Erwinase for Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) (IND 104224)

• Sponsor: Therapeutic Advances in Childhood Leukemia Consortium (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00928200
• Collaborator: (none)
• Enrollment: 1
• Location: 1
• Arm: 1
• Duration (Months): 13.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a phase I study using the Erwinia form of asparaginase in place of the E. coli form using a standard re-induction regimen (Vincristine, Dexamethasone, Doxorubicin) for patients with relapsed ALL who have developed an allergy to the E. coli formulation. This study will administer the drug intravenously instead of the usual intramuscular route. The dose of Erwinia will be escalated in the absence of dose limiting toxicity. Patients must have first or second relapse ALL with a history of prior systemic reaction to E. coli asparaginase.

Condition or Disease	Intervention/Treatment	Phase
Relapsed Acute Lymphoblastic Leukemia; Allergy to PEG e.Coli Asparaginase; Allergy to Native e.Coli Asparaginase	Drug: Erwinase; Drug: Vincristine; Drug: Dexamethasone; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Triple Intrathecal Therapy; Drug: Dexrazoxane	Phase 1

Detailed Description

Significance

1. Substitution of Erwinase after E.coli asparaginase allergy has been standard practice despite the paucity of evidence regarding its efficacy and uncertainty about dose. Definition of an appropriate dose and schedule of Erwinase that provides reliable asparagine depletion may be useful for patients with clinical allergy to E. coli asparaginase, both in first remission or after relapse.

2. Patients in relapse may have a different level of asparagine synthesis than patients maintaining remission and require different asparaginase dosing.5

3. Intravenous administration provides more rapid and predictable asparagine depletion with less discomfort and danger of bleeding for often thrombocytopenic patients than intramuscular administration.

4. Vincristine, doxorubicin, asparaginase, and dexamethasone with dexrazoxane is clinically relevant for a population with first marrow relapse.

5. Vincristine, doxorubicin, asparaginase, and dexamethasone with dexrazoxane is clinically relevant for a population with second marrow relapse, if the duration of CR2 > 18 months year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Intravenous Erwinase for Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia and Allergy to E. Coli Asparaginase (IND 104224)
• Study Start Date: Apr 13, 2009
• Actual Primary Completion Date: Jun 4, 2010
• Actual Study Completion Date: Jun 4, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Single Arm All patients receive Vincristine, Dexamethasone, Doxorubicin, and Cytarabine. Dexrazoxane optional on Day 1. Erwinase is started between Days 3-5 and is given every M-W-F for a total of 10 doses. Patients with CNS 1 or 2 receive Methotrexate intrathecally on Day 15. Patients with CNS 3 receive Triple Intrathecal Therapy (Methotrexate, Cytarabine and Hydrocortisone) on Days 8, 15, and 22.

Drug: Erwinase; The dose of Erwinase will be assigned at study entry. The first dose of Erwinase wil be given between Days 3-5 and will continue on a M-W-F schedule for a total of 10 doses. Erwinase will be administered as a 2-hour intravenous infusion.; Other Names: Asparaginase Elspar Kidrolase L-Asparaginase Erwinia L-Asparaginase ; Drug: Vincristine; 1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22; Other Names: Oncovin Vincasar Pfs Vincristine Sulfate LCR VCR ; Drug: Dexamethasone; 10 mg/m2/day divided BID. Give by mouth days 1-14.; Other Names: Decadron Dexasone Diodex Hexadrol Maxidex Dexamethasone sodium phosphate Dexamethasone acetate ; Drug: Doxorubicin; 60 mg/m2/day IV over 15 minutes on day 1; Other Names: Adriamycin Rubex ; Drug: Cytarabine; Given Intrathecally at the dose defined by age on day 1. 30 mg for age 1-1.99 50 mg for age 2-2.99 70 mg for age 3 and older; Other Names: Cytosar-U Ara-C Arabinosylcytosine ; Drug: Methotrexate; Given Intrathecally to all patients who are CNS 1 or 2 at study entry. Dose defined by age. Given on day 15 8mg for age 1-1.99 10 mg for age 2-2.99 12 mg for age 3-8.99 15 mg for age 9 and older; Other Names: Otrexup Rasuvo Rheumatrex Trexall Amethopterin Methotrexate Sodium MTX ; Drug: Triple Intrathecal Therapy; Methotrexate, Cytarabine and Hydrocortisone given Intrathecally on day 8, 15 and 22 for patients who are CNS 3 at study entry. Doses determined by age.; Drug: Dexrazoxane; Due to the limited availability of Dexrazoxane (Zinecard®), treatment will be at the discretion of the treating physician. Dose should be 600 mg/m2 as a IV push immediately prior to anthracycline dose (the elapsed time from the beginning of the dexrazoxane dose to the end of the anthracycline infusion should be 30 minutes or less).; Other Names: Zinecard

Outcome Measures

Primary Outcome Measures

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

   The MTD in each stratum will be the highest dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy.

Secondary Outcome Measures

1. Response Rate and Minimum Residual Disease [After completion of treatment course]

   Disease response evaluated by examination and labs. MRD evaluated from marrow samples.

2. Asparaginase Activity [PK samples to be collected Pre-Tx, and and Erwinase Doses 3, 6 and 9 and Day 29]

   Activity levels assessed from PK sampling

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 >1 and < 21 years of age when enrolled onto this study.

2. Diagnosis Patients must have relapsed or refractory ALL with a M3 marrow (marrow blasts >25%) who have had no more than two prior therapeutic attempts. Patients with CNS 1, 2, or 3 or testicular disease are eligible. (See section 11.3 for CNS definitions)

3. 1. coli Asparaginase Allergy Patients must have a history of prior systemic allergic reaction to E. coli asparaginase (native or pegylated), such as urticaria, wheezing, or anaphylaxis. Local reactions are not sufficient.

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

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

6. Patients may be in first or second relapse and should not have received more than 2 induction attempts (including frontline therapy).

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

8. 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).

9. Patients may have received previous therapy using intramuscular (IM) Erwinase. Patients who have received Erwinase intravenously will be excluded.

10. Reproductive Function

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

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

13. 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. Prior Stroke Patients with a prior history of asparaginase associated stroke are excluded. Patients with a history of other asparaginase related deep-venous thromboses (including intra-cranial thromboses without evidence of stroke or hemorrhage) are eligible.

2. Down Syndrome Patients with Down Syndrome will be excluded.

3. Prior Pancreatitis Patients with prior history of Grade 2 or greater asparaginase-induced symptomatic pancreatitis will be excluded.

4. Renal Function Patients will be excluded if their serum creatinine is > 1.5 x the upper limit of normal for age at the institution's laboratory.

5. Liver/Pancreatic Function

Patients will be excluded if their lab results are as follows:

1. 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.

2. SGPT (ALT) > 4 x institutional ULN

3. Amylase or Lipase > 2 x institutional ULN

4. Cardiac Function Patients will be excluded if their shortening fraction by echocardiogram is less than the institutional normal for age or an ejection fraction by MUGA is less than the institutional normal for age.

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

6. 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.)

7. Patients planning on receiving other anti-cancer therapies while on this study.

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

9. 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	Childrens Hospital Los Angeles	Los Angeles	California	United States	90027

Sponsors and Collaborators

• Therapeutic Advances in Childhood Leukemia Consortium

Investigators

• Study Chair: Heather Grossman, MD, Children's Hopital New York
• Principal Investigator: Paul Gaynon, MD, Children's Hospital Los Angeles

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Therapeutic Advances in Childhood Leukemia & Lymphoma Consortium web site

Publications

None provided.

• Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
• ClinicalTrials.gov Identifier: NCT00928200
• Other Study ID Numbers: T2006-002
• First Posted: Jun 25, 2009
• Last Update Posted: Feb 19, 2019
• Last Verified: Jul 1, 2018

• 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: Relapsed; Allergy; Erwinia; Acute; Lymphoblastic; Leukemia
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Hypersensitivity; Cytarabine; Dexamethasone; Dexamethasone acetate; Doxorubicin; Methotrexate; Vincristine; Asparaginase; Dexrazoxane; Razoxane; Dexamethasone 21-phosphate; BB 1101

