Clofarabine With Cytarabine for Patients With Minimal Residual Disease Positive Leukemia

• Sponsor: Therapeutic Advances in Childhood Leukemia Consortium (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01158885
• Collaborator: Genzyme, a Sanofi Company (Industry)
• Enrollment: 2
• Locations: 2
• Arm: 1
• Duration (Months): 26.8
• Patient Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study will test the ability of clofarabine + cytarabine to eliminate minimal residual disease (MRD) in acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) patients whose bone marrows exhibit complete remission by morphology. The toxicity profile of this regimen will be evaluated in addition to toxicity experienced by patients who proceed to stem cell transplant. Overall length of remission will also be collected.

Condition or Disease	Intervention/Treatment	Phase
Minimal Residual Disease; Leukemia, Lymphoblastic, Acute; Leukemia, Myelogenous, Acute	Drug: Clofarabine; Drug: Cytarabine intravenous; Drug: Methotrexate; Drug: Intrathecal (IT) Cytarabine	Phase 2

Detailed Description

Recent studies have demonstrated that even low levels of minimum residual disease (MRD) (>0.01% abnormal blasts) after aggressive re-induction therapy indicate a relatively poor outcome in relapsed acute lymphoblastic leukemia (ALL) patients, including those who proceed to allogeneic stem cell transplant (alloSCT). A similarly poor prognosis was seen in pediatric acute myelogenous leukemia patients with sub-morphologic disease prior to alloSCT. Studies to identify therapies that can eliminate persistent leukemia, have low toxicity profiles and can serve as a bridge to transplant are needed.

This study will test the ability of clofarabine + cytarabine to eliminate minimal residual disease (MRD) in acute myelogenous leukemia and acute lymphoblastic leukemia patients whose bone marrows exhibit complete remission by morphology. The toxicity profile of this regimen will be evaluated in addition to toxicity experienced by patients who proceed to stem cell transplant. Overall length of remission will also be collected.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Clofarabine With Cytarabine for MRD Positive Leukemia
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Oct 24, 2012
• Actual Study Completion Date: Oct 24, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Single Arm A maximum of two courses of the following regimen will be administered. Clofarabine: 20 mg/m2/day intravenously (IV) over 2 hours (given at hours 0 to 2) on days 1 through 5. Cytarabine intravenous: 1 gram/m2/day intravenously (IV) over 2 hours to be given 4 hours after the initiation of clofarabine on days 1 through 5. Methotrexate: to be given intrathecally (IT) to all acute lymphoblastic leukemia (ALL) patients on day 1 at the dose defined by age. Intrathecal (IT) cytarabine: is optional for acute myelogenous leukemia (AML) patients.

Drug: Clofarabine; 20 mg/m2/day intravenously (IV) over 2 hours (given at hours 0 to 2) on days 1 through 5.; Other Names: Clolar CAFdA Cl-F-ara-A ; Drug: Cytarabine intravenous; 1 gram/m2/day intravenously (IV) over 2 hours to be given 4 hours after the initiation of clofarabine on days 1 through 5.; Other Names: AraC Cytosine arabinoside Cytosar ; Drug: Methotrexate; Methotrexate to be given intrathecally (IT) to all acute lymphoblastic leukemia (ALL) patients on day 1 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: MTX Amethopterin ; Drug: Intrathecal (IT) Cytarabine; Intrathecal (IT) cytarabine is optional for acute myelogenous leukemia (AML) patients. If intrathecal cytarabine is to be given, it must be given at least 72 hours but not more than 7 days prior to the initiation of intravenous cytarabine. Dose should be given according to age as defined 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: AraC Cytosine arabinoside Cytosar

Outcome Measures

Primary Outcome Measures

1. Minimal Residual Disease (MRD) [Sample collected between Days 22-36 of courses 1 and 2]

   To be assessed in acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) patients whose bone marrows exhibit complete remission by morphology. Patient's bone marrow will be evaluated for the amount of minimal residual disease (MRD) present after treatment on courses 1 and 2.

Secondary Outcome Measures

1. Number of Patients With Dose-Limiting Toxicity (DLT) [Beginning with the first dose of investigational product until day 56 of treatment course, an average of 1 year]

   Treatment related toxicities that preclude proceeding to HSCT by day 56 of the treatment course.

2. Occurrence of Toxicity During Hematopoietic Cell Transplant (HCT) for Patients Who Achieve Remission and Proceed to Transplant [Every 3 months for life following completion of protocol therapy.]

   After the patient completes therapy on this protocol, data will continue to be collected regarding whether the patient proceeded to HCT. Toxicity and adverse event information will be collected.

Eligibility Criteria

Criteria

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

1. INCLUSION CRITERIA

1. Patients must be ≥1 and ≤ 21 years of age when enrolled onto this study.

2. Diagnosis

• Patients must have a diagnosis of relapsed or refractory AML or ALL and,

• Patient must have an M1 marrow based upon a recovered marrow with less than 5% blasts by conventional morphology and,

• Patient must have minimal residual disease (MRD) detected by either multidimensional or conventional flow cytometry greater than 0.1% and less than 5% following any re-induction attempt and

• Patients must be CNS 1.

1. Patient must have an ANC >500/μL off cytokine support for at least 24 hours and platelets >50,000 K/μL without platelet transfusion in the past seven days

2. Performance Level Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤16 years of age.

3. Patient must have adequate venous access.

4. Prior Therapy

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

6. At least 21 days must have elapsed from prior chemotherapy, at least 7 days must have elapsed since receiving biological therapy.

7. It must be at least 45 days from any higher dose cytarabine therapy (>1 gm/ m2/day).

8. Patients on steroid taper must be on less than 0.5mg/kg/day with plans to continue taper and discontinue the steroids.

9. Renal and Hepatic Function Patient must have adequate renal and hepatic functions as indicated by the following laboratory values:

10. Patients must have a normal calculated creatinine clearance as calculated below:

• Pediatric Population (age <18): Calculated creatinine clearance ≥ 90 ml/min/1.73m2 as calculated by the Schwartz formula for estimated glomerular filtration rate (GFR) where GFR (ml/min/1.73 m2) = k*Height (cm)/serum creatinine (mg/dl). k is a proportionality constant which varies with age and is a function of urinary creatinine excretion per unit of body size; 0.45 up to 12 months of age; 0.55 children and adolescent girls; and 0.70 adolescent boys.

• Adult Population (age ≥18): Serum creatinine ≤1.0 mg/dL; if serum creatinine

1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be > 60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.023 x (0.742 if patient is female) x (1.212 if patient is black.

1. Conjugated (direct) serum bilirubin ≤ 1.5 x ULN for age.

2. Alanine transaminase (ALT) ≤ 2.5 × ULN for age.

3. Alkaline phosphatase ≤ 2.5 × ULN for age.

4. Serum amylase ≤ 1.5 ULN for age.

5. Serum Lipase is ≤ ULN for age.

6. Patient must have a shortening fraction > 28% by echocardiogram or an ejection fraction > 50% by MUGA

7. Reproductive Function

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

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

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

11. Patient must agree to submission of blood and bone marrow for MPF assessment of MRD to TACL centralized lab.

1. EXCLUSION CRITERIA

Patients will be excluded if they meet any of the following criteria:

1. Patients with previous HSCT within previous 180 days.

2. Patients who have had prior treatment with clofarabine.

3. Patients with CNS2 or CNS 3 disease or bulky chloromatous disease.

4. Patients with Down Syndrome.

5. Patients with a previous history of veno-occlusive disease (VOD) or findings consistent with a diagnosis of VOD, defined as: conjugated serum bilirubin >1.4 mg/dL AND unexplained weight gain greater than 10% of baseline weight or ascites AND hepatomegaly or right upper quadrant pain without another explanation, OR reversal of portal vein flow on ultrasound, OR pathological confirmation of VOD on liver biopsy.

6. Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).

7. Use of investigational agents within 30 days of planned treatment on this protocol.

8. Patient is receiving or plans to receive concomitant chemotherapy, radiation therapy, immunotherapy or other anti-cancer therapy other than is specified in the protocol.

9. Pregnant or lactating patients.

10. Any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.

11. Have had a diagnosis of another malignancy, unless the patient has been disease-free for at least 3 years following the completion of curative intent therapy with the following exceptions:

12. Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed.

13. Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed.

14. Patient has active acute (greater than grade II) or active chronic extensive GVHD. Patients who are on a tapering dose of immunosuppressants will be permitted (tapering calcineurin inhibitor and/or less than 0.5 mg/kg/day of steroids).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Carolina-Levine Children's Hospital	Charlotte	North Carolina	United States	28204
2	Seattle Children's Hospital	Seattle	Washington	United States	98105

Sponsors and Collaborators

• Therapeutic Advances in Childhood Leukemia Consortium
• Genzyme, a Sanofi Company

Investigators

• Study Chair: Blythe Thomson, MD, Seattle Children's Hospital

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: NCT01158885
• Other Study ID Numbers: T2009-002
• First Posted: Jul 8, 2010
• Last Update Posted: Oct 26, 2021
• Last Verified: Oct 1, 2021

