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Acute Myeloid LeukemiaPhase 1/2NCT05201183

A Dose Escalation Study of Intensity Modulated Total Marrow Irradiation (IMRT-TMI) Followed by Fludarabine as a Myeloablative Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Relapsed and Refractory Hematologic Malignancies

A Phase 1/2 study testing Fludarabine + Total Marrow Irradiation in people with Acute Myeloid Leukemia and Chronic Myeloid Leukemia, run by Naoyuki G. Saito, M.D., Ph.D. at 1 site in United States.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

This is a phase I/II clinical trial to determine the maximum tolerated dose (MTD) of total marrow irradiation (TMI) followed by fludarabine in the context of a myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT), as well as to determine the efficacy of the regimen in… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Fludarabine + Total Marrow Irradiation
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
1 siteUnited States
Study dates
Oct 2023to Apr 2029
Phase
Phase 1/2
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 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Documentation of Disease: Patients must be diagnosed with one of the following conditions:
  • Acute Myeloid Leukemia (AML), with no history of extramedullary disease, who are not in complete remission, who have either primary refractory or relapsed disease, and who do not have more than one of the following adverse factors:
  • Duration of first CR < 6 months (if previously in CR), based on the best overall clinical assessment of the disease course, not solely based on blood test or bone marrow biopsy results
  • Poor risk karyotype including any of the following: complex karyotype with ≥3 clonal abnormalities, 5q-/-5, 7q-/-7, 11q23 abnormalities, inv(3q), 20q or 21q abnormalities, t (6;9), t (9;22), 17p abnormalities [or TP53 mutations] or monosomal karyotype. Molecular typing (except for TP53 mutation) will not be used for eligibility criteria determination.
  • Circulating peripheral blood blasts at time of enrollment
  • Karnofsky performance status <90%
Show all 29Show fewer
  • Acute Lymphocytic Leukemia (ALL) who are not in complete remission, who have either primary refractory or relapsed disease, and who do not have more than one of the following adverse factors:
  • Primary refractory or first relapse. Patients in second or subsequent relapse are excluded.
  • Bone marrow blasts >25% within 30 days before the start of the conditioning regimen
  • Age >40 years
  • Myelodysplasia with a Revised International Prognostic Score (IPSS-R) of greater than 4.5 (i.e., high- or very-high risk).
  • Chronic Myelogenous Leukemia (CML) in accelerated phase, defined by any of the following:
  • 10-19% blasts in peripheral blood white cells or bone marrow
  • Peripheral blood basophils at least 20%
  • Persistent thrombocytopenia (< 100 x 109/l) unrelated to therapy, or persistent thrombocytosis (>1000 x 109/l) unresponsive to therapy
  • Increasing spleen size and increasing white blood cell (WBC) count unresponsive to therapy
  • Cytogenetic evidence of clonal evolution (i.e., the appearance of an additional genetic abnormality that was not present in the initial specimen at the time of diagnosis of chronic phase)
  • The patient must be 18-65 years old at time of consent
  • Signed written informed consent: Patient must be capable of understanding the investigational nature of this study, potential risks and benefits of the study, and be able to provide a valid informed consent.
  • Availability of a consenting human leukocyte antigens (HLA)-matched donor
  • Karnofsky Performance Status 70% or higher
  • Required baseline laboratory values:
  • Estimated creatinine clearance ≥ 60 ml/min
  • Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit of normal value
  • Bilirubin ≤ 1.5 x upper limit of normal value (unless determined to be related to Gilbert's disease)
  • Required baseline cardiac function values:
  • Required baseline cardiac function of left ventricular ejection fraction (LVEF) > 45 % corrected
  • Required baseline pulmonary function values:
  • Required baseline pulmonary function of lung diffusing capacity (DLCO) > 45 % predicted (corrected for hemoglobin))

Who cannot join

  • HIV seropositive patients
  • Pregnant or nursing females.
  • Prior radiation therapy
  • Patients who have had a prior autologous or allogeneic bone marrow or stem cell transplantation
  • Gemtuzumab ozogamicin (trade name: Mylotarg) and/or inotuzumab ozogamicin (trade name: Besponsa) use within 60 days before start of the conditioning regimen
  • Though this is NOT an exclusion criterion, we strongly recommend discontinuation of any steroidal oral contraceptives at least 7 days before start of the conditioning regimen. Use of therapeutic alternatives, including leuprolide should be considered to reduce the risk of SOS/VOD. Of note, for patients already on steroidal oral contraceptives for excessive menorrhagia, the switch to leuprolide should occur at least 2 weeks before the start of the conditioning regimen

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Indiana University Melvin and Bren Simon Comprehensive Cancer Center

    Indianapolis, Indiana, 46202

Other trials in United States

About this study

This is a phase I/II clinical trial to determine the maximum tolerated dose (MTD) of total marrow irradiation (TMI) followed by fludarabine in the context of a myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT), as well as to determine the efficacy of the regimen in patients with high-risk leukemia and myelodysplasia.

Read the detailed description

This is a phase I/II clinical trial to determine the maximum tolerated dose (MTD) of total marrow irradiation (TMI) followed by fludarabine in the context of a myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT), as well as to determine the efficacy of the regimen in patients with high-risk leukemia and myelodysplasia. TMI, which allows for conformal dosing of target bone marrow tissue while giving lower doses to organs at risk, is considered by many to be a superior alternative to conventional total body irradiation (TBI). Through the use of TMI, it is possible to escalate the dose of radiation to the bone marrow while keeping the dose to normal organs at acceptable levels, effectively widening the therapeutic window of this modality. This conditioning regimen will be tried in patients with relapsed or refractory hematologic malignancies.

Primary Objectives:

Phase I: Determine the MTD of TMI (delivered twice a day for 5 days) followed by fludarabine (fixed at 150 mg/m2 given over 5 days) as a conditioning regimen for Allo-HSCT for patients with high risk (relapsed/refractory) acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelogenous leukemia (CML).

Phase II: Single-arm exploratory study to expand the cohort at the MTD level to estimate 1- year overall survival (OS), with the objective of increasing the OS from the historical rate of 30% (null hypothesis) to 50% (alternate hypothesis) with 80% power and a one-sided type I error of 0.05.

Secondary Objectives

  1. Describe the extramedullary toxicity and the incidence of complications, including mucositis, acute and chronic graft versus host disease (GvHD), sinusoidal obstruction syndrome (SOS), and pneumonitis.
  2. Describe the time to engraftment of neutrophils and platelets
  3. Describe the disease response rate at Day 30 after transplantation
  4. Describe the overall survival and disease-free survival
  5. Describe the cumulative incidence of relapse and non-relapse mortality 6
  6. Determine the correlation between plasma/serum markers and radiation induced acute and long term toxicities.
  7. Describe the quality of life metrics of participating subjects
Being tested
Fludarabine + Total Marrow Irradiation
Keywords
Radiation, Total Marrow Irradiation, Fludarabine, Bone Marrow Transplant
Medical subject headings
Leukemia, Myeloid, Acute, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Myelodysplastic Syndromes

What participants receive

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

  • Fludarabine + Total Marrow IrradiationCombination product

    Patients will receive total marrow irradiation TMI on Day -11 to Day -7 in two fractions per day. The TMI dose will be escalated in successive cohorts compromised of 3-6 patients as follows:

    Cohort 1 1.4 (Gy/fraction) Cohort 2: 1.6 (Gy/fraction) Cohort 3 1.8 (Gy/fraction) Cohort 4 2.0 (Gy/fraction) Cohort 5 2.2 (Gy/fraction)

    Patients will receive Fludarabine (30 mg/m2/day) on Day -6 to Day -2 followed by allo-HSCT on Day 0.

