Low-Dose or High-Dose Vincristine and Combination Chemotherapy in Treating Young Patients With Relapsed B-Cell Acute Lymphoblastic Leukemia

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00381680
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 275
• Locations: 173
• Arms: 2
• Patients Per Site: 1.6

Study Details

Study Description

Brief Summary

This randomized phase III trial is studying low-dose vincristine to see how well it works compared with high-dose vincristine when given together with different combination chemotherapy regimens in treating young patients with intermediate-risk relapsed B-cell acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving the drugs in different ways and different doses may kill more cancer cells..

Condition or Disease	Intervention/Treatment	Phase
B-cell Childhood Acute Lymphoblastic Leukemia; L1 Childhood Acute Lymphoblastic Leukemia; L2 Childhood Acute Lymphoblastic Leukemia; Intermediate Risk Recurrent Childhood Acute Lymphoblastic Leukemia	Drug: vincristine sulfate; Drug: prednisone; Drug: doxorubicin hydrochloride; Drug: pegaspargase; Drug: cytarabine; Drug: methotrexate; Drug: dexamethasone; Drug: etoposide; Drug: cyclophosphamide; Drug: leucovorin calcium; Biological: filgrastim; Drug: asparaginase; Drug: mercaptopurine	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the efficacy of an intensive chemotherapy regimen (based on POG-9412) for pediatric patients with intermediate-risk relapsed B-precursor acute lymphoblastic leukemia.

SECONDARY OBJECTIVES:

1. To determine levels of minimal residual disease (MRD) present at the end of the first & third blocks of Induction and determine if higher MRD levels at these times identify patients at higher risk of relapse who might be candidates for alternative therapies in future trials.

2. To determine whether common polymorphisms in candidate genes are associated with the frequency of vincristine adverse effects (peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion [SIADH], or constipation) and with anti-leukemic response (level of end-Induction MRD).

3. Compare, descriptively, the outcomes of patients treated with combination chemotherapy vs those treated with matched sibling-related donor hematopoietic stem cell transplantation (for those with eligible donors).

4. To use deoxyribonucleic acid (DNA) arrays to characterize patterns of gene expression that predict treatment failure, and to compare gene expression profiles at the time of relapse with those at initial diagnosis to gain an understanding of the pathways that may be involved in disease resistance.

OUTLINE: This is a multicenter, randomized study. Patients are randomized to 1 of 2 treatment regimens (randomization closed as of 09/2010).

INDUCTION THERAPY 1 (WEEKS 1-5):

Regimen A: Patients receive low-dose vincristine intravenously (IV) on days 1, 8, 15, and 22; prednisone orally (PO) 3 times daily (TID) on days 1-28; doxorubicin hydrochloride IV over 15 minutes on day 1; pegaspargase intramuscularly (IM) on days 2, 8, 15, and 22; cytarabine intrathecally (IT) on day 1; and methotrexate IT* on days 15 and 29.

Regimen B: (closed to accrual as of 09/2010)**: Patients receive high-dose vincristine IV on days 1, 8, 15, and 22 and prednisone, doxorubicin hydrochloride, pegaspargase, cytarabine, and methotrexate as in Regimen A.

NOTE: Central nervous system (CNS)-positive patients do not receive methotrexate IT. In both arms, CNS-positive patients receive intrathecal triple therapy (ITT) comprising methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1, 8, 15, 22, and 29. CNS-positive patients not achieving remission after induction therapy 1 receive one additional dose of ITT on day 36. Patients in both arms then proceed to induction therapy 2*.

NOTE: **Patients who are CNS-positive at relapse receive induction therapy 3 BEFORE induction therapy 2.

NOTE: ***Patients already enrolled on Regimen B are crossover to Regimen A.

INDUCTION THERAPY 2 (WEEKS 6-10 or 7-11): Once blood counts recover, all patients receive etoposide phosphate IV over = 1 hour and cyclophosphamide IV over 1 hour on days 1-5; high-dose methotrexate IV continuously over 24 hours on day 22; leucovorin calcium IV or PO beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; and methotrexate IT* on days 1 and 22. Patients also receive filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 6 and continuing until blood counts recover.

NOTE: CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on days 1 and 22. Patients with testicular-relapse with persistent testicular disease at the end of induction therapy 1 undergo testicular radiotherapy once daily (QD), 5 days a week, for 12 days during induction therapy 2*.

NOTE: **Radiotherapy should be completed before beginning high-dose methotrexate (week 9) chemotherapy.

All patients then proceed to induction therapy 3.

INDUCTION THERAPY 3 (WEEKS 11-15 or 12-16): All patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9, and asparaginase IM on days 2 and 9. Patients also receive G-CSF IV or SC beginning on day 10 and continuing until blood counts recover. Patients with a suitable HLA-matched related donor are removed from study and proceed to stem cell transplantation. Patients without a suitable HLA-matched related donor proceed to intensification therapy 1 (as per their randomized regimen in induction therapy 1).

INTENSIFICATION THERAPY 1 (WEEKS 16-27 or 17-28):

Regimen A: Patients receive low-dose vincristine IV and high-dose methotrexate IV continuously over 24 hours on day 1; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral mercaptopurine once daily on days 2-6; etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on day 8; and methotrexate IT* on day 15. Treatment repeats every 21 days for 4 courses (with the exception of IT methotrexate which repeats for only 3 courses).

Regimen B: Patients receive high-dose vincristine IV on day 1 and high-dose methotrexate, leucovorin calcium, mercaptopurine, etoposide phosphate, cyclophosphamide, and methotrexate IT* as in Regimen A. (closed to accrual as of 09/2010)

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on day 15. ITT repeats every 3 weeks for 3 courses.

NOTE: ** Patients already enrolled on Regimen B are crossover to Regimen A.

Patients in both regimens then proceed to reinduction therapy (as per their randomized regimen in induction therapy 1).

REINDUCTION THERAPY (WEEKS 28-32 or 29-33):

Regimen A: Patients receive low-dose vincristine IV and doxorubicin hydrochloride IV over 15 minutes on days 1, 8, and 15, oral dexamethasone twice daily on days 1-7 and 15-21, pegaspargase IM on days 2 and 15, and methotrexate IT* on days 1 and 28.

Regimen B: Patients receive high-dose vincristine IV on days 1, 8, and 15 and doxorubicin hydrochloride, dexamethasone, pegaspargase, and methotrexate IT* as in Regimen A. (closed to accrual as of 09/2010)

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on days 1 and 28.

NOTE: ** Patients already enrolled on Regimen B are crossover to Regimen A. Patients in both regimens then proceed to intensification therapy 2 (as per their randomized regimen in induction therapy 1).

INTENSIFICATION THERAPY 2 (WEEKS 33-56 or 34-57):

Regimen A: Once blood counts recover, patients receive high-dose cytarabine IV over 3 hours on days 1 and 2; pegaspargase IM on day 2; low-dose vincristine IV on days 22 and 29; high-dose methotrexate IV on day 22; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral mercaptopurine once daily on days 23-27; etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on day 29; and methotrexate IT* on day 36. Patients also receive G-CSF IV or SC beginning on day 3 and continuing until blood counts recover. Treatment repeats every 42 days for 4 courses (with the exception of IT methotrexate which only repeats for 3 courses).

Regimen B: Patients receive high-dose cytarabine, high-dose methotrexate, leucovorin calcium, pegaspargase, mercaptopurine, etoposide phosphate, cyclophosphamide, methotrexate IT*, and G-CSF as in Regimen A. Patients also receive high-dose vincristine IV on days 22 and 29.

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on day 36. Treatment repeats every 6 weeks for 3 courses.

Patients in both regimens then proceed to maintenance therapy (as per their randomized regimen in induction therapy 1).

MAINTENANCE THERAPY (week 57-106 or 58-107):

Regimen A: Patients receive methotrexate IT on day 1* and then PO on days 8, 15, 22, 29, and 36; mercaptopurine PO QD on days 1-42; dexamethasone PO twice daily (BID) on days 1-5; and low-dose vincristine IV and cyclophosphamide IV over 1 hour on days 43, 50, 57, and 64. Treatment repeats every 70 days for 5 courses.

Regimen B: Patients receive methotrexate*, mercaptopurine, dexamethasone, and cyclophosphamide as in Regimen A. Patients also receive high-dose vincristine IV on days 43, 50, 57, and 64.

NOTE: *CNS-positive patients receive methotrexate IT on day 1, instead of oral methotrexate.

Beginning in week 1 of the first maintenance therapy course, patients with CNS relapse undergo cranial radiotherapy QD, 5 days a week, for 10 days. Patients with CNS relapse do not receive any IT therapy during maintenance therapy.

After completion of study therapy, patients are followed periodically for 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 275 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Intensive Treatment for Intermediate-Risk Relapse of Childhood B-precursor Acute Lymphoblastic Leukemia (ALL): A Randomized Trial of Vincristine Strategies
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Mar 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Regimen A: Standard vincristine dosing See detailed description.	Drug: vincristine sulfate; Given IV; Other Names: leurocristine sulfate VCR Vincasar PFS ; Drug: prednisone; Given PO; Other Names: DeCortin Deltra ; Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Drug: pegaspargase; Given IM; Other Names: L-asparaginase with polyethylene glycol Oncaspar PEG-ASP PEG-L-asparaginase ; Drug: cytarabine; Given IT or IV; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside ; Drug: methotrexate; Given IT or IV; Other Names: amethopterin Folex methylaminopterin Mexate MTX ; Drug: dexamethasone; Given PO; Other Names: Aeroseb-Dex Decaderm Decadron DM DXM ; Drug: etoposide; Given IV; Other Names: EPEG VP-16 VP-16-213 ; Drug: cyclophosphamide; Given IV; Other Names: CPM CTX Cytoxan Endoxan Endoxana ; Drug: leucovorin calcium; Given IV or PO; Other Names: CF CFR LV ; Biological: filgrastim; Given IV or SC; Other Names: G-CSF Neupogen ; Drug: asparaginase; Given IM; Other Names: ASNase Colaspase Crasnitin Elspar L-ASP ; Drug: mercaptopurine; Given PO; Other Names: 6-mercaptopurine 6-MP Leukerin MP
Experimental: Arm B: Randomized High Dose Vincristine regimen See detailed description. Closed to accrual as of 09/2010).	Drug: vincristine sulfate; Given IV; Other Names: leurocristine sulfate VCR Vincasar PFS ; Drug: prednisone; Given PO; Other Names: DeCortin Deltra ; Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Drug: pegaspargase; Given IM; Other Names: L-asparaginase with polyethylene glycol Oncaspar PEG-ASP PEG-L-asparaginase ; Drug: cytarabine; Given IT or IV; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside ; Drug: methotrexate; Given IT or IV; Other Names: amethopterin Folex methylaminopterin Mexate MTX ; Drug: dexamethasone; Given PO; Other Names: Aeroseb-Dex Decaderm Decadron DM DXM ; Drug: etoposide; Given IV; Other Names: EPEG VP-16 VP-16-213 ; Drug: cyclophosphamide; Given IV; Other Names: CPM CTX Cytoxan Endoxan Endoxana ; Drug: leucovorin calcium; Given IV or PO; Other Names: CF CFR LV ; Biological: filgrastim; Given IV or SC; Other Names: G-CSF Neupogen ; Drug: asparaginase; Given IM; Other Names: ASNase Colaspase Crasnitin Elspar L-ASP ; Drug: mercaptopurine; Given PO; Other Names: 6-mercaptopurine 6-MP Leukerin MP

Outcome Measures

Primary Outcome Measures

1. Event Free Survival. EFS [3 years after enrollment]

   Percentage of patients who were event free at 3 years among those on Standard VCR dosing who did not undergo Hematopoietic Stem Cell Transplant (SCT).

Secondary Outcome Measures

1. Frequency and Severity of Adverse Effects [Up to 107 weeks]

   Percentage of patients who developed at least 1 episode of grade 2 to 4 neuropathy.

2. Gene Expression Profile [Up to 36 months]

   Percent of unfavorable gene expression profile of early versus late marrow relapse.

3. Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 1 [End of Block 1 (35 days) of Induction therapy]

   Percentage of patients who had minimal residual disease (MRD) < 0.01% among those with isolated BM or combined BM relapse >= 36 months and had successful MRD determinations at End Block 1

4. Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 3 [End of Block 3 (105 days) of Induction therapy]

   Percentage of patients who had minimal residual disease (MRD) < 0.01% among those with isolated BM or combined BM relapse >= 36 months and had successful MRD determinations at End Block 3.

5. Event Free Survival (EFS) [3 years]

   Percentage of patients who were event free at 3 years among those with isolated BM or combined BM relapse >= 36 months.

