Trial Outcomes & Findings for Bortezomib and Vorinostat in Younger Patients With Refractory or Relapsed MLL Rearranged Hematologic Malignancies (NCT NCT02419755)

NCT ID: NCT02419755

Last Updated: 2018-03-07

Results Overview

For the purpose of the statistical analysis of the primary objective, response is assessed at the end of first treatment block at maximum tolerated dose of vorinostat (i.e., Induction Ia or Ib for myeloid and Induction for lymphoid and mixed lineage). Any eligible patient who starts first treatment block is considered evaluable. Response of CR, CRi, PR, or PRi is considered a success; otherwise a failure, which will include the cases of No-response, as well as off- treatment or off-study before response can be assessed, except cases found ineligible after enrollment. A patient found ineligible after enrollment will be taken off study and replaced by enrolling an additional MLLr patient. The rate (probability) of response will be estimated by the sample proportion of patients who responded (CR, CRi, PR, PRi) to Induction, along with the 99% confidence interval and lower confidence bound. Three interim analyses will be performed to monitor the possible lack of efficacy.

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 12 participants
• Primary outcome timeframe: End of first treatment block (up to 2 months)
• Results posted on: 2018-03-07

Participant Flow

Twelve participants were enrolled at St. Jude Children's Research Hospital between April 2015 and October 2016.

Participant milestones

Measure	Stratum 1: Myeloid Malignancies Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description.	Stratum 2: ALL and MLM Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
Overall Study STARTED	6	6
Overall Study COMPLETED	3	2
Overall Study NOT COMPLETED	3	4

Reasons for withdrawal

Measure	Stratum 1: Myeloid Malignancies Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description.	Stratum 2: ALL and MLM Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
Overall Study Death	1	3
Overall Study Relapse	0	1
Overall Study Ineligible	1	0
Overall Study Withdrawal by Subject	1	0

Baseline Characteristics

Bortezomib and Vorinostat in Younger Patients With Refractory or Relapsed MLL Rearranged Hematologic Malignancies

Baseline characteristics by cohort

Measure	Stratum 1: Myeloid Malignancies n=4 Participants Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description.	Stratum 2: ALL and MLM n=6 Participants Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.	Total n=10 Participants Total of all reporting groups
Age, Continuous	3.39836 years STANDARD_DEVIATION 1.22932 • n=5 Participants	4.58224 years STANDARD_DEVIATION 5.33903 • n=7 Participants	4.10869 years STANDARD_DEVIATION 4.08824 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race/Ethnicity, Customized Not Otherwise Specified, Spanish, Hispanic, Latino	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Non Spanish speaking, Non Hispanic	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race/Ethnicity, Customized South or Central American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian and White	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized White	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants

PRIMARY outcome

Timeframe: End of first treatment block (up to 2 months)

Population: The determination of overall response rate is contingent on the determination of the maximum tolerated dose. The study was terminated before the maximum tolerated dose was determined. Therefore, response rate cannot be calculated.

For the purpose of the statistical analysis of the primary objective, response is assessed at the end of first treatment block at maximum tolerated dose of vorinostat (i.e., Induction Ia or Ib for myeloid and Induction for lymphoid and mixed lineage). Any eligible patient who starts first treatment block is considered evaluable. Response of CR, CRi, PR, or PRi is considered a success; otherwise a failure, which will include the cases of No-response, as well as off- treatment or off-study before response can be assessed, except cases found ineligible after enrollment. A patient found ineligible after enrollment will be taken off study and replaced by enrolling an additional MLLr patient.

The rate (probability) of response will be estimated by the sample proportion of patients who responded (CR, CRi, PR, PRi) to Induction, along with the 99% confidence interval and lower confidence bound. Three interim analyses will be performed to monitor the possible lack of efficacy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Three years after the last enrollment

Population: All eligible patients who started the treatment at the vorinostat maximum tolerated dose will be included in this analysis. The study was terminated before the maximum tolerated dose was determined.

All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. In addition to death for any reason, no-response (i.e., other than CR, CRi, PR or PRi), off-treatment or off-study (except for the reason of being found ineligible), disease progression, relapse, and second malignancies will be considered as failures. The time to EFS will be set to 0 for patients who fail to respond.

Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Five years after the last enrollment

Population: All eligible patients who started the treatment at the vorinostat maximum tolerated dose will be included in this analysis. The study was terminated before the maximum tolerated dose was determined.

All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. In addition to death for any reason, no-response (i.e., other than CR, CRi, PR or PRi), off-treatment or off-study (except for the reason of being found ineligible), disease progression, relapse, and second malignancies will be considered as failures. The time to EFS will be set to 0 for patients who fail to respond.

Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Ten years after the last enrollment

Population: All eligible patients who started the treatment at the vorinostat maximum tolerated dose will be included in this analysis. The study was terminated before the maximum tolerated dose was determined.

All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. In addition to death for any reason, no-response (i.e., other than CR, CRi, PR or PRi), off-treatment or off-study (except for the reason of being found ineligible), disease progression, relapse, and second malignancies will be considered as failures. The time to EFS will be set to 0 for patients who fail to respond.

Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Three years after the last enrollment

Population: All eligible patients who started the treatment at the vorinostat maximum tolerated dose will be included in this analysis. The study was terminated before the maximum tolerated dose was determined.

All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. Death for any reason is considered as a failure.

Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Five years after the last enrollment

Population: All eligible patients who started the treatment at the vorinostat maximum tolerated dose will be included in this analysis. The study was terminated before the maximum tolerated dose was determined.

All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. Death for any reason is considered as a failure.

Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Ten years after the last enrollment

Population: All eligible patients who started the treatment at the vorinostat maximum tolerated dose will be included in this analysis. The study was terminated before the maximum tolerated dose was determined.

All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. Death for any reason is considered as a failure.

Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From on-therapy date up to 18 months

Population: Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for this outcome measures.

Events were graded using CTCAE v. 4.0. All toxicities will be monitored until the completion of therapy (up to 500 days) for patients that do not go on to bone marrow transplant. If a patient goes on to receive a bone marrow transplant, at that point, they will no longer be monitored for toxicity, as any further toxicities may be secondary to the transplant and not the study regimen.

This outcome reports those toxicities that are that were possibly, probably or definitely related to therapy. Participants were separately monitored for frequency of grade 5 events, grade 4 sepsis, grade 4 hemorrhage, and grade 4 hepatic toxicity across all patients in the stratum. Grade 4 and 5 events that are clearly and incontrovertibly due to extraneous causes or disease progression will be excluded. Higher grade events are considered more severe than lower grade.

Outcome measures

Measure	Stratum 1: Myeloid Malignancies n=4 Participants Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description.	Stratum 2: ALL and MLM n=6 Participants Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
Number of Relevant Toxicities Related to Therapy Grade 4: hepatic toxicity	0 events	0 events
Number of Relevant Toxicities Related to Therapy Grade 4: sepsis	0 events	2 events
Number of Relevant Toxicities Related to Therapy Grade 4: hemorrhage	0 events	1 events
Number of Relevant Toxicities Related to Therapy Grade 5: death	1 events	3 events

OTHER_PRE_SPECIFIED outcome

Timeframe: Once at enrollment

Population: The investigator is unable to identify frequency of genomic lesions. To obtain useful information, a much larger sample size is needed. Genomic sequencing is cost-prohibitive to be performed on this small sample size where there are too few samples to obtain any useful information.

Frequencies of the identified lesions will be described by counts and proportions. An established method (Pounds et al., 2013) will be applied to identify genes and pathways frequently hit by the genomic lesions.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Various time points until completion of therapy (up to 18 months)

Population: Data was either not collected or is incomplete for each of the 10 participants, and therefore cannot be analyzed.

MRD will be monitored until the completion of therapy (up to 500 days) for patients that do not go on to bone marrow transplant. If a patient goes on to receive a bone marrow transplant, at that point, they will no longer be monitored for minimal residual disease.

Concordance and associations of the MRD levels across three modalities (flow cytometry, PCR, and deep sequencing) as continuous measurements will be assessed by Pearson's and Spearman's correlations and Kendall's tau; MRD levels categorized into ordinal values will be analyzed by contingency tables with or without ordered margins.

Outcome measures

Outcome data not reported

Adverse Events

Stratum 1: Myeloid Malignancies

Serious events: 1 serious events

Other events: 4 other events

Deaths: 4 deaths

Stratum 2: ALL and MLM

Serious events: 2 serious events

Other events: 6 other events

Deaths: 6 deaths

Serious adverse events

Measure	Stratum 1: Myeloid Malignancies n=4 participants at risk Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description.	Stratum 2: ALL and MLM n=6 participants at risk Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
Respiratory, thoracic and mediastinal disorders Adult respiratory distress syndrome	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	0.00% 0/6 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Cardiac disorders Heart failure	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	0.00% 0/6 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Hypoxia	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	0.00% 0/6 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Bronchopulmonary hemorrhage	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Infections and infestations Lung infection	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.

