Bortezomib With Chemotherapy for Relapsed Pediatric Acute Lymphoblastic Leukemia (ALL)

• Sponsor: Therapeutic Advances in Childhood Leukemia Consortium (Other)
• Overall Status: Completed
• CT.gov ID: NCT00440726
• Collaborator: (none)
• Enrollment: 31
• Locations: 24
• Arms: 2
• Actual Duration (Months): 54.8
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a Phase I/II study of a drug called bortezomib given in combination with chemotherapy drugs used to treat acute lymphoblastic leukemia (ALL) that has come back (recurred). Bortezomib is a drug that has been approved by the Food and Drug Administration (FDA) for treating adults with multiple myeloma which is a type of blood cancer. Bortezomib has been shown to cause cancer cells to die in studies done on animals (mice). Studies have been done that have shown that some adults and children with cancer have shown a response to bortezomib when it is used alone. Studies have also been done in adults to evaluate the dose of bortezomib that can be safely given in combination with other chemotherapy drugs.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia	Drug: Bortezomib; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Vincristine; Drug: Triple IT Therapy	Phase 1/Phase 2

Detailed Description

All patients will receive 1 course of chemotherapy unless medical complications prevent the administration of some of the drugs. Treatment will last about 1 month.

Treatment on this study will consist of a combination of 7 anti-cancer medications. The 7 anti-cancer medicines are bortezomib, vincristine, dexamethasone, PEG-asparaginase, doxorubicin, cytarabine (Ara-C), and methotrexate (MTX).

If you are in the Phase I portion of this study, you will be given an assigned dose of bortezomib. The dose of bortezomib will be based on doses given in previous studies done with adults and children. At each dose level of bortezomib, between 3 and 6 children will receive bortezomib in combination with chemotherapy. If the side effects are not too severe, the next group of children will receive a higher dose. The dose will continue to be increased until we find the dose that causes serious side effects. Your dose of bortezomib will not be increased. If you have bad side effects, your dose may be decreased.

