Back to results

A Phase II Pediatric Study of a Graft-VS.-Host Disease (GVHD) Prophylaxis Regimen With no Calcineurin Inhibitors After Day +60 Post First Allogeneic Hematopoietic Cell Transplant for Hematological Malignancies

Primary Purpose

Hematologic Malignancy, Myeloid Malignancy

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Ruxolitinib

Mesna

Anti-thymocyte globulin (ATG)

Cyclosporine

Cyclophosphamide

Fludarabine

Methotrexate

Total Body Irradiation (radiation treatment)

Bone marrow infusion

Busulfan

Thiotepa

About this trial

This is an interventional treatment trial for Hematologic Malignancy

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria

Diagnosis:

Patients with high risk acute lymphoblastic leukemia in first remission. Examples include, but are not limited to, patients with certain leukemic cell cytogenetic findings (e.g. t(9;22) or t(4;11)); delayed response to induction chemotherapy; re-emergence of leukemic blasts by MRD (at any level) in patients previously MRD negative; persistently detectable MRD at lower levels; early T-cell precursor (ETP) ALL.
Patients with acute lymphoblastic leukemia beyond first remission.
Patients with Hodgkin's disease beyond first remission or with refractory disease.
Patients with chronic myelogenous leukemia.
Patients with primary or secondary myelodysplastic syndrome.
Patients with Non-Hodgkin's lymphoma beyond first remission or with refractory disease.
Patients with de novo acute myeloid leukemia in or beyond first remission or with relapsed or refractory disease, or myeloid sarcoma (extra-medullary AML).
Patients with secondary acute myeloid leukemia.
NK cell lymphoblastic leukemia in any CR.
Biphenotypic, bilineage, or undifferentiated leukemia.
Juvenile Myelomonocytic Leukemia (JMML)
All patients with prior evidence of CNS leukemia must be treated and be in CNS CR.

Patients must have a related or unrelated donor matched at 12 of 12 HLA alleles.

Patient must have a Karnofsky/Lansky score of 70 or higher.

Patients must be 12 years of age or older.

Patients must have a shortening fraction >26% or left ventricular ejection fraction >40%.

Patients must have bilirubin less than or equal to 2.5 mg/dL and alanine aminotransferase (ALT) less than or equal to 5 times the upper limit of normal.

Patients must have creatinine clearance, or a glomerular filtration rate (GFR), greater than 70 mL/min/1.73m2.

Patients must be free of severe infection that upon determination of principal investigator precludes BMT.

Patients must have FVC >50% predicted OR, if unable to perform pulmonary function testing, must maintain pulse oximetry oxygen saturation >92% on room air.

Female patients of childbearing age must have a negative pregnancy test.

Exclusion criteria

Patients who have undergone prior HCT.
Patients who have a peripheral blood stem cell graft source.
Patients who have a non-permissive mismatch at the DPB1 allele.
Patients who are HIV positive.
Patients positive for Hepatitis B surface antigen (HBsAg).
Patients positive for Hepatitis C.
Patients with latent tuberculosis with positive TB IFN gamma release assay.

Sites / Locations

St. Jude Children's Research HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

ArmA- Lymphoid

ArmB-Myeloid

Arm Description

Total Body Irradiation and cyclophosphamide (TBI/Cy)

TBF with comparable NRM in comparison to busulfan and cyclophosphamide (BuCy)

Outcomes

Primary Outcome Measures

Proportion of severe acute GVHD (saGVHD) using a prophylaxis regimen with no calcineurin inhibitors after day 100 post first allogeneic Human Leukocyte antigen (HLA)-matched sibling or unrelated donor HCT for hematological malignancies.

Development of saGVHD at or before Day 100 post transplant is considered as an event.

Secondary Outcome Measures

Incidence of Leukemic Relapse

Bone marrow studies for disease status evaluation will be performed.

Non-relapse mortality

The one-year non-relapse mortality (NRM is defined by the patient who expire while in remission within one year. The probability of NRM is estimated by the cumulative incidence method.

Overall Survival

The one-year survival is defined by the patient who has not died within one year after post transplantation. The probability is estimated by the Kaplan-Meier method.

Incidence of Chronic Graft Versus Host Disease (cGVHD)

Ongoing assessment of toxicity will be done using the NCI CTCAE version 3.0. Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The cumulative incidence of cGvHD will be estimated using Kalbfleisch-Prentice method.

