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Leukemia Lymphoblastic, AcutePhase 1NCT01041508

Clofarabine and Low Dose Total Body Irradiation as a Preparative Regimen for Stem Cell Transplant in Leukemia.

A Phase 1 study testing Clofarabine, Total Body Irradiation and Stem Cell Transplantation in people with Leukemia Lymphoblastic, Acute and Acute Myeloid Leukemia, run by Therapeutic Advances in Childhood Leukemia Consortium at 6 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

Stem cell transplant is an important therapeutic option for pediatric patients with relapsed or refractory leukemia. Although, full myeloablative transplants are widely used for patients with acute leukemia, myeloablative chemo-radiotherapy may not be feasible in some specific settings. Read more about this study

Who is it for?
Ages 1 year to 21 years
What is being tested?
Clofarabine, Total Body Irradiation and Stem Cell Transplantation
Could I receive a placebo?
No, everyone receives an active treatment
How many people
18 participants
Where
6 sitesUnited States
Study dates
29 Jan 2010to Aug 2014
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Since this is a Phase 1 study, any patient who is a candidate for a non-myeloablative SCT because he/she cannot tolerate the standard myeloablative preparative therapy is eligible for this trial. Briefly, the following groups of patients will be targeted and are eligible for this trial:
  • Patients with presence of organ system dysfunction or severe systemic infections that significantly increase the risk of TRM with standard myeloablative regimens.
  • History of previous myeloablative allogeneic or autologous transplantation.
  • Heavily pre-treated leukemia patients, eg. Patients in CR after failure of ≥2 prior regimens.(eg. ALL CR ≥ 3).
  • Combination of toxicities or co-morbidities that leads the investigator to feel that the child is at high risk (>50%) of TRM with standard ablative regimens.
  • The eligibility criteria listed below are interpreted literally and cannot be waived.
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  • Age: Patients must be >1 and < 21 years of age at the of study entry.
  • Diagnosis
  • Patients must have a diagnosis of ALL or AML.
  • ALL patients must be in clinical remission defined as BM morphology <5% blasts and CNS 1 status.
  • AML patients must be in M1 (<5% blasts) or M2 (<20% blasts) marrow status with CNS 1 status.
  • Patient must have an ANC > 750/ul.
  • Donor Selection: Patient must have one of the appropriate donor types as described below:
  • HLA identical sibling donor.
  • Complete matched unrelated donor, (matched at A, B, C, DR B1 and DQ, B1 at the allelic level based on high resolution typing for Class I and II antigens, 10/10 match).
  • 1 allelic mis-matched unrelated donor (antigen mis-matches are not allowed).
  • Stem Cell Source: The stem cell source from the donor must be one of the following:
  • Bone Marrow or Peripheral blood stem cells (PBSC) from a matched related donor.
  • PBSC from an unrelated donor. (Bone marrow is not acceptable for unrelated donors)
  • Performance Level: Karnofsky > 50% for patients > 10 years of age and Lansky > 50% for patients < 10 years of age.
  • Reproductive Function
  • Female patients of childbearing potential must have a negative serum pregnancy test confirmed within 2 weeks prior to enrollment.
  • Female patients with infants must agree not to breastfeed their infants while on this study.
  • Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.
  • Renal and Hepatic Function: Patient must have adequate renal and hepatic functions as indicated by the following laboratory values:
  • Patients must have a calculated creatinine clearance ≥ 70mL/min/m2 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.
  • Total serum bilirubin < 2 mg/dL.
  • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5 × ULN.
  • Cardiac Function: Patient must have a shortening fraction (SF) > 25%. If the SF is <25%, patient must have an ejection fraction (EF) by MUGA of >30%. 3.3.9 Pulmonary Function Patient must have pulmonary function as defined below:
  • DLCO >30%
  • FVC/TLC >30%
  • FEV1 > 30% of predicted
  • Patient is not on continuous oxygen
  • If patient is not old enough or unable to comply with pulmonary function tests, they must have a pulse ox >92% in room air and not be on continuous oxygen.
  • Patients with prior exposure to Clofarabine are eligible.
  • Informed Consent: Patients and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks and benefits of the study. All patients and/or their parents or legal guardians must sign a written informed consent. Age appropriate assent will be obtained per institutional guidelines. To allow non-English speaking patients to participate in this study, bilingual health services will be provided in the appropriate language when feasible.
  • Protocol Approval: All institutional, FDA, and OHRP requirements for human studies must be met.