The dose used during the Phase 2 part of this study will be determined by the outcome of the Phase I study. The highest dose used in Phase I that was tolerated without serious side effects will be the one used in Phase 2.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Study of Bortezomib With Chemotherapy for Relapsed/Refractory Acute Lymphoblastic Leukemia
• Actual Study Start Date: Aug 4, 2006
• Actual Primary Completion Date: Feb 26, 2011
• Actual Study Completion Date: Feb 26, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ph 1 Dose Escalation Intervention: Bortezomib with chemotherapy (dexamethasone, PEG-asparaginase, doxorubicin, cytarabine, methotrexate, and vincristine) and Triple IT therapy for patients who are CNS 2 or 3 at study entry. 3+3 escalation design.	Drug: Bortezomib; Intravenous on days 1, 4, 8 and 11. Dose assigned at study entry.; Other Names: Velcade ; Drug: Dexamethasone; 10 mg/m2/day divided BID, oral administration for 14 days.; Other Names: Decadron ; Drug: PEG-asparaginase; 2500 IU/m2/day, intramuscular injection on Days 2, 8, 15 and 22; Other Names: Oncaspar ; Drug: Doxorubicin; 60 mg/m2/day IV over 15 minutes on Day 1; Other Names: Adriamycin Rubex ; Drug: Cytarabine; Given intrathecally on Day 1 of course 1 at the dose defined by age below. 30 mg for patients age 1-1.99 50 mg for patients age 2-2.99 70 mg for patients >3 years of age; Other Names: Cytosar-U Ara-C Arabinosylcytosine ; Drug: Methotrexate; Given intrathecally to all patients who are CNS 1 at study entry on Day 15 at the dose defined by age below. 8 mg for patients age 1-1.99 10 mg for patients age 2-2.99 12 mg for patients 3-8.99 years of age 15 mg for patients >9 years of age; Other Names: Otrexup Rasuvo Rheumatrex Trexall Amethopterin ; Drug: Vincristine; 1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22.; Other Names: Oncovin Leurocristine ; Drug: Triple IT Therapy; Triple IT therapy will be given intrathecally on Day 8, 15, and 22 for patients who are CNS 2 and CNS 3 at study entry. Regimen/dosing as follows: Methotrexate- <2 years: 8 mg 2 - <3 y: 10 mg 3 - <9 y: 12 mg >=9 y: 15 mg Cytarabine: <2 years: 16 mg 2 - <3 y: 20 mg 3 - <9 y: 24 mg >=9 y: 30 mg Hydrocortisone: <2 years: 8 mg 2 - <3 y: 10 mg 3 - <9 y: 12 mg >=9 y: 15 mg
Experimental: Ph 2 Efficacy and Safety Intervention: Bortezomib with chemotherapy (dexamethasone, PEG-asparaginase, doxorubicin, cytarabine, methotrexate, and vincristine) and Triple IT therapy for patients who are CNS 2 or 3 at study entry. Patients receive bortezomib at maximum tolerated dose (as established in the Phase 1 portion of the study) and are assessed for response and toxicity.	Drug: Bortezomib; Intravenous on days 1, 4, 8 and 11. Dose assigned at study entry.; Other Names: Velcade ; Drug: Dexamethasone; 10 mg/m2/day divided BID, oral administration for 14 days.; Other Names: Decadron ; Drug: PEG-asparaginase; 2500 IU/m2/day, intramuscular injection on Days 2, 8, 15 and 22; Other Names: Oncaspar ; Drug: Doxorubicin; 60 mg/m2/day IV over 15 minutes on Day 1; Other Names: Adriamycin Rubex ; Drug: Cytarabine; Given intrathecally on Day 1 of course 1 at the dose defined by age below. 30 mg for patients age 1-1.99 50 mg for patients age 2-2.99 70 mg for patients >3 years of age; Other Names: Cytosar-U Ara-C Arabinosylcytosine ; Drug: Methotrexate; Given intrathecally to all patients who are CNS 1 at study entry on Day 15 at the dose defined by age below. 8 mg for patients age 1-1.99 10 mg for patients age 2-2.99 12 mg for patients 3-8.99 years of age 15 mg for patients >9 years of age; Other Names: Otrexup Rasuvo Rheumatrex Trexall Amethopterin ; Drug: Vincristine; 1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22.; Other Names: Oncovin Leurocristine ; Drug: Triple IT Therapy; Triple IT therapy will be given intrathecally on Day 8, 15, and 22 for patients who are CNS 2 and CNS 3 at study entry. Regimen/dosing as follows: Methotrexate- <2 years: 8 mg 2 - <3 y: 10 mg 3 - <9 y: 12 mg >=9 y: 15 mg Cytarabine: <2 years: 16 mg 2 - <3 y: 20 mg 3 - <9 y: 24 mg >=9 y: 30 mg Hydrocortisone: <2 years: 8 mg 2 - <3 y: 10 mg 3 - <9 y: 12 mg >=9 y: 15 mg

Outcome Measures

Primary Outcome Measures

1. Occurrence of a Dose-Limiting Toxicity (Phase 1) [Beginning with the first dose of investigational product until 30 days following the last dose of bortezomib]

   Toxicity will be graded using the CTCAE criteria, version 3.0. Dose-limiting toxicity will be defined as any of the following events that are deemed by the investigator as possibly, probably or definitely attributable to bortezomib: Grade 3 or 4 Sensory Neuropathy; Grade 3 or 4 Neuropathic pain (Neuralgia or peripheral nerve) lasting longer than 24 hours despite medical intervention; Marrow hypoplasia, which continues 6 weeks from the start of each course (less than 10% cellularity); and Grade 4 Non-Hematologic Toxicity excluding the following: Infection (septic shock, typhlitis), Fever/Neutropenia, Fatigue, Electrolyte abnormalities, Hyper/Hypoglycemia, Nausea or Vomiting, AST/ALT/Bilirubin elevations that return to grade 1 by the time of the next course.

2. Achievement of Complete Remission (CR) [Day 29 of Course 1]

   Complete Remission (CR): M1 (< 5% blasts) BM with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (ANC>750/uL and platelet count >75 000/uL); Complete Remission without Platelet Recovery (CRp): M1 BM with no circulating blasts or extramedullary disease and recovery of ANC (>750/uL) but insufficient recovery of platelets (<75 000/uL). Partial Remission (PR): the disappearance of circulating blasts and achievement of M2 (5%-25% blasts) marrow status, without new sites of extramedullary disease, and with recovery of ANC (>750/uL). Stable disease (SD): not satisfying the criterion for progressive disease (PD), or a recovery of ANC (>750/uL) but fails to qualify for CR, CRp, or PR. Progressive Disease (PD): increase of at least 25% in the absolute number of circulating leukemia cells, development of new sites of extramedullary disease, or other lab or clinical evidence of PD, with or without recovery of ANC or platelets.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

The eligibility criteria listed below are interpreted literally and cannot be waived.

