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Clofarabine With Cytarabine for Patients With Minimal Residual Disease Positive Leukemia

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ClinicalTrials.gov Identifier: NCT01158885
Recruitment Status : Terminated (Study terminated for lack of accrual.)
First Posted : July 8, 2010
Results First Posted : October 7, 2019
Last Update Posted : October 7, 2019
Sponsor:
Collaborator:
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
Therapeutic Advances in Childhood Leukemia Consortium

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Clofarabine With Cytarabine for MRD Positive Leukemia
Study Start Date : August 2010
Actual Primary Completion Date : October 24, 2012
Actual Study Completion Date : October 24, 2012


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




Primary Outcome Measures :
  1. Minimal Residual Disease (MRD) [ Time Frame: 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. Occurrence of a Dose-Limiting Toxicity [ Time Frame: Beginning with the first dose of investigational product until 30 days following the last dose of clofarabine ]
    All toxicities and adverse events will be collected from the first dose of study drug until 30 days following the last dose of Clofarabine

  2. Occurrence of Toxicity During Hematopoietic Cell Transplant (HCT) for Patients Who Achieve Remission and Proceed to Transplant [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

A. 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.
  3. 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
  4. Performance Level Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤16 years of age.
  5. Patient must have adequate venous access.
  6. Prior Therapy

    1. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
    2. At least 21 days must have elapsed from prior chemotherapy, at least 7 days must have elapsed since receiving biological therapy.
    3. It must be at least 45 days from any higher dose cytarabine therapy (>1 gm/ m2/day).
    4. Patients on steroid taper must be on less than 0.5mg/kg/day with plans to continue taper and discontinue the steroids.
  7. Renal and Hepatic Function Patient must have adequate renal and hepatic functions as indicated by the following laboratory values:

    1. 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.
    2. Conjugated (direct) serum bilirubin ≤ 1.5 x ULN for age.
    3. Alanine transaminase (ALT) ≤ 2.5 × ULN for age.
    4. Alkaline phosphatase ≤ 2.5 × ULN for age.
    5. Serum amylase ≤ 1.5 ULN for age.
    6. Serum Lipase is ≤ ULN for age.
  8. Patient must have a shortening fraction > 28% by echocardiogram or an ejection fraction > 50% by MUGA
  9. Reproductive Function

    1. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
    2. Female patients with infants must agree not to breastfeed their infants while on this study.
    3. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.
  10. Patient must agree to submission of blood and bone marrow for MPF assessment of MRD to TACL centralized lab.

B. 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:

    1. 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.
    2. 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.
  12. 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01158885


Locations
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United States, North Carolina
Carolina-Levine Children's Hospital
Charlotte, North Carolina, United States, 28204
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
Sponsors and Collaborators
Therapeutic Advances in Childhood Leukemia Consortium
Genzyme, a Sanofi Company
Investigators
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Study Chair: Blythe Thomson, MD Seattle Children's Hospital

Additional Information:
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Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier: NCT01158885     History of Changes
Other Study ID Numbers: T2009-002
First Posted: July 8, 2010    Key Record Dates
Results First Posted: October 7, 2019
Last Update Posted: October 7, 2019
Last Verified: September 2019

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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:
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Leukemia
Neoplasm, Residual
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Neoplastic Processes
Pathologic Processes
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cytarabine
Methotrexate
Clofarabine
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors