Trial Outcomes & Findings for Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia (NCT NCT00666588)

NCT ID: NCT00666588

Last Updated: 2018-05-22

Results Overview

Number of participants with dose limiting toxicity.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

52 participants

Primary outcome timeframe

During Course 1

Results posted on

2018-05-22

Participant Flow

Participant milestones

Participant milestones
Measure	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age \< 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Overall Study STARTED	18	6	6	22
Overall Study COMPLETED	14	6	6	20
Overall Study NOT COMPLETED	4	0	0	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age \< 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Overall Study ineligible	2	0	0	2
Overall Study inevaluable	2	0	0	0

Baseline Characteristics

Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure n=18 Participants Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age \< 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp n=6 Participants Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp n=6 Participants Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp n=22 Participants Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Total n=52 Participants Total of all reporting groups
Age, Continuous	4121.72 days STANDARD_DEVIATION 2569.95 • n=5 Participants	5637.0 days STANDARD_DEVIATION 1757.39 • n=7 Participants	2812.5 days STANDARD_DEVIATION 1769.83 • n=5 Participants	3365.0 days STANDARD_DEVIATION 2227.99 • n=4 Participants	3984.06 days STANDARD_DEVIATION 2081.29 • n=21 Participants
Age, Categorical <=18 years	15 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants	21 Participants n=4 Participants	46 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	3 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	6 Participants n=21 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	13 Participants n=4 Participants	30 Participants n=21 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	9 Participants n=4 Participants	22 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	5 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	7 Participants n=21 Participants
Race (NIH/OMB) White	11 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	18 Participants n=4 Participants	35 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	5 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants	7 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	13 Participants n=5 Participants	6 Participants n=7 Participants	5 Participants n=5 Participants	17 Participants n=4 Participants	41 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants	4 Participants n=21 Participants
Region of Enrollment United States	17 participants n=5 Participants	5 participants n=7 Participants	6 participants n=5 Participants	20 participants n=4 Participants	48 participants n=21 Participants
Region of Enrollment Canada	1 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants	3 participants n=21 Participants
Region of Enrollment Australia	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants	1 participants n=21 Participants

PRIMARY outcome

Timeframe: During Course 1

Number of participants with dose limiting toxicity.

Outcome measures

Outcome measures
Measure	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure n=14 Participants Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age \< 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp n=6 Participants Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp n=6 Participants Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp n=20 Participants Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Dose Limiting Toxicity	0 participants	1 participants	0 participants	0 participants

PRIMARY outcome

Timeframe: After course 1

Overall response (complete remission \[CR\] and CR with partial recovery \[CRp\]) during course 1.

Outcome measures

Outcome measures
Measure	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure n=14 Participants Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age \< 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp n=6 Participants Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp n=6 Participants Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp n=20 Participants Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Overall Response (Complete Remission [CR] and CR With Partial Recovery [CRp]) During Course 1	4 participants	2 participants	2 participants	9 participants

SECONDARY outcome

Timeframe: At baseline, prior to and up to 24 hours after bortezomib treatment

Population: Ineligible patients (n=4) are excluded. Patients without available data (n=36) are excluded.

NF-kB activity will be measured as a continuous variable (ng NF-kB/Mg protein). Differences in NF-κB activity between time points will be assessed using summary statistics such as mean, standard deviation, and range. We may perform exploratory analyses to determine if single time point measurements, or the difference between time points, correlate with treatment response.

Outcome measures

Outcome measures
Measure	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure n=5 Participants Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age \< 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp n=1 Participants Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp n=1 Participants Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp n=5 Participants Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA) 24 Hrs after treatment	774.1925 ng/Mg protein Standard Deviation 410.667711	345.46 ng/Mg protein	855.96 ng/Mg protein	497.31 ng/Mg protein Standard Deviation 449.312899
NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA) Baseline	718.218 ng/Mg protein Standard Deviation 418.149339	655.4 ng/Mg protein	974.66 ng/Mg protein	408.144 ng/Mg protein Standard Deviation 484.084297

SECONDARY outcome

Timeframe: At baseline

Population: Ineligible patients (n=4) are excluded. Patients without available data (n=36) are excluded. The data summarized are only at baseline as that is the only data available.

Mean and standard deviation of β1 and β5- Results are ratios (proteasome subunit/β-actin based on loading of 15 µg total protein, normalized to CEM).

Outcome measures

Outcome measures
Measure	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure n=4 Participants Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age \< 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp n=1 Participants Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp n=7 Participants Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Proteasome Inhibition Activity Baseline β1	0.08115 ratio Standard Deviation 0.0860893	0.7894 ratio	—	0.2895143 ratio Standard Deviation 0.2974052
Proteasome Inhibition Activity Baseline β5	0.121575 ratio Standard Deviation 0.0691725	0.2576 ratio	—	0.3721286 ratio Standard Deviation 0.7140883

SECONDARY outcome

Timeframe: At baseline, prior to and up to 24 hours after bortezomib treatment

Population: These data will never be collected because the investigators decided not to perform quantitative biologic analysis.

