Primary Objective phase 1:- To determine the Recommended Phase 2 Dose (RP2D) of bosutinib for R/I (RP2DR/I) and ND chronic phase (RP2DND) pediatric patients withCML, based on the pharmacokinetic, safety and tolerability profile of bosutinib observed…
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
Phase 1 part:
* Primary endpoints
* - Incidence and severity of Dose-Limiting Toxicities (DLTs) assessed during
the first 28 days of treatment.
* - PK parameters of bosutinib: Maximum observed plasma concentration (Cmax),
time to Cmax (Tmax), area under the plasma concentration versus time curve from
time zero to the dosing interval (AUC*), pre-dose concentration (Ctrough) and
apparent clearance (CL/F).
*
Phase 2 part:
* Primary endpoints
* - AEs, as characterized by type, frequency, severity (as graded using CTCAE
version,
v4.03), timing, seriousness, and relation to study therapy (pooled across ND
and R/I CML patients and by line of therapy).
* - PK parameters of bosutinib: Maximum observed plasma concentration (Cmax),
time to Cmax (Tmax), area under the plasma concentration versus time curve from
time zero the dosing interval (AUC*), predose concentration (Ctrough) and
apparent clearance CL/F.
* - Population PK parameters of bosutinib including clearance and volume of
distribution based on combined PK data from Phase 1 and Phase 2
Secondary outcome
Phase 1:
* Secondary endpoints
* - AEs, as characterized by type, frequency, severity (as graded using CTCAE
version, v4.03), timing, seriousness, and relation to study therapy;
* - Laboratory abnormalities as characterized by type, frequency, severity and
timing;
* - ECG and performance status abnormalities
* - Overall cumulative disease response: complete hematologic response (CHR),
major cytogenetic response (MCyR, defined as complete cytogenetic response
[CCyR] plus partial cytogenetic response [PCyR]), CCyR, major molecular
response (MMR) and deep molecular response (definitions in appendix 2).
* Exploratory endpoints:
* - Parameters of bone metabolism and growth, including linear growth, bone
age, bone mineral density of lumbar spine, physical signs of pubertal
maturation (Tanner stage and testicular volume of boys), and hormones
associated with growth and pubertal development (IGF-1, LH, FSH, estradiol for
girls, and testosterone for boys) and a marker of bone formation and bone
resorption (bone alkaline phosphatase and CTX).
* - Patient and/or caregiver-reported assessments of gastrointestinal symptoms,
as measured by selected domains from the PedsQL Gastrointestinal Symptom Scale.
* - Patient and/or caregiver-reported assessment of the taste and ability to
swallow the medicine, as measured by the Palatability Questionnaire for
Bosutinib in patients aged 4-18 years of age.
Phase 2
* Secondary endpoints
* - Overall cumulative disease response by the line of therapy: complete
hematologic response (CHR), major cytogenetic response (MCyR, defined as
complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]),
CCyR, major molecular response (MMR) and deep molecular response.
* - Time to and duration of the respective responses by line of therapy.
* - Event-free survival (EFS; including time to transformation to AP and BP
CML) by
line of therapy (definition in appendix 2).
* - Overall survival (OS) in pediatric patients with Ph+ CML by line of therapy
.
* - Laboratory abnormalities as characterized by type, frequency, severity and
timing (pooled across ND and R/I CML and by line of therapy).
* - ECG and performance status abnormalities
* - Relationships between PK parameters of bosutinib and key safety and
efficacy metrics.
* Exploratory endpoints
* - Parameters of bone metabolism and growth, including linear growth, bone
age, bone mineral density of lumbar spine, physical signs of pubertal
maturation (Tanner stage and testicular volume of boys), Vitamin D and
hormones associated with growth and pubertal development (IGF-1, LH, FSH,
estradiol for girls, and testosterone for boys) and a marker of bone formation
and bone resorption (bone alkaline phosphatase and CTX)
* - Patient and/or caregiver-reported assessments of gastrointestinal symptoms,
as measured by selected domains from the PedsQL Gastrointestinal Symptom Scale.
* - Patient and/or caregiver-reported assessment of the taste and ability to
swallow the medicine, as measured by the Palatability Questionnaire for
Bosutinib in patients aged 4-18 years of age.
Background summary
Bosutinib is an orally bioavailable, potent, multi-targeted, dual Src-Abl
tyrosine kinase inhibitor (TKI) that has been approved in the United States for
the treatment of adult patients with chronic, accelerated, or blast phase
Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with
resistance or intolerance to prior therapy, and in Europe for the treatment of
adult patients with chronic phase (CP), accelerated phase (AP), and blast phase
(BP) Ph+ CML previously treated with one or more TKIs, and for whom imatinib,
nilotinib and dasatinib are not considered appropriate treatment options
(Bosulif USPI and SmPC).
