Trial Outcomes & Findings for Tacrolimus and Methotrexate With or Without Sirolimus in Preventing Graft-Versus-Host Disease in Young Patients Undergoing Donor Stem Cell Transplant for Acute Lymphoblastic Leukemia in Complete Remission (NCT NCT00382109)

NCT ID: NCT00382109

Last Updated: 2019-08-07

Results Overview

An event is defined as relapse or transplant-related mortality. Relapse is defined in section 3.3 study protocol.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

146 participants

Primary outcome timeframe

at 2 years

Results posted on

2019-08-07

Participant Flow

Participant milestones

Participant milestones
Measure	Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors) and oral sirolimus (dose 2.5mg/m2/day - 4 mg max starting dose) daily starting on day 0 followed by a taper starting on day 180 through day 207.	Tacro-MTX GVHD Prophylaxis Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally (when able) daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors).
Overall Study STARTED	76	70
Overall Study COMPLETED	64	66
Overall Study NOT COMPLETED	12	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors) and oral sirolimus (dose 2.5mg/m2/day - 4 mg max starting dose) daily starting on day 0 followed by a taper starting on day 180 through day 207.	Tacro-MTX GVHD Prophylaxis Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally (when able) daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors).
Overall Study Adverse Event	3	0
Overall Study Physician Decision	6	1
Overall Study Withdrawal by Subject	1	0
Overall Study ineligible	2	0
Overall Study Other	0	2
Overall Study consent withdrawal	0	1

Baseline Characteristics

Tacrolimus and Methotrexate With or Without Sirolimus in Preventing Graft-Versus-Host Disease in Young Patients Undergoing Donor Stem Cell Transplant for Acute Lymphoblastic Leukemia in Complete Remission

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen n=76 Participants Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors) and oral sirolimus (dose 2.5mg/m2/day - 4 mg max starting dose) daily starting on day 0 followed by a taper starting on day 180 through day 207.	Tacro-MTX GVHD Prophylaxis n=70 Participants Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally (when able) daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors).	Total n=146 Participants Total of all reporting groups
Age, Continuous	9 Year n=5 Participants	10 Year n=7 Participants	9 Year n=5 Participants
Sex: Female, Male Female	30 Participants n=5 Participants	29 Participants n=7 Participants	59 Participants n=5 Participants
Sex: Female, Male Male	46 Participants n=5 Participants	41 Participants n=7 Participants	87 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 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
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
Race (NIH/OMB) White	59 Participants n=5 Participants	51 Participants n=7 Participants	110 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	10 Participants n=5 Participants	12 Participants n=7 Participants	22 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	23 Participants n=5 Participants	16 Participants n=7 Participants	39 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	51 Participants n=5 Participants	53 Participants n=7 Participants	104 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment United States	71 participants n=5 Participants	62 participants n=7 Participants	133 participants n=5 Participants
Region of Enrollment Canada	3 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants
Region of Enrollment Australia	2 participants n=5 Participants	6 participants n=7 Participants	8 participants n=5 Participants

PRIMARY outcome

Timeframe: at 2 years

Population: Two ineligible patients on experimental arm excluded from analysis.

An event is defined as relapse or transplant-related mortality. Relapse is defined in section 3.3 study protocol.

Outcome measures

Outcome measures
Measure	Experimental n=74 Participants Tacro-MTX/Sirolimus GVHD Prophylaxis	Control n=70 Participants Tacro-MTX GVHD Prophylaxis
Estimated Percentage of Participants With Event Free Survival	45 percentage of participants Interval 34.0 to 60.0	54 percentage of participants Interval 41.0 to 69.0

SECONDARY outcome

Timeframe: At 2 years

Population: 2 ineligible patients on experimental arm excluded from analysis.Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation. For the purpose of this study, relapse is defined by either morphological or cytogenetic evidence of ALL consistent with pre-transplant features.

An event is defined as relapse.

Outcome measures

Outcome measures
Measure	Experimental n=74 Participants Tacro-MTX/Sirolimus GVHD Prophylaxis	Control n=70 Participants Tacro-MTX GVHD Prophylaxis
Rate of Relapses	41 percentage of participants Interval 29.0 to 57.0	33 percentage of participants Interval 23.0 to 49.0

SECONDARY outcome

Timeframe: 100 days

Population: 2 ineligible patients on experimental arm excluded from analysis.

Death in a patient who had not relapsed after transplant is defined as transplant-related mortality event.

Outcome measures

Outcome measures
Measure	Experimental n=74 Participants Tacro-MTX/Sirolimus GVHD Prophylaxis	Control n=70 Participants Tacro-MTX GVHD Prophylaxis
Estimated Transplant Related Mortality Percentage	13 percentage of participants Interval 7.0 to 24.0	6 percentage of participants Interval 2.0 to 15.0

SECONDARY outcome

Timeframe: At 200 days

Population: 2 ineligible patients on experimental arm excluded from analysis. Definition of Acute GVHD: APPENDIX II: COG STEM CELL COMMITTEE CONSENSUS GUIDELINES FOR ESTABLISHING ORGAN STAGE AND OVERALL GRADE OF ACUTE GRAFT VERSUS HOST DISEASE (GVHD) page 90-96 protocol.