6. Adjusted Event Free Survival [3 years]

   Adjusted percentage of patients who were event free at 3 years. For patients who received matched donor SCT, EFS was adjusted to start from the actual SCT date. For patients who did not undergo SCT, EFS was adjusted to start from median time to SCT based on patients who received matched related SCT (where patients who had events prior to SCT date were excluded from the calculation of median time to SCT).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 29 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of acute lymphoblastic leukemia (ALL)

• Bone marrow with > 25% L1 or L2 lymphoblasts (M3 marrow)

• Patients with > 25% L3 marrow lymphoblasts and/or evidence of c-myc translocation are not eligible (considered Burkitt's or mature B-cell leukemia)

• Intermediate-risk relapsed disease, meeting 1 of the following criteria:

• Bone marrow relapse ≥ 36 months after initial diagnosis (defined as M3 marrow after previous remission from ALL)

• Combined bone marrow and extramedullary (CNS* and/or testicular**) relapse ≥ 36 months after initial diagnosis

• Isolated extramedullary (CNS* and/or testicular**) relapse < 18 months after initial diagnosis

• The following subtypes are not allowed:

• T-lineage ALL

• Mature B-cell (Burkitt's) leukemia (defined as L3 morphology and/or evidence of c-myc translocation)

• Philadelphia-chromosome positive disease

• No Down syndrome (trisomy 21)

• Shortening fraction >= 27% by echocardiogram OR ejection fraction >= 50% by radionuclide angiogram

• Bilirubin < 3.0 mg/dL

• Not pregnant

• Fertile patients must use effective contraception

• No history of peripheral neuropathy >= grade 3 within the past month

• No toxicity (i.e. peripheral neuropathy) >= grade 3 attributable to vincristine within the past month

• At least 5 days since prior intrathecal chemotherapy

• No prior hematopoietic stem cell or marrow transplantation

• No prior cranial radiotherapy > 1200 cGy (for patients with CNS relapse)

• No concurrent stem cell transplant

• No concurrent alternative therapy

• No concurrent itraconazole in patients receiving vincristine

• No concurrent intensity-modulated radiotherapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
3	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
4	University of Arizona Health Sciences Center	Tucson	Arizona	United States	85724
5	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
6	Children's Oncology Group	Arcadia	California	United States	91006-3776
7	Southern California Permanente Medical Group	Downey	California	United States	90242
8	City of Hope Medical Center	Duarte	California	United States	91010
9	Loma Linda University Medical Center	Loma Linda	California	United States	92354
10	Miller Children's Hospital	Long Beach	California	United States	90806
11	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
12	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
13	Children's Hospital Central California	Madera	California	United States	93636-8762
14	Children's Hospital and Research Center at Oakland	Oakland	California	United States	94609-1809
15	Kaiser Permanente-Oakland	Oakland	California	United States	94611
16	Childrens Hospital of Orange County	Orange	California	United States	92868-3874
17	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
18	Sutter General Hospital	Sacramento	California	United States	95816
19	UC Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
20	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
21	University of California San Francisco Medical Center-Parnassus	San Francisco	California	United States	94143
22	Santa Barbara Cottage Hospital	Santa Barbara	California	United States	93102
23	Children's Hospital Colorado	Aurora	Colorado	United States	80045
24	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
25	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
26	Yale University	New Haven	Connecticut	United States	06520-8032
27	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
28	Children's National Medical Center	Washington	District of Columbia	United States	20010
29	Lombardi Comprehensive Cancer Center at Georgetown University	Washington	District of Columbia	United States	20057
30	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
31	Lee Memorial Health System	Fort Myers	Florida	United States	33901
32	University of Florida	Gainesville	Florida	United States	32610
33	Nemours Children's Clinic - Jacksonville	Jacksonville	Florida	United States	32207-8426
34	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
35	Miami Children's Hospital	Miami	Florida	United States	33155
36	Baptist Hospital of Miami	Miami	Florida	United States	33176
37	Florida Hospital	Orlando	Florida	United States	32803
38	M D Anderson Cancer Center- Orlando	Orlando	Florida	United States	32806
39	Nemours Childrens Clinic - Orlando	Orlando	Florida	United States	32806
40	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
41	All Children's Hospital	Saint Petersburg	Florida	United States	33701
42	Saint Joseph Children's Hospital of Tampa	Tampa	Florida	United States	33607
43	Saint Mary's Hospital	West Palm Beach	Florida	United States	33407
44	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
45	Georgia Regents University	Augusta	Georgia	United States	30912
46	Memorial Health University Medical Center	Savannah	Georgia	United States	31403
47	University of Hawaii	Honolulu	Hawaii	United States	96813
48	Saint Luke's Mountain States Tumor Institute	Boise	Idaho	United States	83712
49	University of Illinois	Chicago	Illinois	United States	60612
50	Childrens Memorial Hospital	Chicago	Illinois	United States	60614
51	Loyola University Medical Center	Maywood	Illinois	United States	60153
52	Advocate Hope Children's Hospital	Oak Lawn	Illinois	United States	60453
53	Advocate Lutheran General Hospital	Park Ridge	Illinois	United States	60068
54	Southern Illinois University	Springfield	Illinois	United States	62702
55	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
56	Saint Vincent Hospital and Health Services	Indianapolis	Indiana	United States	46260
57	Raymond Blank Children's Hospital	Des Moines	Iowa	United States	50309
58	University of Kentucky	Lexington	Kentucky	United States	40536
59	Kosair Children's Hospital	Louisville	Kentucky	United States	40202
60	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
61	Children's Hospital-Main Campus	New Orleans	Louisiana	United States	70118
62	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
63	Eastern Maine Medical Center	Bangor	Maine	United States	04401
64	Maine Children's Cancer Program	Scarborough	Maine	United States	04074
65	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland	United States	21201-1595
66	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
67	Johns Hopkins University	Baltimore	Maryland	United States	21287-8936
68	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
69	University of Massachusetts Medical School	Worcester	Massachusetts	United States	01655
70	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
71	Wayne State University	Detroit	Michigan	United States	48202
72	Hurley Medical Center	Flint	Michigan	United States	48502
73	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
74	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
75	Kalamazoo Center for Medical Studies	Kalamazoo	Michigan	United States	49008
76	Michigan State University - Breslin Cancer Center	Lansing	Michigan	United States	48910
77	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
78	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota	United States	55455
79	Mayo Clinic	Rochester	Minnesota	United States	55905
80	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
81	University of Missouri-Columbia	Columbia	Missouri	United States	65212
82	The Childrens Mercy Hospital	Kansas City	Missouri	United States	64108
83	Saint John's Mercy Medical Center	Saint Louis	Missouri	United States	63141
84	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
85	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
86	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
87	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
88	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
89	Saint Barnabas Medical Center	Livingston	New Jersey	United States	07039
90	Morristown Memorial Hospital	Morristown	New Jersey	United States	07962
91	Saint Peter's University Hospital	New Brunswick	New Jersey	United States	08901
92	UMDNJ - Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
93	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
94	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
95	Overlook Hospital	Summit	New Jersey	United States	07902
96	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87106
97	Montefiore Medical Center	Bronx	New York	United States	10467-2490
98	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
99	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York	United States	11040
100	New York University Langone Medical Center	New York	New York	United States	10016
101	Mount Sinai Medical Center	New York	New York	United States	10029
102	Columbia University Medical Center	New York	New York	United States	10032
103	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
104	New York Medical College	Valhalla	New York	United States	10595
105	Mission Hospitals Inc	Asheville	North Carolina	United States	28801
106	University of North Carolina	Chapel Hill	North Carolina	United States	27599
107	Carolinas Medical Center	Charlotte	North Carolina	United States	28203
108	Presbyterian Hospital	Charlotte	North Carolina	United States	28204
109	Duke University Medical Center	Durham	North Carolina	United States	27710
110	East Carolina University	Greenville	North Carolina	United States	27858
111	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
112	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
113	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
114	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
115	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
116	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
117	The Children's Medical Center of Dayton	Dayton	Ohio	United States	45404
118	Mercy Children's Hospital	Toledo	Ohio	United States	43608
119	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
120	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
121	Legacy Emanuel Hospital and Health Center	Portland	Oregon	United States	97227
122	Oregon Health and Science University	Portland	Oregon	United States	97239
123	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania	United States	18017
124	Penn State Hershey Children's Hospital	Hershey	Pennsylvania	United States	17033
125	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
126	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
127	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
128	Rhode Island Hospital	Providence	Rhode Island	United States	02903
129	Palmetto Health Richland	Columbia	South Carolina	United States	29203
130	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
131	Greenville Cancer Treatment Center	Greenville	South Carolina	United States	29605
132	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
133	T C Thompson Children's Hospital	Chattanooga	Tennessee	United States	37403
134	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
135	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
136	Texas Tech University Health Science Center-Amarillo	Amarillo	Texas	United States	79106
137	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
138	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
139	Medical City Dallas Hospital	Dallas	Texas	United States	75230
140	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
141	Brooke Army Medical Center	Fort Sam Houston	Texas	United States	78234
142	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
143	Baylor College of Medicine	Houston	Texas	United States	77030
144	Covenant Children's Hospital	Lubbock	Texas	United States	79410
145	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229-3900
146	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
147	Scott and White Memorial Hospital	Temple	Texas	United States	76508
148	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113
149	University of Virginia	Charlottesville	Virginia	United States	22908
150	Childrens Hospital-King's Daughters	Norfolk	Virginia	United States	23507
151	Carilion Clinic Children's Hospital	Roanoke	Virginia	United States	24014
152	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
153	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington	United States	98405
154	Madigan Army Medical Center	Tacoma	Washington	United States	98431
155	West Virginia University Charleston	Charleston	West Virginia	United States	25304
156	Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301
157	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
158	Marshfield Clinic	Marshfield	Wisconsin	United States	54449
159	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
160	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
161	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
162	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
163	IWK Health Centre	Halifax	Nova Scotia	Canada	B3J 3G9
164	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
165	Chedoke-McMaster Hospitals	Hamilton	Ontario	Canada	L8S 4L8
166	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario	Canada	K7L 5P9
167	Children's Hospital	London	Ontario	Canada	N6A 5W9
168	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
169	Hospital Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
170	Allan Blair Cancer Centre	Regina	Saskatchewan	Canada	S4T 7T1
171	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4
172	Swiss Pediatric Oncology Group - Bern	Bern		Switzerland	3010
173	Swiss Pediatric Oncology Group - Lausanne	Lausanne		Switzerland	1011

