Preparation for bone marrow transplantation through the combined use of chemo and radiotherapy (Reduced intensity: with lower doses or different combinations).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion Publica Andaluza Para La Gestion De La Investigacion En Salud De Sevilla

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Feb 2025 → ongoing

Decision date (initial)

2024-11-13

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

ISCIII institute public funding

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Dose response, Safety, Therapy

The antitumor activity of TMLI administered, in combination with fludarabine and melphalan for (AHSCT) in patients with risk MDS or AML who are not candidates for myeloablative conditions, as assessed by 2-year progression-free survival.

Secondary objectives 4

1. To estimate overall survival, cumulative incidence (CI) of recurrence/progression, and non-relapse mortality (NRM) at 100 days, 1 year, and 2 years post-transplantation.
2. To determine the complete remission (CR) rate at day +30.
3. Minimal residual disease (MRD) monitoring at 30, 90, 180, 270, 360, 575 and 720 days post-transplant.
4. To assess early and late toxicities/complications by organ/severity (including graft-versus-host disease (GVHD) in its acute and chronic variants), as well as to characterize toxicities by dose/dose-volume across organs.

Conditions and MedDRA coding

High-Risk Myelodisplastic Syndrome OR Acute Myeloid Leukemia.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 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).
2. 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.
3. Age: ≥ 50 years or HCT-CI pre-transplant score ≥ 3 or any other condition that precludes the use of a fully myeloablative conditioning regimen.
4. Karnofsky's performance status ≥ 70%
5. Patients with myelodysplastic syndrome/acute myeloid leukemia (per ICC 2022 criteria) or acute myeloid leukemia with relapsed/refractory active disease (i.e. ≥5% bone marrow blasts), or in complete remission (CR) or morphologic leukemia-free state (MLFS) with evidence of measurable residual disease as assessed by multiparameter flow cytometry (≥ 0,1%) or next-generation sequencing (in the case of FLT3-ITD-mutated AML).
6. All candidates for this study must have an 8/8 HLA-identical (A, B, C, DR) or an unrelated donor with at least 8/8 HLA 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).
7. The time elapsed since the end of the last induction or re-induction cycle must be greater than or equal to 14 days.
8. Total bilirubin ≤ 1.5 mg/dL x Upper Limit of Normality (ULN) OR 3 x ULN for Gilbert's disease.
9. Serum glutamic-oxaloacetic transaminase (SGOT) & serum glutamic-pyruvic transaminase (SGPT) ≤ 5 x ULN.
10. Serum creatinine ≤ 1.3 mg/dL or creatinine clearance measured ≥ 80 mL/min for 24 hours of urine collection.
11. Women of childbearing age only: Negative urine or serum pregnancy test.
12. 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.
13. Pulmonary function tests: forced expiratory volume in one second (FEV1) and Carbon Monoxide Diffusion Capacity (DLCO) (adjusted for Hb) ≥ 50% from expected normal value.
14. Patients should undergo cardiac evaluation with an electrocardiogram showing no ischemic changes or clinically relevant arrhythmia, and a ≥50% ejection fraction established by MUGA or echocardiogram.

Exclusion criteria 10

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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The primary endpoint for the primary patient safety segment of this study is toxicity. Toxicity will be graded on both the Bearman Scale (Appendix I) and the NCI CTCAE Scale and v5.0 (Appendix II).
2. The primary endpoint is 2 year progression-free survival (PFS). PFS will be defined as time from the start of treatment to the date of death, disease relapse/progression, or date of last follow-up, and estimated using the Kaplan-Meier method. Patients are considered a failure for this endpoint if they die or if they relapse/progress. The time to this event is the time from the start of protocol therapy to death, relapse/progression, or the last follow-up, whichever comes first.

Secondary endpoints 9

1. Overall survival (OS): Patients are considered a failure for this endpoint if they die, regardless of the cause. The time to this event is the time from the start of protocol therapy to death, or the last follow-up, whichever comes first.
2. Cumulative incidence (CI) of recurrence/progression: The event is relapse/progression either extramedullary (EM) or at bone marrow (BM) (date and place). The time to this event is measured from the start of therapy. Death without relapse/progression is considered a competing risk. Surviving patients with no history of relapse/progression are censored at the time of last follow-up.
3. Complete remission (CR) rate at day 30 post-transplant: The event is whether or not the patient has a documented CR on day 30. Time to event is measured from the day of infusion to the time of CR.
4. Non-relapse mortality (NRM): Patients are considered a failure for this endpoint if they die from causes other than relapse or progression. NRM is measured from the start of therapy until non-disease-related death, or the last follow-up, whichever comes first.
5. Measurable residual disease (MRD): MRD monitoring assessed by multiparameter flow cytometry at 30, 90, 180, 360, 575 days, and 2 years post-transplant.
6. Incidence of infection: Microbiologically documented infections will be reported by site of illness, date of onset, severity, and resolution, if applicable. This data will be captured through the case report form and will be collected from day 0 to 100 days after transplantation.
7. Toxicities/Adverse Events: The Bearman Scale (non-hematologic) and CTCAE v. 5.0 (hematologic) will be employed. Dose/dose-volume toxicity characterization across organs will be assessed.
8. Acute graft-versus-host disease (GVHD) grades 2-4 and 3-4: Acute graft-versus-host disease is classified according to the consensus classification. The first day of onset of acute GVHD to a certain degree will be used to calculate the cumulative incidence curves for that grade of GVHD. The endpoint will be assessed from day 0 to 100 days post-transplant.
9. Chronic graft-versus-host disease (GVHD): Chronic graft-versus-host disease is graded according to the NIH consensus staging. The first day of onset of chronic GVHD will be used to calculate cumulative incidence curves.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Publica Andaluza Para La Gestion De La Investigacion En Salud De Sevilla

Sponsor organisation

Fundacion Publica Andaluza Para La Gestion De La Investigacion En Salud De Sevilla

Address

Avenida De Manuel Siurot Sn

City

Sevilla

Postcode

41013

Country

Spain

Scientific contact point

Organisation

Fundacion Publica Andaluza Para La Gestion De La Investigacion En Salud De Sevilla

Contact name

Clara María Rosso Fernández

Public contact point

Organisation

Fundacion Publica Andaluza Para La Gestion De La Investigacion En Salud De Sevilla

Contact name

Clara María Rosso Fernández

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications