Trial Outcomes & Findings for Combination Chemotherapy and Surgery With or Without Isotretinoin in Treating Young Patients With Neuroblastoma (NCT NCT00499616)

NCT ID: NCT00499616

Last Updated: 2021-07-06

Results Overview

OS time is calculated from date of enrollment until death, or until last contact if the patient is alive.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

464 participants

Primary outcome timeframe

3 years

Results posted on

2021-07-06

Participant Flow

Participant milestones

Participant milestones
Measure	Group 2 (Chemotherapy, Surgery) 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Non-intermediate Risk Enrolled on Intermediate Risk Trial The no treatment group assignment patients may have received some treatment on ANBL0531 but they were not evaluable on this study due to being non-intermediate risk and hence did not receive a treatment assignment on ANBL0531. Surgery: With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.
Overall Study STARTED	176	142	89	57
Overall Study COMPLETED	161	114	53	0
Overall Study NOT COMPLETED	15	28	36	57

Reasons for withdrawal

Reasons for withdrawal
Measure	Group 2 (Chemotherapy, Surgery) 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Non-intermediate Risk Enrolled on Intermediate Risk Trial The no treatment group assignment patients may have received some treatment on ANBL0531 but they were not evaluable on this study due to being non-intermediate risk and hence did not receive a treatment assignment on ANBL0531. Surgery: With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.
Overall Study Death	1	5	3	1
Overall Study Lack of Efficacy	5	0	19	0
Overall Study Lost to Follow-up	0	0	1	0
Overall Study Physician Decision	6	16	9	0
Overall Study Withdrawal by Subject	1	0	1	0
Overall Study Ineligible	1	2	0	15
Overall Study Not evaluable	0	0	0	41
Overall Study Patient/Parent Refusal	1	5	3	0

Baseline Characteristics

Combination Chemotherapy and Surgery With or Without Isotretinoin in Treating Young Patients With Neuroblastoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Group 2 (Chemotherapy, Surgery) n=176 Participants 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) n=142 Participants 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) n=89 Participants 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S disease who achieve a very good PR (VGPR) to chemo (with the exception of resolution of skin or liver metastases in stage 4S patients) proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Non-intermediate Risk Enrolled on Intermediate Risk Trial n=57 Participants The no treatment group assignment patients may have received some treatment on ANBL0531 but they were not evaluable on this study due to being non-intermediate risk and hence did not receive a treatment assignment on ANBL0531. Surgery: With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.	Total n=464 Participants Total of all reporting groups
Age, Categorical <=18 years	176 Participants n=5 Participants	142 Participants n=7 Participants	89 Participants n=5 Participants	57 Participants n=4 Participants	464 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Continuous	1.23 years STANDARD_DEVIATION 1.47 • n=5 Participants	.74 years STANDARD_DEVIATION .89 • n=7 Participants	.60 years STANDARD_DEVIATION .36 • n=5 Participants	1.51 years STANDARD_DEVIATION 1.83 • n=4 Participants	0.99 years STANDARD_DEVIATION 1.26 • n=21 Participants
Sex: Female, Male Female	70 Participants n=5 Participants	72 Participants n=7 Participants	49 Participants n=5 Participants	26 Participants n=4 Participants	217 Participants n=21 Participants
Sex: Female, Male Male	106 Participants n=5 Participants	70 Participants n=7 Participants	40 Participants n=5 Participants	31 Participants n=4 Participants	247 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	18 Participants n=5 Participants	26 Participants n=7 Participants	7 Participants n=5 Participants	6 Participants n=4 Participants	57 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	150 Participants n=5 Participants	109 Participants n=7 Participants	74 Participants n=5 Participants	49 Participants n=4 Participants	382 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	8 Participants n=5 Participants	7 Participants n=7 Participants	8 Participants n=5 Participants	2 Participants n=4 Participants	25 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) Asian	5 Participants n=5 Participants	8 Participants n=7 Participants	4 Participants n=5 Participants	2 Participants n=4 Participants	19 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	3 Participants n=5 Participants	4 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	8 Participants n=21 Participants
Race (NIH/OMB) Black or African American	23 Participants n=5 Participants	12 Participants n=7 Participants	8 Participants n=5 Participants	9 Participants n=4 Participants	52 Participants n=21 Participants
Race (NIH/OMB) White	133 Participants n=5 Participants	92 Participants n=7 Participants	59 Participants n=5 Participants	40 Participants n=4 Participants	324 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	12 Participants n=5 Participants	26 Participants n=7 Participants	16 Participants n=5 Participants	5 Participants n=4 Participants	59 Participants n=21 Participants
Region of Enrollment New Zealand	2 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	0 participants n=4 Participants	3 participants n=21 Participants
Region of Enrollment Canada	16 participants n=5 Participants	6 participants n=7 Participants	10 participants n=5 Participants	5 participants n=4 Participants	37 participants n=21 Participants
Region of Enrollment United States	153 participants n=5 Participants	131 participants n=7 Participants	78 participants n=5 Participants	50 participants n=4 Participants	412 participants n=21 Participants
Region of Enrollment Australia	5 participants n=5 Participants	5 participants n=7 Participants	0 participants n=5 Participants	2 participants n=4 Participants	12 participants n=21 Participants