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Glen Lew, MD, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00381680
• Other Study ID Numbers: AALL0433; NCI-2009-00306; COG-AALL0433; CDR0000495359; U10CA098543
• First Posted: Sep 28, 2006
• Last Update Posted: May 12, 2017
• Last Verified: Dec 1, 2016

• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leucovorin; Cytarabine; Dexamethasone; Prednisone; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Etoposide; Vincristine; Etoposide phosphate; Asparaginase; Mercaptopurine; Pegaspargase; Levoleucovorin

Study Results

Participant Flow

Arm/Group Title	Regimen A: Standard Vincristine Dosing	Regimen B: Randomized High Dose Vincristine Regimen
Arm/Group Description	Standard VCR dosing (1.5 mg/m^2, max 2 mg)	Intensive VCR dosing (2 mg/m^2, max 2.5 mg)
Period Title: Overall Study
STARTED	206	69
COMPLETED	81	19
NOT COMPLETED	125	50

Baseline Characteristics

Arm/Group Title	Regimen A: Standard Vincristine Dosing	Arm B: Randomized High Dose Vincristine Regimen	Total
Arm/Group Description	Standard VCR dosing (1.5 mg/m^2, max 2 mg)	Intensive VCR dosing (2 mg/m^2, max 2.5 mg)	Total of all reporting groups
Overall Participants	206	69	275
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	17.21 (5.20)	19.62 (4.84)	17.82 (5.21)
Sex: Female, Male (Count of Participants)
Female	96 46.6%	25 36.2%	121 44%
Male	110 53.4%	44 63.8%	154 56%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	55 26.7%	8 11.6%	63 22.9%
Not Hispanic or Latino	145 70.4%	51 73.9%	196 71.3%
Unknown or Not Reported	6 2.9%	10 14.5%	16 5.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 1.5%	0 0%	3 1.1%
Asian	5 2.4%	2 2.9%	7 2.5%
Native Hawaiian or Other Pacific Islander	1 0.5%	0 0%	1 0.4%
Black or African American	12 5.8%	3 4.3%	15 5.5%
White	157 76.2%	55 79.7%	212 77.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	28 13.6%	9 13%	37 13.5%

Outcome Measures

1. Primary Outcome

Title	Event Free Survival. EFS
Description	Percentage of patients who were event free at 3 years among those on Standard VCR dosing who did not undergo Hematopoietic Stem Cell Transplant (SCT).
Time Frame	3 years after enrollment

Outcome Measure Data

Analysis Population Description

The analysis is limited to eligible patients on regimen A (Standard VCR dosing) who did not undergo SCT.

Arm/Group Title	Regimen A: Standard Vincristine Dosing
Arm/Group Description	Standard VCR dosing (1.5 mg/m^2, max 2 mg)
Measure Participants	142
Number (95% Confidence Interval) [percentage of participants EFS at 3 yrs3]	66.0 32%

2. Secondary Outcome

Title	Frequency and Severity of Adverse Effects
Description	Percentage of patients who developed at least 1 episode of grade 2 to 4 neuropathy.
Time Frame	Up to 107 weeks

Outcome Measure Data

Analysis Population Description

The total number of patients for CC or CT genotype is 81 and for high-risk CEP72 genotype is 18. No related by arm data were provided.

Arm/Group Title	All Patients
Arm/Group Description	This analysis looks at all eligible patients with CC or CT genotypes as well as all eligible patients with the high-risk CEP72 genotype (TT at rs924607).
Measure Participants	99
CC or CT genotype	17.3 8.4%
High-risk CEP72 genotype (TT at rs924607)	44.4 21.6%

3. Secondary Outcome

Title	Gene Expression Profile
Description	Percent of unfavorable gene expression profile of early versus late marrow relapse.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

The data were not collected due to the lack of funds.

Arm/Group Title	Regimen A: Standard Vincristine Dosing	Arm B: Randomized High Dose Vincristine Regimen
Arm/Group Description	Standard VCR dosing (1.5 mg/m^2, max 2 mg)	Intensive VCR dosing (2 mg/m^2, max 2.5 mg)
Measure Participants	0	0

4. Secondary Outcome

Title	Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 1
Description	Percentage of patients who had minimal residual disease (MRD) < 0.01% among those with isolated BM or combined BM relapse >= 36 months and had successful MRD determinations at End Block 1
Time Frame	End of Block 1 (35 days) of Induction therapy

Outcome Measure Data

Analysis Population Description

This analysis is limited to all eligible patients with isolated BM or combined BM relapse >= 36 months and had successful MRD determinations at End Block 1.