Study Results

Participant Flow

Arm/Group Title	Single Arm
Arm/Group Description	All patients receive Vincristine, Dexamethasone, Doxorubicin, and Cytarabine. Dexrazoxane optional on Day 1. Erwinase is started between Days 3-5 and is given every M-W-F for a total of 10 doses. Patients with CNS 1 or 2 receive Methotrexate intrathecally on Day 15. Patients with CNS 3 receive Triple Intrathecal Therapy (Methotrexate, Cytarabine and Hydrocortisone) on Days 8, 15, and 22. Erwinase: The dose of Erwinase will be assigned at study entry. The first dose of Erwinase wil be given between Days 3-5 and will continue on a M-W-F schedule for a total of 10 doses. Erwinase will be administered as a 2-hour intravenous infusion. Vincristine: 1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22 Dexamethasone: 10 mg/m2/day divided BID. Give by mouth days 1-14. Doxorubicin: 60 mg/m2/day IV over 15 minutes on day 1 Cytarabine: Given Intrathecally at the dose defined by age on day 1. 30 mg for age 1-1.99 50 mg for age 2-2.99 70 mg for age 3
Period Title: Overall Study
STARTED	1
COMPLETED	1
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Single Arm
Arm/Group Description	All patients receive Vincristine, Dexamethasone, Doxorubicin, and Cytarabine. Dexrazoxane optional on Day 1. Erwinase is started between Days 3-5 and is given every M-W-F for a total of 10 doses. Patients with CNS 1 or 2 receive Methotrexate intrathecally on Day 15. Patients with CNS 3 receive Triple Intrathecal Therapy (Methotrexate, Cytarabine and Hydrocortisone) on Days 8, 15, and 22. Erwinase: The dose of Erwinase will be assigned at study entry. The first dose of Erwinase wil be given between Days 3-5 and will continue on a M-W-F schedule for a total of 10 doses. Erwinase will be administered as a 2-hour intravenous infusion. Vincristine: 1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22 Dexamethasone: 10 mg/m2/day divided BID. Give by mouth days 1-14. Doxorubicin: 60 mg/m2/day IV over 15 minutes on day 1 Cytarabine: Given Intrathecally at the dose defined by age on day 1. 30 mg for age 1-1.99 50 mg for age 2-2.99 70 mg for age 3
Overall Participants	1
Age (Count of Participants)
<=18 years	1 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	1 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	1 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 100%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Occurrence of a Dose-Limiting Toxicity
Description	The MTD in each stratum will be the highest dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy.
Time Frame	Beginning with the first dose of investigational product until 30 days following the last dose of Erwinase

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm
Arm/Group Description	All patients receive Vincristine, Dexamethasone, Doxorubicin, and Cytarabine. Dexrazoxane optional on Day 1. Erwinase is started between Days 3-5 and is given every M-W-F for a total of 10 doses. Patients with CNS 1 or 2 receive Methotrexate intrathecally on Day 15. Patients with CNS 3 receive Triple Intrathecal Therapy (Methotrexate, Cytarabine and Hydrocortisone) on Days 8, 15, and 22. Erwinase: The dose of Erwinase will be assigned at study entry. The first dose of Erwinase wil be given between Days 3-5 and will continue on a M-W-F schedule for a total of 10 doses. Erwinase will be administered as a 2-hour intravenous infusion. Vincristine: 1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22 Dexamethasone: 10 mg/m2/day divided BID. Give by mouth days 1-14. Doxorubicin: 60 mg/m2/day IV over 15 minutes on day 1 Cytarabine: Given Intrathecally at the dose defined by age on day 1. 30 mg for age 1-1.99 50 mg for age 2-2.99 70 mg for age 3
Measure Participants	1
Count of Participants [Participants]	0 0%

2. Secondary Outcome

Title	Response Rate and Minimum Residual Disease
Description	Disease response evaluated by examination and labs. MRD evaluated from marrow samples.
Time Frame	After completion of treatment course

Outcome Measure Data

Analysis Population Description

Study closed early due to lack of accrual, and insufficient data were collected for performing this analysis.

Arm/Group Title	Single Arm
Arm/Group Description	All patients receive Vincristine, Dexamethasone, Doxorubicin, and Cytarabine. Dexrazoxane optional on Day 1. Erwinase is started between Days 3-5 and is given every M-W-F for a total of 10 doses. Patients with CNS 1 or 2 receive Methotrexate intrathecally on Day 15. Patients with CNS 3 receive Triple Intrathecal Therapy (Methotrexate, Cytarabine and Hydrocortisone) on Days 8, 15, and 22. Erwinase: The dose of Erwinase will be assigned at study entry. The first dose of Erwinase wil be given between Days 3-5 and will continue on a M-W-F schedule for a total of 10 doses. Erwinase will be administered as a 2-hour intravenous infusion. Vincristine: 1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22 Dexamethasone: 10 mg/m2/day divided BID. Give by mouth days 1-14. Doxorubicin: 60 mg/m2/day IV over 15 minutes on day 1 Cytarabine: Given Intrathecally at the dose defined by age on day 1. 30 mg for age 1-1.99 50 mg for age 2-2.99 70 mg for age 3
Measure Participants	0

