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Myelodysplastic SyndromesPhase 2TMLI-RINCT06602323

TMLI/Fludarabine/Melphalan Conditioning for Allogeneic Transplantation in High-risk Myelodysplastic Syndrome or Acute Myeloid Leukemia.

A Phase 2 study testing TMLI/Flu/Mel in people with Myelodysplastic Syndromes and Acute Myeloid Leukemia, run by Fundación Pública Andaluza para la gestión de la Investigación en Sevilla.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
Search all trials

Trial summary

The goal of this clinical trial is to learn if drugs (fludarabine and melphalan) combinated with a targeted irradiation (in bone marrow and in lymphoid tissue) works to treat blood cancers (high risk myelodysplastic syndrome or acute myeloid leukemia) in adults. Read more about this study

Who is it for?
Ages 50 to 99 years
What is being tested?
TMLI/Flu/Mel
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
34 participants
Where
No sites listed yet
Study dates
1 Oct 2024to 1 Oct 2028
Phase
Phase 2
Are there results?
Not yet: the study is under way

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 50 to 99 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • The participant has the ability and willingness to sign the informed consent document. (For adults, only participants with mild cognitive abilities may use a legally authorized representative).
  • Documented (signed) informed consent. The patient, family member, and doctor of the transplant staff (doctor, nurse, and social worker) meet at least once before the transplant procedure begins. During this meeting, all relevant information regarding the risks and benefits to the donor and recipient will be presented. Alternative treatment modalities will be discussed. The risks are explained in detail in the attached consent forms.
  • Age: ≥ 50 years or Haematopoietic Cell Transplantation-Comorbidity Index pre-transplant score ≥ 3 or any other condition that precludes the use of a fully myeloablative conditioning regimen.
  • Karnofsky's performance status ≥ 70%.
  • Patients with myelodysplastic syndrome/acute myeloid leukemia or acute myeloid leukemia with relapsed/refractory active disease (i.e. ≥5% bone marrow blasts), or in complete remission or morphologic leukemia-free state with evidence of measurable residual disease as assessed by multiparameter flow cytometry (≥ 0,1%) or next-generation sequencing (in the case of fms-like tyrosine kinase-3 internal tandem duplication-mutated AML).
  • All candidates for this study must have an 8/8 human leukocyte antigens-identical (A, B, C, DR) sibling donor or an unrelated donor with at least 8/8 human leukocyte antigens matching. A single allele mismatch in A, B, C, DR or dq and a kir mismatch in C shall be allowed. All combinations of donor/recipient "abo" blood types are acceptable; as even major "abo" compatibilities can be treated using a variety of techniques (red blood cell exchange or plasma exchange).
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  • The time elapsed since the end of the last induction or re-induction cycle must be greater than or equal to 14 days.
  • Total bilirubin ≤ 1.5 mg/dL x Upper Limit of Normality OR 3 x upper limit of normal for Gilbert's disease.
  • Serum glutamate oxaloacetate transaminase \& serum glutamate pyruvate transaminase ≤ 5 x Upper Limit of Normality.
  • Serum creatinine ≤ 1.3 mg/dL or creatinine clearance measured ≥ 80 mL/min for 24 hours of urine collection.
  • Women of childbearing age only: Negative urine or serum pregnancy test.
  • Men AND women of childbearing potential agree to use appropriate contraceptives (hormonal or barrier contraception or abstinence) prior to study entry and for six months following the duration of study participation. If a woman becomes pregnant or suspects she is pregnant while participating in the trial, she should inform her treating physician immediately.
  • Pulmonary function tests: forced expiratory volume in one second (FEV1) and Carbon Monoxide Diffusion Capacity (DLCO) (adjusted for Hb) ≥ 50% from expected normal value.
  • Patients should undergo cardiac evaluation with an electrocardiogram showing no ischemic changes or clinically relevant arrhythmia, and a ≥50% ejection fraction established by multigated acquisition scan or echocardiogram.
  • ECG showing no ischemic changes or clinically significant arrhythmia.
  • The time elapsed since the end of the last induction or reinduction cycle must be greater than or equal to 14 days.