Full Information

NCT ID

NCT05579769

First Posted

October 11, 2022

Last Updated

November 7, 2022

Sponsor

St. Jude Children's Research Hospital

1. Study Identification

Unique Protocol Identification Number

NCT05579769

Brief Title

A Phase II Pediatric Study of a Graft-VS.-Host Disease (GVHD) Prophylaxis Regimen With no Calcineurin Inhibitors After Day +60 Post First Allogeneic Hematopoietic Cell Transplant for Hematological Malignancies

Official Title

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Recruiting

Study Start Date

November 4, 2022 (Actual)

Primary Completion Date

April 2026 (Anticipated)

Study Completion Date

April 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

St. Jude Children's Research Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

5. Study Description

Brief Summary

The participants are being asked to take part in this clinical trial because the participant have a lymphoid or myeloid based cancer diagnosis that requires a bone marrow transplant. Primary Objectives To estimate the incidence of severe acute GVHD (saGVHD) using a prophylaxis regimen with no calcineurin inhibitors after day +60 post first allogeneic Human Leukocyte antigen (HLA)-matched sibling or unrelated donor HCT for hematological malignancies. Secondary objective Determine the cumulative incidence of relapse, NRM, chronic GVHD, and OS in study participants at one year post-transplant. Exploratory objectives To evaluate the pharmacokinetic/pharmacodynamic (PK/PD) profiles of ruxolitinib, fludarabine, and rATG. To assess immune reconstitution in study participants within the first year post-HCT.

Detailed Description

The investigator propose to employ two preparative regimens based on the underlying hematological malignancy. For hematological malignancies of the lymphoid lineage we will use a standard preparative regimen consisting of Total Body Irradiation and cyclophosphamide (TBI/Cy), unless TBI is contraindicated. For myeloid malignancies we will use thiotepa, busulfan, and fludarabine (TBF), a preparative regimen that has been associated with a reduced risk of relapse and trend for improved survival with comparable NRM in comparison to busulfan and cyclophosphamide (BuCy), our current regimen. All HCT recipients will receive cyclosporine in combination with methotrexate and ruxolitinib as GVHD prophylaxis. Recipients of MUD HCT will receive rATG for additional immunosuppression as is standard for unrelated donor transplants

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hematologic Malignancy, Myeloid Malignancy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

32 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

ArmA- Lymphoid

Arm Type

Active Comparator

Arm Description

Total Body Irradiation and cyclophosphamide (TBI/Cy)

Arm Title

ArmB-Myeloid

Arm Type

Active Comparator

Arm Description

TBF with comparable NRM in comparison to busulfan and cyclophosphamide (BuCy)

Intervention Type

Drug

Intervention Name(s)

Ruxolitinib

Other Intervention Name(s)

(Jakafi®)

Intervention Description

Day +40 Dosage and Route of Administration-Ruxolitinib tablets should be administered orally BID, approximately every 12 hours, continuously, Oral

Intervention Type

Drug

Intervention Name(s)

Mesna

Other Intervention Name(s)

(Mesnex)

Intervention Description

Days -3 and -2 Dosage and Route of Administration-Mesna is dosed based on the cyclophosphamide dose and generally administered in fractionated doses at approximately 20% of the total cyclophosphamide dose, Intravenous.

Intervention Type

Drug

Intervention Name(s)

Anti-thymocyte globulin (ATG)

Other Intervention Name(s)

(Thymoglobulin®, rabbit ATG)

Intervention Description

Days -3, -2 and -1 Dosage and Route of Administration-(7 mg/kg total dose); intravenous.

Intervention Type

Drug

Intervention Name(s)

Cyclosporine

Other Intervention Name(s)

(Gengraf)

Intervention Description

Day -1 Dosage and Route of Administration-3 mg/kg; dose will be adjusted to maintain a steady concentration between 250-350 ng/mL or trough concentration between 175-250 ng/mL when transitioned to intermittent dosing.

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

(Cytoxan)

Intervention Description

Days -3 and -2 Dosage and Route of Administration-60 mg/kg for 2 consecutive days, (120 mg/kg total dose); intravenous.

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

(Fludara)

Intervention Description

Days -4, -3 and -2 Dosage and Route of Administration-50 mg/m2 daily for 3 consecutive days (150 mg/m2 total dose) intravenous

Intervention Type

Drug

Intervention Name(s)

Methotrexate

Intervention Description

Days +1, +3, +6 and +11 Dosage and Route of Administration-10 mg/m2/dose, intravenous

Intervention Type

Radiation

Intervention Name(s)

Total Body Irradiation (radiation treatment)

Other Intervention Name(s)

TBI

Intervention Description

Days -7, -6, -5 and -4 6.2.3 Target Dose 1200 cGy total dose delivered 150 cGy per treatment fraction delivered BID over 4 days with 6 MV photons. Dose rate should be < 10 cGy/min in patients treated at extended SSD (450-500 cm) in the TBI couch and will be less than 15 cGy/min in young children and infants treated at extended SSD (200-220 cm) on the floor. Intra-fraction interval should be 6 hours. Custom posteriorly placed (PA only) partial transmission lung shields (blocks) will be used to reduce the average dose to the lung to approximately 1000 cGy total dose. An additional 400 cGy supplemental testicular radiation delivered in 2 fractions of 200 cGy delivered for males with lymphoid lineage leukemia.