3. Secondary Outcome

Title	Asparaginase Activity
Description	Activity levels assessed from PK sampling
Time Frame	PK samples to be collected Pre-Tx, and and Erwinase Doses 3, 6 and 9 and Day 29

Outcome Measure Data

Analysis Population Description

Study closed early due to lack of accrual and insufficient data were collected to perform this analysis.

Arm/Group Title	Single Arm
Arm/Group Description	All patients receive Vincristine, Dexamethasone, Doxorubicin, and Cytarabine. Dexrazoxane optional on Day 1. Erwinase is started between Days 3-5 and is given every M-W-F for a total of 10 doses. Patients with CNS 1 or 2 receive Methotrexate intrathecally on Day 15. Patients with CNS 3 receive Triple Intrathecal Therapy (Methotrexate, Cytarabine and Hydrocortisone) on Days 8, 15, and 22. Erwinase: The dose of Erwinase will be assigned at study entry. The first dose of Erwinase wil be given between Days 3-5 and will continue on a M-W-F schedule for a total of 10 doses. Erwinase will be administered as a 2-hour intravenous infusion. Vincristine: 1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22 Dexamethasone: 10 mg/m2/day divided BID. Give by mouth days 1-14. Doxorubicin: 60 mg/m2/day IV over 15 minutes on day 1 Cytarabine: Given Intrathecally at the dose defined by age on day 1. 30 mg for age 1-1.99 50 mg for age 2-2.99 70 mg for age 3
Measure Participants	0

Adverse Events

Time Frame	6 months
Adverse Event Reporting Description	The definition of AE and SAE do not differ from the clinicaltrials.gov definitions.
Arm/Group Title	Single Arm
Arm/Group Description	All patients receive Vincristine, Dexamethasone, Doxorubicin, and Cytarabine. Dexrazoxane optional on Day 1. Erwinase is started between Days 3-5 and is given every M-W-F for a total of 10 doses. Patients with CNS 1 or 2 receive Methotrexate intrathecally on Day 15. Patients with CNS 3 receive Triple Intrathecal Therapy (Methotrexate, Cytarabine and Hydrocortisone) on Days 8, 15, and 22. Erwinase: The dose of Erwinase will be assigned at study entry. The first dose of Erwinase wil be given between Days 3-5 and will continue on a M-W-F schedule for a total of 10 doses. Erwinase will be administered as a 2-hour intravenous infusion. Vincristine: 1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22 Dexamethasone: 10 mg/m2/day divided BID. Give by mouth days 1-14. Doxorubicin: 60 mg/m2/day IV over 15 minutes on day 1 Cytarabine: Given Intrathecally at the dose defined by age on day 1. 30 mg for age 1-1.99 50 mg for age 2-2.99 70 mg for age 3
All Cause Mortality
	Single Arm
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Serious Adverse Events
	Single Arm
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Metabolism and nutrition disorders
Hyperglycemia	1/1 (100%)
Hyponatremia	1/1 (100%)
Other (Not Including Serious) Adverse Events
	Single Arm
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Blood and lymphatic system disorders
Hemoglobin	1/1 (100%)
Leukopenia NOS	1/1 (100%)
Neutrophil count	1/1 (100%)
Platelet count decreased	1/1 (100%)
Gastrointestinal disorders
Vomiting NOS	1/1 (100%)
Injury, poisoning and procedural complications
Injection site reaction NOS	1/1 (100%)
Investigations
Alanine aminotransferase increased	1/1 (100%)
Blood fibrinogen	1/1 (100%)
Metabolism and nutrition disorders
Hyperkalemia	1/1 (100%)
Hypocalcemia	1/1 (100%)
Hypokalemia	1/1 (100%)
Hypophosphatemia	1/1 (100%)
Nervous system disorders
Agitation	1/1 (100%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/1 (100%)
Skin and subcutaneous tissue disorders
Pruritus	1/1 (100%)

Limitations/Caveats

The study closed early due to lack of accrual and insufficient funding. Only one patient was enrolled. This patient completed the protocol therapy.

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.