1. Age Patients must be < 21 years of age when originally diagnosed with ALL. Patient must be > 1 year of age at study entry.

2. Diagnosis Patients must have relapsed or refractory ALL with a M3 marrow (marrow blasts >25%). Patients with CNS I, II or III or testicular disease are eligible.

3. Performance Level Karnofsky > 50% for patients > 10 years of age and Lansky > 50% for patients < 10 years of age.

4. Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

5. Prior anthracycline exposure: Patients must have less than 400mg/m2 lifetime exposure of anthracycline chemotherapy.

6. Stem Cell Transplant (SCT): Patients are eligible after allogeneic stem cell transplant as long as patients are not actively being treated for graft-versus-host-disease (GvHD).

7. Patients should not have received previous therapy using bortezomib (Velcdade® or PS-341).

8. During the phase I portion of the trial, there is no limit on the number of prior treatment regimens. Patients with persistent disease after an induction attempt are eligible.

9. During the phase II portion of the trial, patients must have had two or more prior therapeutic attempts defined as:

• Persistent initial disease after two induction attempts, or

• Relapse after one-reinduction attempt (2nd relapse), or

• Persistent disease after first relapse and initial re-induction attempt

(Patients in first relapse are not eligible for the phase II portion of the study)

1. During the phase II portion of the trial, patients must have no more than 3 prior therapeutic attempts and it must be at least 3 months since the last treatment with a "VPLD" induction/re-induction regimen.

2. Reproductive Function

3. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.

4. Female patients with infants must agree not to breastfeed their infants while on this study.

5. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.

Exclusion Criteria

1. Drug Allergies

Patients will be excluded if they have allergies to the following:

• Asparaginase products

• Boron

• Mannitol

1. Renal Function Patients will be excluded if their serum creatinine is > 2 x the upper limit of normal for age at the institution's laboratory.

2. Liver/Pancreatic Function

3. Direct bilirubin > 1.5x the institutional ULN for age. A total bilirubin result that is less than 1.5 times the institutional ULN for age may be used for eligibility if a direct bilirubin result is not available.

4. SGPT (ALT) > 4 x institutional ULN

5. Grade 3 or greater pancreatitis as defined by the CTCAE v3.0

6. History of any L-asparaginase induced pancreatitis

7. Amylase or Lipase > 2 x institutional ULN

8. Cardiac Function Patients will be excluded if their shortening fraction by echocardiogram is less than 30%.

9. Patients with Down Syndrome are excluded.

10. Infection

• Patients will be excluded if they have an active uncontrolled infection.

• Patients will be excluded if they have had a positive culture within 2 weeks of study entry.

1. Patients with grade 2 or greater motor or sensory neuropathy per CTC 3.0 criteria.

2. Patients planning on receiving other investigational agents while on this study. (An investigational agent is defined as any drug not currently approved for use in humans.)

3. Patients planning on receiving other anti-cancer therapies while on this study. Hydroxyurea for cyto-reduction is allowed prior to the start of therapy.

4. Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.

