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Acute Myeloid LeukemiaPhase 1NCT03696537

IMRT-TMI With Fludarabine as Myeloablative Conditioning for Allogeneic HSCT

A Phase 1 study testing Fludarabine and Total Marrow Irradiation (TMI) 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.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This is a phase I/II clinical trial on the use of total marrow irradiation (TMI) given concurrently with fludarabine, a chemotherapy drug commonly used to treat leukemia, as a myeloablative therapy for patients undergoing Allo-HSCT. Read more about this study

Who is it for?
Ages 18 to 65 years
What is being tested?
Fludarabine and Total Marrow Irradiation (TMI)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
6 participants
Where
1 siteUnited States
Study dates
29 Aug 2018to 13 Apr 2021
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 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients must be diagnosed with one of the following conditions:
  • Acute Myeloid Leukemia (AML) who are not in complete remission, and 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)
  • 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 31Show fewer
  • Acute Lymphocytic Leukemia (ALL) who are not in complete remission, and who have either primary refractory or relapsed disease, and who do not have more than one of the following adverse factors:
  • First refractory relapse. Patients in second or subsequent relapse are excluded.
  • Donor is CMV seropositive
  • Bone marrow blasts >25% (within 30 days of admission)
  • 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 either
  • 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)
  • Chronic phase provided a complete hematologic remission was not achieved by 3 months or a complete cytogenetic remission by 18 months and the patient had received at least 2 tyrosine kinase inhibitors.
  • Patient age 18-65 years old at time of 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 aminotransferease ≤ 2.5 x upper limit of normal value
  • Bilirubin ≤ 1.5 x upper limit of normal value
  • Required baseline cardiac function of left ventricular ejection fraction (LVEF) > 45
  • corrected
  • Required baseline pulmonary function of lung diffusing capacity (DLCO) > 45 % predicted (corrected for hemoglobin)
  • 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.

Who cannot join

  • Patients with ALL who are in second or subsequent relapse
  • HIV seropositive patients.
  • Pregnant or nursing females are excluded from this study.
  • Prior radiation therapy
  • Patients who have had a prior autologous or allogeneic bone marrow or stem cell transplantation

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Indiana University Melvin & Bren Simon Cancer Center

    Indianapolis, Indiana, 46202

Other trials in United States

About this study

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

This is a phase I/II clinical trial on the use of total marrow irradiation (TMI) given concurrently with fludarabine, a chemotherapy drug commonly used to treat leukemia, as a myeloablative therapy for patients undergoing Allo-HSCT. TMI is a targeted technique to deliver radiation to the bone marrow while minimizing dose to other normal organs in the body. In phase I of the clinical study, the dose of radiation to the bone marrow will be incrementally increased to determine the highest tolerated TMI dose. In phase II, the effectiveness of the TMI-fludarabine conditioning regimen utilizing that dose of radiation will be studied. Acute and long-term toxicity data as well as quality of life data will also be studied.

*Stopping criteria was met during the first dose level cohort in Phase l. The trial will not continue into Phase II as originally planned.

Read the detailed description

This is a phase I/II clinical trial to determine the maximum tolerated dose (MTD) of intensity modulated radiation therapy based total marrow irradiation (TMI) concurrent with fludarabine as 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 and relapsed or refractory 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)

Primary Objectives:

Phase I:

Determine the MTD of TMI given concurrently with fludarabine (fixed at 150 mg/m2) 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. 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
  • Stopping criteria was met during the first dose level cohort in Phase l. The trial will not continue into Phase II as originally planned.
Being tested
Fludarabine, Total Marrow Irradiation (TMI)
Keywords
Radiation, Total Marrow Irradiation, Fludarabine, Bone Marrow Transplantation
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.

  • FludarabineDrug

    Fludarabine 30 mg/m2/day IV (total 5 doses) administered days -7 through -3 of conditioning regimen

  • Total Marrow Irradiation (TMI)Radiation

    TMI will be delivered twice a day, at least 6 hours apart, on days -7 through -3 (total of 10 fractions) of conditioning regimen

Study groups in NCT03696537
Study groupRoleWhat they receive
Fludarabine + Total Marrow IrradiationExperimentalNot described
Receives: Drug: Fludarabine; Radiation: Total Marrow Irradiation (TMI)

What is being measured

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

  1. Dose limiting toxicity (DLT) of Total Marrow Irradiation (TMI) in combination with 150 mg/m2 fludarabine- Phase I only

    Measured: Day -7 of conditioning regimen through 30 days post transplant (37 days)

  2. Maximum-tolerated dose (MTD) of Total Marrow Irradiation (TMI) in combination with 150 mg/m2 fludarabine-Phase I only

    Measured: Day -7 of conditioning regimen through 30 days post transplant (37 days)

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

    Measured: 1 year

Secondary outcomes (19)

  1. Frequency of non hematologic toxicities

    Measured: 100 days

  2. Incidence of infection

    Measured: 100 days

  3. Type of infections

    Measured: 100 days

  4. Incidence of graft versus host disease (GvHD)

    Measured: 100 days

  5. Incidence of chronic graft versus host disease (GvHD)

    Measured: 2 years

  6. Incidence of sinusoidal obstruction syndrome (SOS)

    Measured: 100 days

  7. Incidence of pneumonitis

    Measured: 100 days

  8. Incidence of mucositis

    Measured: 100 days

  9. Time to engraftment of neutrophils

    Measured: from 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

  10. Time to engraftment of platelets

    Measured: from date of transplant until he first of seven consecutive days after transplantation during which the platelet count is greater than or equal to 20 x10^9/liters without transfusion.

  11. Disease response rate

    Measured: Day 30 after transplant (30 days)

  12. Incidence of relapse mortality

    Measured: 30 days

  13. Incidence of relapse mortality

    Measured: 100 days

  14. Incidence of relapse mortality

    Measured: 1 year

  15. Incidence of non-relapse mortality

    Measured: 30 days

  16. Incidence of non-relapse mortality

    Measured: 100 days

  17. Incidence of non-relapse mortality

    Measured: 1 year

  18. Disease-Free Survival

    Measured: 2 years

  19. 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: Screening (at simulation), day +180, day +365, + 2 years from transplant (approximately 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 posted4 Oct 2018
  2. Study start29 Aug 2018
  3. Primary completion8 Jul 2020
  4. Study completion13 Apr 2021

Why it stopped: Extreme toxicity

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
Sequential
Model description
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. \*Stopping criteria was met during the first dose level cohort in Phase l. The trial will not continue into Phase II as originally planned.
Masking
None (open label)
Enrolment
6 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03696537
Sponsor's protocol ID
IUSCC-0652
Status last verified
Feb 2022
First submitted
2 Oct 2018
Last updated
9 Mar 2022
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 and Total Marrow Irradiation (TMI) 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 31 inclusion and 5 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: stopped early, as of the sponsor's last update on 9 Mar 2022. 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?

The study was stopped early (reason given: Extreme toxicity). 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?

Dose limiting toxicity (DLT) of Total Marrow Irradiation (TMI) in combination with 150 mg/m2 fludarabine- Phase I only (time frame: Day -7 of conditioning regimen through 30 days post transplant (37 days)). The study lists 3 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 NCT03696537.

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 9 Mar 2022; AzTrials last refreshed its copy on 6 Nov 2026.

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