Thiotepa Plus Fludarabine+ Melphalan as the Preparative Regime for Alternative Donor Transplantation

A Phase II Study of Thiotepa Added to Fludarabine and Melphalan as the Preparative Regime for Alternative Donor Transplantation

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03342196

Enrollment

Registered

2017-11-14

Start date

2018-03-21

Completion date

2024-06-12

Last updated

2025-12-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Leukemia

Keywords

Thiotepa, Fludarabine, Melphalan

Brief summary

In the United States, thiotepa has been utilized in reduced intensity conditioning regimens for alternative donor courses (double umbilical cord blood transplant (dUCBT) and haplo-identical transplants). The hypothesis is that thiotepa at a dose of 10mg/kg, in combination with melphalan (100mg/m2) and fludarabine (160mg/m2) as a reduced intensity conditioning regimen for alternative donor transplant is safe and effective in patients with hematologic malignancies. Given that this regimen has been investigated extensively, and the current study proposes to confirm those previous observations with a small modification (melphalan dose reduction due to previous mucositis rates with higher doses), this will be a phase II study designed to measure disease-free-survival.

Detailed description

Primary Objective: To assess the effectiveness of Thiotepa, Fludarabine, and Melphalan in alternative donor transplants as measured by leukemia free survival. Secondary Objective: To assess the 1- year OS, Relapse, TRM, aGVHD and cGVHD rates and the rates of neutrophil and platelet engraftment. Study Design This is a Phase II study of Thiotepa, Fludarabine, and Melphalan in alternative donor transplants. Subjects will be assessed for safety and tolerability (including adverse events, serious adverse events, and clinical/laboratory assessments) using a continuous monitoring approach. Subjects will be followed for up to 1 year or until progression of disease, relapse, or death.

Interventions

DRUGMelphalan

Alkylating agent which is a derivative of mechlorethamine that inhibits DNA and RNA synthesis via formation of carbonium ions; cross-links strands of DNA; acts on both resting and rapidly dividing tumor cells. Melphalan may cause a lowering of the white blood cell or platelet counts, leading to an increased risk of infection and frequent bruising or bleeding. It may cause damage to the GI tract causing mouth sores, nausea, vomiting, and diarrhea. Other side effects may include loss of appetite, liver abnormalities, hair loss, swelling, fatigue, sleepiness, skin rash.

DRUGThiotepa

Thiotepa is an alkylating agent which produces cross-linking of DNA strands leading to inhibition of DNA, RNA, and protein synthesis; thiotepa is cell-cycle independent. Thiotepa may cause a lowering of the white blood cell or platelet counts, leading to an increased risk of infection and frequent bruising or bleeding. It may cause damage to the GI tract causing mouth sores, nausea, vomiting, and diarrhea. Other side effects may include loss of appetite, liver abnormalities, hair loss, swelling, fatigue, sleepiness, skin rash.

DRUGFludarabine

Fludarabine is an antineoplastic fluorinated nucleoside analog and inhibits DNA synthesis through inhibition of polymoerase alpha after incorporation into DNA. Fludarabine may cause a lowering of the white blood cell or platelet counts, leading to an increased risk of infection and frequent bruising or bleeding. Other side effects may include loss of appetite, liver abnormalities, hair loss, swelling, fatigue, sleepiness, skin rash, and lower limb weakness.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

