Effect of Moderate Renal Impairment and Race/Ethnicity on Treosulfan Pharmacokinetics

Myelodysplastic Syndrome (MDS) Clinical Trial

Official title:

An Open-label, Non-randomized, Prospective Trial to Evaluate the Effect of Renal Function Impairment and Race/Ethnicity on Treosulfan Pharmacokinetics in Patients With AML or MDS Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05534620
• Other study ID #: MC-FludT.19/PK
• Status: Recruiting
• Phase: Phase 1
• Start date: February 1, 2024
• Est. completion date: December 2025

Study information

• Verified date: February 2024
• Source: medac GmbH
• Contact: Ute Eckenbach
• Phone: +49 6074 486 2036
• Email: ute.eckenbach[@]synteract.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study aim is to assess, if treosulfan pharmacokinetics are influenced by declined renal function and by race/ethnicity of patients. The study also aims to determine an appropriate safe dose of treosulfan, when patient's renal function is impaired. The participants of this study are undergoing allogenic hematopoietic stem cell transplantation for treatment of acute myeloid leukemia or myelodysplastic syndrome.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: December 2025
• Est. primary completion date: August 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Participants with AML or MDS who qualify for treosulfan-based conditioning treatment, indicated for alloHSCT.

2. Have available matched-related, matched-unrelated, haploidentical, or a mismatched unrelated donor. Match is defined as at least 9/10 allele matches in human leucocyte antigen (HLA)-A, -B, -C, -DRB1 and DQB1 or 7/8 allele matches in (HLA)-A, -B, -C and -DRB1. Haploidentical is defined as any family member with 2, 3 or 4 (out of 8) HLA-loci mismatch; at the same time, the donor and recipient must be HLA identical for at least one antigen at the following genetic loci: (HLA)-A, -B, -C, and -DRB1. High resolution deoxyribonucleic acid (DNA) typing must be used.

3. Are adults of either sex, age 18-80 years (inclusive).

4. Have a Karnofsky Index of greater than or equal to (>=) 60 percent (%).

5. Have a creatinine clearance (CLcre) >=30 milliliters per minute (mL/min) (Cockcroft Gault: normal renal function: CLcre >=90 mL/min, mild renal impairment: CLcre 60-89 mL/min, moderate renal impairment: CLcre 30-59 mL/min).

6. Are willing to consent to using a highly effective method of birth control, such as condoms, implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence or vasectomised partner while on treatment and for at least 6 months thereafter, if females of childbearing potential (defined according to the Clinical Trials Facilitation and Coordination Group guidelines as a fertile woman, following menarche and until becoming postmenopausal unless permanently sterile) and males capable of reproduction.

7. Have a negative pregnancy test, if females of childbearing potential.

8. Have provided a written informed consent.

Exclusion Criteria:

1. Participants considered not eligible for alloHSCT, for instance due to severe concomitant illness, within 3 weeks before the scheduled Baseline Visit:

• Have severe renal impairment, example, are on dialysis, have renal transplantation history, or calculated CLcre of less than (<) 30 mL/min.

• Have severe pulmonary impairment, single-breath diffusion capacity of the lung for carbon monoxide (DLCO) (haemoglobin adjusted) or forced expiratory volume (FEV1) of <50%, or severe dyspnoea at rest or requiring oxygen supplementation.

• Have moderate or severe hepatic impairment (Child-Pugh B or C classification, respectively) and with documented medical history of chronic liver disease..

2. Have a known coronary artery disease, history of myocardial infarction, cardiac dysfunction, including cardiomyopathies, heart failure (New York Heart Association Class II and above), and cardiac arrhythmias (including paroxysmal and permanent atrial fibrillation), interventricular conduction delay and / or bundle branch block (QRS duration >120 milliseconds [ms]).

3. Have Fredericia-corrected QTc (QTcF) interval >450 ms in men and >470 ms in women.

4. Have active malignant involvement of the central nervous system.

5. Are human immunodeficiency virus (HIV) positive or have an active non controlled infectious disease under treatment including fungal infection, active viral liver infection, or known severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) viral infection at the time of enrolment.

6. Have previously had more than one alloHSCT.

7. Have pleural effusion or ascites of >1.0 liters (L).

8. Are pregnant or breast-feeding.

9. Have uncontrolled or severe intercurrent medical condition.

10. Have known hypersensitivity to treosulfan, fludarabine, and / or related ingredients, Fanconi anaemia and other disorders resulting from DNA repair disorders.