Study groups in NCT05201183
Study groupRoleWhat they receive
Fludarabine + Total Marrow IrradiationExperimentalFludarabine will be administered sequentially after the administration of TMI. TMI will be delivered on Days -11, -10, -9, -8, and -7 (1.4-2.2 gray (GY)/fraction, twice a day) followed by fludarabine on Days -6, -5, -4, -3, and -2 (150 mg/m2, 30 mg/m2/day)
Receives: Combination Product: Fludarabine + Total Marrow Irradiation

What is being measured

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

  1. Maximum tolerated dose of Total Marrow Irradiation (TMI) followed by 150 mg/m2 fludarabine- Phase I only

    Measured: Day -10 of conditioning regimen through 30 days post transplant (40 days)

  2. Overall survival (OS) rate 1 year post transplant-Phase II only

    Measured: 1 year

Secondary outcomes (17)

  1. Frequency of non hematologic toxicity

    Measured: 100 days

  2. Incidence of mucositis

    Measured: 100 days

  3. Incidence of acute graft versus host disease

    Measured: 100 days

  4. Incidence of chronic graft versus host disease

    Measured: 100 days

  5. Incidence of sinusoidal obstruction syndrome

    Measured: 100 days

  6. Incidence of pneumonitis

    Measured: 100 days

  7. Time to engraftment of neutrophils

    Measured: rom date of transplant to the first of three consecutive days after transplantation during which the absolute neutrophil count (ANC) is greater than or equal to 0.5 x 10^9/liter

  8. Time to engraftment of platelets

    Measured: the time from Day 0 to the first of seven consecutive days after transplantation during which the platelet count is at least 20 x109/l without transfusion support.

  9. Disease free survival

    Measured: 3 years

  10. Mean Quality of Life (QOL) as measured by Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) version 4

    50 item likert type scale with responses measuring from 0-4 (where 0 = not at all; 1 = a little bit; 2 = somewhat, 3 = quite; and 4 = very much) with higher scores correlating to higher QOL

    Measured: At screening, Day +30, Day +180, Day +365, Day +730 and Day +1095 from transplant (approximately 3 years)

  11. Incidence of non-relapse mortality

    Measured: 30 days

  12. Incidence of non-relapse mortality

    Measured: 100 days

  13. Incidence of non-relapse mortality

    Measured: 1 year

  14. Incidence of relapse mortality

    Measured: 1 year

  15. Incidence of relapse mortality

    Measured: 30 days

  16. Incidence of relapse mortality

    Measured: 100 days

  17. Overall Survival

    Measured: Day +30, Day +100 and 1 year (approximately 3 years)

Timeline

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

  1. First posted21 Jan 2022
  2. Study startOct 2023 (estimated)
  3. Primary completionApr 2027 (estimated)
  4. Study completionApr 2029 (estimated)

Why it stopped: insufficient staff and updates in standard practice have made it difficult to recruit participants

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 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Sequential
Model description
A standard "3+3" phase I design of dose escalation using 3 patients per dose level cohort with an expansion to 6 patients at the MTD will be used in Phase I. We will treat 3 patients at the initial dose level of TMI. If no dose-limiting toxicity (DLT) is observed, the next cohort of three patients is treated at the next higher dose level. If 1 of the 3 patients demonstrates DLT, an additional 3 patients are treated at that dose level. If only 1 of the 6 shows DLT, the next cohort of three patients is entered at the next dose level. If 2 or more of the 6 demonstrate DLT, the MTD is defined as the previous dose level. If no DLT is observed in the final dose level, the number of patients treated will be expanded to 6. In phase II, we will enroll additional patients at the defined MTD level.
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05201183
Sponsor's protocol ID
CTO-IUSCCC-0747
Status last verified
Dec 2023
First submitted
7 Jan 2022
Last updated
11 Dec 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
Yes
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Fludarabine + Total Marrow Irradiation in people with Acute Myeloid Leukemia and Chronic Myeloid Leukemia, run by Naoyuki G. Saito, M.D., Ph.D. 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 29 inclusion and 6 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: withdrawn, as of the sponsor's last update on 11 Dec 2023. 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 combined 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.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

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 tolerated dose of Total Marrow Irradiation (TMI) followed by 150 mg/m2 fludarabine- Phase I only (time frame: Day -10 of conditioning regimen through 30 days post transplant (40 days)). The study lists 2 primary outcomes in all. 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 NCT05201183.

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 11 Dec 2023.

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