This is a Phase 1-2, multicenter, international, single-arm, open-label study designed to identify a recommended dose of bosutinib administered orally once daily in pediatric patients with newly diagnosed chronic phase Ph+ CML (ND CML) and pediatric patients with Ph+CML who have received at least one prior TKI therapy (R/I CML), to preliminary estimate the safety and tolerability and efficacy, and to evaluate the PK of bosutinib in this patient population.
Recruiting
Phase 1/Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| Bosutinib | Single Agent Bosutinib |
The Phase 1 part of the study employs a 6+4 design (no DLT in 6 patients or 1 DLT in 10
patients) and incorporates additional PK information before escalating to the next dose
level. If there is unacceptable toxicity or if PK results have exceeded the acceptable
exposure levels for the adult equivalent dose, further dose escalation will be prohibited.
The Recommended Phase 2 Dose (RP2D) is defined as the dose that results in
equivalent(approximately ±20% of the adult values) PK exposure to 500 mg/day in adults and
with 0 of 6 or <2 DLTs observed out of 10 evaluable patients with Ph+ CML and resistance or
intolerance to prior TKI therapy. The phase 2 part of the study will enroll the following
patient populations.
- Newly diagnosed (ND): newly diagnosed pediatric Ph + CML patients in chronic phase (CP)
- Resistant/intolerant (R/I): chronic phase or advanced (accelerated (AP) or blast phase
(BP) pediatric Ph+ CML patients with resistance or intolerance to at least 1 prior TKI
| Name | Type | Description | Interventions |
|---|---|---|---|
| Single Agent Bosutinib | Experimental | Bosutinib administered orally once daily in pediatric patients with newly diagnosed chronic phase Ph+ CML (ND CML) and pediatric patients with Ph+CML who have received at least one prior TKI therapy (R/I CML). A treatment cycle is defined as 28 days |
|
Inclusion Criteria:
Inclusion criteria Phase 1 (R/I patients only)
1. Cytogenetic and molecular diagnosis of Philadelphia chromosome-positive CML[2] 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 (IFISH) 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
BCRABL protein weight (P210, rarely P230 or P190).
2. Resistance (suboptimal response or failure, as defined by 2013 European Leukemia Net
guidelines[3]) or intolerance (with or without suboptimal response or failure) to at
least one prior tyrosine kinase inhibitor (TKI) The 2013 European LeukemiaNet
guidelines[3] will be used to define suboptimal response and failure to prior TKI
therapy. Details are provided in appendices 3 (intolerance or failure after one TKI)
and 4 (Failure after more than one TKIs).
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) ≥
60mL/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 added to a suitable
foodstuff (from capsule contents, added to either apple sauce or yoghurt); or tablets
and/or capsules dissolved in water as an oral syringe drinking solution, or tablets
dissolved and administered by NG tube when needed.
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.
Exclusion criteria Phase 1 (R/I patients only)
Patients presenting with any of the following will not be included in the study:
1. Diagnosis of primary Ph+ acute lymphoblastic leukemia.
2. In patients with AP/BP 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 starting bosutinib treatment, or
other antitumor or anti-leukemia treatment (with the exception of hydroxyurea and/or
anagrelide) within 14 days prior to start of bosutinib treatment.
6. Prior growth factors or biologic agents within 7 days prior to bosutinib treatment.
7. Use of strong or moderate CYP3A4 inhibitors and inducers (see Appendix 8) within 7
days prior and/or concomitant to bosutinib treatment
8. Use of proton pump inhibitors (Ph-modifying agents) within 7 days prior and/or
concomitant to bosutinib treatment.
9. Prior radiotherapy within 3 months prior to bosutinib treatment.
10. Allogeneic stem cell transplantation within 3 months prior to bosutinib treatment.
11. Donor lymphocyte infusion (DLI) within 1 month prior to bosutinib treatment.
12. Hereditary bone marrow failure disorder.
13. Graft-versus-host disease (GVHD) within 60 days prior to bosutinib treatment.
14. Major surgery within 14 days prior to bosutinib treatment (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.
Inclusion criteria Phase 2
- Resistant/Intolerant CML patients: R/I The inclusion criteria for the R/I patients in
Phase 2 are identical to the Phase 1 inclusion criteria.
- Newly Diagnosed CML patients
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 (IFISH) 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 e13a2 (also known as b3a2 and b2a2), or much more rarely e19a2, or e1a2,
indicating the BCRABL protein weight (P210, rarely P230 or P190).
2. 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.
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 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).
6. 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.
7. Able to reliably swallow whole capsules, whole tablets; or drug added to a
suitable foodstuff (from capsule contents, added to either apple sauce or
yogurt); or tablets and/or capsules dissolved as an oral syringe drinking
solution, or tablets dissolved and administered by NG tube when needed.
8. Serum/urine pregnancy test (for all girls ≥ age of menarche) negative at
screening.
9. 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.
10. Written informed consent of parent(s)/legal guardian(s) and/or patients (when
applicable depending on age and local law and regulations)
11. 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.
Exclusion criteria Phase 2
- Resistant/Intolerant (R/I) CML patients: The exclusion criteria for the R/I cohort in
Phase 2 are identical to the Phase 1 exclusion criteria.
- Newly Diagnosed CML patients:
Patients presenting with any of the following will not be included in the study:
1. Diagnosis of primary Ph+ acute lymphoblastic leukemia.
2. Extramedullary disease only.
3. 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).
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 treatment.
6. Use of strong or moderate CYP3A4 inhibitors and inducers (see Appendix 8) within 7
days prior and/or concomitant to bosutinib treatment
7. Use of proton pump inhibitors (Ph-modifying agents) within 7 days prior and/or
concomitant to bosutinib treatment)
8. Hereditary bone marrow failure disorder.
9. Major surgery within 14 days prior to bosutinib treatment (recovery from any previous
surgery should be complete before day 1).
10. 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.
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.
| Maximum Eligible Age: | 18 Years |
| Minimum Eligible Age: | 1 Year |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | 1. Incidence (and severity) of Dose-Limiting Toxicities (DLTs) assessed during the first 28 days of treatment. |
| Time Frame: | First 28 days of treatment (first cycle) |
| Safety Issue: | |
| Description: | Data from Phase 1; Dose-limiting toxicities determined as adverse events occurring in the first cycle (28 days) of treatment, which are attributable to bosutinib. Assessment will be done according the following DLT definition: Non-hematologic AEs: grade ≥3 toxicities, except those that have not been optimally treated; any grade ≥2 toxicity requiring discontinuation/interruption for ≥7 days during the first 28 days of treatment; clinically significant laboratory abnormalities grade ≥3 or lasting ≥7 days despite optimal treatment Hematologic AEs: grade 4 neutropenia or thrombocytopenia lasting ≥7 days (not explained by persistent leukemia). |
| Measure: | AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy; |
| Time Frame: | From signing informed consent, continuously during the study until 28 days after last dose (on average 2 years). |
| Safety Issue: | |
| Description: | Data from Phase 1. AEs will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment emergent AEs (TEAEs) are defined as those with initial onset or increasing in severity after the first dose of study medication. Endpoints include maximum toxicity, time to first event (time from first dose to date of first event including only non-partial dates), duration of any stage/grade event (time from start date to stop date including only non-partial dates).] |
| Measure: | Occurrence of laboratory abnormalities of hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy tests values, as characterized by type, frequency, severity and timing summarized in an overview table |
| Time Frame: | Screening; cycle 1 days 1, 8, 14, 22; cycles 2 to 7: at start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days) |
| Safety Issue: | |
| Description: | Data from Phase 1. Test abnormalities in hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy test will be recorded. Severity of laboratory test abnormalities will be graded using NCI CTCAE version, v4.03. For those laboratory abnormalities without CTCAE grade definitions, results will be categorized as normal, abnormal or not done. Coagulation and HBsAG only tested at screening. Urinalysis and pregnancy test and contraception check not tested at days 8, 14, 15 and 22 of cycle 1. Urinalysis not performed at beginning of cycles 2, 3, 5 and 6 |
| Measure: | ECG abnormalities: QT interval |
| Time Frame: | For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days) |
| Safety Issue: | |
| Description: | Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points. Kamofsky or Lansky performance score is collected to evaluate performance status. |
| Measure: | ECG abnormalities: RR interval |
| Time Frame: | For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days) |
| Safety Issue: | |
| Description: | Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points. |
| Measure: | ECG abnormalities: PR interval |
| Time Frame: | For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days) |
| Safety Issue: | |