1 Years to 65 Years

Healthy volunteers

Inclusion criteria

* Patients with the following hematologic malignancies: * Acute myelogenous leukemia (AML): High-risk AML including: * Antecedent hematological disease (e.g., myelodysplasia (MDS)) * Treatment-related leukemia * Complete Remission (CR1) with poor-risk cytogenetics or molecular markers (e.g. Flt 3 mutation, 11q23, del 5, del 7, complex cytogenetics) * Second complete remission (CR2) or third complete remission (CR3) * Induction failure or 1st relapse with ≤ 10% blasts in the marrow * Acute lymphoblastic leukemia (ALL) * High-risk CR1 including: * Poor-risk cytogenetics (e.g., Philadelphia chromosome t(9;22)or 11q23 rearrangements) * Presence of minimal disease by flow cytometry after 2 or more cycles of chemotherapy * No CR within 4 weeks of initial treatment * Induction failure with ≤ 10% blasts in the marrow * CR2 or CR3 * Myelodysplastic syndromes (MDS), Intermediate, High or Very High Risk by the revised international prognostic scoring system (IPSS-R) * Mixed Phenotypic Leukemia / Biphenotypic Leukemiain CR * Chronic Myelogenous Leukemia (CML) in second chronic phase after accelerated or blast crisis. * Myelofibrosis (MF): * Intermediate-1, Intermediate-2 or high risk by Dynamic International Prognostic Scoring System (DIPSS-plus) or * Monosomal karyotype or * Presence of inv(3)/i(17q) abnormalities or * Other unfavorable karyotype OR leukocytes ≥40 × 10(9) /L and * Circulating blasts ≤ 9% * Chronic Myelomonocytic Leukemia * Relapsed or Refractory Lymphoid Malignancies (including non-Hodgkin Lymphoma, Hodgkin Lymphoma and Chronic Lymphocytic Leukemia) meeting the following criteria: * Disease status: Stable Disease, Partial Remission or 2nd and 3rd Complete Remission. OR * Have relapsed after autologous transplant or who have failed to collect for an autologous transplant. * Age \> 1 years, \< 65yrs * KPS Performance status ≥80 * Patients without a matched related or unrelated donor * Patient with either one or both: * Two 5/8 human leukocyte antigen (HLA) high resolution matched umbilical cord blood (UCB) grafts with a cell dose of 2.0x10\^7 total number of nucleated cells per kilogram (TNC/kg) each, or * A related haplo-identical donor * Concurrent Therapy for Extramedullary Leukemia or central nervous system (CNS) Lymphoma: Concurrent therapy or prophylaxis for testicular leukemia, CNS leukemia, and CNS lymphoma including standard intrathecal chemotherapy and/or radiation therapy will be allowed as clinically indicated. Such treatment may continue until the planned course is completed. Subjects must be in CNS remission at the time of protocol enrollment if there is a history of CNS involvement. Maintenance therapy after transplant is allowed. * Subjects must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion criteria

* Patients with inadequate Organ Function as defined by: * Creatinine clearance \<50ml/min * Bilirubin \> twice institutional upper limit of normal * aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) ≥ three times institutional upper limit of normal * Alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) ≥ three times institutional upper limit of normal * Pulmonary function: diffusing capacity of the lung for carbon monoxide corrected for hemoglobin (DLCOc) \< 60% normal * Cardiac: left ventricular ejection fraction \< 50% * Karnofsky Performance Statue (KPS) \< 80 * Patients with uncontrolled inter-current illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant or breastfeeding women are excluded from this study because chemotherapy involved with Reduced Intensity Conditioning (RIC) have the significant potential for teratogenic or abortifacient effects. * Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data. * Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds * Presence of donor-specific antibodies against chosen graft source.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Patients With Disease Free Survival	Up to 1 year after transplant	Leukemia Free Survival (LFS) at 1 year is the percentage of patients alive and without evidence of hematologic malignancy at 1 year after transplant.
Percentage of Patients With Leukemia Free Survival	Up to 1 year after transplant	—