Who cannot join

  • Patients will be excluded if they meet any of the following criteria:
  • Infection
  • Patients will be excluded if they have evidence of an active, progressive invasive infection. All patients with existing infections at the time study entry should be discussed with the study chair.
  • Patients may have stable invasive infections and still be eligible.
  • Patients with infections that are responsive to medical or surgical treatment as shown by radiographic and or microbial assessment may still be eligible.
  • Patients will be excluded if they have an active, uncontrolled systemic fungal, bacterial, viral or other infection. All patients with existing infections at the time of study entry should be discussed with the study chair.
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  • An active uncontrolled infection is defined as exhibiting ongoing signs and symptoms related to the infection (fevers, positive blood cultures, chills, tachycardia, etc) despite appropriate antibiotics or other treatment.
  • Patient has a diagnosis of CML or MDS.
  • Patient has CNS 2 or CNS 3 status.
  • Patient is HIV positive.
  • Current or planned treatment with chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
  • Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry.
  • Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney (including dialysis patients), liver, or other organ system that may place the patient at undue risk to undergo treatment.
  • 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).
  • Any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, study participation, follow up, or interpretation of study results.

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

United States6 sites

  • Nationwide Childrens Hospital

    Columbus, Ohio, 43205

  • Childrens Hospital Los Angeles

    Los Angeles, California, 90027

  • Vanderbilt Children's Hospital

    Nashville, Tennessee, 37232

  • Oregon Health and Science University

    Portland, Oregon, 97239

  • Primary Children's Hospital

    Salt Lake City, Utah, 84113

  • Seattle Children's Hospital

    Seattle, Washington, 98105

Other trials in United States

About this study

Official title: Phase I Feasibility Study of Clofarabine and Low Dose Total Body Irradiation (TBI) as a Non-myeloablative Preparative Regimen for Stem Cell Transplantation (SCT) for Hematologic Malignancies

Stem cell transplant is an important therapeutic option for pediatric patients with relapsed or refractory leukemia. Although, full myeloablative transplants are widely used for patients with acute leukemia, myeloablative chemo-radiotherapy may not be feasible in some specific settings. These settings include 1) patients with pre-existing health issues and organ toxicities; 2) patients who have relapsed post-ablative transplant and need a second stem cell transplant; and 3) leukemia patients with advanced disease who have been heavily pre-treated. Clofarabine, a new purine nucleoside anti-metabolite, has the advantage of significant antileukemic activity in addition to its possible immuno-suppressive properties. In this study we plan to determine the maximum feasible dose (MFD) of Clofarabine in combination with total body irradiation that can achieve durable donor engraftment without causing excessive toxicity.

Read the detailed description

Standard non-myeloablative regimens use Fludarabine and low dose total body irradiation (TBI) as pioneered by the Seattle group. Fludarabine is mainly used for its immuno-suppressive properties and has limited anti-leukemic effects. Since, the non-myeloablative and RIC regimens do not include intensive chemotherapy; relapse rates can be higher in RIC regimens compared to full myeloablative regimens. One way to improve overall survival in non-myeloablative / RIC setting is to add more effective anti-leukemia agents to prevent post-transplant relapses, without increasing TRM. Clofarabine, a new purine nucleoside anti-metabolite, has the advantage of significant antileukemic activity in addition to its possible immuno-suppressive properties. Combining Clofarabine with low dose TBI as a non-myeloablative preparative regimen may improve overall outcomes of SCT in advanced hematological malignancies. Therefore, in this study we plan to determine the maximum feasible dose (MFD) of Clofarabine in combination with 2Gy TBI that can achieve durable donor engraftment without causing excessive toxicity. The MFD determined from this pilot will be used in the next phase to study the outcomes after using this combination for SCT in this very high risk population.

Being tested
Clofarabine, Total Body Irradiation, Stem Cell Transplantation, Cyclosporine, Mycophenolate Mofetil
Keywords
ALL, AML, Recurrence, Relapsed, Stem Cell Transplant, Non-myeloablative
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Myeloid, Acute, Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ClofarabineDrug

    Also called Clolar, Evoltra

    Clofarabine will be given as an intravenous infusion over 2 hours on days -6 though -2. The dose of Clofarabine will be assigned at study entry (30, 40 or 52 mg/m2).

  • Total Body IrradiationRadiation

    Also called TBI

    Low dose (2 Gy) TBI will be administered from a linear accelerator at ≤ 20 cGy/min on day "0" according to institutional guidelines.

  • Stem Cell TransplantationOther

    Also called SCT

    Patients will be infused with 'unmanipulated' hematopoietic stem cells from a related or unrelated donor on day 0 of the treatment regimen according to institutional practice guidelines.