PRIMARY outcome

Timeframe: 3 years

Population: Eligible intermediate risk patients.

OS time is calculated from date of enrollment until death, or until last contact if the patient is alive.

Outcome measures

Outcome measures
Measure	Group 2 (Chemotherapy, Surgery) n=175 Participants 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) n=140 Participants 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) n=89 Participants 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
Overall Survival (OS) Rates	99.4 percentage of participants Interval 98.3 to 100.0	93.5 percentage of participants Interval 89.4 to 97.7	88.4 percentage of participants Interval 81.5 to 95.3

PRIMARY outcome

Timeframe: At baseline

Population: Eligible intermediate risk patients with 1p and 11q data.

Addressed by a descriptive comparison of the EFS and OS rates for patients with 1p loss vs without 1p loss, and for those with unbalanced 11q vs normal 11q.

Outcome measures

Outcome measures
Measure	Group 2 (Chemotherapy, Surgery) n=175 Participants 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) n=104 Participants 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) n=62 Participants 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
Definitive Determination of the Prognostic Ability of 1p and 11q EFS Eligible & evaluable patients with normal 11q	87.2 percentage of 3 yr EFS/OS rate Interval 82.0 to 92.4	87.5 percentage of 3 yr EFS/OS rate Interval 80.7 to 94.2	73.3 percentage of 3 yr EFS/OS rate Interval 59.5 to 87.0
Definitive Determination of the Prognostic Ability of 1p and 11q EFS Eligible & evaluable patients without 1p loss	87.2 percentage of 3 yr EFS/OS rate Interval 82.0 to 92.4	84.6 percentage of 3 yr EFS/OS rate Interval 76.8 to 92.5	65.4 percentage of 3 yr EFS/OS rate Interval 50.0 to 80.8
Definitive Determination of the Prognostic Ability of 1p and 11q OS Eligible & evaluable patients without 1p loss	99.4 percentage of 3 yr EFS/OS rate Interval 98.3 to 100.0	92.8 percentage of 3 yr EFS/OS rate Interval 87.2 to 98.4	83.7 percentage of 3 yr EFS/OS rate Interval 71.6 to 95.8
Definitive Determination of the Prognostic Ability of 1p and 11q EFS Eligible & evaluable patients with 1p loss	—	94.7 percentage of 3 yr EFS/OS rate Interval 84.7 to 100.0	81.8 percentage of 3 yr EFS/OS rate Interval 65.2 to 98.4
Definitive Determination of the Prognostic Ability of 1p and 11q OS Eligible & evaluable patients with 1p loss	—	94.7 percentage of 3 yr EFS/OS rate Interval 84.7 to 100.0	95.5 percentage of 3 yr EFS/OS rate Interval 86.5 to 100.0
Definitive Determination of the Prognostic Ability of 1p and 11q OS Eligible & evaluable patients with normal 11q	99.4 percentage of 3 yr EFS/OS rate Interval 98.3 to 100.0	93.7 percentage of 3 yr EFS/OS rate Interval 88.7 to 98.7	87.7 percentage of 3 yr EFS/OS rate Interval 77.4 to 98.1
Definitive Determination of the Prognostic Ability of 1p and 11q EFS Eligible & evaluable patients w/unbalanced 11q	—	75.0 percentage of 3 yr EFS/OS rate Interval 45.0 to 100.0	65.5 percentage of 3 yr EFS/OS rate Interval 42.7 to 88.2
Definitive Determination of the Prognostic Ability of 1p and 11q OS Eligible & evaluable patients w/unbalanced 11q	—	87.5 percentage of 3 yr EFS/OS rate Interval 64.6 to 100.0	88.2 percentage of 3 yr EFS/OS rate Interval 72.9 to 100.0

PRIMARY outcome

Timeframe: Up to 3 years

Population: Eligible and evaluable patients with Stage 4 neuroblastoma, 12-18 months of age, and favorable biological features.

Addressed by the interim stopping rule and the comparison, by INSS stage, to the historical EFS rate of the analogous cohort of patients \< 1 yrs of age.

Outcome measures

Outcome measures
Measure	Group 2 (Chemotherapy, Surgery) 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) n=9 Participants 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
Comparison Between Reduce Intensity of Therapy for Patients With Stage 4 Neuroblastoma and Favorable Biological Features and Patients < 1 Year of Age With Stage 4 Neuroblastoma Treated on COG-A3961	—	66.7 percentage of 3 yr EFS rate Interval 35.9 to 97.5	—

PRIMARY outcome

Timeframe: Up to 3 years

Population: Eligible and evaluable patients with Stage 3 neuroblastoma, 12-18 months of age, MYCN non-amplified, and unfavorable histology.

Addressed by the interim stopping rule and the comparison, by INSS stage, to the historical EFS rate of the analogous cohort of patients \< 1 yrs of age

Outcome measures

Outcome measures
Measure	Group 2 (Chemotherapy, Surgery) 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) n=2 Participants 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
Comparison Between Reduce Intensity of Therapy for Patients With Unfavorable Histology Neuroblastoma and Patients Unfavorable Histology Neuroblastoma Treated on COG-A3961	—	100.0 percentage of 3 yr EFS rate	—

PRIMARY outcome

Timeframe: Up to 3 years

Population: Eligible and evaluable patients with Stage 4S neuroblastoma that had a biopsy or resection.

Descriptive analyses of the proportion of stage 4S infants that experience a surgical or post-operative event.

Outcome measures

Outcome measures
Measure	Group 2 (Chemotherapy, Surgery) n=17 Participants 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) n=19 Participants 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) n=7 Participants 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
Reduced Surgical Morbidity for Patients With Stage 4S Neuroblastoma	0.18 Proportion Interval 0.06 to 0.41	0.11 Proportion Interval 0.03 to 0.31	0 Proportion Interval 0.0 to 0.0

PRIMARY outcome

Timeframe: From baseline to up to 10 years

Population: Eligible and evaluable patients with Stage 4S neuroblastoma unable to undergo biopsy.

Kaplan-Meier curves and lifetables of Event Free Survival (EFS) and Overall Survival (OS) rates will be generated to describe the outcome of the stage 4S infants unable to undergo biopsy.

Outcome measures

Outcome measures
Measure	Group 2 (Chemotherapy, Surgery) n=4 Participants 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
Outcome of Patients With Stage 4S Neuroblastoma Who Are Unable to Undergo Biopsy for Biology-based Risk Assignment OS	50.0 percentage survival Interval 1.0 to 99.0	—	—
Outcome of Patients With Stage 4S Neuroblastoma Who Are Unable to Undergo Biopsy for Biology-based Risk Assignment EFS	25.0 percentage survival Interval 0.0 to 67.4	—	—

PRIMARY outcome

Timeframe: Up to 10 years

Population: Eligible and evaluable intermediate risk patients with reported surgery

To test the predictive ability of the extent of surgical resection for EFS, log-rank tests will be performed comparing complete surgical resection vs. without complete surgical resection.