Arm/Group Title	Regimen A	Regimen B
Arm/Group Description	Standard VCR dosing (1.5 mg/m^2, max 2 mg)	Intensive VCR dosing (2 mg/m^2, max 2.5 mg)
Measure Participants	122	53
Number [percentage of participants]	50.8 24.7%	41.5 60.1%

5. Secondary Outcome

Title	Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 3
Description	Percentage of patients who had minimal residual disease (MRD) < 0.01% among those with isolated BM or combined BM relapse >= 36 months and had successful MRD determinations at End Block 3.
Time Frame	End of Block 3 (105 days) of Induction therapy

Outcome Measure Data

Analysis Population Description

This analysis is limited to all eligible patients with isolated BM or combined BM relapse >= 36 months and had successful MRD determinations at End Block 3.

Arm/Group Title	Regimen A	Regimen B
Arm/Group Description	Standard VCR dosing (1.5 mg/m^2, max 2mg)	Intensive VCR dosing (2 mg/m^2, max 2.5 mg)
Measure Participants	70	27
Number [percentage of participants]	81.4 39.5%	88.9 128.8%

6. Secondary Outcome

Title	Event Free Survival (EFS)
Description	Percentage of patients who were event free at 3 years among those with isolated BM or combined BM relapse >= 36 months.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

The percentage of patients (pts) who were event free at 3 years among those with isolated BM or combined BM relapse >= 36 months. Pts with MRD <0.01% at the end of Block 1 (MRD < 0.01% BL1); MRD >= 0.01% at the end of Block 1 (MRD>= 0.01% BL1); MRD < 0.01% at the end of Block 3 (MRD < 0.01% BL3);MRD >=0.01% at the end of Block 3.

Arm/Group Title	Regimen A	Regimen B
Arm/Group Description	Standard VCR dosing (1.5 mg/m^2, max 2mg)	Intensive VCR dosing (2 mg/m^2, max 2.5 mg)
Measure Participants	127	54
MRD < 0.01% BL1	88.5 43%	77.3 112%
MRD >= 0.01% BL1	60.0 29.1%	46.2 67%
MRD < 0.01% BL3	83.8 40.7%	83.3 120.7%
MRD >= 0.01% BL3	61.5 29.9%	33.3 48.3%

7. Secondary Outcome

Title	Adjusted Event Free Survival
Description	Adjusted percentage of patients who were event free at 3 years. For patients who received matched donor SCT, EFS was adjusted to start from the actual SCT date. For patients who did not undergo SCT, EFS was adjusted to start from median time to SCT based on patients who received matched related SCT (where patients who had events prior to SCT date were excluded from the calculation of median time to SCT).
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

The analysis is limited to eligible patients on Standard VCR dosing who received matched related SCT, excluding patients who had events prior to receiving SCT. And those patients on Regimen A who did not undergo SCT, excluding patients who went off therapy prior to the adjusted starting time.

Arm/Group Title	Regimen A: Standard Vincristine Dosing
Arm/Group Description	Standard VCR dosing (1.5 mg/m^2, max 2 mg)
Measure Participants	152
Received SCT	82.2 39.9%
Did not receive SCT	64.2 31.2%