Any grade acute graft vs host disease (defined in APPENDIX II study protocol).

Outcome measures

Outcome measures
Measure	Experimental n=74 Participants Tacro-MTX/Sirolimus GVHD Prophylaxis	Control n=70 Participants Tacro-MTX GVHD Prophylaxis
Estimated Rate of Acute Graft VS Host Disease (GVHD)	32 percentage of participants Interval 22.0 to 45.0	49 percentage of participants Interval 38.0 to 63.0

SECONDARY outcome

Timeframe: At 2 years

Population: 2 ineligible patients on experimental arm excluded from analysis. Definition of Chronic GVHD: APPENDIX III: DEFINING CHRONIC GRAFT VS. HOST DISEASE (FROM BMT CTN MOP SEPT. 2005) on page 97 protocol.

Chronic graft vs host disease is defined in APPENDIX III of study protocol.

Outcome measures

Outcome measures
Measure	Experimental n=74 Participants Tacro-MTX/Sirolimus GVHD Prophylaxis	Control n=70 Participants Tacro-MTX GVHD Prophylaxis
Estimated Rate of Overall Chronic Graft VS Host Disease	22 percentage of participants Interval 14.0 to 36.0	27 percentage of participants Interval 18.0 to 40.0

SECONDARY outcome

Timeframe: Up to 1 year

Population: We made a large number of xenograft models but were not able to correlate resistance to rapamycin in mice with outcome on the trial with the numbers that we had. For this reason, no specific publications addressing this aim were put forward.

An event is defined as relapse or transplant-related mortality.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At 1 year

Population: Number at risk among no aGVHD and number at risk among aGVHD at 1 year. The two treatment regimens were intended to be analyzed together (combined data), as pre-specified in the study protocol, therefore results are not reported for each Arm of study.

An event is defined as relapse; estimated probability of relapse.

Outcome measures

Outcome measures
Measure	Experimental n=67 Participants Tacro-MTX/Sirolimus GVHD Prophylaxis	Control Tacro-MTX GVHD Prophylaxis
Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse) Experienced aGVHD, later relapsed	5 percentage of participants	—
Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse) No aGVHD occurence, relapsed	24 percentage of participants	—

SECONDARY outcome

Timeframe: At 2 months

Population: The two treatment regimens were intended to be analyzed together (combined data), as pre-specified in the study protocol. However, we are not able to perform this analysis given the low numbers of blast samples available.

An event is defined as relapse; relapse risk is reported. Not able to be performed given the low numbers of blast samples available.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 12 months

Population: We are not able to perform this analysis given the low numbers of blast samples available.

Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post transplantation.

Outcome measures

Outcome data not reported

Adverse Events

Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen

Serious events: 9 serious events

Other events: 38 other events

Deaths: 0 deaths

Tacro-MTX GVHD Prophylaxis

Serious events: 5 serious events

Other events: 30 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 Must obtain prior sponsor approval.
Publication restrictions are in place

Restriction type: OTHER

Measure	Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen n=72 participants at risk Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors) and oral sirolimus (dose 2.5mg/m2/day - 4 mg max starting dose) daily starting on day 0 followed by a taper starting on day 180 through day 207.	Tacro-MTX GVHD Prophylaxis n=70 participants at risk Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally (when able) daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors).
Renal and urinary disorders Acute kidney injury	1.4% 1/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	2.9% 2/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Respiratory, thoracic and mediastinal disorders Adult respiratory distress syndrome	1.4% 1/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	1.4% 1/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Gastrointestinal disorders Ascites	1.4% 1/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	1.4% 1/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Investigations Blood bilirubin increased	1.4% 1/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	1.4% 1/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Respiratory, thoracic and mediastinal disorders Bronchopulmonary hemorrhage	1.4% 1/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	0.00% 0/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Cardiac disorders Cardiac disorders - Other, specify	0.00% 0/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	1.4% 1/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
General disorders Death NOS	0.00% 0/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	1.4% 1/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Blood and lymphatic system disorders Disseminated intravascular coagulation	1.4% 1/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	0.00% 0/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Nervous system disorders Encephalopathy	0.00% 0/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	1.4% 1/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Hepatobiliary disorders Hepatic failure	0.00% 0/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	2.9% 2/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Hepatobiliary disorders Hepatobiliary disorders - Other, specify	1.4% 1/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	0.00% 0/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Vascular disorders Hypotension	0.00% 0/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	1.4% 1/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
General disorders Multi-organ failure	2.8% 2/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	1.4% 1/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Cardiac disorders Pericardial effusion	1.4% 1/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	0.00% 0/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Respiratory, thoracic and mediastinal disorders Pneumonitis	1.4% 1/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	1.4% 1/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Renal and urinary disorders Renal and urinary disorders - Other, specify	1.4% 1/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	0.00% 0/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders - Other, specify	0.00% 0/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	1.4% 1/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Nervous system disorders Seizure	0.00% 0/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	1.4% 1/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Vascular disorders Thromboembolic event	1.4% 1/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	0.00% 0/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).
Vascular disorders Vascular disorders - Other, specify	1.4% 1/72 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).	0.00% 0/70 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). This study did not collect information about grade 1 and 2 AEs. The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. 4 experimental patients were excluded (2 ineligible, 2 no data).