In this study, bosutinib will be evaluated in pediatric patients with CML who
are resistant or intolerant to other TKIs as these patients have an unmet
medical need and require new treatment options that improve efficacy and/or
have improved safety profile compared to currently available TKIs.
Study objective
Primary Objective phase 1:
- To determine the Recommended Phase 2 Dose (RP2D) of bosutinib for R/I
(RP2DR/I) and ND chronic phase (RP2DND) pediatric patients with
CML, based on the pharmacokinetic, safety and tolerability profile of bosutinib
observed at various dose levels in pediatric patients with CML
who are resistant or intolerant to prior TKI therapy.
Primary Objectives phase 2:
- To assess the PK of bosutinib at the RP2D ND and RP2D R/I in pediatric
patients with ND or R/I Ph + CML.
- To assess the population PK of bosutinib.
- To assess the pooled safety and tolerability profile (based on AEs) of
bosutinib in pediatric patients with ND and R/I Ph+ CML.
Dutch
Fase 1 doel:
In deze studie zal de aanbevolen dosis voor de fase 2 van de studie van
bosutinib worden bepaald voor de behandeling van kinderen met CML,
die resistent of intolerant zijn op tenminste 1 eerder gegeven TKI, op basis
van farmacokinetiek, veiligheid en verdraagbaarheid.
Fase 2 doel:
In het fase 2 deel van deze studie zal er gekeken worden naar de veiligheid en
tolerabiliteit van Bosutinib in kinderen met CML die
resistent of intolerant zijn op tenminste 1 eerder gegeven TKI en in kinderen
met nieuw gediagnostiseerde CML in chronische fase
Ook zal er in dezelfde patienten populaties gekeken worden naar de PK van
Bosutinib en populatie PK resultaten
Secondary objectives:
English Secondary Objectives phase 1:
- To evaluate the overall safety profile during the first cycle of therapy (28
days)
- To evaluate the safety and tolerability profile during the prolonged exposure
to bosutinib
- To preliminary evaluate the anti-leukemic activity in pediatric patients with
Philadelphia chromosome positive CML following resistance or
intolerance to one or more TKIs
Secondary Objectives phase 2:
-To describe the clinical efficacy of bosutinib in pediatric patients with
newly diagnosed Ph+ CML in chronic phase;
-To describe the clinical efficacy of bosutinib in pediatric patients with Ph +
CML in any phase of disease following resistance or intolerance to
one or more TKIs
-To assess other safety parameters of bosutinib
-To assess the relationship between the PK of bosutinib and key safety and
efficacy metrics
Exploratory:
-Evaluate effects on growth bone metabolism;
-Assess changes in GI symptoms during therapy
-Assess palatability of bosutinib
Dutch Fase 1:
- evalueren van de veiligheid tijdens de eerste 28 dagen
- evalueren van de veiligheid bij langere behandeling met bosutinib
- evalueren van het antileukemische effect in kinderen met CML die resistent of
intolerant zijn op tenminste 1 eerder gegeven TKI.
Fase 2:
-beschrijven van het klinische effect van bosutinib in kinderen met CML die
resistent of intolerant zijn op tenminste 1 eerder gegeven TKI
-beschrijven van het klinische effect van bosutinib in kinderen met nieuw
gediagnostiseerde CML in chronische fase
-het onderzoeken van andere veiliheidsparameters van bosutinib
-het onderzoeken van de relatie tussen de PK van bosutinib en de belangrijke
veiligheid en effectiviteit gegevens
Exploratory:
- evalueren van de effecten van Bosutinib op groei en bot metabolisme
- kijken naar veranderingen in gastrointestinale symptomen tijdens behandeling
- kijken naar de smaak en inname van de bosutinib
Study design
This is a Phase 1-2, multicenter, international, single-arm, open-label study
design in pediatric patients with CML who have received at least one prior TKI
therapy (R/I) and in newly diagnosed (ND) CP CML patients, to identify a
recommended Phase 2 dose of bosutinib administered orally once daily for both
ND and R/I patient populations, to preliminary assess the safety and
tolerability of the selected bosutinib dose and evaluate the PK in this patient
populations (and to preliminary assess the efficacy in the phase 2).
Intervention
Once daily oral administration of bosutinib on a continuous basis for the
maximum duration of 4.5 years
Study burden and risks
The patient burden is considered to be acceptable since the treatment would
otherwise be commenced with another second generation TKI with the same
response parameters and planned assessment procedures, perhaps less frequent
though (eg. growth evaluation once a year). The PK sampling is however
additional.