Outcome measures

Outcome measures
Measure	Group 2 (Chemotherapy, Surgery) n=174 Participants 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) n=137 Participants 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) n=81 Participants 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Event Free Survival (EFS) EFS w/complete surgical resection	95.4 percentage of 3 yr EFS survival Interval 90.0 to 100.0	88.4 percentage of 3 yr EFS survival Interval 78.7 to 98.1	78.6 percentage of 3 yr EFS survival Interval 63.4 to 93.8
Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Event Free Survival (EFS) EFS w/o complete surgical resection	82.2 percentage of 3 yr EFS survival Interval 74.6 to 89.8	85.1 percentage of 3 yr EFS survival Interval 77.7 to 92.4	69.2 percentage of 3 yr EFS survival Interval 56.3 to 82.1

PRIMARY outcome

Timeframe: Up to 10 years

Population: Eligible and evaluable intermediate risk patients with reported surgery.

To test the predictive ability of the extent of surgical resection for OS, log-rank tests will be performed comparing complete surgical resection vs. without complete surgical resection.

Outcome measures

Outcome measures
Measure	Group 2 (Chemotherapy, Surgery) n=174 Participants 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) n=137 Participants 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) n=81 Participants 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Overall Survival (OS) Rates OS w/complete surgical resection	100.0 percentage of OS rate Interval 100.0 to 100.0	95.4 percentage of OS rate Interval 89.0 to 100.0	96.4 percentage of OS rate Interval 89.4 to 100.0
Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Overall Survival (OS) Rates OS w/o complete surgical resection	99.1 percentage of OS rate Interval 97.2 to 100.0	93.5 percentage of OS rate Interval 88.4 to 98.6	86.5 percentage of OS rate Interval 77.0 to 96.0

PRIMARY outcome

Timeframe: Up to 10 years

Population: Eligible and evaluable intermediate risk patients with reported surgery

To test for the association of the extent of surgical resection (CR vs \<CR) with surgical complications rate (complications of any kind vs no complications at all), a chi-square test will be performed.

Outcome measures

Outcome measures
Measure	Group 2 (Chemotherapy, Surgery) n=174 Participants 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) n=137 Participants 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) n=81 Participants 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Surgical Complication Rate CR with no complications	.14 Proportion with surgical complications Interval 0.09 to 0.21	.13 Proportion with surgical complications Interval 0.07 to 0.21	.09 Proportion with surgical complications Interval 0.04 to 0.2
Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Surgical Complication Rate CR with complications	.32 Proportion with surgical complications Interval 0.22 to 0.44	.19 Proportion with surgical complications Interval 0.1 to 0.33	.18 Proportion with surgical complications Interval 0.08 to 0.36

SECONDARY outcome

Timeframe: From the time of the first progressive, non-metastatic event until the subsequent occurrence of relapse, progressive disease, secondary malignancy, or death; up to 3 years

Population: Eligible patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy

E2FS (from time of first event) will be calculated to describe the outcome for patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy.

Outcome measures

Outcome measures
Measure	Group 2 (Chemotherapy, Surgery) n=7 Participants 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
Second-event-free Survival (E2FS)	57.14 Percentage Interval 20.49 to 93.79	—	—

SECONDARY outcome

Timeframe: From the time of the first progressive, non-metastatic event; up to 3 years

Population: Eligible patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy.

OS (from the time of first event) will be calculated to describe the outcome for patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy.

Outcome measures

Outcome measures
Measure	Group 2 (Chemotherapy, Surgery) n=7 Participants 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
Second-Overall Survival	85.71 Percentage Interval 59.78 to 100.0	—	—

SECONDARY outcome

Timeframe: At baseline and surgery

Population: The data was not collected to assess this study aim.

Multivariable analyses will be performed to identify variables of prognostic interest.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At baseline

Population: All eligible and evaluable patients enrolled on ANBL0531

Percentage of patients with neurologic symptoms will be calculated. Includes patients with paraspinal or intraspinal tumors, including epidural tumors with or without spinal cord compression. Neurologic symptoms include back or extremities neurologic symptoms, motor deficit, abnormal sensation, abnormal bladder/bowel sphincteric function, chronic pain in back or extremities, scoliosis, kyphosis, or clinically relevant/functional abnormality in size or contour of leg or foot.