Other adverse events

Measure	Stratum 1: Myeloid Malignancies n=4 participants at risk Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description.	Stratum 2: ALL and MLM n=6 participants at risk Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
Gastrointestinal disorders Abdominal pain	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Acidosis	25.0% 1/4 • Number of events 4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Renal and urinary disorders Acute kidney injury	25.0% 1/4 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	0.00% 0/6 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Adult respiratory distress syndrome	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	0.00% 0/6 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Psychiatric disorders Agitation	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Investigations Alanine aminotransferase increased	25.0% 1/4 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	50.0% 3/6 • Number of events 9 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Blood and lymphatic system disorders Anemia	75.0% 3/4 • Number of events 33 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	50.0% 3/6 • Number of events 23 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Anorexia	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Psychiatric disorders Anxiety	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Apnea	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Investigations Aspartate aminotransferase increased	50.0% 2/4 • Number of events 8 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	50.0% 3/6 • Number of events 7 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Aspiration	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Atelectasis	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Investigations Blood bilirubin, increased	25.0% 1/4 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Bronchial stricture	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Bronchopulmonary hemorrhage	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Investigations CPK increased	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	0.00% 0/6 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Gastrointestinal disorders Colitis	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Renal and urinary disorders Cystitis noninfective	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	0.00% 0/6 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Dehydration	25.0% 1/4 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Gastrointestinal disorders Diarrhea	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
General disorders Edema, trunk	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Infections and infestations Enterocolitis, infectious	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Blood and lymphatic system disorders Febrile neutropenia	75.0% 3/4 • Number of events 4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
General disorders Fever	50.0% 2/4 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Investigations Fibrinogen, decreased	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Investigations GGT, increased	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Gastrointestinal disorders Gastric hemorrhage	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Gastrointestinal disorders Gastric ulcer	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Gastrointestinal disorders Gastroesophageal reflux disease	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Vascular disorders Hematoma	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Hypercalcemia	25.0% 1/4 • Number of events 4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	0.00% 0/6 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Hyperglycemia	75.0% 3/4 • Number of events 5 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	83.3% 5/6 • Number of events 19 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Hyperkalemia	50.0% 2/4 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	66.7% 4/6 • Number of events 7 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Hypernatremia	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 5 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Vascular disorders Hypertension	50.0% 2/4 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	66.7% 4/6 • Number of events 8 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Hypertriglyceridemia	25.0% 1/4 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	50.0% 3/6 • Number of events 12 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Hyperuricemia	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Hypoalbuminemia	50.0% 2/4 • Number of events 7 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	83.3% 5/6 • Number of events 8 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Hypocalcemia	75.0% 3/4 • Number of events 9 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	50.0% 3/6 • Number of events 13 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Hypoglycemia	50.0% 2/4 • Number of events 4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Hypokalemia	100.0% 4/4 • Number of events 29 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	83.3% 5/6 • Number of events 26 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Hypophosphatemia	75.0% 3/4 • Number of events 8 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	83.3% 5/6 • Number of events 14 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Vascular disorders Hypotension	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Hypoxia	75.0% 3/4 • Number of events 4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	100.0% 6/6 • Number of events 13 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Investigations INR increased	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Gastrointestinal disorders Ileus	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Infections and infestations Infections and infestations, other	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Nervous system disorders Intracranial hemorrhage	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Infections and infestations Lip infection	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	0.00% 0/6 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Investigations Lipase increased	25.0% 1/4 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Infections and infestations Lung Infection	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Investigations Lymphocyte count decreased	50.0% 2/4 • Number of events 14 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	50.0% 3/6 • Number of events 14 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Infections and infestations Mucosal infection	25.0% 1/4 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Nervous system disorders Nervous system disorders, other	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Nervous system disorders Neuralgia	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	50.0% 3/6 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Investigations Neutrophil count, decreased	50.0% 2/4 • Number of events 7 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	50.0% 3/6 • Number of events 7 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Cardiac disorders General disorders	25.0% 1/4 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	0.00% 0/6 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Cardiac disorders Pericardial effusion	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Infections and infestations Periorbital infection	25.0% 1/4 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	0.00% 0/6 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Investigations Platelet count, decreased	75.0% 3/4 • Number of events 43 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	50.0% 3/6 • Number of events 43 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Pleural effusion	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Pulmonary edema	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Nervous system disorders Reversible posterior leukoencephalopathy syndrome	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Nervous system disorders Seizure	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Infections and infestations Sepsis	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	50.0% 3/6 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Investigations Serum amylase, increased	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Cardiac disorders Sinus bradycardia	25.0% 1/4 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Infections and infestations Sinusitis	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Infections and infestations Skin infection	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Stridor	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Metabolism and nutrition disorders Tumor lysis syndrome	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Gastrointestinal disorders Typhlitis	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Gastrointestinal disorders Upper gastrointestinal hemorrhage	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Infections and infestations Upper respiratory infection	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	50.0% 3/6 • Number of events 3 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Renal and urinary disorders Urinary retention	50.0% 2/4 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Renal and urinary disorders Urinary tract obstruction	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	0.00% 0/6 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Gastrointestinal disorders Vomiting	25.0% 1/4 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	33.3% 2/6 • Number of events 2 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Wheezing	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Investigations White blood cell decreased	50.0% 2/4 • Number of events 7 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	50.0% 3/6 • Number of events 17 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.
Infections and infestations Wound infection	0.00% 0/4 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.	16.7% 1/6 • Number of events 1 • Adverse events were recorded from a participant's on-study date until they were taken off study, up to 8 months. Although only 3 Stratum 1 and 4 Stratum 2 participants completed the trial, there were 4 Stratum 1 participants and 6 Stratum 2 participants evaluable for adverse events.

Additional Information

Tanja A. Gruber, MD, PhD

St. Jude Children's Research Hospital

Phone: 901-595-2252

Email: tanja.gruber@stjude.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place