Adverse Events

Adverse Event Reporting Description	Only eligible patients are included in the toxicity adverse events for both serious and other.
Arm/Group Title	Regimen A: Standard Vincristine Dosing		Arm B: Randomized High Dose Vincristine Regimen
Arm/Group Description	See detailed description. vincristine sulfate: Given IV prednisone: Given PO doxorubicin hydrochloride: Given IV pegaspargase: Given IM cytarabine: Given IT or IV methotrexate: Given IT or IV dexamethasone: Given PO etoposide: Given IV cyclophosphamide: Given IV leucovorin calcium: Given IV or PO filgrastim: Given IV or SC asparaginase: Given IM mercaptopurine: Given PO		See detailed description. Closed to accrual as of 09/2010). vincristine sulfate: Given IV prednisone: Given PO doxorubicin hydrochloride: Given IV pegaspargase: Given IM cytarabine: Given IT or IV methotrexate: Given IT or IV dexamethasone: Given PO etoposide: Given IV cyclophosphamide: Given IV leucovorin calcium: Given IV or PO filgrastim: Given IV or SC asparaginase: Given IM mercaptopurine: Given PO
All Cause Mortality
	Regimen A: Standard Vincristine Dosing		Arm B: Randomized High Dose Vincristine Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Regimen A: Standard Vincristine Dosing		Arm B: Randomized High Dose Vincristine Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/203 (19.7%)		11/68 (16.2%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation	1/203 (0.5%)	1	1/68 (1.5%)	1
Febrile neutropenia	4/203 (2%)	4	0/68 (0%)	0
Cardiac disorders
Sinus tachycardia	2/203 (1%)	2	0/68 (0%)	0
Ventricular arrhythmia	1/203 (0.5%)	1	0/68 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/203 (0.5%)	1	0/68 (0%)	0
Anal necrosis	1/203 (0.5%)	1	0/68 (0%)	0
Anal ulcer	1/203 (0.5%)	1	0/68 (0%)	0
General disorders
Death NOS	15/203 (7.4%)	15	1/68 (1.5%)	1
Edema face	1/203 (0.5%)	1	0/68 (0%)	0
Fever	1/203 (0.5%)	1	0/68 (0%)	0
Multi-organ failure	2/203 (1%)	2	1/68 (1.5%)	1
Hepatobiliary disorders
Hepatic failure	0/203 (0%)	0	1/68 (1.5%)	1
Infections and infestations
Appendicitis	1/203 (0.5%)	1	0/68 (0%)	0
Catheter related infection	2/203 (1%)	2	0/68 (0%)	0
Infections and infestations - Other, specify	7/203 (3.4%)	9	6/68 (8.8%)	7
Lung infection	2/203 (1%)	2	1/68 (1.5%)	1
Meningitis	1/203 (0.5%)	1	0/68 (0%)	0
Mucosal infection	1/203 (0.5%)	1	0/68 (0%)	0
Sepsis	8/203 (3.9%)	8	1/68 (1.5%)	1
Upper respiratory infection	1/203 (0.5%)	1	0/68 (0%)	0
Investigations
Alanine aminotransferase increased	1/203 (0.5%)	1	0/68 (0%)	0
Aspartate aminotransferase increased	1/203 (0.5%)	1	0/68 (0%)	0
Blood bilirubin increased	2/203 (1%)	2	0/68 (0%)	0
Neutrophil count decreased	3/203 (1.5%)	3	1/68 (1.5%)	1
Platelet count decreased	3/203 (1.5%)	3	2/68 (2.9%)	2
White blood cell decreased	1/203 (0.5%)	1	0/68 (0%)	0
Metabolism and nutrition disorders
Acidosis	1/203 (0.5%)	1	0/68 (0%)	0
Dehydration	1/203 (0.5%)	1	0/68 (0%)	0
Hypernatremia	1/203 (0.5%)	1	0/68 (0%)	0
Hyponatremia	1/203 (0.5%)	1	0/68 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Leukemia secondary to oncology chemotherapy	2/203 (1%)	3	0/68 (0%)	0
Myelodysplastic syndrome	1/203 (0.5%)	1	1/68 (1.5%)	1
Treatment related secondary malignancy	1/203 (0.5%)	1	0/68 (0%)	0
Nervous system disorders
Intracranial hemorrhage	0/203 (0%)	0	2/68 (2.9%)	2
Myelitis	1/203 (0.5%)	1	0/68 (0%)	0
Seizure	0/203 (0%)	0	1/68 (1.5%)	1
Stroke	1/203 (0.5%)	1	0/68 (0%)	0
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/203 (0.5%)	1	0/68 (0%)	0
Bronchopulmonary hemorrhage	2/203 (1%)	2	0/68 (0%)	0
Hypoxia	1/203 (0.5%)	1	0/68 (0%)	0
Pleural effusion	1/203 (0.5%)	1	0/68 (0%)	0
Pneumonitis	1/203 (0.5%)	1	0/68 (0%)	0
Pneumothorax	1/203 (0.5%)	1	0/68 (0%)	0
Respiratory failure	1/203 (0.5%)	1	0/68 (0%)	0
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other, specify	1/203 (0.5%)	1	0/68 (0%)	0
Vascular disorders
Hypotension	4/203 (2%)	4	1/68 (1.5%)	1
Thromboembolic event	2/203 (1%)	2	0/68 (0%)	0
Other (Not Including Serious) Adverse Events
	Regimen A: Standard Vincristine Dosing		Arm B: Randomized High Dose Vincristine Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	189/203 (93.1%)		66/68 (97.1%)
Blood and lymphatic system disorders
Anemia	51/203 (25.1%)	102	22/68 (32.4%)	40
Bone marrow hypocellular	1/203 (0.5%)	1	0/68 (0%)	0
Disseminated intravascular coagulation	1/203 (0.5%)	1	1/68 (1.5%)	1
Febrile neutropenia	127/203 (62.6%)	250	48/68 (70.6%)	89
Hemolysis	2/203 (1%)	2	0/68 (0%)	0
Leukocytosis	1/203 (0.5%)	1	0/68 (0%)	0
Cardiac disorders
Cardiac arrest	1/203 (0.5%)	1	0/68 (0%)	0
Chest pain - cardiac	1/203 (0.5%)	1	0/68 (0%)	0
Heart failure	0/203 (0%)	0	1/68 (1.5%)	1
Left ventricular systolic dysfunction	4/203 (2%)	4	1/68 (1.5%)	1
Myocarditis	1/203 (0.5%)	1	0/68 (0%)	0
Sinus tachycardia	1/203 (0.5%)	1	0/68 (0%)	0
Wolff-Parkinson-White syndrome	1/203 (0.5%)	1	0/68 (0%)	0
Ear and labyrinth disorders
Ear pain	1/203 (0.5%)	1	0/68 (0%)	0
Hearing impaired	1/203 (0.5%)	1	1/68 (1.5%)	1
Middle ear inflammation	0/203 (0%)	0	1/68 (1.5%)	1
Eye disorders
Eye pain	1/203 (0.5%)	1	1/68 (1.5%)	2