5. Patients who have started protocol therapy prior to enrollment. Patient may still enroll if IT therapy was given within 72 hours of study enrollment as part of the diagnostic lumbar procedure.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Miller Children's Hospital	Long Beach	California	United States	90806
3	Childrens Hospital Los Angeles	Los Angeles	California	United States	90027
4	Children's Hospital & Research Center Oakland	Oakland	California	United States	94618
5	Stanford University Medical Center	Palo Alto	California	United States	94304-1812
6	UCSF School of Medicine	San Francisco	California	United States	94143-0106
7	Children's National Medical Center	Washington	District of Columbia	United States	20010
8	University of Miami Cancer Center	Miami	Florida	United States	33136
9	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
10	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
11	Johns Hopkins / Sydney Kimmel Cancer Center	Baltimore	Maryland	United States	21231
12	Dana Farber Cancer Center	Boston	Massachusetts	United States	02215
13	C.S. Mott Children's Hospital	Ann Arbor	Michigan	United States	48109-0914
14	Childrens Hospital & Clinics of Minnesota	Minneapolis	Minnesota	United States	55404-4597
15	New York University Medical Center	New York	New York	United States	10016
16	Children's Hospital New York-Presbyterian	New York	New York	United States	10032
17	Levine Children's Hospital	Charlotte	North Carolina	United States	28203
18	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
19	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
20	Seattle Children's Hospital	Seattle	Washington	United States	98105
21	Sydney Children's Hospital	Randwick	New South Wales	Australia	2031
22	The Children's Hospital at Westmead	Westmead	New South Wales	Australia	2145
23	Universidade Federale de Sao Paulo/Hospital Sao Paulo	São Paulo		Brazil	04023-062
24	Sick Kids	Toronto	Ontario	Canada	M5G1X8

Sponsors and Collaborators

• Therapeutic Advances in Childhood Leukemia Consortium

Investigators

• Study Chair: Yoav Messinger, MD, Children's Hospital and Clinics of Minnesota

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for more information about this protocol and the Therapeutic Advances in Childhood Leukemia Consortium

Publications

None provided.

• Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
• ClinicalTrials.gov Identifier: NCT00440726
• Other Study ID Numbers: T2005-003
• First Posted: Feb 27, 2007
• Last Update Posted: Feb 19, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium: Acute Lymphoblastic Leukemia; Pediatrics; Relapsed; Recurrence; Bortezomib; Velcade; Therapeutic Advances in Childhood Leukemia; Investigational; Childhood; ALL; Relapsed ALL; Refractory ALL; Relapsed pediatric ALL; Refractory pediatric ALL; TACL; Recurrent Pediatric ALL
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Cytarabine; Dexamethasone; Doxorubicin; Methotrexate; Vincristine; Bortezomib; Asparaginase; Pegaspargase

Study Results

Participant Flow

Recruitment Details	31 unique individual participants were enrolled into the study collectively for both Phase 1 and 2. The breakdown is as follows: 10 in the Phase I study and 21 in the Phase II study. There was, however, one patient that started on Phase I, Cohort 2 that was later eligible and rolled into the Phase II study.

Arm/Group Title	Phase 1: Cohort 1 Bortezomib 1mg/m2/Day (Dose Level 1)	Phase 1: Cohort 2 Bortezomib 1.3 mg/m2/Day (Dose Level 2)	Phase 2: Bortezomib 1.3 mg/m2/Day (Efficacy)
Arm/Group Description	The starting dose level of bortezomib will be 1 mg/m2/day given 2x week for 2 weeks on Days 1, 4, 8, and 11. The dose will be escalated to 1.3 mg/m2/day assuming that the maximum tolerated dose (MTD) is not exceeded. If the MTD is exceeded, the study will back down to the next whole dose level.	If the MTD is not exceeded at Dose Level 1, the next group of patients enrolled will escalate to Dose Level 2 of bortezomib at 1.3 mg/m2/day given on Days 1, 4, 8, and 11. This dose level is the highest possible dose level.	After the MTD of bortezomib is defined with Phase 1, Phase 2 will enroll patients to receive bortezomib on Day 1, 4, 8 and 11 to evaluate activity of the regimen.
Period Title: Phase 1
STARTED	4	6	0
COMPLETED	3	5	0
NOT COMPLETED	1	1	0
Period Title: Phase 1
STARTED	0	0	22
COMPLETED	0	0	20
NOT COMPLETED	0	0	2