The associated risk with participation is mainly due to (possibly) unknown
adverse events in this population since it is not assessed before. The
expectation however, based on the pre-clinical research, is that the adverse
event profile will be different: less growth problems, less muscle and joint
toxicity, but more GI-toxicity.
Bosutinib is registered for adults use so there is substantial knowledge.
Wytemaweg 80
Rotterdam 3015 CN
NL
Wytemaweg 80
Rotterdam 3015 CN
NL
Listed location countries
Age
Inclusion criteria
Phase 1 (R/I patients only)
1. Cytogenetic and molecular diagnosis of Philadelphia chromosome positive CML
at either time of initial CML diagnosis or at time of study screening:
-Cytogenetics must be performed by chromosome banding analysis
(CBA) of bone marrow cell metaphases, and requires at least 20 metaphases.
-Only if dividing marrow cells cannot be obtained, or if there is an
insufficient number of metaphases, CBA can be substituted by interphase
fluorescence in situ hybridization (I-FISH) of bone marrow or peripheral blood
cells, using dual color dual fusion probes, that allow the detection
of BCR-ABL+ nuclei; at least 200 nuclei should be counted.
-Qualitative RT-PCR should be performed on RNA extracted from freshly collected
bone marrow or peripheral blood cells. It identifies the transcript type,
either e14a2 or 13a2 (also known as b3a2 and b2a2), or much more rarely e19a2,
or e1a2, indicating the BCR-ABL protein weight
(P210, rarely P230 or P190). 2. Resistance (suboptimal response or failure, as
defined by 2013
European Leukemia Net guidelines) or intolerance (with or without suboptimal
response or failure) to at least one prior tyrosine kinase inhibitor (TKI).
• The 2013 European LeukemiaNet guidelines will be used to define suboptimal
response and failure to prior TKI therapy. Details are provided in appendices 3
and 4.
-Intolerance to prior TKI therapy will be determined by the treating
investigator, but generally applies to patients who are unable to receive
standard or reduced doses of a TKI due to significant drug-related toxicity
and/or when the drug-related toxicity is not responding to appropriate medical
management. Patients who enroll as a result of intolerance to prior TKI therapy
may have any level of response to their prior therapy and still be eligible.
3. Age >=1 and <18 years at day of attaining the informed consent.
4. Lansky performance status >=50% for patients <=16 years of age, or Karnofsky
scale >=50% for patients >16 years of age (appendix 5).
5. Adequate bone marrow function:
-For second-line and third-line CP CML patients:
-Absolute neutrophil count >1000/mm3 (>1.0 x109/L);
-Platelets >=75,000/mm3 (>=75 x109/L) without any platelet transfusions during
the preceding 7 days.
-For fourth-line CP and all for all AP/BP CML patients:
-Absolute neutrophil count >500/mm3 (>0.5 x109/L);
-Platelets >=50,000/mm3 (>=50 x109/L) without any platelet transfusions during
the preceding 7 days.
6. Adequate Renal Function: Subjects must have a calculated creatinine
clearance (CrCl) >= 60 mL/min/1.73 m2, using the Schwartz formula to estimate
GFR (see appendix 11).
7. Adequate liver function, including:
• AST/ALT <=2.5 x upper limit normal (ULN) or <=5 x ULN if attributable to
disease involvement of the liver;
• Total bilirubin <=1.5 x ULN unless the patient has documented Gilbert syndrome.
8. Recovered to Grade 0-1, or to baseline, from any acute toxicities of prior
chemotherapy, immunotherapy, radiotherapy, differentiation therapy, or biologic
therapy, with the exception of alopecia
9.Able to reliably swallow whole capsules, whole tablets, or drug substance
(from capsule contents) added to a suitable foodstuff.
10. Serum/urine pregnancy test (for all girls >= age of menarche) negative at
screening.
11. Male and female patients of childbearing potential and at risk for
pregnancy must agree to use a highly effective method of contraception
throughout the study and for at least 30 days after the last dose of assigned
treatment. A patient is of childbearing potential if, in the opinion of the
Investigator, he/she is biologically capable of having children and is sexually
active.
12. Written informed consent of parent(s)/legal guardian(s) and/or patients
(when applicable depending on age and local law and regulations)
13. Patients (including legally acceptable representative for minors where
applicable) who are willing and able to comply with scheduled visits, treatment
plan, laboratory tests, and other study procedures
For phase 2 ND patients:
Criterium 2 replaced with: Newly diagnosed CP Ph+ CML of <= 6 months (from
initial diagnosis) without any previous TKI treatment (with the exception of
hydroxyurea and/or anagrelide) for CML. Diagnosis of CP CML will be defined as
per Appendix 1.
