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

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.

Study Overview

• Status: Recruiting
• Conditions: Hematologic Malignancy; Myeloid Malignancy
• Intervention / Treatment: Drug: Ruxolitinib; Drug: Mesna; Drug: Anti-thymocyte globulin (ATG); Drug: Cyclosporine; Drug: Cyclophosphamide; Drug: Methotrexate; Radiation: Total Body Irradiation (radiation treatment); Drug: Bone marrow infusion; Drug: Fludarabine; Drug: Busulfan; Drug: Thiotepa

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

• Study Type: Interventional
• Enrollment (Anticipated): 32
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ashok Srinivasan, MD; Phone Number: 866-278-5833; Email: referralinfo@stjude.org

Study Locations

• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • Recruiting
      • St. Jude Children's Research Hospital
      • Contact: Ashok Srinivasan, MD; Phone Number: 866-278-5833; Email: referralinfo@stjude.org
      • Principal Investigator: Ashok Srinivasan, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: ArmA- Lymphoid; Total Body Irradiation and cyclophosphamide (TBI/Cy)	Drug: Ruxolitinib; Day +40 Dosage and Route of Administration-Ruxolitinib tablets should be administered orally BID, approximately every 12 hours, continuously, Oral; Other Names: (Jakafi®); Drug: Mesna; 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.; Other Names: (Mesnex); Drug: Anti-thymocyte globulin (ATG); Days -3, -2 and -1 Dosage and Route of Administration-(7 mg/kg total dose); intravenous.; Other Names: (Thymoglobulin®, rabbit ATG); Drug: Cyclosporine; 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.; Other Names: (Gengraf); Drug: Cyclophosphamide; Days -3 and -2 Dosage and Route of Administration-60 mg/kg for 2 consecutive days, (120 mg/kg total dose); intravenous.; Other Names: (Cytoxan); Drug: Methotrexate; Days +1, +3, +6 and +11 Dosage and Route of Administration-10 mg/m2/dose, intravenous; Radiation: Total Body Irradiation (radiation treatment); 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.; Other Names: TBI; Drug: Bone marrow infusion; Day 0
Active Comparator: ArmB-Myeloid; TBF with comparable NRM in comparison to busulfan and cyclophosphamide (BuCy)	Drug: Ruxolitinib; Day +40 Dosage and Route of Administration-Ruxolitinib tablets should be administered orally BID, approximately every 12 hours, continuously, Oral; Other Names: (Jakafi®); Drug: Anti-thymocyte globulin (ATG); Days -3, -2 and -1 Dosage and Route of Administration-(7 mg/kg total dose); intravenous.; Other Names: (Thymoglobulin®, rabbit ATG); Drug: Cyclosporine; 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.; Other Names: (Gengraf); Drug: Methotrexate; Days +1, +3, +6 and +11 Dosage and Route of Administration-10 mg/m2/dose, intravenous; Drug: Bone marrow infusion; Day 0; Drug: Fludarabine; Days -4, -3 and -2 Dosage and Route of Administration-50 mg/m2 daily for 3 consecutive days (150 mg/m2 total dose) intravenous; Other Names: (Fludara); Drug: Busulfan; Days -4, -3 and -2 Dosage and Route of Administration-3.2 mg/kg/day; intravenous.; Other Names: Busulfex); Drug: Thiotepa; Days -6 and -5 Dosage and Route of Administration-(10 mg/kg total dose); intravenous; Other Names: TESPA; TSPA; Triplex by Immunex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	100 days post transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Leukemic Relapse	Bone marrow studies for disease status evaluation will be performed.	One-year post-transplantation.
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.	One-year post-transplantation
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.	one year post-transplantation
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.	1 year post transplant

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital

Publications and helpful links

Helpful Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2022
• Primary Completion (Anticipated): April 1, 2026
• Study Completion (Anticipated): April 1, 2027

Study Registration Dates

• First Submitted: October 11, 2022
• First Submitted That Met QC Criteria: October 11, 2022
• First Posted (Actual): October 14, 2022

Study Record Updates

• Last Update Posted (Actual): November 10, 2022
• Last Update Submitted That Met QC Criteria: November 7, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Antifungal Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Cyclophosphamide; Fludarabine; Methotrexate; Thiotepa; Busulfan; Thymoglobulin; Antilymphocyte Serum; Cyclosporine; Cyclosporins
• Other Study ID Numbers: CNI60

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes