NHL16: Study For Newly Diagnosed Patients With Acute Lymphoblastic Lymphoma

• Sponsor: St. Jude Children's Research Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01451515
• Collaborator: National University, Singapore (Other)
• Enrollment: 23
• Locations: 2
• Arm: 1
• Actual Duration (Months): 120.2
• Patients Per Site: 11.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a phase II clinical trial using risk-adapted therapy. The treatment is acute lymphoblastic leukemia (ALL)-based therapy, using multi-agent regimens comprising of induction, consolidation, and continuation (maintenance) phases delivered over 24-30 months. Participants will be classified into 3 treatment stratums, based on bone marrow/peripheral blood lymphoma cells involvement at diagnosis and day 8 for T-lymphoblastic lymphoma and bone marrow/peripheral blood lymphoma cells involvement at diagnosis for B-lymphoblastic lymphoma.

The Primary Objective of this study is:

To improve the outcome of children with lymphoblastic lymphoma (LL) who have minimal disseminated disease (MDD) equal to or more than 1% at diagnosis by using MDD- and minimal residual disease (MRD)- based risk-adapted therapy.

The Secondary Objectives of this study are:

• To estimate the event-free survival and overall survival of children with lymphoblastic lymphoma who are treated with MDD- or MRD-based risk- directed therapy.

• To evaluate the prognostic value of levels of MDD at diagnosis and MRD on day 8 of remission induction.

Condition or Disease	Intervention/Treatment	Phase
Lymphoblastic Lymphoma	Drug: Prednisone; Drug: Vincristine; Drug: Daunorubicin; Drug: PEG-asparaginase; Drug: Erwinia asparaginase; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Thioguanine; Drug: Clofarabine; Drug: Methotrexate; Drug: Mercaptopurine; Drug: Dexamethasone; Drug: Hydrocortisone; Drug: Etoposide	Phase 2

Detailed Description

TREATMENT PLAN

Treatment will consist of 3 main phases: remission induction, consolidation [only for patients with any central nervous system (CNS) disease and/or testicular involvement], and continuation.

• Induction (6-7 weeks).

• Consolidation for participants with CNS involvement or those with testicular disease only (10 weeks).

• Reintensification - Participants with residual disease any time after induction therapy may receive 1-2 cycles of re-intensification therapy and may proceed to allogeneic stem cell transplant if suitable donor is available.

• Continuation Therapy (98-120 weeks).

• Intrathecal Chemotherapy (days 1 and 15; if needed also on days 8 and 22)

TREATMENT SCHEME

T lymphoblastic lymphoma: bone marrow/peripheral blood (BM/PB) involvement (MDD/MRD):

Diagnosis: less than 1%; Day 8: +/- (Stratum 1)

• Induction

• Single dose of Cyclophosphamide

• Steroid: prednisone

• Continuation: 98 weeks

T lymphoblastic lymphoma: BM/PB involvement (MDD/MRD): Diagnosis: equal to or greater than 1%; Day 8: - (Stratum 2)

• Induction

• Fractionated Cyclophosphamide

• Steroid: prednisone

• Continuation : 98 weeks

T lymphoblastic lymphoma: BM/PB involvement (MDD/MRD): Diagnosis: equal to or greater than 1%; Day 8: + (Stratum 3)

• Induction

• Fractionated Cyclophosphamide

• Steroid: prednisone and dexamethasone

• Continuation: 120 weeks

B lymphoblastic lymphoma: Stage I-III (Stratum 1)

• Induction

• Single dose of Cyclophosphamide

• Steroid: prednisone

• Continuation: 98 weeks

B lymphoblastic lymphoma: Stage IV or testicular (Stratum 2)

• Induction

• Fractionated Cyclophosphamide

• Steroid: prednisone

• Continuation: 98 weeks

Patients with CNS or testicular involvement will receive Consolidation therapy prior to continuation therapy and receive extended maintenance therapy (120 weeks).

Any patient with detectable disease (MRD, bone marrow or biopsy of residual mass) at the end of induction may be considered for reintensification and/or hematopoietic stem cell transplantation (HSCT).

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: NHL16: Study For Newly Diagnosed Patients With Acute Lymphoblastic Lymphoma
• Actual Study Start Date: May 25, 2012
• Actual Primary Completion Date: May 8, 2021
• Actual Study Completion Date: May 31, 2022

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment Patients will undergo treatment as described in the intervention section. Interventions include: Remission induction: prednisone, vincristine, daunorubicin, PEG-asparaginase (or Erwinia asparaginase), IT-MHA (Methotrexate, hydrocortisone, and cytarabine), cyclophosphamide, cytarabine, thioguanine Consolidation: PEG-asparaginase, High-dose methotrexate (HD-MTX), mercaptopurine Postremission continuation: Dexamethasone, doxorubicin, vincristine, mercaptopurine, PEG-asparaginase, cyclophosphamide, cytarabine, methotrexate Reintensification: dexamethasone, cytarabine, etoposide, PEG-asparaginase, clofarabine, cyclophosphamide All patients receive IT-MHA on days 1 and 15. Some patients also receive additional IT-MHA on days 8 and 22.

Drug: Prednisone; Given orally (PO).; Other Names: Prednisolone ; Drug: Vincristine; Given intravenously (IV).; Other Names: Oncovin® Vincristine sulfate ; Drug: Daunorubicin; Given IV.; Other Names: Daunomycin Cerubidine® ; Drug: PEG-asparaginase; Given intramuscularly (IM) or IV.; Other Names: Pegaspargase Oncaspar® ; Drug: Erwinia asparaginase; Given IM or IV if allergy occurs with the first or second PEG-asparaginase dose.; Other Names: Erwinase® ; Drug: Doxorubicin; Given IV.; Other Names: Adriamycin® ; Drug: Cyclophosphamide; Given IV.; Other Names: Cytoxan® ; Drug: Cytarabine; Given IV or IT.; Other Names: Ara-C Cytosar-U® ; Drug: Thioguanine; Given PO.; Other Names: Purine antimetabolite ; Drug: Clofarabine; Given IV.; Other Names: Cl-F-Ara-A CAFdA 2-Chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-9H-purin-6-amine Clofarex Clolar^TM ; Drug: Methotrexate; Given IV, IM or IT.; Other Names: MTX High-dose methotrexate (HD-MTX) ; Drug: Mercaptopurine; Given PO.; Other Names: 6-MP Purinethol® ; Drug: Dexamethasone; Given PO or IV.; Other Names: Decadron® ; Drug: Hydrocortisone; Given IT.; Other Names: Cortef® ; Drug: Etoposide; Given IV.; Other Names: VP-16 Vepesid®

Outcome Measures

Primary Outcome Measures

1. Probability of Event-free Survival (EFS) [Two years post therapy.]

   For EFS, relapse and second malignancies are considered as failures in addition to death in complete remission. The time to EFS will be set to 0 for patients who fail to achieve complete remission. Kaplan-Meier estimates of the OS and EFS curves are computed, along with estimates of standard errors by Peto's method. Please note the unit of measurement of probabilities are percentages.

Secondary Outcome Measures

1. Probability of Overall Survival (OS) [Two years post therapy.]

   For OS, only deaths are considered failures for OS. Kaplan-Meier estimates of the OS curves are computed along with estimates of standard errors by Peto's method. Please note the unit of measurement of probabilities are percentages.

2. Minimal Disseminated Disease (MDD) [At Diagnosis]

   Detectable disease in bone marrow or blood: A binary measure, positive (detectable), negative (non-detectable)

3. Minimal Residual Disease (MRD) [Day 8]

   Detectable disease in bone marrow or blood: A binary measure, positive (detectable), negative (non-detectable)

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Diagnosis of newly diagnosed lymphoblastic lymphoma (patients must have <25% tumor cells in bone marrow by morphology)

2. Age ≤ 21 years

3. Limited prior therapy, including systemic glucocorticoids for 1 week or less, 1 dose of vincristine, emergency radiation therapy to the mediastinum, and 1 dose of IT chemotherapy. Other circumstances must be cleared by PI or co-PI.

4. Written, informed consent and assent following guidelines of the Institutional Review Board, National Cancer Institute (NCI), Food and Drug Administration (FDA), and Office of Human Research Protections (OHRP).

Exclusion Criteria:

1. Participants with prior therapy, other than therapy specified in 3 above.

2. Participants who are pregnant or lactating.

3. Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rady Children's Hospital San Diego	San Diego	California	United States	92123
2	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105

Sponsors and Collaborators

• St. Jude Children's Research Hospital
• National University, Singapore

Investigators

• Principal Investigator: Hiroto Inaba, MD,PhD, St. Jude Children's Research Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 27, 2015

More Information

Additional Information:

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Publications

None provided.

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT01451515
• Other Study ID Numbers: NHL16; NCI-2012-00496
• First Posted: Oct 13, 2011
• Last Update Posted: Jun 28, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by St. Jude Children's Research Hospital: Lymphoblastic lymphoma
• Additional relevant MeSH terms: Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, Non-Hodgkin; Cytarabine; Dexamethasone; Prednisone; Prednisolone; Hydrocortisone; Cyclophosphamide; Doxorubicin; Methotrexate; Etoposide; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Clofarabine; Pegaspargase; Thioguanine; Antimetabolites

Study Results

Participant Flow

Recruitment Details	23 eligible patients were recruited between 23MAY2012 and 06DEC2016

Arm/Group Title	Stratum 1	Stratum 2	Stratum 3
Arm/Group Description	Minimal disseminated disease (MDD) <1% at diagnosis in T-lymphoblastic lymphoma No bone marrow involvement microscopically at diagnosis in B-lymphoblastic lymphoma Patients should not have: Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) Overt testicular involvement (evidenced by ultrasonogram).	MDD ≥1% and MRD negative (<0.01%) on day 8 in T-lymphoblastic lymphoma Bone marrow involvement microscopically present at diagnosis in B-lymphoblastic lymphoma Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) but does not fulfill the criteria of stratum 3 Overt testicular involvement (evidenced by ultrasonogram) but does not fulfill the criteria of stratum 3	Any patients with MDD ≥1% and MRD positive (≥0.01%) on day 8 in T-lymphoblastic lymphoma
Period Title: Overall Study
STARTED	12	7	4
COMPLETED	11	4	3
NOT COMPLETED	1	3	1

Baseline Characteristics

Arm/Group Title	Stratum 1	Stratum 2	Stratum 3	Total
Arm/Group Description	Minimal disseminated disease (MDD) <1% at diagnosis in T-lymphoblastic lymphoma No bone marrow involvement microscopically at diagnosis in B-lymphoblastic lymphoma Patients should not have: Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) Overt testicular involvement (evidenced by ultrasonogram).	MDD ≥1% and MRD negative (<0.01%) on day 8 in T-lymphoblastic lymphoma Bone marrow involvement microscopically present at diagnosis in B-lymphoblastic lymphoma Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) but does not fulfill the criteria of stratum 3 Overt testicular involvement (evidenced by ultrasonogram) but does not fulfill the criteria of stratum 3	Any patients with MDD ≥1% and MRD positive (≥0.01%) on day 8 in T-lymphoblastic lymphoma	Total of all reporting groups
Overall Participants	12	7	4	23
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.23 (4.48)	11.27 (5.73)	12.58 (4.43)	12.00 (4.69)
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	13.0	12.3	13.0	12.9
Age, Customized (Count of Participants)
<10 years	5 41.7%	2 28.6%	1 25%	8 34.8%
>=10 years	7 58.3%	5 71.4%	3 75%	15 65.2%
Sex: Female, Male (Count of Participants)
Female	5 41.7%	3 42.9%	1 25%	9 39.1%
Male	7 58.3%	4 57.1%	3 75%	14 60.9%
Race/Ethnicity, Customized (Count of Participants)
White	10 83.3%	4 57.1%	3 75%	17 73.9%
Black	2 16.7%	2 28.6%	1 25%	5 21.7%
Multiple Race (NOS)	0 0%	1 14.3%	0 0%	1 4.3%
NOS Spanish,Hispanic,Latino	0 0%	1 14.3%	0 0%	1 4.3%
Non Spanish speaking, Non Hispanic	12 100%	6 85.7%	4 100%	22 95.7%