Optic nerve disorder	1/203 (0.5%)	5	1/68 (1.5%)	1
Photophobia	2/203 (1%)	2	1/68 (1.5%)	1
Retinopathy	0/203 (0%)	0	1/68 (1.5%)	1
Gastrointestinal disorders
Abdominal distension	1/203 (0.5%)	1	0/68 (0%)	0
Abdominal pain	14/203 (6.9%)	16	7/68 (10.3%)	11
Anal fistula	2/203 (1%)	2	0/68 (0%)	0
Anal mucositis	0/203 (0%)	0	1/68 (1.5%)	1
Anal pain	2/203 (1%)	2	1/68 (1.5%)	1
Anal ulcer	1/203 (0.5%)	1	0/68 (0%)	0
Ascites	1/203 (0.5%)	1	0/68 (0%)	0
Colitis	9/203 (4.4%)	10	1/68 (1.5%)	1
Constipation	2/203 (1%)	2	0/68 (0%)	0
Dental caries	1/203 (0.5%)	1	1/68 (1.5%)	1
Diarrhea	17/203 (8.4%)	18	11/68 (16.2%)	12
Duodenal hemorrhage	0/203 (0%)	0	1/68 (1.5%)	1
Duodenal perforation	0/203 (0%)	0	1/68 (1.5%)	1
Duodenal ulcer	0/203 (0%)	0	1/68 (1.5%)	1
Dysphagia	1/203 (0.5%)	1	0/68 (0%)	0
Enterocolitis	1/203 (0.5%)	1	0/68 (0%)	0
Esophageal pain	1/203 (0.5%)	1	0/68 (0%)	0
Esophagitis	1/203 (0.5%)	1	0/68 (0%)	0
Fecal incontinence	0/203 (0%)	0	1/68 (1.5%)	1
Gastric fistula	1/203 (0.5%)	1	0/68 (0%)	0
Gastritis	1/203 (0.5%)	1	0/68 (0%)	0
Ileus	1/203 (0.5%)	1	0/68 (0%)	0
Malabsorption	0/203 (0%)	0	1/68 (1.5%)	1
Mucositis oral	43/203 (21.2%)	53	17/68 (25%)	27
Nausea	7/203 (3.4%)	7	6/68 (8.8%)	7
Oral pain	3/203 (1.5%)	4	6/68 (8.8%)	9
Pancreatitis	10/203 (4.9%)	11	0/68 (0%)	0
Rectal hemorrhage	0/203 (0%)	0	1/68 (1.5%)	1
Rectal mucositis	1/203 (0.5%)	1	0/68 (0%)	0
Rectal pain	1/203 (0.5%)	1	1/68 (1.5%)	1
Rectal ulcer	1/203 (0.5%)	1	0/68 (0%)	0
Small intestinal mucositis	1/203 (0.5%)	1	1/68 (1.5%)	1
Stomach pain	1/203 (0.5%)	1	0/68 (0%)	0
Toothache	1/203 (0.5%)	1	0/68 (0%)	0
Typhlitis	6/203 (3%)	7	1/68 (1.5%)	1
Vomiting	15/203 (7.4%)	16	6/68 (8.8%)	6
General disorders
Edema limbs	2/203 (1%)	2	0/68 (0%)	0
Facial pain	0/203 (0%)	0	1/68 (1.5%)	1
Fatigue	2/203 (1%)	2	1/68 (1.5%)	2
Fever	32/203 (15.8%)	37	4/68 (5.9%)	4
Flu like symptoms	0/203 (0%)	0	1/68 (1.5%)	1
General disorders and administration site conditions - Other, specify	1/203 (0.5%)	2	0/68 (0%)	0
Infusion related reaction	2/203 (1%)	2	0/68 (0%)	0
Irritability	1/203 (0.5%)	1	0/68 (0%)	0
Localized edema	1/203 (0.5%)	1	0/68 (0%)	0
Non-cardiac chest pain	2/203 (1%)	2	0/68 (0%)	0
Pain	9/203 (4.4%)	9	7/68 (10.3%)	7
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	1/203 (0.5%)	1	0/68 (0%)	0
Portal hypertension	0/203 (0%)	0	1/68 (1.5%)	1
Immune system disorders
Allergic reaction	5/203 (2.5%)	5	0/68 (0%)	0
Anaphylaxis	10/203 (4.9%)	12	7/68 (10.3%)	8
Immune system disorders - Other, specify	0/203 (0%)	0	1/68 (1.5%)	1
Infections and infestations
Anorectal infection	3/203 (1.5%)	3	1/68 (1.5%)	1
Appendicitis	5/203 (2.5%)	5	0/68 (0%)	0
Appendicitis perforated	0/203 (0%)	0	1/68 (1.5%)	2
Bladder infection	3/203 (1.5%)	3	0/68 (0%)	0
Bone infection	2/203 (1%)	2	0/68 (0%)	0
Bronchial infection	3/203 (1.5%)	3	0/68 (0%)	0
Catheter related infection	30/203 (14.8%)	35	3/68 (4.4%)	4
Device related infection	1/203 (0.5%)	1	0/68 (0%)	0
Enterocolitis infectious	9/203 (4.4%)	9	5/68 (7.4%)	7
Eye infection	0/203 (0%)	0	1/68 (1.5%)	1
Hepatic infection	2/203 (1%)	2	1/68 (1.5%)	1
Infections and infestations - Other, specify	101/203 (49.8%)	207	47/68 (69.1%)	135
Joint infection	1/203 (0.5%)	1	0/68 (0%)	0
Lip infection	1/203 (0.5%)	1	0/68 (0%)	0
Lung infection	22/203 (10.8%)	27	7/68 (10.3%)	8
Lymph gland infection	1/203 (0.5%)	1	0/68 (0%)	0
Meningitis	1/203 (0.5%)	1	0/68 (0%)	0
Mucosal infection	5/203 (2.5%)	5	0/68 (0%)	0
Otitis media	4/203 (2%)	5	0/68 (0%)	0
Pancreas infection	1/203 (0.5%)	3	0/68 (0%)	0
Paronychia	3/203 (1.5%)	4	0/68 (0%)	0
Penile infection	1/203 (0.5%)	1	0/68 (0%)	0
Peripheral nerve infection	2/203 (1%)	2	0/68 (0%)	0
Pleural infection	2/203 (1%)	2	0/68 (0%)	0
Sepsis	25/203 (12.3%)	32	4/68 (5.9%)	4
Sinusitis	4/203 (2%)	5	2/68 (2.9%)	3
Skin infection	16/203 (7.9%)	16	2/68 (2.9%)	2
Soft tissue infection	2/203 (1%)	2	1/68 (1.5%)	1
Upper respiratory infection	9/203 (4.4%)	9	1/68 (1.5%)	1
Urinary tract infection	13/203 (6.4%)	17	3/68 (4.4%)	3
Wound infection	5/203 (2.5%)	6	1/68 (1.5%)	1
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications - Other, specify	1/203 (0.5%)	1	0/68 (0%)	0
Vascular access complication	1/203 (0.5%)	1	1/68 (1.5%)	1
Investigations
Activated partial thromboplastin time prolonged	5/203 (2.5%)	5	4/68 (5.9%)	4
Alanine aminotransferase increased	79/203 (38.9%)	153	24/68 (35.3%)	43
Alkaline phosphatase increased	3/203 (1.5%)	5	0/68 (0%)	0
Aspartate aminotransferase increased	54/203 (26.6%)	74	18/68 (26.5%)	24
Blood bilirubin increased	15/203 (7.4%)	18	10/68 (14.7%)	10
Cholesterol high	4/203 (2%)	5	0/68 (0%)	0
Creatinine increased	4/203 (2%)	4	0/68 (0%)	0
Ejection fraction decreased	1/203 (0.5%)	1	0/68 (0%)	0
Fibrinogen decreased	8/203 (3.9%)	8	4/68 (5.9%)	4
GGT increased	12/203 (5.9%)	16	2/68 (2.9%)	4
INR increased	0/203 (0%)	0	1/68 (1.5%)	1
Investigations - Other, specify	2/203 (1%)	2	0/68 (0%)	0
Lipase increased	17/203 (8.4%)	19	4/68 (5.9%)	4
Lymphocyte count decreased	15/203 (7.4%)	34	5/68 (7.4%)	9
Neutrophil count decreased	127/203 (62.6%)	421	44/68 (64.7%)	152
Platelet count decreased	93/203 (45.8%)	201	32/68 (47.1%)	72
Serum amylase increased	11/203 (5.4%)	13	3/68 (4.4%)	4
Weight gain	1/203 (0.5%)	1	1/68 (1.5%)	1
Weight loss	3/203 (1.5%)	3	1/68 (1.5%)	1
White blood cell decreased	61/203 (30%)	174	25/68 (36.8%)	70
Metabolism and nutrition disorders
Acidosis	1/203 (0.5%)	1	2/68 (2.9%)	3
Alkalosis	1/203 (0.5%)	1	0/68 (0%)	0
Anorexia	20/203 (9.9%)	23	10/68 (14.7%)	18
Dehydration	14/203 (6.9%)	16	7/68 (10.3%)	9
Glucose intolerance	1/203 (0.5%)	1	0/68 (0%)	0
Hypercalcemia	1/203 (0.5%)	1	1/68 (1.5%)	1
Hyperglycemia	26/203 (12.8%)	35	12/68 (17.6%)	13
Hyperkalemia	8/203 (3.9%)	9	2/68 (2.9%)	2
Hypermagnesemia	0/203 (0%)	0	1/68 (1.5%)	2
Hypernatremia	3/203 (1.5%)	3	0/68 (0%)	0
Hypertriglyceridemia	11/203 (5.4%)	17	2/68 (2.9%)	3
Hyperuricemia	2/203 (1%)	2	2/68 (2.9%)	2
Hypoalbuminemia	19/203 (9.4%)	21	7/68 (10.3%)	9
Hypocalcemia	20/203 (9.9%)	23	8/68 (11.8%)	15
Hypokalemia	63/203 (31%)	103	20/68 (29.4%)	35
Hypomagnesemia	2/203 (1%)	2	0/68 (0%)	0
Hyponatremia	31/203 (15.3%)	40	12/68 (17.6%)	15
Hypophosphatemia	20/203 (9.9%)	22	4/68 (5.9%)	4
Iron overload	0/203 (0%)	0	1/68 (1.5%)	1
Tumor lysis syndrome	0/203 (0%)	0	1/68 (1.5%)	1
Musculoskeletal and connective tissue disorders
Avascular necrosis	1/203 (0.5%)	1	1/68 (1.5%)	1
Back pain	6/203 (3%)	6	5/68 (7.4%)	11
Bone pain	1/203 (0.5%)	1	5/68 (7.4%)	6
Buttock pain	1/203 (0.5%)	1	0/68 (0%)	0
Flank pain	1/203 (0.5%)	1	0/68 (0%)	0
Generalized muscle weakness	1/203 (0.5%)	1	1/68 (1.5%)	1
Muscle weakness lower limb	1/203 (0.5%)	1	0/68 (0%)	0
Musculoskeletal and connective tissue disorder - Other, specify	1/203 (0.5%)	1	0/68 (0%)	0
Myalgia	4/203 (2%)	4	0/68 (0%)	0
Myositis	2/203 (1%)	2	0/68 (0%)	0
Neck pain	0/203 (0%)	0	1/68 (1.5%)	1
Pain in extremity	7/203 (3.4%)	7	7/68 (10.3%)	11
Nervous system disorders
Ataxia	1/203 (0.5%)	1	1/68 (1.5%)	1
Depressed level of consciousness	0/203 (0%)	0	2/68 (2.9%)	2
Dizziness	2/203 (1%)	2	1/68 (1.5%)	1
Encephalopathy	2/203 (1%)	2	2/68 (2.9%)	3
Extrapyramidal disorder	0/203 (0%)	0	1/68 (1.5%)	1
Headache	5/203 (2.5%)	5	5/68 (7.4%)	9
Intracranial hemorrhage	1/203 (0.5%)	1	0/68 (0%)	0
Leukoencephalopathy	0/203 (0%)	0	1/68 (1.5%)	1
Nervous system disorders - Other, specify	0/203 (0%)	0	1/68 (1.5%)	1
Neuralgia	2/203 (1%)	2	2/68 (2.9%)	2
Paresthesia	1/203 (0.5%)	1	0/68 (0%)	0
Peripheral motor neuropathy	9/203 (4.4%)	11	7/68 (10.3%)	11
Peripheral sensory neuropathy	7/203 (3.4%)	15	10/68 (14.7%)	19
Reversible posterior leukoencephalopathy syndrome	2/203 (1%)	2	0/68 (0%)	0
Seizure	3/203 (1.5%)	3	0/68 (0%)	0
Syncope	7/203 (3.4%)	7	3/68 (4.4%)	3
Tremor	1/203 (0.5%)	1	1/68 (1.5%)	1
Trigeminal nerve disorder	0/203 (0%)	0	2/68 (2.9%)	2
Psychiatric disorders
Agitation	0/203 (0%)	0	1/68 (1.5%)	1
Anxiety	1/203 (0.5%)	1	2/68 (2.9%)	2
Confusion	0/203 (0%)	0	2/68 (2.9%)	2
Depression	1/203 (0.5%)	1	4/68 (5.9%)	5
Hallucinations	1/203 (0.5%)	1	0/68 (0%)	0
Insomnia	2/203 (1%)	2	1/68 (1.5%)	1
Personality change	0/203 (0%)	0	1/68 (1.5%)	3
Psychosis	1/203 (0.5%)	1	0/68 (0%)	0
Renal and urinary disorders
Acute kidney injury	6/203 (3%)	6	1/68 (1.5%)	1
Renal and urinary disorders - Other, specify	2/203 (1%)	2	2/68 (2.9%)	2
Renal calculi	2/203 (1%)	2	0/68 (0%)	0
Urinary incontinence	0/203 (0%)	0	1/68 (1.5%)	1
Urinary retention	0/203 (0%)	0	1/68 (1.5%)	1
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/203 (0.5%)	1	0/68 (0%)	0
Aspiration	2/203 (1%)	2	0/68 (0%)	0
Atelectasis	1/203 (0.5%)	1	0/68 (0%)	0
Bronchopleural fistula	1/203 (0.5%)	1	0/68 (0%)	0
Bronchospasm	0/203 (0%)	0	1/68 (1.5%)	1
Cough	1/203 (0.5%)	1	1/68 (1.5%)	1
Dyspnea	3/203 (1.5%)	3	3/68 (4.4%)	3
Epistaxis	7/203 (3.4%)	7	0/68 (0%)	0
Hypoxia	20/203 (9.9%)	25	11/68 (16.2%)	14
Pharyngeal mucositis	2/203 (1%)	2	0/68 (0%)	0
Pharyngolaryngeal pain	1/203 (0.5%)	1	0/68 (0%)	0
Pleural effusion	1/203 (0.5%)	1	1/68 (1.5%)	1
Pleuritic pain	0/203 (0%)	0	1/68 (1.5%)	1
Pneumonitis	7/203 (3.4%)	7	3/68 (4.4%)	3
Pneumothorax	1/203 (0.5%)	1	1/68 (1.5%)	1
Pulmonary edema	1/203 (0.5%)	1	0/68 (0%)	0
Respiratory failure	4/203 (2%)	4	0/68 (0%)	0
Respiratory, thoracic and mediastinal disorders - Other, specify	2/203 (1%)	2	2/68 (2.9%)	2
Skin and subcutaneous tissue disorders
Pain of skin	0/203 (0%)	0	1/68 (1.5%)	1
Pruritus	1/203 (0.5%)	1	0/68 (0%)	0
Rash maculo-papular	3/203 (1.5%)	3	1/68 (1.5%)	1
Skin and subcutaneous tissue disorders - Other, specify	3/203 (1.5%)	3	0/68 (0%)	0
Skin ulceration	1/203 (0.5%)	1	1/68 (1.5%)	1
Urticaria	0/203 (0%)	0	1/68 (1.5%)	1
Social circumstances
Social circumstances - Other, specify	1/203 (0.5%)	1	0/68 (0%)	0
Surgical and medical procedures
Surgical and medical procedures - Other, specify	2/203 (1%)	2	0/68 (0%)	0
Vascular disorders
Capillary leak syndrome	1/203 (0.5%)	1	0/68 (0%)	0
Hematoma	1/203 (0.5%)	1	0/68 (0%)	0
Hypertension	4/203 (2%)	5	5/68 (7.4%)	6
Hypotension	31/203 (15.3%)	36	9/68 (13.2%)	9
Thromboembolic event	8/203 (3.9%)	11	1/68 (1.5%)	1
Vascular disorders - Other, specify	2/203 (1%)	2	0/68 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Must obtain prior Sponsor approval.