| Description: | Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points. |
| Measure: | ECG abnormalities: QRS duration |
| Time Frame: | For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days) |
| Safety Issue: | |
| Description: | Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points. |
| Measure: | Performance status abnormalities |
| Time Frame: | Screening; on day 1 of every subsequent cycle end of treatment (each cycle is 28 days) |
| Safety Issue: | |
| Description: | Data from Phase 1. Kamofsky or Lansky (depending on age) performance score as assessed by physician is collected to evaluate performance status |
| Measure: | Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response |
| Time Frame: | Hematologic response:Screening; Cycles 2 to 7: start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days). |
| Safety Issue: | |
| Description: | Data from Phase 1. MCyR is defined as complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]. (definitions in appendix 2).] |
| Measure: | Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response |
| Time Frame: | Screening; Cycles 2 to 7: start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days).] |
| Safety Issue: | |
| Description: | Data from Phase 2. MCyR is defined as complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]. (definitions in appendix 2). |
| Measure: | Time to the respective responses by line of therapy |
| Time Frame: | Through study completion, a maximum of around 10 years |
| Safety Issue: | |
| Description: | Time to response is defined as the time period from start of treatment with bosutinib to first response, unconfirmed for molecular and cytogenetic and confirmed for hematologic. Patients without events are censored at the last molecular, cytogenetic, or hematologic assessment where response could be assessed for the respective endpoint |
| Measure: | Duration of the respective responses by line of therapy |
| Time Frame: | Through study completion, a maximum of around 10 years |
| Safety Issue: | |
| Description: | Data from Phase 2. Duration of response is defined is defined as the time period from the date of the earliest demonstration of a response until the earliest date of confirmed loss of that response. |
| Measure: | Event-free survival (EFS; including time to transformation to AP and BP CML) by line of therapy (definition in appendix 2). |
| Time Frame: | Through study completion, a maximum of around 10 years |
| Safety Issue: | |
| Description: | Data from Phase 2. EFS is defined as the interval from the date of first dose of bosutinib until the earlier date of EFS events. Patients without the event will be censored at the last evaluation date. |
| Measure: | Overall survival (OS) in pediatric patients with Ph+ CML by line of therapy |
| Time Frame: | Through study completion, a maximum of around 10 years |
| Safety Issue: | |
| Description: | Data from Phase 2. OS or survival time is defined as the interval from the date of first dose of bosutinib until the date of death due to any cause. Patients without the event will be censored at the last evaluation date |
| Measure: | Occurrence of laboratory abnormalities of hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy tests values, as characterized by type, frequency, severity and timing summarized in an overview table |
| Time Frame: | Screening; cycle 1 days 1, 8, 14, 22; cycles 2 to 7: at start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days) |
| Safety Issue: | |
| Description: | Data from Phase 2. Pooled across ND and R/I CML and by line of therapy. Test abnormalities in hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy test and contraception will be recorded. Severity of laboratory test abnormalities will be graded using NCI CTCAE version, v4.03. For those laboratory abnormalities without CTCAE grade definitions, results will be categorized as normal, abnormal or not done. Coagulation and HBsAG only tested at screening. Urinalysis and pregnancy test and contraception check not tested at days 8, 14, 15 and 22 of cycle 1. Urinalysis not performed at beginning of cycles 2, 3, 5 and 6 |
| Measure: | ECG abnormalities: QT interval |
| Time Frame: | For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days) |
| Safety Issue: | |
| Description: | Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points |
| Measure: | ECG abnormalities: RR interval |
| Time Frame: | For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days) |
| Safety Issue: | |
| Description: | Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points |
| Measure: | ECG abnormalities: PR interval |
| Time Frame: | For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days) |
| Safety Issue: | |
| Description: | Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points |
| Measure: | ECG abnormalities: QRS duration |
| Time Frame: | For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days) |
| Safety Issue: | |
| Description: | Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points |
| Measure: | Performance status abnormalities |
| Time Frame: | Screening; on day 1 of every subsequent cycle end of treatment (each cycle is 28 days) |
| Safety Issue: | |
| Description: | Data from Phase 2. Kamofsky or Lansky (depending on age) performance score as assessed by physician is collected to evaluate performance status. |
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Children's Oncology Group |
August 16, 2021