Relative expression of apoptotic and cell cycle proteins will be characterized using descriptive statistics. If differences are noted between pre and post-treatment protein expression, pairwise comparisons will be made using paired t-test or an equivalent nonparametric test if the data are non-normally distributed. The normality assumption will be assessed on the log-transformed data prior to paired t-test evaluation.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At baseline and after completion of course 1

Population: Ineligible patients (n=4) are excluded. Patients without available data (n=42) are excluded.

Descriptive statistics to assess mean +/- standard deviation for the percentage leukemia initiation cells (LIC) depletion.

Outcome measures

Outcome measures
Measure	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure n=3 Participants Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age \< 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp n=1 Participants Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp n=2 Participants Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Feasibility of Stem Cell Quantitation: Percentage of Leukemia Initiation Cells (LIC) Depletion Prior to Treatment	0.013667 percentage of LIC depletion Standard Deviation 0.02108	—	0.2 percentage of LIC depletion	1.6385 percentage of LIC depletion Standard Deviation 2.06887
Feasibility of Stem Cell Quantitation: Percentage of Leukemia Initiation Cells (LIC) Depletion Post Treatment	0.021 percentage of LIC depletion Standard Deviation 0.036373	—	0.43 percentage of LIC depletion	0.0435 percentage of LIC depletion Standard Deviation 0.0615183

Adverse Events

Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure

Serious events: 3 serious events

Other events: 14 other events

Deaths: 0 deaths

Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp

Serious events: 3 serious events

Other events: 5 other events

Deaths: 0 deaths

Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp

Serious events: 5 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Results Reporting Coordinator

Children's Oncology Group

Phone: 626-447-0064

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure n=16 participants at risk Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age \< 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp n=6 participants at risk Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp n=6 participants at risk Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp n=20 participants at risk Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Gastrointestinal disorders Abdominal pain	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Renal and urinary disorders Acute kidney injury	6.2% 1/16 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Respiratory, thoracic and mediastinal disorders Adult respiratory distress syndrome	6.2% 1/16 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Investigations Alanine aminotransferase increased	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Gastrointestinal disorders Anal pain	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Metabolism and nutrition disorders Anorexia	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Investigations Aspartate aminotransferase increased	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Investigations Blood bilirubin increased	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Infections and infestations Catheter related infection	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Investigations Creatinine increased	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
General disorders Death NOS	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Gastrointestinal disorders Diarrhea	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Blood and lymphatic system disorders Disseminated intravascular coagulation	6.2% 1/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Investigations GGT increased	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Nervous system disorders Headache	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Metabolism and nutrition disorders Hyperglycemia	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	10.0% 2/20 The ineligible patients are not included in the adverse event reporting.
Metabolism and nutrition disorders Hyperkalemia	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Metabolism and nutrition disorders Hyperuricemia	6.2% 1/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Metabolism and nutrition disorders Hypoalbuminemia	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Metabolism and nutrition disorders Hypocalcemia	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Metabolism and nutrition disorders Hypokalemia	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	10.0% 2/20 The ineligible patients are not included in the adverse event reporting.
Metabolism and nutrition disorders Hypomagnesemia	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Metabolism and nutrition disorders Hypophosphatemia	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Vascular disorders Hypotension	6.2% 1/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Respiratory, thoracic and mediastinal disorders Hypoxia	6.2% 1/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	10.0% 2/20 The ineligible patients are not included in the adverse event reporting.
Infections and infestations Infections and infestations - Other, specify	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	33.3% 2/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Cardiac disorders Left ventricular systolic dysfunction	6.2% 1/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Gastrointestinal disorders Mucositis oral	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Cardiac disorders Myocarditis	6.2% 1/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Gastrointestinal disorders Oral pain	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Respiratory, thoracic and mediastinal disorders Pneumonitis	6.2% 1/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Psychiatric disorders Psychosis	6.2% 1/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Respiratory, thoracic and mediastinal disorders Pulmonary edema	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	5.0% 1/20 The ineligible patients are not included in the adverse event reporting.
Cardiac disorders Right ventricular dysfunction	6.2% 1/16 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/20 The ineligible patients are not included in the adverse event reporting.
Infections and infestations Sepsis	0.00% 0/16 The ineligible patients are not included in the adverse event reporting.	16.7% 1/6 The ineligible patients are not included in the adverse event reporting.	0.00% 0/6 The ineligible patients are not included in the adverse event reporting.	10.0% 2/20 The ineligible patients are not included in the adverse event reporting.