Intervention Type

Drug

Intervention Name(s)

Bone marrow infusion

Intervention Description

Day 0

Intervention Type

Drug

Intervention Name(s)

Busulfan

Other Intervention Name(s)

Busulfex)

Intervention Description

Days -4, -3 and -2 Dosage and Route of Administration-3.2 mg/kg/day; intravenous.

Intervention Type

Drug

Intervention Name(s)

Thiotepa

Other Intervention Name(s)

Triplex by Immunex, TESPA, TSPA

Intervention Description

Days -6 and -5 Dosage and Route of Administration-(10 mg/kg total dose); intravenous

Primary Outcome Measure Information:

Title

Description

Development of saGVHD at or before Day 100 post transplant is considered as an event.

Time Frame

100 days post transplant

Secondary Outcome Measure Information:

Title

Incidence of Leukemic Relapse

Description

Bone marrow studies for disease status evaluation will be performed.

Time Frame

One-year post-transplantation.

Title

Non-relapse mortality

Description

The one-year non-relapse mortality (NRM is defined by the patient who expire while in remission within one year. The probability of NRM is estimated by the cumulative incidence method.

Time Frame

One-year post-transplantation

Title

Overall Survival

Description

The one-year survival is defined by the patient who has not died within one year after post transplantation. The probability is estimated by the Kaplan-Meier method.

Time Frame

one year post-transplantation

Title

Incidence of Chronic Graft Versus Host Disease (cGVHD)

Description

Time Frame

1 year post transplant

10. Eligibility

Sex

All

Minimum Age & Unit of Time

12 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria Diagnosis: Patients with high risk acute lymphoblastic leukemia in first remission. Examples include, but are not limited to, patients with certain leukemic cell cytogenetic findings (e.g. t(9;22) or t(4;11)); delayed response to induction chemotherapy; re-emergence of leukemic blasts by MRD (at any level) in patients previously MRD negative; persistently detectable MRD at lower levels; early T-cell precursor (ETP) ALL. Patients with acute lymphoblastic leukemia beyond first remission. Patients with Hodgkin's disease beyond first remission or with refractory disease. Patients with chronic myelogenous leukemia. Patients with primary or secondary myelodysplastic syndrome. Patients with Non-Hodgkin's lymphoma beyond first remission or with refractory disease. Patients with de novo acute myeloid leukemia in or beyond first remission or with relapsed or refractory disease, or myeloid sarcoma (extra-medullary AML). Patients with secondary acute myeloid leukemia. NK cell lymphoblastic leukemia in any CR. Biphenotypic, bilineage, or undifferentiated leukemia. Juvenile Myelomonocytic Leukemia (JMML) All patients with prior evidence of CNS leukemia must be treated and be in CNS CR. Patients must have a related or unrelated donor matched at 12 of 12 HLA alleles. Patient must have a Karnofsky/Lansky score of 70 or higher. Patients must be 12 years of age or older. Patients must have a shortening fraction >26% or left ventricular ejection fraction >40%. Patients must have bilirubin less than or equal to 2.5 mg/dL and alanine aminotransferase (ALT) less than or equal to 5 times the upper limit of normal. Patients must have creatinine clearance, or a glomerular filtration rate (GFR), greater than 70 mL/min/1.73m2. Patients must be free of severe infection that upon determination of principal investigator precludes BMT. Patients must have FVC >50% predicted OR, if unable to perform pulmonary function testing, must maintain pulse oximetry oxygen saturation >92% on room air. Female patients of childbearing age must have a negative pregnancy test. Exclusion criteria Patients who have undergone prior HCT. Patients who have a peripheral blood stem cell graft source. Patients who have a non-permissive mismatch at the DPB1 allele. Patients who are HIV positive. Patients positive for Hepatitis B surface antigen (HBsAg). Patients positive for Hepatitis C. Patients with latent tuberculosis with positive TB IFN gamma release assay.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Ashok Srinivasan, MD

Phone

866-278-5833

referralinfo@stjude.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ashok Srinivasan, MD

Organizational Affiliation

St. Jude Children's Research Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

St. Jude Children's Research Hospital

City

Memphis

State/Province

Tennessee

ZIP/Postal Code

38105

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Ashok Srinivasan, MD

Phone

866-278-5833

referralinfo@stjude.org

First Name & Middle Initial & Last Name & Degree

Ashok Srinivasan, MD

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.

IPD Sharing Time Frame

Data will be made available at the time of article publication.

IPD Sharing Access Criteria

Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.

Links:

URL

http://www.stjude.org

Description

St. Jude Children's Research Hospital

URL

http://www.stjude.org/protocols

Description

Clinical Trials Open at St. Jude

Learn more about this trial

We'll reach out to this number within 24 hrs