Baseline Characteristics

Arm/Group Title	Phase 1 Dose Level 1	Phase 1 Dose Level 2	Phase 2 Efficacy	Total
Arm/Group Description	Bortezomib (Velcade): Intravenous on days 1, 4, 8 and 11, dose-escalation Dexamethasone: Intravenous or oral administration for 14 days. PEG-asparaginase: Intramuscular injection Doxorubicin: Intravenous infusion Cytarabine: Intrathecal administration on day 1 Methotrexate: Intrathecal administration Vincristine: Intravenous push on days 1, 8, 15, 22 The starting dose level of bortezomib will be 1 mg/m2/day given 2x week for 2 weeks on Days 1, 4, 8, and 11. The dose will be escalated to 1.3 mg/m2/day assuming that the maximum tolerated dose (MTD) is not exceeded. If the MTD is exceeded, the study will back down to the next whole dose level.	If the MTD is not exceeded at Dose Level 1, the next group of patients enrolled will escalate to Dose Level 2 of bortezomib at 1.3 mg/m2/day given on Days 1, 4, 8, and 11. This dose level is the highest possible dose level	After the MTD of bortezomib is defined with Phase 1, Phase 2 will enroll patients to receive bortezomib on Day 1, 4, 8 and 11 to evaluate activity of the regimen. Bortezomib (Velcade): Intravenous on days 1, 4, 8 and 11 at 1.3 mg/m2/day Dexamethasone: Intravenous or oral administration for 14 days. PEG-asparaginase: Intramuscular injection Doxorubicin: Intravenous infusion Cytarabine: Intrathecal administration on day 1 Methotrexate: Intrathecal administration Vincristine: Intravenous push on days 1, 8, 15, 22	Total of all reporting groups
Overall Participants	4	6	21	31
Age (Count of Participants)
<=18 years	4 100%	6 100%	19 90.5%	29 93.5%
Between 18 and 65 years	0 0%	0 0%	2 9.5%	2 6.5%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	3 75%	5 83.3%	7 33.3%	15 48.4%
Male	1 25%	1 16.7%	14 66.7%	16 51.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 75%	1 16.7%	5 23.8%	9 29%
Not Hispanic or Latino	1 25%	5 83.3%	12 57.1%	18 58.1%
Unknown or Not Reported	0 0%	0 0%	4 19%	4 12.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	2 9.5%	2 6.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	4 100%	6 100%	19 90.5%	29 93.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Lineage (Count of Participants)
B-precursor ALL	19 475%	19 316.7%
T-cell ALL	2 50%	2 33.3%
Prior Treatment Attempts (Count of Participants)
One	1 25%	4 66.7%	0 0%	5 16.1%
Two	3 75%	1 16.7%	16 76.2%	20 64.5%
Three	0 0%	0 0%	5 23.8%	5 16.1%
Four	0 0%	1 16.7%	0 0%	1 3.2%
Previous Bone Marrow Transplant (Count of Participants)
None	17 425%	17 283.3%
Yes	4 100%	4 66.7%
Bone Marrow M3 at study entry (Count of Participants)
Count of Participants [Participants]	21 525%	21 350%

Outcome Measures

1. Primary Outcome

Title	Occurrence of a Dose-Limiting Toxicity (Phase 1)
Description	Toxicity will be graded using the CTCAE criteria, version 3.0. Dose-limiting toxicity will be defined as any of the following events that are deemed by the investigator as possibly, probably or definitely attributable to bortezomib: Grade 3 or 4 Sensory Neuropathy; Grade 3 or 4 Neuropathic pain (Neuralgia or peripheral nerve) lasting longer than 24 hours despite medical intervention; Marrow hypoplasia, which continues 6 weeks from the start of each course (less than 10% cellularity); and Grade 4 Non-Hematologic Toxicity excluding the following: Infection (septic shock, typhlitis), Fever/Neutropenia, Fatigue, Electrolyte abnormalities, Hyper/Hypoglycemia, Nausea or Vomiting, AST/ALT/Bilirubin elevations that return to grade 1 by the time of the next course.
Time Frame	Beginning with the first dose of investigational product until 30 days following the last dose of bortezomib

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ph 1, Dose Level 1 (1 mg/m2)	Ph 1, Dose Level 2 (1.3 mg/m2)
Arm/Group Description	Phase 1 patients receiving 1 mg/m2 dose of bortezomib	Phase 1 patients receiving 1.3 mg/m2 dose of bortezomib
Measure Participants	4	6
DLT	0 0%	1 16.7%
No DLT	4 100%	5 83.3%