Criterium 5 deleted
Exclusion criteria
Phase 1 (R/I patients only):
1. Diagnosis of primary Ph+ acute lymphoblastic leukemia.
2. In patients with AP/BC CML: leptomeningeal leukemia, defined as positive
cytology on lumbar puncture (including both CNS2 and CNS3 status), or clinical
symptoms or signs present. This assessment is not required for inclusion of CP
CML patients.
3. Extramedullary disease only.
4. Documented prior history of T315I or V299L BCR-ABL1 mutations (Note:
BCR-ABL1 mutation testing will be performed at screening for a baseline
assessment, but results are not used to determine eligibility. This exclusion
criterion is based on whether there is a known history of
these mutations at the time of study entry. If these mutations become evident
during the study the patient will go off study).
5. Any prior treatment with a TKI within 7 days prior to study entry, or other
anti-tumor or anti-leukemia treatment (with the exception of hydroxyurea and/or
anagrelide) within 14 days prior to study entry.
6. Prior growth factors or biologic agents within 7 days prior to study entry.
7. Concomittant use of moderate or strong CYP3A inducers/inhibitors (see
appendix 8)within 7 days prior to study entry and during treatment.
8. Concomittant use of proton pump inhibitors within 7 days prior to study
entry and during treatment.
9. Prior radiotherapy within 3 months prior to study entry.
10. Allogeneic stem cell transplantation within 3 months prior to study entry.
11. Donor lymphocyte infusion (DLI) within 1 month prior to study entry.
12. Hereditary bone marrow failure disorder.
13. Graft-versus-host disease (GVHD) within 60 days prior to study entry.
14. Major surgery within 14 days prior to study entry (recovery from any
previous surgery should be complete before day 1).
15. History of clinically significant or uncontrolled cardiac disease,
including:
• History of or active congestive heart failure;
• Clinically significant ventricular arrhythmia (such as ventricular
tachycardia, ventricular fibrillation, or Torsades de pointes);
• Diagnosed or suspected congenital or acquired prolonged QT syndrome;
• History of prolonged QTc.
16. Prolonged QTc (>450 msec, average of triplicate ECGs).
17. Need for medications known to prolong the QT interval.
18. Pregnant and/or nursing women
19. Uncorrected hypomagnesemia or hypokalemia due to potential effects on the
QT interval.
20. Left ventricular ejection fraction <50% or shortening fraction <28%.
21. Recent or ongoing clinically significant gastrointestinal disorder that may
interfere with the intake or absorption of the drug.
22. Evidence of serious active or uncontrolled bacterial, fungal or viral
infection.
23. Known history of hepatitis B (HBV), hepatitis C (HCV), or human
immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome
(AIDS)-related illness.
24. Other severe acute or chronic medical or psychiatric condition or
laboratory abnormality that may increase the risk associated with study
participation or investigational product administration or may interfere with
the interpretation of study results and, in the judgment of the Investigator,
would make the patient inappropriate for entry into this study.
For phase 2 ND patients:
1. Diagnosis of primary Ph+ ALL
2. EMD only.
3. Documented prior history of T315I or V299L BCR-ABL1 mutations
4. Any prior treatment with a TKI or other anti-tumor or anti-leukemia
treatment (with the exception of hydroxyurea and/or anagrelide)
5. Prior growth factors or biologic agents within 7 days prior to bosutinib
6. Use of strong or moderate CYP3A4 inhibitors and inducers within 7 days prior
and/or concomitant to bosutinib
7. Use of proton pump inhibitors within 7 days prior and/or concomitant to
bosutinib
8. Hereditary bone marrow failure disorder
9. Major surgery within 14 days prior to bosutinib
10. History of clinically significant or uncontrolled cardiac disease,
11. Prolonged QTc (>450 msec, average of triplicate ECGs).
12. Need for medications known to prolong the QT interval.
13. Pregnant and/or nursing women
14. Uncorrected hypomagnesemia or hypokalemia due to potential effects on the
QT interval.
15. Left ventricular ejection fraction <50% or shortening fraction <28%.
16. Recent or ongoing clinically significant gastrointestinal disorder that may
interfere with the intake or absorption of the drug.
17. Evidence of serious active or uncontrolled bacterial, fungal or viral
infection.
18. Known history of hepatitis B (HBV), hepatitis C (HCV), or human
immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome
(AIDS)-related illness.
19. Other severe acute or chronic medical or psychiatric condition or
laboratory abnormality that may increase the risk associated with study
participation or investigational product administration or may interfere with
the interpretation of study results and, in the judgment of the Investigator,
would make the patient inappropriate for entry into this study
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 |
---|---|
EudraCT | EUCTR2015-002916-34-NL |
CCMO | NL55463.078.15 |
Other | NTR (5501) |