11. Are participating in another experimental drug trial (except those for coronavirus disease [COVID 19] vaccines) within 4 weeks prior to the Day 7 Baseline Visit. This exception serves to comply with subject's interests as this population is at a high risk of COVID 19 complications, if the disease occurs. COVID 19 vaccination details (including vaccine name, batch and manufacturer, dose, date of administration, and whether the right or left arm was injected) should be captured as a concomitant medication to enable better assessment of the overall effect of COVID 19 vaccination on oncology trial results.

12. Exhibit non cooperative behaviour or non compliance.

13. Have psychiatric diseases or conditions that might compromise the ability to give informed consent.

Related Conditions & MeSH terms

• Acute Myeloid Leukaemia (AML)
• Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome (MDS)
• Myelodysplastic Syndromes
• Preleukemia

Intervention

Drug:
• Treosulfan
IV infusion
• Fludarabine
IV infusion

Locations

Country	Name	City	State
United States	University of Illinois	Chicago	Illinois
United States	The Ohio State University	Columbus	Ohio
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	VCU Massey Cancer Center	Richmond	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
medac GmbH	Synteract, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Concentration-time Curve From Time of Administration to the Last Measurable Concentration (AUClast) for Treosulfan		Day -4 and Day -2: Pre-dose, at end of infusion and at 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose
Primary	Area Under the Concentration-time Curve From Time of Administration to Time of Infinity (AUCinf) for Treosulfan		Day -4 and Day -2: Pre-dose, at end of infusion and at 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose
Secondary	Maximum Observed Plasma Concentration (Cmax) for Treosulfan and its Metabolite Treosulfan Monoepoxide		Day -4 and Day -2: Pre-dose, at end of infusion and at 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose
Secondary	Area Under the Concentration-time Curve From Time of Administration to the Last Measurable Concentration (AUClast) for Treosulfan Metabolite (Treosulfan Monoepoxide)		Day -4 and Day -2: Pre-dose, at end of infusion and at 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose
Secondary	Area Under the Plasma Concentration-time Curve From Time of Administration to Time of Infinity (AUCinf) for Treosulfan Metabolite (Treosulfan Monoepoxide)		Day -4 and Day -2: Pre-dose, at end of infusion and at 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose
Secondary	Time to Maximum Observed Plasma Concentration (Tmax) for Treosulfan and its Metabolite Treosulfan Monoepoxide		Day -4 and Day -2: Pre-dose, at end of infusion and at 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose
Secondary	Time to Last Quantifiable Concentration (Tlast) for Treosulfan and its Metabolite Treosulfan Monoepoxide		Day -4 and Day -2: Pre-dose, at end of infusion and at 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose
Secondary	Renal Clearance (CL) for Treosulfan and its Metabolite Treosulfan Monoepoxide		Day -4 and Day -2: Pre-dose, at end of infusion and at 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose
Secondary	Volume of Distribution (Vd) for Treosulfan and its Metabolite Treosulfan Monoepoxide		Day -4 and Day -2: Pre-dose, at end of infusion and at 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose
Secondary	Terminal Elimination Half-life (t1/2) for Treosulfan and its Metabolite Treosulfan Monoepoxide		Day -4 and Day -2: Pre-dose, at end of infusion and at 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose
Secondary	Area Under the Concentration-time Curve From Time of Administration to 24 hours (AUC0-24) for Treosulfan and its Metabolite Treosulfan Monoepoxide		At Day -4: Pre-dose, at end of infusion and at 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose
Secondary	Number of Participants With Engraftment With Treosulfan-based Therapy in Moderate Renal Impairment	Time to engraftment is defined as the time between Day 0 and neutrophil/leukocyte/platelet engraftment. Engraftment includes Neutrophil engraftment, Leukocyte engraftment and Platelet engraftment. Neutrophil engraftment is defined the first of 3 consecutive days with an absolute neutrophil count (ANC) greater than (>) 0.5*10^9 per liter (/L) in peripheral blood (PB) in the first of 3 consecutive days ;Leukocyte engraftment is defined as the first of 3 consecutive days with a total leukocyte count of more than 1*10^9/L in PB. Platelet engraftment is defined as the first of 3 consecutive days with a platelet count of at least 20*10^9/L or of at least 50*10^9/L in PB in the absence of platelet transfusion. Consecutive days is defined as 3 consecutive blood samples, if these are taken on different days.	Day 0 to Day 28
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	A TEAE is defined as any Adverse Event (AE) that has an onset on or after the first dose of investigation medicinal product (IMP) or any pre existing condition that has worsened on or after the first dose of IMP. An SAE or serious adverse reaction (SAR) is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is another medically important event.	Day -7 to Day 28