2. Primary Outcome

Title	Achievement of Complete Remission (CR)
Description	Complete Remission (CR): M1 (< 5% blasts) BM with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (ANC>750/uL and platelet count >75 000/uL); Complete Remission without Platelet Recovery (CRp): M1 BM with no circulating blasts or extramedullary disease and recovery of ANC (>750/uL) but insufficient recovery of platelets (<75 000/uL). Partial Remission (PR): the disappearance of circulating blasts and achievement of M2 (5%-25% blasts) marrow status, without new sites of extramedullary disease, and with recovery of ANC (>750/uL). Stable disease (SD): not satisfying the criterion for progressive disease (PD), or a recovery of ANC (>750/uL) but fails to qualify for CR, CRp, or PR. Progressive Disease (PD): increase of at least 25% in the absolute number of circulating leukemia cells, development of new sites of extramedullary disease, or other lab or clinical evidence of PD, with or without recovery of ANC or platelets.
Time Frame	Day 29 of Course 1

Outcome Measure Data

Analysis Population Description

One Ph 1 patient received incorrect doses of Dexamethasone, so not evaluable for response. One Phase 2 patient achieved BM M1 but was treated with additional chemotherapy before peripheral recovery, so response to protocol treatment could not be evaluated.

Arm/Group Title	Ph 1 Dose Escalation	Ph 2 B-Precursor ALL Patients	Ph 2 T-Cell ALL Patients
Arm/Group Description	Patients enrolled into the Phase 1 portion of the study	Patients enrolled into the Phase 2 portion of the study having B-Precursor ALL	Patients enrolled into the Phase 2 portion of the study having T-Cell ALL
Measure Participants	9	19	2
CR	6 150%	14 233.3%	0 0%
CRp	0 0%	2 33.3%	0 0%
SD/PD	1 25%	0 0%	2 9.5%
BM-CR, CNS-SD	1 25%	0 0%	0 0%
Death	1 25%	3 50%	0 0%

3. Post-Hoc Outcome

Title	Bone Marrow Response
Description	M1: Less than 5% blasts in a bone marrow aspirate and at least 200 cells counted. M2: 5-25% blasts in a bone marrow aspirate with at least 200 cells counted. M3: Greater than 25% blasts in a bone marrow aspirate with at least 200 cells counted.
Time Frame	Day 29 of Course 1

Outcome Measure Data

Analysis Population Description

All patients who enrolled and treated under Phase 2 will be evaluated at the end of Course 1 for treatment response as indicated by measure of bone marrow (M1, M2, or M3) or patient survival if death occurred.

Arm/Group Title	Phase 2 B-Precursor ALL Patients	Phase 2 T-cell ALL Patients
Arm/Group Description	Patients enrolled into the Phase 2 portion of the study having B-Precursor ALL	Patients enrolled into the Phase 2 portion of the study having T-Cell ALL
Measure Participants	20	2
M1	17 425%	0 0%
M2/M3	0 0%	2 33.3%
Death	3 75%	0 0%

