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Acute Lymphoblastic LeukemiaPhase 1NCT03494569

Total Marrow and Lymphoid Irradiation, Fludarabine, and Melphalan Before Donor Stem Cell Transplant in Treating Participants With High-Risk Acute Leukemia or Myelodysplastic Syndrome

A Phase 1 study testing Fludarabine, Laboratory Biomarker Analysis and Melphalan in people with Acute Lymphoblastic Leukemia and Acute Lymphoblastic Leukemia in Remission, run by City of Hope Medical Center at 1 site in United States.

Suspended

Paused. Enrolment is on hold for now and may resume.

Official record
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Trial summary

This phase I studies the side effects and best dose of total marrow and lymphoid irradiation when given together with fludarabine and melphalan before donor stem cell transplant in treating participants with high-risk acute leukemia or myelodysplastic syndrome. Read more about this study

Who is it for?
Ages 12 years and older
What is being tested?
Fludarabine, Laboratory Biomarker Analysis and Melphalan
Could I receive a placebo?
No, everyone receives an active treatment
How many people
36 participants
Where
1 siteUnited States
Study dates
6 Jul 2018to 7 Sep 2027
Phase
Phase 1
Are there results?
None posted in the registry

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 12 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Eligible patients with a histopathological confirmed diagnosis of hematologic malignancy in one of the following categories:
  • Acute myelogenous leukemia:
  • Patients with de novo or secondary disease in unfavorable risk group including poor risk cytogenetics according to National Comprehensive Cancer Network (NCCN) guidelines for AML i.e., monosomal karyotype, -5, 5q-, -7, 7q-, 11q23-non t (9;11), inv (3), t (3;3),t (6;9), t (9;22) and complex karyotypes (≥ 3 unrelated abnormalities), or all patient in intermediate risk groups accept patients with FLT3-NPM1+ disease
  • Patients with active disease
  • Patients with chemosensitive active disease
  • Acute lymphocytic leukemia:
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  • Patients with de novo or secondary disease according to NCCN guidelines for ALL hypoploidy (< 44 chromosomes); t (v;11q23): MLL rearranged; t (9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomal abnormalities); high white blood cell (WBC) at diagnosis (≥ 30,000 for B lineage or ≥ 50,000 for T lineage); iAMP21loss of 13q, and abnormal 17p
  • Patients with active disease
  • Patients with chemosensitive active disease
  • Myelodysplastic syndrome in high-intermediate (int-2) and high risk categories
  • Patients ≥ 12 years and < 55 years are also included if they are not candidates for myeloablative conditioning regimens due to comorbidities
  • Karnofsky or Lansky performance status of ≥ 70
  • A pretreatment measured creatinine clearance (absolute value) of ≥ 60 ml/minute
  • Patients must have a serum bilirubin ≤ 2.0 mg/dl
  • Serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) ≤ 2.5 times the institutional upper limits of normal
  • Ejection fraction measured by echocardiogram or multigated acquisition (MUGA) ≥ 50%
  • Carbon monoxide diffusing capacity (DLCO) and forced expiratory volume FEV1 > 50% predicted
  • PATIENT-SPECIFIC INCLUSION CRITERIA
  • Patients should have discontinued all previous intensive therapy, chemotherapy or radiotherapy for 2 weeks prior to commencing therapy on this study
  • NOTE: low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted; these include hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs); FLT-3 inhibitors can also be given up to 3 days before conditioning regimen
  • All patients with prior radiation treatment to the lung, liver, and kidney will be excluded; for other scenarios of prior radiation treatment, up to 2000 cGY at 2 gray Gy per day will be allowed; inclusion of patients with previous radiation exposure will be determined based on the radiation oncologist MD evaluation and judgment
  • DONOR: Arm A: All candidates for this study must have an human leukocyte antigen (HLA) (A, B, C, and DR) identical sibling who is willing to donate primed blood stem cells (preferred) or bone marrow, or have a 10/10 (A, B, C, DR and DQ) allele matched unrelated donor; DQ or DP mismatch is allowed per discretion of the principal investigator
  • DONOR: Arm B: The recipient must have a related donor genotypically HLA-A, B, C and DRB1 loci haploidentical to the recipient; no HLA matched sibling or matched unrelated donor is available; DSA is allowed with desensitization done if recommended by donor selection committee (DSC) per City of Hope (COH) standard operating procedures (SOP)
  • DONOR: Both arms: All donors in both arms should be evaluated and approved by DSC