Outcome Measures

1. Primary Outcome

Title	Probability of Event-free Survival (EFS)
Description	For EFS, relapse and second malignancies are considered as failures in addition to death in complete remission. The time to EFS will be set to 0 for patients who fail to achieve complete remission. Kaplan-Meier estimates of the OS and EFS curves are computed, along with estimates of standard errors by Peto's method. Please note the unit of measurement of probabilities are percentages.
Time Frame	Two years post therapy.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stratum 1	Stratum 2	Stratum 3	All Enrollments
Arm/Group Description	Minimal disseminated disease (MDD) <1% at diagnosis in T-lymphoblastic lymphoma No bone marrow involvement microscopically at diagnosis in B-lymphoblastic lymphoma Patients should not have: Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) Overt testicular involvement (evidenced by ultrasonogram).	MDD ≥1% and MRD negative (<0.01%) on day 8 in T-lymphoblastic lymphoma Bone marrow involvement microscopically present at diagnosis in B-lymphoblastic lymphoma Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) but does not fulfill the criteria of stratum 3 Overt testicular involvement (evidenced by ultrasonogram) but does not fulfill the criteria of stratum 3	Any patients with MDD ≥1% and MRD positive (≥0.01%) on day 8 in T-lymphoblastic lymphoma	Twenty-three (23) eligible patients
Measure Participants	12	7	4	23
Number (95% Confidence Interval) [percentage of event-free patients]	91.7	71.4	100	86.96

2. Secondary Outcome

Title	Probability of Overall Survival (OS)
Description	For OS, only deaths are considered failures for OS. Kaplan-Meier estimates of the OS curves are computed along with estimates of standard errors by Peto's method. Please note the unit of measurement of probabilities are percentages.
Time Frame	Two years post therapy.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stratum 1	Stratum 2	Stratum 3	All Enrollments
Arm/Group Description	Minimal disseminated disease (MDD) <1% at diagnosis in T-lymphoblastic lymphoma No bone marrow involvement microscopically at diagnosis in B-lymphoblastic lymphoma Patients should not have: Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) Overt testicular involvement (evidenced by ultrasonogram).	MDD ≥1% and MRD negative (<0.01%) on day 8 in T-lymphoblastic lymphoma Bone marrow involvement microscopically present at diagnosis in B-lymphoblastic lymphoma Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) but does not fulfill the criteria of stratum 3 Overt testicular involvement (evidenced by ultrasonogram) but does not fulfill the criteria of stratum 3	Any patients with MDD ≥1% and MRD positive (≥0.01%) on day 8 in T-lymphoblastic lymphoma	Twenty-three (23) eligible patients
Measure Participants	12	7	4	23
Number (95% Confidence Interval) [percentage of patients alive]	91.7	71.4	100	86.96

3. Secondary Outcome

Title	Minimal Disseminated Disease (MDD)
Description	Detectable disease in bone marrow or blood: A binary measure, positive (detectable), negative (non-detectable)
Time Frame	At Diagnosis

Outcome Measure Data

Analysis Population Description

Fourteen patients had MDD data at diagnosis.

Arm/Group Title	Stratum 1	Stratum 2	Stratum 3
Arm/Group Description	Minimal disseminated disease (MDD) <1% at diagnosis in T-lymphoblastic lymphoma No bone marrow involvement microscopically at diagnosis in B-lymphoblastic lymphoma Patients should not have: Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) Overt testicular involvement (evidenced by ultrasonogram).	MDD ≥1% and MRD negative (<0.01%) on day 8 in T-lymphoblastic lymphoma Bone marrow involvement microscopically present at diagnosis in B-lymphoblastic lymphoma Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) but does not fulfill the criteria of stratum 3 Overt testicular involvement (evidenced by ultrasonogram) but does not fulfill the criteria of stratum 3	Any patients with MDD ≥1% and MRD positive (≥0.01%) on day 8 in T-lymphoblastic lymphoma
Measure Participants	5	5	4
Negative	4 33.3%	2 28.6%	0 0%
Positive	1 8.3%	3 42.9%	4 100%

4. Secondary Outcome

Title	Minimal Residual Disease (MRD)
Description	Detectable disease in bone marrow or blood: A binary measure, positive (detectable), negative (non-detectable)
Time Frame	Day 8