Adverse Events

Time Frame	60 days, beginning with the first dose of investigational product until 30 days following the last dose of bortezomib
Adverse Event Reporting Description	The definition of adverse event used for data collection does not differ from that in the clinicaltrials.gov Definitions. For the purpose of reporting SAEs, all Grade 3 and 4 toxicities (CTCAE) are reported in this study record. Patients were evaluated regularly by the treating physician.
Arm/Group Title	1 mg/m2 Dose Group		1.3 mg/m2 Dose Group
Arm/Group Description	Patients receiving a 1 mg/m2 dose of bortezomib (known as Dose Level 1 in the Phase 1 portion). All patients in this group were from the Phase 1 portion of the study.		Patients receiving a 1.3 mg/m2 dose of bortezomib (known as Dose Level 2 in the Phase 1 portion). This group includes patients from both the Phase 1 and Phase 2 portions of the study.
All Cause Mortality
	1 mg/m2 Dose Group		1.3 mg/m2 Dose Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		5/27 (18.5%)
Serious Adverse Events
	1 mg/m2 Dose Group		1.3 mg/m2 Dose Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/4 (50%)		17/27 (63%)
Blood and lymphatic system disorders
Bone marrow depression NOS	0/4 (0%)		1/27 (3.7%)
Febrile neutropenia	1/4 (25%)		2/27 (7.4%)
Gastrointestinal disorders
Caecitis	1/4 (25%)		0/27 (0%)
Diarrhea NOS	0/4 (0%)		1/27 (3.7%)
Lower gastrointestinal hemorrhage	0/4 (0%)		1/27 (3.7%)
Infections and infestations
Infection w/ Gr 3/4 ANC, Blood	1/4 (25%)		8/27 (29.6%)
Infection w/ Gr 3/4 ANC, Brain	0/4 (0%)		1/27 (3.7%)
Infection w/ Gr 3/4 ANC, Skin	0/4 (0%)		1/27 (3.7%)
Infection w/ norm ANC, Blood	0/4 (0%)		1/27 (3.7%)
Infection w/ unk ANC, Mucosa	0/4 (0%)		1/27 (3.7%)
Infection-Other	0/4 (0%)		1/27 (3.7%)
Investigations
Activated partial thromboplastin time prolonged	0/4 (0%)		1/27 (3.7%)
Blood bilirubin increased	0/4 (0%)		1/27 (3.7%)
Lipase increased	1/4 (25%)		1/27 (3.7%)
Neutrophil count	0/4 (0%)		3/27 (11.1%)
Platelet count decreased	0/4 (0%)		2/27 (7.4%)
Metabolism and nutrition disorders
Dehydration	0/4 (0%)		1/27 (3.7%)
Hyperglycemia NOS	0/4 (0%)		2/27 (7.4%)
Hypocalcaemia	0/4 (0%)		1/27 (3.7%)
Hypokalemia	0/4 (0%)		1/27 (3.7%)
Hyponatremia	1/4 (25%)		2/27 (7.4%)
Hypophosphatemia	0/4 (0%)		1/27 (3.7%)
Musculoskeletal and connective tissue disorders
Myalgia	0/4 (0%)		1/27 (3.7%)
Myositis	0/4 (0%)		1/27 (3.7%)
Nervous system disorders
Depressed level of consciousness	0/4 (0%)		1/27 (3.7%)
Encephalopathy	0/4 (0%)		1/27 (3.7%)
Peripheral motor neuropathy	0/4 (0%)		2/27 (7.4%)
Peripheral sensory neuropathy	0/4 (0%)		2/27 (7.4%)
Syncope	0/4 (0%)		1/27 (3.7%)
Psychiatric disorders
Confusion	0/4 (0%)		1/27 (3.7%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	0/4 (0%)		2/27 (7.4%)
Pleural effusion	0/4 (0%)		1/27 (3.7%)
Pneumonia NOS	0/4 (0%)		1/27 (3.7%)
Pneumonitis NOS	0/4 (0%)		1/27 (3.7%)
Vascular disorders
Cerebral ischaemia	0/4 (0%)		2/27 (7.4%)
Hypertension	0/4 (0%)		1/27 (3.7%)
Hypotension NOS	0/4 (0%)		2/27 (7.4%)
Other (Not Including Serious) Adverse Events
	1 mg/m2 Dose Group		1.3 mg/m2 Dose Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		27/27 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	1/4 (25%)		2/27 (7.4%)
Hemoglobin	4/4 (100%)		20/27 (74.1%)
Leukopenia NOS	4/4 (100%)		22/27 (81.5%)
Lymphopenia	1/4 (25%)		5/27 (18.5%)