Who cannot join

  • Patients who have received a previous autologous (within the last year) or allogeneic transplant (at any time) are excluded.
  • Previous radiation therapy which would preclude the use of TMLI.
  • Plans during the trial to receive any other investigational (non-trial-related) agents.
  • Uncontrolled disease, including ongoing or active infection.
  • History of allergic reactions attributed to compounds of chemical or biological composition similar to cyclophosphamide or etoposide.
  • Patients with other active malignancies are not eligible for this study, other than the malignancies discussed.
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  • Patients with a psychological or medical condition that the patient's physician deems unacceptable to proceed with allogeneic hematopoietic stem cell transplantation.
  • Women who plan to become pregnant or breastfeed during the trial.
  • Patients who do not agree to practice effective forms of contraception.
  • Subjects who, in the opinion of the investigator, may not be able to meet the safety control requirements of the study.

Trial locations and contacts

No sites are listed yet. Contact the study team or a site near you to ask about taking part.

Clara Mª Rosso Fernández contact

+34 955013428

claram.rosso.sspa@juntadeandalucia.es

About this study

Official title: Phase II Study of Total Marrow and Lymphoid Irradiation (TMLI) Administered in Combination With a Reduced-intensity Regimen Based on Fludarabine and Melphalan as Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT) in Patients With High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia.

The goal of this clinical trial is to learn if drugs (fludarabine and melphalan) combinated with a targeted irradiation (in bone marrow and in lymphoid tissue) works to treat blood cancers (high risk myelodysplastic syndrome or acute myeloid leukemia) in adults. It will also learn about the safety of this combination of drugs and irradiation. The main questions it aims to answer are:

  • Does this combined therapy result in an improved survival and decreased relapse/progression rate after a bone marrow transplant?
  • What toxicities or complications do participants have when taking this combined therapy?
Read more

Researchers will use this combined therapy to see if it works to treat high risk myelodysplastic syndrome or acute myeloid leukemia through the evaluation of the length of time (during the treatment and 2 years after the treatment) that a patient lives with the disease but it does not get worse (progression-free survival).

Participants will:

  • Receive the combined therapy (study treatment) one week before the bone marrow transplant.
  • Receive too post-transplant medication as per usual clinical practice.

Patients will have to attend medical visits (checkups and tests) for 2 years.

Read the detailed description

This is a single-arm, single center phase II trial to evaluate the antileukemic activity and safety of the AHSCT TMLI/Flu/Mel conditioning regimen in patients with high-risk myelodysplastic syndrome or acute myeloid leukemia. A patient safety-lead phase will be carried out to ensure there are no unexpected toxicities. Ultimately, a total of 34 patients will be treated at the TMLI/Flu/Mel dose level deemed safe as determined during the introductory patient safety segment of this study.

Up to three dose levels can be studied. A 3+3 de-escalation design comprising a patient safety-lead phase will be applied in successive patient cohorts to evaluate the safety of the TMLI schedule and identify the optimal treatment dose:

Initially, 3 patients will be treated at the starting TMLI dose (Dose Level 1, 1200 cGy). If 0 or 1 DLT is observed among the first 6 patients at Dose Level 1, then 28 additional patients will be treated at this dose level (allowing for the evaluation of 34 patients treated at the target dose level). If ≥2/6 patients experience a DLT at Dose Level 1, then the MTD has been exceeded and the next lower TMLI dose (Dose Level -1, 1100 cGy) will be expanded to up to 6 patients. If 0 or 1 patient out of 6 experiences a DLT, this dose level will be further evaluated (n=28 additional patients). If ≥2/6 patients experience a DLT, the next lower dose (Dose Level -2, 1000 cGy) level will be expanded applying the same criteria. No further dose level reductions will be allowed beyond Dose Level -2.

No more than 3 patients may be \<30 days after stem cell infusion at any time during patient safety introduction. The tacrolimus dose and MMF dose will remain fixed for all defined dose levels and will not be reduced at any time.

Considering this proposed design, the expected sample size of the study will be n=34 patients, with a potential minimum and maximum size of n=34 and n=46, respectively.

Being tested
TMLI/Flu/Mel
Keywords
Myelodysplastic Syndromes, Acute Myeloid Leukemia
Medical subject headings
Myelodysplastic Syndromes, Leukemia, Myeloid, Acute

What participants receive

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

  • TMLI/Flu/MelCombination product

    Targeted total bone marrow and lymphoid irradiation (TMLI) conformal therapy administered in combination with a reduced-intensity regimen based on Fludarabine and Melphalan.