Outcome Measure Data

Analysis Population Description

Seventeen participants had MRD data at day 8

Arm/Group Title	Stratum 1	Stratum 2	Stratum 3
Arm/Group Description	Minimal disseminated disease (MDD) <1% at diagnosis in T-lymphoblastic lymphoma No bone marrow involvement microscopically at diagnosis in B-lymphoblastic lymphoma Patients should not have: Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) Overt testicular involvement (evidenced by ultrasonogram).	MDD ≥1% and MRD negative (<0.01%) on day 8 in T-lymphoblastic lymphoma Bone marrow involvement microscopically present at diagnosis in B-lymphoblastic lymphoma Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) but does not fulfill the criteria of stratum 3 Overt testicular involvement (evidenced by ultrasonogram) but does not fulfill the criteria of stratum 3	Any patients with MDD ≥1% and MRD positive (≥0.01%) on day 8 in T-lymphoblastic lymphoma
Measure Participants	8	5	4
Negative	8 66.7%	4 57.1%	0 0%
Positive	0 0%	1 14.3%	4 100%

Adverse Events

Time Frame	From the start of treatment to 30 days after the last treatment is taken. Treatment last for 2 to 2½ years.
Arm/Group Title	Stratum 1		Stratum 2		Stratum 3		All Enrollments
Arm/Group Description	Minimal disseminated disease (MDD) <1% at diagnosis in T-lymphoblastic lymphoma No bone marrow involvement microscopically at diagnosis in B-lymphoblastic lymphoma Patients should not have: Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) Overt testicular involvement (evidenced by ultrasonogram).		MDD ≥1% and MRD negative (<0.01%) on day 8 in T-lymphoblastic lymphoma Bone marrow involvement microscopically present at diagnosis in B-lymphoblastic lymphoma Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (<5 WBC/µL of CSF with blasts) or traumatic LP (>10 RBC/µL of CSF with blasts) but does not fulfill the criteria of stratum 3 Overt testicular involvement (evidenced by ultrasonogram) but does not fulfill the criteria of stratum 3		Any patients with MDD ≥1% and MRD positive (≥0.01%) on day 8 in T-lymphoblastic lymphoma		Twenty-three (23) eligible patients
All Cause Mortality
	Stratum 1		Stratum 2		Stratum 3		All Enrollments
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/12 (16.7%)		2/7 (28.6%)		0/4 (0%)		4/23 (17.4%)
Serious Adverse Events
	Stratum 1		Stratum 2		Stratum 3		All Enrollments
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		1/7 (14.3%)		0/4 (0%)		1/23 (4.3%)
Gastrointestinal disorders
Pancreatitis	0/12 (0%)		1/7 (14.3%)	1	0/4 (0%)	0	1/23 (4.3%)	1
Other (Not Including Serious) Adverse Events
	Stratum 1		Stratum 2		Stratum 3		All Enrollments
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/12 (100%)		7/7 (100%)		4/4 (100%)		23/23 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	11/12 (91.7%)		4/7 (57.1%)		4/4 (100%)		19/23 (82.6%)
Anemia	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Cardiac disorders
Pericardial effusion	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Endocrine disorders
Endocrine disorders - Other, specify	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Gastrointestinal disorders
Vomiting	4/12 (33.3%)		1/7 (14.3%)		0/4 (0%)		5/23 (21.7%)
Abdominal pain	1/12 (8.3%)		1/7 (14.3%)		1/4 (25%)		3/23 (13%)
Colitis	2/12 (16.7%)		2/7 (28.6%)		2/4 (50%)		6/23 (26.1%)
Diarrhea	0/12 (0%)		0/7 (0%)		3/4 (75%)		3/23 (13%)
Nausea	2/12 (16.7%)		1/7 (14.3%)		1/4 (25%)		4/23 (17.4%)