Neutrophil count	4/4 (100%)		12/27 (44.4%)
Platelet count decreased	3/4 (75%)		21/27 (77.8%)
Cardiac disorders
Sinus bradycardia	1/4 (25%)		1/27 (3.7%)
Endocrine disorders
Cushingoid	0/4 (0%)		2/27 (7.4%)
Gastrointestinal disorders
Abdominal pain NOS	1/4 (25%)		8/27 (29.6%)
Constipation	2/4 (50%)		6/27 (22.2%)
Diarrhea NOS	3/4 (75%)		8/27 (29.6%)
Nausea	2/4 (50%)		8/27 (29.6%)
Oral pain	1/4 (25%)		2/27 (7.4%)
Pancreatitis NOS	1/4 (25%)		1/27 (3.7%)
Proctalgia	1/4 (25%)		0/27 (0%)
Stomatitis	2/4 (50%)		3/27 (11.1%)
Vomiting NOS	2/4 (50%)		6/27 (22.2%)
General disorders
Edema: limb	0/4 (0%)		2/27 (7.4%)
Fatigue	0/4 (0%)		6/27 (22.2%)
Hypothermia	0/4 (0%)		2/27 (7.4%)
Myalgia	0/4 (0%)		2/27 (7.4%)
Pain NOS	0/4 (0%)		3/27 (11.1%)
Pain, External ear	0/4 (0%)		2/27 (7.4%)
Pain-Other	0/4 (0%)		6/27 (22.2%)
Pyrexia	1/4 (25%)		5/27 (18.5%)
Rigors	1/4 (25%)		3/27 (11.1%)
Hepatobiliary disorders
Hepatobiliary/Pancreas-Other	1/4 (25%)		0/27 (0%)
Infections and infestations
Clostridial infection NOS	1/4 (25%)		0/27 (0%)
Implant site infection	1/4 (25%)		0/27 (0%)
Infection w/ Gr 3/4 ANC, Blood	0/4 (0%)		2/27 (7.4%)
Infection-Other	0/4 (0%)		2/27 (7.4%)
Investigations
Activated partial thromboplastin time prolonged	3/4 (75%)		3/27 (11.1%)
Alanine aminotransferase increased	3/4 (75%)		19/27 (70.4%)
Aspartate aminotransferase increased	2/4 (50%)		17/27 (63%)
Blood alkaline phosphatase increased	1/4 (25%)		7/27 (25.9%)
Blood amylase increased	1/4 (25%)		2/27 (7.4%)
Blood bicarbonate decreased	1/4 (25%)		1/27 (3.7%)
Blood bilirubin increased	1/4 (25%)		7/27 (25.9%)
Blood creatinine increased	0/4 (0%)		4/27 (14.8%)
Blood fibrinogen	2/4 (50%)		4/27 (14.8%)
Electrocardiogram QT prolonged	1/4 (25%)		0/27 (0%)
Lipase increased	0/4 (0%)		2/27 (7.4%)
Metabolic/Lab-Other	0/4 (0%)		2/27 (7.4%)
Prothrombin time prolonged	1/4 (25%)		6/27 (22.2%)
Metabolism and nutrition disorders
Anorexia	0/4 (0%)		3/27 (11.1%)
Dehydration	0/4 (0%)		2/27 (7.4%)
Hypercalcemia	1/4 (25%)		3/27 (11.1%)
Hyperglycemia NOS	3/4 (75%)		18/27 (66.7%)
Hyperkalemia	0/4 (0%)		9/27 (33.3%)
Hypermagnesemia	2/4 (50%)		5/27 (18.5%)
Hypernatraemia	0/4 (0%)		2/27 (7.4%)
Hypertriglyceridemia	1/4 (25%)		2/27 (7.4%)
Hypoalbuminemia	2/4 (50%)		23/27 (85.2%)
Hypocalcemia	3/4 (75%)		20/27 (74.1%)
Hypoglycemia NOS	2/4 (50%)		8/27 (29.6%)
Hypokalaemia	3/4 (75%)		11/27 (40.7%)
Hypomagnesemia	1/4 (25%)		4/27 (14.8%)
Hyponatremia	3/4 (75%)		21/27 (77.8%)
Hypophosphatemia	2/4 (50%)		14/27 (51.9%)
Musculoskeletal and connective tissue disorders
Pain in extremity	0/4 (0%)		3/27 (11.1%)
Nervous system disorders
Convulsions NOS	0/4 (0%)		2/27 (7.4%)
Dizziness	0/4 (0%)		3/27 (11.1%)
Headache	1/4 (25%)		2/27 (7.4%)
Hypotension NOS	1/4 (25%)		7/27 (25.9%)
Peripheral sensory neuropathy	0/4 (0%)		3/27 (11.1%)
Tremor	0/4 (0%)		2/27 (7.4%)
Psychiatric disorders
Depression	1/4 (25%)		0/27 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/4 (25%)		2/27 (7.4%)
Epistaxis	2/4 (50%)		4/27 (14.8%)
Pleural effusion	1/4 (25%)		0/27 (0%)
Pleuritic pain	1/4 (25%)		0/27 (0%)
Skin and subcutaneous tissue disorders
Alopecia	0/4 (0%)		2/27 (7.4%)
Dermatitis exfoliative NOS	0/4 (0%)		2/27 (7.4%)
Dermatology-Other	0/4 (0%)		2/27 (7.4%)
Dry skin	0/4 (0%)		4/27 (14.8%)
Pruritus	0/4 (0%)		2/27 (7.4%)
Vascular disorders
Hypertension	0/4 (0%)		7/27 (25.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.