• 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; relapse; refractory; Minimal Residual disease; MRD; MRD positive; MRD+; ALL; Acute lymphoblastic leukemia; AML; Acute myelogenous leukemia; Relapsed AML
• Additional relevant MeSH terms: Leukemia; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Cytarabine; Methotrexate; Clofarabine

Study Results

Participant Flow

Arm/Group Title	Single Arm
Arm/Group Description	Clofarabine, Cytarabine, Methotrexate See detailed description in Interventions section.
Period Title: Treatment Course 1
STARTED	2
COMPLETED	2
NOT COMPLETED	0
Period Title: Treatment Course 1
STARTED	0
COMPLETED	0
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Single Arm
Arm/Group Description	Clofarabine, Cytarabine, Methotrexate See detailed description in Interventions section.
Overall Participants	2
Age (Count of Participants)
<=18 years	1 50%
Between 18 and 65 years	1 50%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	2 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	1 50%
Unknown or Not Reported	1 50%
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	0 0%
White	2 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Minimal Residual Disease (MRD)
Description	To be assessed in acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) patients whose bone marrows exhibit complete remission by morphology. Patient's bone marrow will be evaluated for the amount of minimal residual disease (MRD) present after treatment on courses 1 and 2.
Time Frame	Sample collected between Days 22-36 of courses 1 and 2

Outcome Measure Data

Analysis Population Description

Study was closed prematurely and none of the patients treated were eligible for analysis of disease response.

Arm/Group Title	Single Arm
Arm/Group Description	Clofarabine, Cytarabine, Methotrexate See detailed description in Interventions section.
Measure Participants	0

2. Secondary Outcome

Title	Number of Patients With Dose-Limiting Toxicity (DLT)
Description	Treatment related toxicities that preclude proceeding to HSCT by day 56 of the treatment course.
Time Frame	Beginning with the first dose of investigational product until day 56 of treatment course, an average of 1 year

Outcome Measure Data

Analysis Population Description

All patients treated on Treatment Course 1.

Arm/Group Title	Single Arm
Arm/Group Description	Clofarabine, Cytarabine, Methotrexate See detailed description in Interventions section.
Measure Participants	2
Count of Participants [Participants]	0 0%

3. Secondary Outcome

Title	Occurrence of Toxicity During Hematopoietic Cell Transplant (HCT) for Patients Who Achieve Remission and Proceed to Transplant
Description	After the patient completes therapy on this protocol, data will continue to be collected regarding whether the patient proceeded to HCT. Toxicity and adverse event information will be collected.
Time Frame	Every 3 months for life following completion of protocol therapy.

Outcome Measure Data

Analysis Population Description

None of the patients treated on Treatment Course 1 proceeded to HCT. 1 patient upon completion of Treatment Course 1 proceeded with Bone Marrow Transplant and 1 patient was removed early from protocol treatment during Course 1 due to progressive disease.

Arm/Group Title	Single Arm
Arm/Group Description	Clofarabine, Cytarabine, Methotrexate See detailed description in Interventions section.
Measure Participants	0

Adverse Events

Time Frame	Approximately 2 years
Adverse Event Reporting Description	The definition of AE and SAE used to collect adverse event information does not differ from the clinicaltrials.gov definitions.
Arm/Group Title	Single Arm
Arm/Group Description	Clofarabine, Cytarabine, Methotrexate See detailed description in Interventions section.
All Cause Mortality
	Single Arm
	Affected / at Risk (%)	# Events
Total	0/2 (0%)
Serious Adverse Events
	Single Arm
	Affected / at Risk (%)	# Events
Total	1/2 (50%)
Blood and lymphatic system disorders
Febrile neutropenia	1/2 (50%)	1
Platelet count decreased	1/2 (50%)	1
Infections and infestations
Grade 4 Infection	1/2 (50%)	1
Other (Not Including Serious) Adverse Events
	Single Arm
	Affected / at Risk (%)	# Events
Total	1/2 (50%)
Blood and lymphatic system disorders
Febrile neutropenia	1/2 (50%)	2
Hemoglobin	1/2 (50%)	1
Leukopenia NOS	1/2 (50%)	1
Lymphopenia	1/2 (50%)	1
Neutrophil count	1/2 (50%)	1
Platelet count decreased	1/2 (50%)	2
Investigations
Alanine aminotransferase	1/2 (50%)	1
Metabolism and nutrition disorders
Hypokalemia	1/2 (50%)	1

Limitations/Caveats

The study only enrolled two patients and closed early due to low accrual.

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.