Pancreatitis	2/12 (16.7%)		0/7 (0%)		1/4 (25%)		3/23 (13%)
Mucositis oral	0/12 (0%)		2/7 (28.6%)		0/4 (0%)		2/23 (8.7%)
Rectal pain	1/12 (8.3%)		1/7 (14.3%)		0/4 (0%)		2/23 (8.7%)
Anal pain	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Enterocolitis	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Gastritis	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Oral pain	0/12 (0%)		1/7 (14.3%)		0/4 (0%)		1/23 (4.3%)
Pancreatic necrosis	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
General disorders
Fever	5/12 (41.7%)		3/7 (42.9%)		1/4 (25%)		9/23 (39.1%)
Pain	2/12 (16.7%)		0/7 (0%)		1/4 (25%)		3/23 (13%)
Edema limbs	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Malaise	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	2/12 (16.7%)		0/7 (0%)		1/4 (25%)		3/23 (13%)
Cholecystitis	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Hepatic failure	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Immune system disorders
Allergic reaction	1/12 (8.3%)		1/7 (14.3%)		0/4 (0%)		2/23 (8.7%)
Allergic reaction to Asparaginase	1/12 (8.3%)		0/7 (0%)		1/4 (25%)		2/23 (8.7%)
Anaphylaxis	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Infections and infestations
Upper respiratory infection	10/12 (83.3%)		3/7 (42.9%)		3/4 (75%)		16/23 (69.6%)
Mucosal Infection	5/12 (41.7%)		2/7 (28.6%)		1/4 (25%)		8/23 (34.8%)
Skin infection	6/12 (50%)		3/7 (42.9%)		1/4 (25%)		10/23 (43.5%)
Sinusitis	5/12 (41.7%)		2/7 (28.6%)		1/4 (25%)		8/23 (34.8%)
Otitis media	4/12 (33.3%)		2/7 (28.6%)		1/4 (25%)		7/23 (30.4%)
Urinary tract infection	3/12 (25%)		1/7 (14.3%)		1/4 (25%)		5/23 (21.7%)
Enterocolitis infectious	1/12 (8.3%)		2/7 (28.6%)		2/4 (50%)		5/23 (21.7%)
Lung infection	3/12 (25%)		1/7 (14.3%)		1/4 (25%)		5/23 (21.7%)
Abdominal infection	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Infections and infestations - Other, specify	1/12 (8.3%)		2/7 (28.6%)		0/4 (0%)		3/23 (13%)
Paronychia	2/12 (16.7%)		0/7 (0%)		0/4 (0%)		2/23 (8.7%)
Vaginal infection	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Wound infection	0/12 (0%)		2/7 (28.6%)		0/4 (0%)		2/23 (8.7%)
Lip infection	1/12 (8.3%)		0/7 (0%)		1/4 (25%)		2/23 (8.7%)
Pharyngitis	2/12 (16.7%)		0/7 (0%)		0/4 (0%)		2/23 (8.7%)
Tooth infection	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Anorectal infection	0/12 (0%)		1/7 (14.3%)		0/4 (0%)		1/23 (4.3%)
Sepsis	0/12 (0%)		1/7 (14.3%)		0/4 (0%)		1/23 (4.3%)
Small intestine infection	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Soft tissue infection	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Injury, poisoning and procedural complications
Fall	0/12 (0%)		1/7 (14.3%)		1/4 (25%)		2/23 (8.7%)
Fracture	0/12 (0%)		1/7 (14.3%)		1/4 (25%)		2/23 (8.7%)
Injury, poisoning and procedural complications - Other, specify	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Vascular access complication	0/12 (0%)		2/7 (28.6%)		0/4 (0%)		2/23 (8.7%)
Ankle fracture	0/12 (0%)		1/7 (14.3%)		0/4 (0%)		1/23 (4.3%)
Spinal fracture	0/12 (0%)		1/7 (14.3%)		0/4 (0%)		1/23 (4.3%)
Investigations
Alanine aminotransferase increased	4/12 (33.3%)		2/7 (28.6%)		1/4 (25%)		7/23 (30.4%)
Blood bilirubin increased	4/12 (33.3%)		1/7 (14.3%)		1/4 (25%)		6/23 (26.1%)
Lipase increased	1/12 (8.3%)		0/7 (0%)		1/4 (25%)		2/23 (8.7%)
Cholesterol high	2/12 (16.7%)		1/7 (14.3%)		1/4 (25%)		4/23 (17.4%)
Aspartate aminotransferase increased	3/12 (25%)		0/7 (0%)		0/4 (0%)		3/23 (13%)
