVHD.
Concurrent Conditions
2. Received an investigational agent within 28 days before enrollment.
3. Received donor lymphocyte infusion (DLI) within 56 days before
enrollment.
4. Progressive underlying malignant disease or active post-transplant
lymphoproliferative disease.
5. Ongoing anticoagulation treatment with warfarin or equivalent
vitamin K antagonist.
6. History of other malignancy (not including the underlying
malignancy that was the indication for transplant), with the
following exceptions:
• Malignancy treated with curative intent and with no evidence of
active disease present for more than 3 years prior to enrollment
and felt to be at low risk for recurrence by treating physician
• Adequately treated non-melanomatous skin cancer or lentigo
maligna melanoma without current evidence of disease
• Adequately treated cervical carcinoma in situ without current
evidence of disease
7. History of major surgery within 28 days before enrollment or lack
of full recovery from surgery.
8. Any life-threatening illness, medical condition, or organ system
dysfunction that, in the investigator*s opinion, could compromise
the subject*s safety or put the study outcomes at undue risk.
9. Female subject who is pregnant, breastfeeding, or planning to
become pregnant while enrolled in this study or within 3 months of
the last dose of study drug. Male subject who plans to father a child
while enrolled in this study or within 3 months after the last dose of
study drug.
10. Unwilling or unable to participate in all required study evaluations
and procedures.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-507330-24-00 |
| EudraCT | EUCTR2017-004558-41-NL |
| CCMO | NL67071.041.19 |