Who cannot join

  • Having any uncontrolled illness including ongoing or active bacterial, viral or fungal infection
  • Receiving any investigational agents or concurrent biological, intensive chemotherapy or radiation therapy for the previous 2 weeks from conditioning
  • NOTE: low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted; these include: hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs), FLT-3 inhibitors can also be given up to 3 days before conditioning regimen
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to any in the regimen
  • Patients with other malignancies are ineligible for this study, other than non-melanoma skin cancers
  • The recipient has another medical problem or neurologic/psychiatric dysfunction which would impair his/her ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery in which the opinion of the principal investigator would place the recipient at unacceptable risk
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  • Patients may not have had a prior autologous or allogeneic transplant
  • Patients may not have received more than 3 prior lines of intensive chemotherapy, where the regimen intent was to induce remission
  • In the opinion of the principal investigator (PI), the participant has a condition that will preclude them from complying with study treatment
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
  • All subjects must have the ability to understand and the willingness to sign a written informed consent; they are to give voluntary written informed consent before performance if any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care; cognitively impaired subjects will be included only if their guardian or legal representative agrees to sign the written informed consent
  • DONOR: Donor selection for both arms must be approved by the donor selection committee
  • DONOR: Evidence of active infection
  • DONOR: Medical or physical reason which makes the donor unlikely to tolerate or cooperate with growth factor therapy or leukapheresis
  • DONOR: Factors which place the donor at increased risk for complications from leukapheresis or granulocyte-colony stimulating factor (G-CSF) therapy could be harvested for bone marrow (BM) if safer for the donor and if approved by the principal investigator (PI)
  • DONOR: Human immunodeficiency virus (HIV) positive

Trial locations and contacts

1 site in 1 country.

United States1 site

  • City of Hope Medical Center

    Duarte, California, 91010

Other trials in United States

About this study

Official title: Phase I Study of Escalating Doses of Total Marrow and Lymphoid Irradiation (TMLI) Combined With Fludarabine and Melphalan as Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients With High-Risk Acute Leukemia or Myelodysplastic Syndrome

This phase I studies the side effects and best dose of total marrow and lymphoid irradiation when given together with fludarabine and melphalan before donor stem cell transplant in treating participants with high-risk acute leukemia or myelodysplastic syndrome. Giving chemotherapy, such as fludarabine and melphalan, and total marrow and lymphoid irradiation before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the maximum tolerated dose/recommended phase II dose (MTD/RP2D) of total marrow and lymphoid irradiation (TMLI) with fixed doses of fludarabine and melphalan (FM100) as a preparative regimen in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHCT) and who are not eligible for standard myeloablative regimens, with either a matched donor (Arm A) or a haploidentical donor (Arm B).

II. To describe toxicities attributable to TMLI by dose level in patients treated under this regimen.

SECONDARY OBJECTIVES:

  1. To evaluate the safety of the regimen, at each dose level, by assessing the following: type, frequency, severity, attribution, time course and duration of adverse events, including acute/chronic graft versus host disease (GVHD), infection and delayed engraftment.

II. To investigate the temporal effect of bone marrow residual damage in alloHCT patients after TMLI/FM100.

III. To estimate overall survival (OS), event-free survival (EFS), cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100 days, 1 year and 2 years.

IV. Assess minimal residual disease (MRD) from bone marrow aspirates on days 30, 100, and 180 post-transplant and describe its relation to TMLI dose level and patient disease status.

  1. To evaluate effect of TMLI/FM100 conditioning on immune reconstitution after alloHCT in patients receiving stem cells from matched or haploidentical donors.

OUTLINE: This is a dose-escalation study of TMLI.

Participants undergo TMLI twice daily (BID) on days -8 to -5, and receive fludarabine intravenously (IV) on days -4 to -2 and melphalan on day -2. Participants then undergo alloHCT on day 0.

After completion of study treatment, participants are followed up twice weekly for 100 days, twice monthly for 6 months, and then monthly or yearly for up to 2 years.

Being tested
Fludarabine, Laboratory Biomarker Analysis, Melphalan, Total Marrow Irradiation
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Myeloid, Acute, Neoplasm, Residual, Myelodysplastic Syndromes

What participants receive

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

  • FludarabineDrug

    Also called Fluradosa

    Given IV

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • MelphalanDrug

    Also called Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard

    Given as per City of Hope Standard Operating Procedure

  • Total Marrow IrradiationRadiation

    Undergo TMLI

Study groups in NCT03494569
Study groupRoleWhat they receive
Treatment (TMLI, fludarabine, melphalan)ExperimentalParticipants undergo TMLI BID on days -8 to -5, and receive fludarabine IV on days -4 to -2 and melphalan on day -2. Participants then undergo alloHCT on day 0.
Receives: Drug: Fludarabine; Other: Laboratory Biomarker Analysis; Drug: Melphalan; Radiation: Total Marrow Irradiation

What is being measured

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

  1. Incidence of toxicity

    Toxicity will be scored on both the Bearman scale and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5 scale. Toxicity information recorded in each patient will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity, and dose levels in each arm.

    Measured: Up to 2 years

Secondary outcomes (13)

  1. Overall survival

    Participants are considered a failure for this endpoint if they die, regardless of cause. Survival estimates will be calculated using the Kaplan-Meier method.

    Measured: From start of protocol therapy up to 2 years

  2. Event-free survival

    Participants are considered a failure for this endpoint if they relapse/progress or die, regardless of cause. Survival estimates will be calculated using the Kaplan-Meier method.

    Measured: From start of protocol therapy up to 2 years

  3. Relapse/progression

    Death without relapse/progression is considered a competing risk.

    Measured: From start of protocol therapy up to 2 years

  4. Complete remission proportion

    Measured: At day 30

  5. Non-relapse mortality

    Participants are considered a failure for this endpoint if they die from causes other than disease relapse or progression.

    Measured: Up to 2 years

  6. Incidence of infection

    Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any. These data will be captured via case report form.

    Measured: Up to day 100 post-transplant

  7. Incidence of toxicities/adverse events (AEs)

    Toxicities that meet grade 3, 4, or 5 per the Bearman scale and CTCAE v 4.03 from day -9 to day -1, from day 0 to day +30, and again from day +31 to +100 post-transplant will be collected. Any AEs occurring from day -9 to day +30 will be followed until they resolve. Start and stop dates will also be recorded for any grade 4 neutropenia.

    Measured: Up to 100 days post-transplant

  8. Neutrophil recovery

    This will be measured from stem cell infusion to the first to three consecutive days with neutrophil count greater than 0.5 x 10^9/l.

    Measured: Up to 2 years

  9. Acute graft versus host disease of grades 2-4 and 3-4

    Documented/biopsy proven acute graft versus host disease is graded according to National Institutes of Health (NIH) consensus staging. This measurement will be used to estimate the cumulative incidence.

    Measured: Up to 100 days post-transplant

  10. Chronic graft versus host disease

    This will be scored according to NIH consensus staging and will be used to estimate the cumulative incidence.

    Measured: Up to 2 years

  11. CD4+, CD8+ and CD56+16+

    Immunophenotyping of lymphocyte subsets will be determined by flow cytometry.

    Measured: Up to 2 years

  12. Bone marrow (BM) residual damage

    BM cellularity will be assessed using histology and clonogenic in vitro assays.

    Measured: Up to 2 years

  13. Immune reconstitution

    This will be monitored by flow cytometry analysis of peripheral blood mononuclear cells.

    Measured: Up to 2 years

Timeline

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

  1. First posted11 Apr 2018
  2. Study start6 Jul 2018
  3. Primary completion7 Sep 2027 (estimated)
  4. Study completion7 Sep 2027 (estimated)

Why it stopped: Accrual goal

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
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
36 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03494569
Sponsor's protocol ID
17505
Other IDs
NCI-2018-00497, 17505
Status last verified
Sep 2026
First submitted
4 Apr 2018
Last updated
28 Sep 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Fludarabine, Laboratory Biomarker Analysis and Melphalan in people with Acute Lymphoblastic Leukemia and Acute Lymphoblastic Leukemia in Remission, run by City of Hope Medical Center at 1 site 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 24 inclusion and 16 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: paused, as of the sponsor's last update on 28 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site 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?

Results are not available in the source record.

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?

Incidence of toxicity (time frame: Up to 2 years). 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 NCT03494569.

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 28 Sep 2026.

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