Serum amylase increased	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
GGT increased	2/12 (16.7%)		0/7 (0%)		0/4 (0%)		2/23 (8.7%)
Neutrophil count decreased	0/12 (0%)		0/7 (0%)		1/4 (25%)		0/23 (0%)
Weight loss	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Metabolism and nutrition disorders
Hypoalbuminemia	3/12 (25%)		3/7 (42.9%)		2/4 (50%)		8/23 (34.8%)
Hypertriglyceridemia	3/12 (25%)		2/7 (28.6%)		1/4 (25%)		6/23 (26.1%)
Dehydration	3/12 (25%)		3/7 (42.9%)		0/4 (0%)		6/23 (26.1%)
Hyponatremia	2/12 (16.7%)		2/7 (28.6%)		2/4 (50%)		6/23 (26.1%)
Hyperglycemia	3/12 (25%)		1/7 (14.3%)		1/4 (25%)		5/23 (21.7%)
Hypokalemia	2/12 (16.7%)		0/7 (0%)		1/4 (25%)		3/23 (13%)
Anorexia	1/12 (8.3%)		2/7 (28.6%)		1/4 (25%)		4/23 (17.4%)
Hypocalcemia	2/12 (16.7%)		1/7 (14.3%)		0/4 (0%)		3/23 (13%)
Hyperuricemia	0/12 (0%)		1/7 (14.3%)		1/4 (25%)		2/23 (8.7%)
Glucose intolerance	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Hyperkalemia	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Hypernatremia	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Hypoglycemia	0/12 (0%)		1/7 (14.3%)		0/4 (0%)		1/23 (4.3%)
Hypophosphatemia	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Tumor lysis syndrome	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Musculoskeletal and connective tissue disorders
Avascular necrosis	8/12 (66.7%)		4/7 (57.1%)		3/4 (75%)		15/23 (65.2%)
Pain in extremity	2/12 (16.7%)		0/7 (0%)		0/4 (0%)		2/23 (8.7%)
Bone pain	0/12 (0%)		1/7 (14.3%)		0/4 (0%)		1/23 (4.3%)
Nervous system disorders
Peripheral sensory neuropathy	5/12 (41.7%)		0/7 (0%)		2/4 (50%)		7/23 (30.4%)
Neuralgia	3/12 (25%)		4/7 (57.1%)		1/4 (25%)		8/23 (34.8%)
Peripheral motor neuropathy	2/12 (16.7%)		0/7 (0%)		1/4 (25%)		3/23 (13%)
Syncope	2/12 (16.7%)		1/7 (14.3%)		0/4 (0%)		3/23 (13%)
Cognitive disturbance	1/12 (8.3%)		0/7 (0%)		1/4 (25%)		2/23 (8.7%)
Seizure	1/12 (8.3%)		1/7 (14.3%)		0/4 (0%)		2/23 (8.7%)
Akathisia	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Headache	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Presyncope	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Radiculitis	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Psychiatric disorders
Depression	2/12 (16.7%)		2/7 (28.6%)		3/4 (75%)		7/23 (30.4%)
Agitation	0/12 (0%)		1/7 (14.3%)		1/4 (25%)		2/23 (8.7%)
Psychiatric disorders - Other, specify	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Anxiety	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Suicidal ideation	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Renal and urinary disorders
Acute kidney injury	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	2/12 (16.7%)		0/7 (0%)		0/4 (0%)		2/23 (8.7%)
Pleural effusion	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Pneumothorax	0/12 (0%)		1/7 (14.3%)		0/4 (0%)		1/23 (4.3%)
Pulmonary edema	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Pain of skin	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Pruritus	0/12 (0%)		0/7 (0%)		1/4 (25%)		1/23 (4.3%)
Rash acneiform	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)
Vascular disorders
Hypotension	3/12 (25%)		0/7 (0%)		1/4 (25%)		4/23 (17.4%)
Thromboembolic event	1/12 (8.3%)		1/7 (14.3%)		0/4 (0%)		2/23 (8.7%)
Hypertension	0/12 (0%)		1/7 (14.3%)		1/4 (25%)		2/23 (8.7%)
Vascular disorders - Other, specify	1/12 (8.3%)		0/7 (0%)		0/4 (0%)		1/23 (4.3%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.