Outcome measures

Outcome measures
Measure	Group 2 (Chemotherapy, Surgery) n=175 Participants 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) n=141 Participants 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) n=88 Participants 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
Neurologic Symptoms	36.57 percentage of patients	35.46 percentage of patients	27.27 percentage of patients

SECONDARY outcome

Timeframe: During and after surgery

Population: The data was not collected to assess this study aim.

A chi-square test will be performed.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At baseline

Population: All eligible and evaluable patients enrolled on ANBL0531

Percentage of patients with presence of one or more IDRFs will be calculated. IDRFs describe anatomic features which may make surgical resection more difficult.

Outcome measures

Outcome measures
Measure	Group 2 (Chemotherapy, Surgery) n=175 Participants 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) n=141 Participants 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) n=88 Participants 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.
Image Defined Risk Factor (IDRF)	54.86 percentage of patients	60.28 percentage of patients	56.82 percentage of patients

Adverse Events

Group 2 (Chemotherapy, Surgery)

Serious events: 2 serious events

Other events: 135 other events

Deaths: 0 deaths

Group 3 (Chemotherapy, Surgery)

Serious events: 5 serious events

Other events: 114 other events

Deaths: 0 deaths

Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy)

Serious events: 8 serious events

Other events: 76 other events

Deaths: 0 deaths

Non-intermediate Risk Enrolled on Intermediate Risk Trial

Serious events: 1 serious events

Other events: 23 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	Group 2 (Chemotherapy, Surgery) n=175 participants at risk 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.	Group 3 (Chemotherapy, Surgery) n=140 participants at risk 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Group 4 (Chemotherapy, Surgery, Antineoplastic Therapy) n=89 participants at risk 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients \< 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.	Non-intermediate Risk Enrolled on Intermediate Risk Trial n=42 participants at risk The no treatment group assignment patients may have received some treatment on ANBL0531 but they were not evaluable on this study due to being non-intermediate risk and hence did not receive a treatment assignment on ANBL0531. Surgery: With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.
Respiratory, thoracic and mediastinal disorders 71600-Respiratory thoracic and mediastinal disorders - Other specify	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/89 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	2.4% 1/42 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Blood and lymphatic system disorders 13200-Anemia	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	1.1% 1/89 • Number of events 3 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Gastrointestinal disorders 46300-Intra-abdominal hemorrhage	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	1.1% 1/89 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
General disorders 24600-Death NOS	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	1.4% 2/140 • Number of events 2 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	1.1% 1/89 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
General disorders 55700-Multi-organ failure	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	1.1% 1/89 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Hepatobiliary disorders 40600-Hepatobiliary disorders - Other specify	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	1.1% 1/89 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	2.4% 1/42 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Infections and infestations 44800-Infections and infestations - Other specify	1.1% 2/175 • Number of events 2 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.71% 1/140 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	2.2% 2/89 • Number of events 2 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Infections and infestations 73700-Sepsis	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.71% 1/140 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/89 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Injury, poisoning and procedural complications 80700-Tracheal obstruction	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	1.1% 1/89 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Investigations 17400-Blood bilirubin increased	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	2.2% 2/89 • Number of events 2 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Investigations 58300-Neutrophil count decreased	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	1.1% 1/89 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Investigations 65800-Platelet count decreased	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	1.1% 1/89 • Number of events 3 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Metabolism and nutrition disorders 10700-Acidosis	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	1.1% 1/89 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Renal and urinary disorders 11100-Acute kidney injury	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	1.1% 1/89 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	2.4% 1/42 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Renal and urinary disorders 71000-Renal and urinary disorders - Other specify	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	1.1% 1/89 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Respiratory, thoracic and mediastinal disorders 19200-Bronchopulmonary hemorrhage	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.71% 1/140 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/89 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Respiratory, thoracic and mediastinal disorders 43900-Hypoxia	0.57% 1/175 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/89 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Respiratory, thoracic and mediastinal disorders 71500-Respiratory failure	0.00% 0/175 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	1.1% 1/89 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Vascular disorders 43600-Hypotension	0.57% 1/175 • Number of events 1 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/140 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/89 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.	0.00% 0/42 SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.