Secondary

Measure	Time frame	Description
Treatment Related Mortality	Up to 1 year after transplant	Treatment Related Mortality (TRM) at 1 year is the percentage of patients who expire from treatment related toxicity attributed to transplant up to 1 year after transplant.
Incidence of Acute GVHD	Up to 1 year after transplant	Acute graft versus host disease (aGVHD) 1 year cumulative incidence is the percentage of patients who experience any aGVHD up to 1 year after transplant.
Average Overall Survival	Up to 1 year after transplant	Overall Survival (OS) at 1 year is the percentage of patients alive at 1 year after transplant.
Rate of Neutrophil Engraftment	Up to 1 year after transplant	Neutrophil engraftment will be calculated as the days from transplant where the absolute neutrophil count (ANC) reaches \>500cells/ul x 3 days.
Rate of Platelet Engraftment	Up to 1 year after transplant	Platelet engraftment will be calculated as the days from transplant where the platelet count reaches 20,000 platelets /ul without the need of transfusion of platelets for 7 days.
Incidence of Chronic GVHD	Up to 1 year after transplant	Chronic graft versus host disease (cGVHD) 1-year cumulative incidence is the percentage of patients who experience any cGVHD up to 1 year after transplant.
Relapse Incidence	Up to 1 year after transplant	Relapse incidence at 1 year is the percentage of patients who experience relapse of their hematologic malignancy up to 1 year after transplant.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Thiotepa + Fludarabine + Melphalan Melphalan 100 mg/m2 on day -8 Thiotepa 10 mg/kg on day -7 Fludarabine 160 mg/m2 in divided doses given on days -6, -5, -4 and -3. Melphalan: Alkylating agent which is a derivative of mechlorethamine that inhibits DNA and RNA synthesis via formation of carbonium ions; cross-links strands of DNA; acts on both resting and rapidly dividing tumor cells. Melphalan may cause a lowering of the white blood cell or platelet counts, leading to an increased risk of infection and frequent bruising or bleeding. It may cause damage to the GI tract causing mouth sores, nausea, vomiting, and diarrhea. Other side effects may include loss of appetite, liver abnormalities, hair loss, swelling, fatigue, sleepiness, skin rash. Thiotepa: Thiotepa is an alkylating agent which produces cross-linking of DNA strands leading to inhibition of DNA, RNA, and protein synthesis; thiotepa is cell-cycle independent. Thiotepa may cause a lowering of the white blood cell or platelet counts, leading to an increased risk of infection and frequent bruising or bleeding. It may cause damage to the GI tract causing mouth sores, nausea, vomiting, and diarrhea. Other side effects may include loss of appetite, liver abnormalities, hair loss, swelling, fatigue, sleepiness, skin rash. Fludarabine: Fludarabine is an antineoplastic fluorinated nucleoside analog and inhibits DNA synthesis through inhibition of polymoerase alpha after incorporation into DNA.	40
Total	40

Arm

Count

Thiotepa + Fludarabine + Melphalan

Melphalan 100 mg/m2 on day -8 Thiotepa 10 mg/kg on day -7 Fludarabine 160 mg/m2 in divided doses given on days -6, -5, -4 and -3. Melphalan: Alkylating agent which is a derivative of mechlorethamine that inhibits DNA and RNA synthesis via formation of carbonium ions; cross-links strands of DNA; acts on both resting and rapidly dividing tumor cells. Melphalan may cause a lowering of the white blood cell or platelet counts, leading to an increased risk of infection and frequent bruising or bleeding. It may cause damage to the GI tract causing mouth sores, nausea, vomiting, and diarrhea. Other side effects may include loss of appetite, liver abnormalities, hair loss, swelling, fatigue, sleepiness, skin rash. Thiotepa: Thiotepa is an alkylating agent which produces cross-linking of DNA strands leading to inhibition of DNA, RNA, and protein synthesis; thiotepa is cell-cycle independent. Thiotepa may cause a lowering of the white blood cell or platelet counts, leading to an increased risk of infection and frequent bruising or bleeding. It may cause damage to the GI tract causing mouth sores, nausea, vomiting, and diarrhea. Other side effects may include loss of appetite, liver abnormalities, hair loss, swelling, fatigue, sleepiness, skin rash. Fludarabine: Fludarabine is an antineoplastic fluorinated nucleoside analog and inhibits DNA synthesis through inhibition of polymoerase alpha after incorporation into DNA.

Total

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Physician Decision	1

Baseline characteristics

Characteristic	Thiotepa + Fludarabine + Melphalan
Age, Customized 10-19	1 Participants
Age, Customized 20-29	4 Participants
Age, Customized 30-39	7 Participants
Age, Customized 40-49	3 Participants
Age, Customized 50-59	12 Participants
Age, Customized 60-69	12 Participants
Age, Customized 70-79	1 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	40 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	8 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	32 Participants
Sex: Female, Male Female	11 Participants
Sex: Female, Male Male	29 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	14 / 40
other Total, other adverse events	35 / 40
serious Total, serious adverse events	18 / 40

Outcome results

Primary

Percentage of Patients With Disease Free Survival

Leukemia Free Survival (LFS) at 1 year is the percentage of patients alive and without evidence of hematologic malignancy at 1 year after transplant.