Study groups in NCT06602323
Study groupRoleWhat they receive
TMLI/Flu/Mel conditioning regimen (Single-arm)OtherSingle-arm. TMLI: Dose level 1: 1200 cGy = 150 cGy x 8 doses (liver, brain, and hepatic portal limited to 720 cGy) Dose level -1: 1100 cGy = 137.5 cGy x 8 doses (liver, brain, and hepatic portal limited to 720 cGy) Dose level -2: 1000 cGy = 125 cGy x 8 doses (liver, brain, and hepatic portal limited to 720 cGy) Dose levels above 1,200 cGy will not be considered in this protocol, as the dose to off-target avoidance organs would exceed the recommended levels in reduced-intensity transplants. TMLI will be administered by helical tomotherapy for 4 consecutive days (day -7 to day -4), delivering 2 fractions per day (a total of 8 doses) with a minimum of 6 hours between fractions. FLURADABINE: Dose: 25 mg/m2 Route of administration: intravenous. Treatment duration: for 4 consecutive days (day -7 to day -4 pre-transplant). MELPHALAN: Dose: 140 mg/m2 Route of administration: intravenous Treatment duration: for 1 day (day -2 pre-transplant).
Receives: Combination Product: TMLI/Flu/Mel

What is being measured

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

  1. Progression-free survival

    Time from the start of treatment to the date of death, disease relapse/progression, or date of last follow-up.

    Measured: From the start of therapy to 2 years after study treatment

Secondary outcomes (9)
  1. Overall survival

    Quantification of time of patients who are still alive.

    Measured: From the start of therapy to 2 years after post-transplant.

  2. Cumulative incidence of recurrence/progression

    The event is relapse/progression either extramedullary or at bone marrow

    Measured: From the start of therapy to 2 years after post-transplant.

  3. Complete remission date

    The event is whether or not the patient has a documented complete remission.

    Measured: From the day of infusion to the day 30 post-transplant.

  4. Non-relapse mortality

    Number of deaths from causes other than relapse or progression.

    Measured: From the start of therapy until 2 years after post-transplant.

  5. Measurable residual disease

    Measurable residual disease monitoring assessed by multiparameter flow cytometry.

    Measured: At 30, 90, 180 days and 1 year, 1.5 years and 2 years post-transplant.

  6. Incidence of infection

    Microbiologically documented infections.

    Measured: 2 years after post-transplant.

  7. Adverse events

    Any untoward medical occurrence in a patient participating in clinical research that is associated in time with the use of a medicinal product, whether or not it is considered to be related to the investigational products.

    Measured: 2 years after post-transplant.

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

    This point is classified according to the NIH criteria.

    Measured: 100 days post-transplant.

  9. Chronic graft-versus-host disease

    Chronic graft-versus-host disease is graded according to the NIH consensus staging.

    Measured: 2 years after post-transplant.

Timeline

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

  1. First posted19 Sep 2024
  2. Study start1 Oct 2024 (estimated)
  3. Primary completion1 Oct 2028 (estimated)
  4. Study completion1 Oct 2028 (estimated)

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 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Sequential
Model description
A 3+3 de-escalation design comprising a patient safety-lead phase will be applied in successive patient cohorts: Initially, 3 patients will be treated at the starting TMLI dose (Dose Level 1, 1200 cGy). If 0 or 1 dose-limiting toxicity is observed among the first 6 patients at Dose Level 1, then 28 additional patients will be treated at this dose level (allowing for the evaluation of 34 patients treated at the target dose level). If ≥2/6 patients experience a dose-limiting toxicity at Dose Level 1, then the maximum tolerated dose has been exceeded and the next lower TMLI dose (Dose Level -1, 1100 cGy) will be expanded to up to 6 patients. If 0 or 1 patient out of 6 experiences a dose-limiting toxicity, this dose level will be further evaluated (n=28 additional patients). If ≥2/6 patients experience a dose-limiting toxicity, the next lower dose (Dose Level -2, 1000 cGy) level will be expanded applying the same criteria.
Masking
None (open label)
Enrolment
34 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06602323
Sponsor's protocol ID
TMLI-RI
Other IDs
2024-514483-11-00
Acronym
TMLI-RI
Status last verified
Sep 2024
First submitted
16 Sep 2024
Last updated
19 Sep 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing TMLI/Flu/Mel in people with Myelodysplastic Syndromes and Acute Myeloid Leukemia, run by Fundación Pública Andaluza para la gestión de la Investigación en Sevilla.

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 16 inclusion and 10 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: opening soon, as of the sponsor's last update on 19 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.

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 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?

This study is still under way. Results are not available in the source record yet.

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

Contact Clara Mª Rosso Fernández (+34 955013428, claram.rosso.sspa@juntadeandalucia.es), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-free survival (time frame: From the start of therapy to 2 years after study treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?
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 19 Sep 2024.

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