  • CyclosporineDrug

    Also called Gengraf, Neoral, Sandimmune

    Cyclosporine is given IV based on body weight at:

    • Age ≤ 6 years old: 6 mg/kg IV QD. in divided doses (e.g. 2 mg/kg q8hrs).
    • Age > 6 years old: 3 mg/kg IV QD in divided doses (1.5mg/kg q12hrs)

    Cyclosporine should be started on day -1 after completion of Clofarabine. Levels should be maintained between 300-400 ng/ml.

  • Mycophenolate MofetilDrug

    Also called MMF

    MMF will be at 15 mg/kg, based on adjusted body weight, q 8 hours (45 mg/kg/day; max.3g/day) PO, or IV if indicated, from the evening of day 0 (i.e. first dose 4-6 hours following stem cell infusion) to day +40 post-transplant. Oral doses will be rounded to the nearest 250 mg (capsules are 250 mg). MMF is also available in oral suspension form. MMF will be given until day +40 post transplant and then tapered by 10% per week to be discontinued by day +90.

Study groups in NCT01041508
Study groupRoleWhat they receive
Related Donor ArmExperimentalPatients with related stem cell donors. Patients will receive Clofarabine in combination with 2Gy total body irradiation (TBI) as a preparative regimen for stem cell transplantation, in turn followed by cyclosporine and Mycophenolate Mofetil as GVHD prophylaxis.
Receives: Drug: Clofarabine; Radiation: Total Body Irradiation; Other: Stem Cell Transplantation; Drug: Cyclosporine; Drug: Mycophenolate Mofetil
Unrelated Donor ArmExperimentalPatients with unrelated stem cell donors. Patients will receive Clofarabine in combination with 2Gy total body irradiation (TBI) as a preparative regimen for stem cell transplantation, in turn followed by cyclosporine and Mycophenolate Mofetil as GVHD prophylaxis.
Receives: Drug: Clofarabine; Radiation: Total Body Irradiation; Other: Stem Cell Transplantation; Drug: Cyclosporine; Drug: Mycophenolate Mofetil

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum Feasible Dose of Clofarabine

    The primary objective of the study is to determine the maximum feasible dose (MFD) of Clofarabine that can be given in combination with 2Gy total body irradiation as a non-myeloablative preparative regimen for allogeneic stem cell transplantation in pediatric patients with relapsed leukemia. The MFD is defined as the highest clofarabine dose associated with both an acceptably low toxicity and low non-engraftment (NE) rate. NE is defined as < 5% donor T cells at any time point during serial monitoring. Monitoring during the evaluation period is required Day +30, +60 and +100.

    Measured: Day +100

Secondary outcomes (3)

  1. Days of Engraftment in Both Matched Related Donor (MRD) and Matched Unrelated Donor (MUD)

    Donor engraftment will be assessed by serial monitoring of T-cell (CD3) and myeloid (CD33) chimerism at day +30, 60, 100, 180 and 1 year at the local institution using PCR based VNTR/STR amplification techniques. Neutrophil engraftment is defined as first day of an ANC ≥500/μL on 3 consecutive measurements.

    Measured: Days +30, 60, 100, 180

  2. Transplant Related Mortality (TRM) at Day +100

    TRM is defined as any mortality within the first 100 days post stem cell infusion associated with regimen related toxicity, infection, or GVHD.

    Measured: Day 100

  3. Days to Platelet Recovery

    Platelet recovery is defined as the first day of 3 consecutive measurements of platelets ≥20,000/μL after at least 7 days without transfusion support.

    Measured: Days +30, 60, 100, 180

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Dec 2009 (estimated)
  2. Study start29 Jan 2010
  3. Primary completionAug 2014
  4. Study completionAug 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
18 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01041508
Sponsor's protocol ID
T2008-005
Other IDs
IND 101588
Status last verified
May 2023
First submitted
29 Dec 2009
Last updated
1 Feb 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Soni S, Abdel-Azim H, McManus M, Nemecek E, Sposto R, Woolfrey A, Frangoul H. Phase I Study of Clofarabine and 2-Gy Total Body Irradiation as a Nonmyeloablative Preparative Regimen for Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hematologic Malignancies: A Therapeutic Advances in Childhood Leukemia Consortium Study. Biol Blood Marrow Transplant. 2017 Jul;23(7):1134-1141. doi: 10.1016/j.bbmt.2017.03.037. Epub 2017 Apr 7.

    PubMed 28396162

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Clofarabine, Total Body Irradiation and Stem Cell Transplantation in people with Leukemia Lymphoblastic, Acute and Acute Myeloid Leukemia, run by Therapeutic Advances in Childhood Leukemia Consortium at 6 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 37 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 1 Feb 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Feasible Dose of Clofarabine (time frame: Day +100). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01041508, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2024.

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